ARTICLE | doi:10.20944/preprints202308.0920.v1
Subject: Biology And Life Sciences, Food Science And Technology Keywords: agaricus bisporus; chitosan; polysaccharide; lipid absorption; pancreatic lipase; obesity
Online: 11 August 2023 (09:36:31 CEST)
Agaricus bisporus is well known as a source of polysaccharides that could improve human health. The objective of this study was to explore anti-obesity effect of A. bisporus extract (H2Oslim®) abundant in polysaccharides and its underlying mechanism. Pancreatic lipase inhibitory activity in vitro was determined after treatment with H2Oslim® and chitosan. Treatment with H2Oslim® and chitosan significantly decreased pancreatic lipase activity. Five-week-old male SD rats were randomly divided into three groups for acute feeding with vehicle, H2Oslim® at 80 mg/kg body weight (BW)/day, and H2Oslim® at 160 mg/kg BW/day. H2Oslim® does-dependently increased plasma lipid clearance in an oral lipid tolerance test. Five-week-old male C57BL/6N mice were fed a control diet (CD), a high fat diet (HFD), an HFD with H2Oslim® at 80 mg/kg BW/day, H2Oslim® at 160 mg/kg BW/day, or chitosan at 160 mg/kg BW/day for eight weeks. HFD-fed mice showed significant increases of body weight, fat mass, white adipose tissue, average lipid droplet size, and serum levels of glucose, triglyceride, ALT, and AST compared to those in the CD group. However, H2Oslim® or chitosan administration ameliorated these increases. H2Oslim® or chitosan signifi-cantly reduced dietary efficiency and increased fecal excretion levels of lipid, triglyceride, and total cholesterol. These in vitro and in vivo findings suggest that H2Oslim® might act as an anti-obesity agent by inhibiting pancreatic lipase-mediated lipid absorption, at least in part.
REVIEW | doi:10.20944/preprints202308.1917.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Pancreatic ductal adenocarcinoma; pancreatic stellate cells; pancreatic cancer-related diabetes; natural product
Online: 29 August 2023 (03:22:01 CEST)
Pancreatic ductal adenocarcinoma (PDAC) a highly malignant neoplasm, is classified as one of the most severe and devastating types of cancer. PDAC is a notable malignancy that exhibits a discouraging prognosis and a rising occurrence. The interplay between diabetes and pancreatic cancer exhibits a reciprocal causation. The identified metabolic disorder has been observed to possess noteworthy consequences on health outcomes, resulting in elevated rates of morbidity. The principal mechanisms involve the suppression of the immune system, the activation of pancreatic stellate cells (PSCs), and the onset of systemic metabolic disease caused by dysfunction of the islets. From this point forward, it is important to recognize that pancreatic cancer-related diabetes (PCRD) has the ability to increase the likelihood of developing pancreatic cancer. This highlights the complex relationship that exists between these two physiological states. Therefore, we investigate into the complex domain of PSCs, elucidating their intricate signaling pathways and the profound influence of chemokines on their behavior and final outcome. In order to surmount the obstacle of drug resistance and eliminate PDAC, researchers have undertaken extensive efforts to explore and cultivate novel natural compounds of the next generation. Additional investigation is necessary in order to comprehensively comprehend the effect of PCRD-mediated apoptosis on the progression and onset of PDAC through the utilization of natural compound. This study aims to examine the potential anticancer properties of natural compound in individuals with diabetes who are undergoing chemotherapy, targeted therapy, or immunotherapy. It is anticipated that these compounds will exhibit increased potency and possess enhanced pharmacological benefits. According to our research findings, it is indicated that naturally derived chemical compounds hold potential in the development of PDAC therapies that are both safe and efficacious.
REVIEW | doi:10.20944/preprints202011.0733.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: endoscopic ultrasound; pancreatic tumor; pancreatic neuroendocrine neoplasms
Online: 30 November 2020 (14:38:16 CET)
Although pancreatic neuroendocrine neoplasms (PNENs) are relatively rare tumors, their number is increasing with advances in diagnostic imaging modalities. Even small lesions that are difficult to detect using computed tomography or magnetic resonance imaging can be detected with endoscopic ultrasound (EUS). Contrast-enhanced EUS is useful, and not only diagnosis but also malignancy detection have become possible by evaluating the vascularity of tumors. Pathological diagnosis using EUS with fine-needle aspiration (EUS-FNA) is useful when diagnostic imaging is difficult. EUS-FNA can also evaluate the grade of malignancy. Pooling the data of the studies which compared the PNENs grading between EUS-FNA samples and surgical specimen, the concordance rate was 77.5% (κ-statistic: 0.65, 95% confidence interval = 0.59 - 0.71, P< 0.01). EUS is a particularly important modality for the treatment of PNENs.
ARTICLE | doi:10.20944/preprints201912.0250.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: fatty infiltration; main pancreatic duct dilatation; pancreatic invasive ductal adenocaricinoma
Online: 19 December 2019 (07:19:10 CET)
Background: Pancreatic invasive ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in Japan. The early diagnosis of pancreatic cancer, which will increase the number of patients with resectable tumors, is urgently needed. The purpose of the present study was to examine the earliest signs of pancreatic abnormalities on CT in order to facilitate the diagnosis and treatment of PDAC. Methods: Forty-one patients with pancreatic cancer and their 154 CTs were selected for the present study. We used the images that were acquired prior to the diagnosis and examined the pancreas in these images to observe serial changes in the morphology of the pancreas after selecting CT images in which PDAC was suspected. We also confirmed whether the main pancreatic duct was observed around that area of the pancreas. Four thousand two hundred seventy-seven patients without pancreato-biliary disease with 4630 CTs were selected for the control group. Results: Two pancreas shapes were detected: localized constriction of the pancreatic parenchyma referred to as the K-shaped sign, and localized fatty changes. Twenty-four (58.5%) of 41 patients showed the K-shaped sign. The main pancreatic duct without dilatation was noted around the K-shaped sign in 9 of the 24 patients. Eight of 41 patients (19.5%) showed localized fatty changes. Nine of 41 patients (21.9%) showed no abnormality. In the control group, only seven of 4277 patients (0.16%) showed the K-shaped sign. Conclusions: The K-shaped sign including localized fatty changes is the earliest CT sign that presents with pancreatic abnormalities. The K-shaped sign does not indicate PDAC itself but may predict its future development.
ARTICLE | doi:10.20944/preprints202306.1374.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: pancreatic cancer; claudins; zolbetuximab; prognosis
Online: 19 June 2023 (15:00:31 CEST)
Claudin-18.2 (CLDN18.2) is specifically expressed in pancreatic precancerous lesions and pancreatic ductal adenocarcinoma (PDAC). We assessed clinical characteristics of patients with CLDN18.2 overexpressing pancreatic cancer to identify patients who might benefit from CLDN18 targeted treatment. 130 patients with surgically resected PDAC were investigated the immunohistochemical expression of claudin-18 (CLDN18). The CLDN18 staining intensities (0-3+) and relative proportion of positive tumor cells were analyzed by two independent raters. Tumor as positive for CLDN18 expression was defined as ≥80% of tumor cells with 2+ or 3+ staining intensity on CLDN18 immunohistochemical assay. Positive CLDN18 expression was present in 41/130 (31.5%) surgically resected PDAC and the relative proportion of positive tumor cells and the staining intensity were directly correlated (p < 0.001). Positive CLDN18 expression was significantly associated with well-differentiated tumor (p<0.001) and less regional node involvement (p=0.045). The positive CLDN18 expressing group showed no statistical difference in median overall survival (17.4 months vs. 20.6 months, p=0.770) compared to negative CLDN18 expressing group. Distant nodal metastasis was more frequent in positive CLDN18 expressing group (p=0.011). CLDN18 is frequently expressed in PDAC, and high CLDN18 expressing PDAC showed some different clinicopathologic characteristics. High CLDN18 expression was not associated with prognosis in patients with surgically resected PDAC.
ARTICLE | doi:10.20944/preprints202306.1044.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: pancreatic neuroendocrine neoplasm; metastasis; markers
Online: 14 June 2023 (10:16:03 CEST)
Due to the lack of a diagnostic tumor marker (TM), the diagnosis of pancreatic neuroendocrine neoplasia (PNEN) is usually delayed, and a large part of patients present with regional (RM) and distant metastases (DM). The project aimed to assess the serum TM levels in PNEN and their relationships with disease extent and grade. One hundred fifteen patients with PNEN and 40 healthy subjects (HS) were enrolled. Most of the PNEN were well-differentiated (93.04%) and non-functional (93.91%). Beta-2 microglobulin (BMG), carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), cytokeratin 18 (CY18), and ferritin concentrations in PNEN patients were significantly higher than in HS (p < 0.01). The highest area under the curve (AUC) ≥ 0.7 for differentiating PNEN patients from HS had CY18, CA19-9, and ferritin (p < 0.001). PNEN disease was localized (LD) in 63 patients, 8 had RM, and 44 exhibited DM. Patients with metastatic PNEN (RM, DM) also showed significantly higher levels of CY18, CA125, and CEA than those without metastases (p < 0.05). In conclusion, CY18, CA19-9, and ferritin were serum biomarkers that fair diagnosed PNEN disease. Elevated CY18, CA125, and CEA levels correlated with clinical stages (RM, DM) and elevated CY18, CA125 with high grade (G3) of disease.
ARTICLE | doi:10.20944/preprints201801.0092.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: pancreatic cancer; saliva; metabolomics; polyamines
Online: 10 January 2018 (15:32:48 CET)
Detection of pancreatic cancer (PC) at a resectable stage is still difficult because of the lack of accurate detection tests. The development of accurate biomarkers in low or non-invasive biofluids is essential to enable frequent tests, which would help increase the opportunity of PC detection in early stages. Polyamines have been reported as possible biomarkers in urine and saliva samples in various cancers. Here, we analyzed salivary metabolites, including polyamines, using capillary electrophoresis-mass spectrometry. Salivary samples were collected from patients with PC (n=39), chronic pancreatitis (CP, n=14) and controls (C, n=26). Polyamines, such as spermine, N1-acetylspermidine, and N1-acetylspermine, showed a significant difference between PC and C, and the combination of four metabolites including N1-acetylspermidine showed high accuracy in discriminating PC from the other two groups. These data showed the potential of saliva as a screening test for PC.
ARTICLE | doi:10.20944/preprints201611.0107.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: pancreatic cancer; deguelin; autophagy; doxorubicin
Online: 21 November 2016 (10:01:23 CET)
Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.
ARTICLE | doi:10.20944/preprints202305.0222.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Amino acid derivatives; Digestive enzymes; Pancreatic lipase; Pancreatic α-Amylase; α-Glucosidase; Metabolic disorders
Online: 4 May 2023 (07:59:29 CEST)
Over the last decades, the increased incidence of metabolic disorders such as type 2 diabetes and obesity has motivated researchers to investigate new enzyme inhibitors. In this study, the inhibitory effects of synthetic amino acid derivatives (PPC80, PPC82, PPC84, PPC89, and PPC101) on the activity of digestive enzymes was assessed by in vitro assays. The inhibitory effect was determined by the inhibition percentage and the 50% inhibitory concentration (IC50), and the mechanism of action was investigated by Lineweaver–Burk plots. PPC80, PPC82, and PPC84 inhibited pancreatic lipase (IC50 of 1.67–10.23 x 10-1 mmol/L). The activity of pancreatic α-amylase was suppressed by PPC80, PPC82, PPC84, PPC89, and PPC101 (IC50 of 1.62–5.19 x 10-1 mmol/L). Finally, PPC84, PPC89, and PPC101 also showed a potent inhibitory effect on α-glucosidase (IC50 of 0.51–3.53 x 10-1 mmol/L). PPC80 and PPC82 followed a non-competitive inhibition mechanism against pancreatic lipase, while PPC84 acted through competitive inhibition. The inhibition of pancreatic α-amylase by the derivatives was non-competitive, as well as for PPC84, PPC89 and PPC101 against α-glucosidase. The results suggest that these synthetic amino acid derivatives have inhibitory potential against digestive enzymes and may be used as therapeutic agents to control metabolic disorders.
ARTICLE | doi:10.20944/preprints202103.0658.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Pancreatic cancer; RNAseq; Humans; Weight loss; Prognosis; Rectus Abdominis; Carcinoma, Pancreatic Ductal; Adipose Tissue; Pancreatic Carcinoma; Pancreatic Neoplasms; Subcutaneous Fat; High-Throughput Nucleotide Sequencing; Body Composition; Muscles; Cachexia; Muscular Atrophy; Gene Expression
Online: 26 March 2021 (11:24:10 CET)
The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n=11) and patients with PDAC (n=24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using Ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.
ARTICLE | doi:10.20944/preprints202305.1838.v1
Subject: Medicine And Pharmacology, Endocrinology And Metabolism Keywords: pancreatic neuroendocrine neoplasms; bone metastasis; biomarker
Online: 26 May 2023 (04:11:51 CEST)
We investigated the diagnostic capacity of selected circulating biomarkers (CBMs) for the early detection of bone metastasis (BMets) in patients with pancreatic neuroendocrine neoplasms (PanNENs). 115 patients with PanNENs and 40 controls were enrolled. We measured the serum levels of ferritin, cytokeratin 18 (CY18), CA19-9, CA125, AFP, CEA, and beta-2 microglobulin (B2M). 8 PanNENs patients developed BMets, and 107 remained BMets-free. We observed a significantly higher level of CA125 and CY18 in BM-PanNENs patients vs. non-BM-PanNENs patients (p = 0.01 and p = 0.04, respectively). CA125, CY18, and B2M area under receiver operator characteristic (AUROC) analyses differentiated BM-PanNENs from non-BM-PanNENs patients; CA125 area under the curve (AUC) 0.77, p < 0.01; CY18 AUC data were 0.72, p = 0.03, and B2M AUC 0.67, p = 0.02. Based on CBMs metrics in both subgroups, we reached a sensitivity/specificity for CA125 of 75/76%; for CY18 of 75/69%, for B2M of 100/50%, for CA125 and CY18 combination 93/90%, respectively. The useful CBMs for BM-PanNENs patients detection were CA125, CY18, and B2M. They seem to have the diagnostic capacity as a fair single biomarker and CA125&CY18 combination panel for the detection of BMets.
ARTICLE | doi:10.20944/preprints202211.0068.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pancreatic cancer; metabolism; metformin; NAD; NAMPT
Online: 3 November 2022 (03:38:59 CET)
Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use was associated with reduced pancreatic cancer incidence or better survival in diabetics. Metformin has been shown to inhibit PDAC cells survival and growth in vitro and in vivo. However, clinical trials using metformin failed to decrease pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirm that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio turned PDAC cells resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cells xenografts but not in mice with PANC1 xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress providing new insights about the mechanisms leading to cancer cell death.
REVIEW | doi:10.20944/preprints201901.0133.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: pancreatic cancer, CT, MRI, ERCP, EUS
Online: 14 January 2019 (11:25:46 CET)
Early detection of pancreatic ductal adenocarcinoma (PDAC) requires further examination after selecting cases with risk factors for the condition, such as family history, hereditary pancreatic carcinoma syndrome, intraductal papillary mucinous neoplasms, or chronic pancreatitis. The Japan Study Group on the Early Detection of Pancreatic Cancer has investigated and clarified the clinicopathological features for the early diagnosis of PDAC. Further approaches for the early diagnosis of PDAC are warranted.
REVIEW | doi:10.20944/preprints201903.0133.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pancreatic cancer; PDAC (Pancreatic Ductal Adenocarcinoma); immune microenvironment; immune biomarkers; personalized cancer care; inflammation; PD1; CTLA-4
Online: 12 March 2019 (03:15:16 CET)
It is estimated that pancreatic cancer will be the 2nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.
ARTICLE | doi:10.20944/preprints202308.1629.v1
Subject: Biology And Life Sciences, Agricultural Science And Agronomy Keywords: piglets rearing; pancreatic-like enzymes (PLEM); IUGR
Online: 24 August 2023 (03:21:30 CEST)
The present study aimed to develop a feeding strategy for pregnant sows which involved the prenatal administration of a mixture of pancreatic-like fungal enzymes, such as lipase, amylase, and protease, at (1) 1–115 days of gestation (group D1) and (2) 80–115 days of gestation (group D2) and to carry out a comparison with groups of sows that were not receiving such supplementation (negative control [NC] and positive control [PC]). It was found that the administration of the enzyme supplement resulted in a significant shortening of gestation (P ≤ 0.01). The pancreatic enzymes administered to sows had a significant effect on the number of liveborn piglets and weaned piglets, which was higher compared to the control groups that did not receive supplementation respectively: D1-12.1±1.1 and 11.12±1.1; D2- 12.8±1.3 and 11.75±0.07 vs. control groups KN-10.7±1.0 and 9.62±0,95 and KP 10.9±1.2 and 10.15±1.0 (P<0.006). Significant changes in piglet growth were observed after weaning up to 70 days of age. During this period, the most favorable growth parameters were found in groups D2 (420±91g) and PC (407±103g), in which piglets were given a mixture of pancreatic enzymes (lipase, amylase, and protease) at 3 weeks of age, and significantly higher weight gain and feed intake were observed compared to groups NC (378±114g) and D1 (381±96g) (P ≤ 0.007). In contrast, insulin levels were significantly lower in groups D1 and D2, respectively 6,8 IU/ml and 6,7 IU/ml compared to groups NC (14,6 IU/ml) and PC (16,6 IU/ml) ( (P ≤ 0.01). Piglets in group D2 had a significantly better feed conversion ratio (FCR) 1.604±0.10 compared to the other dietary groups: KN– 1.986±0.14; KP– 1.704±0.11; D1 – 1.932±0.15 (P ≤ 0.03). Histological imaging confirmed significantly thicker intestinal epithelium and intestinal mesenteron in animals from groups D2 and PC (P ≤ 0.03). Animals from the groups KP, D1 and D2 receiving enzymes showed a highly significant increase in the surface area of pancreatic follicles and pancreatic surface area compared to the group without KN supplementation (P<0.01). Furthermore, significantly higher activity of the brush border enzyme lactase was observed in groups D1; D2 and PC compared, respectively 32.90±3.99; 30.00±6.83 and 29.60±29.60 to group NC – 21.80± 3.27 (P ≤ 0.01).
REVIEW | doi:10.20944/preprints202307.0985.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: pancreatic cancer; necroptosis; tumor microenvironment; cell death
Online: 14 July 2023 (09:07:24 CEST)
Pancreatic cancer (PC) is the seventh leading cause of cancer-related death. PC incidence has con-tinued to increase by about 1% each year in both men and women. Although the 5‐year relative survival rate of PC has increased from 3% to 12%, it is still the lowest among cancers. Hence, novel therapeutic strategies are urgently needed. Challenges in PC-targeted therapeutic strate-gies stem from the high PC heterogeneity and from the poorly understood interplay between cancer cells and the surrounding microenvironment. Signaling pathways that drive PC cell growth have been the subject of intense scrutiny and interest has been attracted by necroptosis, a distinct type of programmed cell death. In this review, we provide a historical background on necroptosis and a detailed analysis of the ongoing debate on the role of necroptosis in PC malignant progression.
ARTICLE | doi:10.20944/preprints202203.0342.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: albumin-globulin ratio; postoperative pancreatic fistula; pancreaticoduodenectomy
Online: 25 March 2022 (09:00:37 CET)
Background and aim: The albumin-globulin ratio (AGR) is one of the indicators of inflammation and immunity and it has a prognostic significance in many malignant diseases. Previous studies have shown the relationship between inflammatory mediators and POPF. This study aimed to evaluate the relation of AGR, which is a relatively new indicator, with postoperative pancreatic fistula (POPF). Methods: Pancreaticoduodenectomy (PD) patients between 2017 and 2020 were retrospectively analyzed and divided into two groups as those with and without clinically relevant POPF (CR-POPF). They were compared in terms of preoperative-postoperative AGR and clinicodemographic characteristics. AGR was calculated as Albumin / (Total protein-albumin) and the cutoff point for AGR was determined according to Youden’s index. Results: CR-POPF developed in 21% of 121 patients who underwent PD. There was no difference between the groups in terms of age, gender, comorbid disease status, pancreatic duct width, and anastomosis technique. Preoperative and postoperative day-3 (POD3) albumin levels and AGR were found to be significantly lower in the CR-POPF group. Multivariate analysis showed that AGR and pancreatic tissue stiffness are independent risk factors for the development of POPF. Conclusions: Low AGR is an independent risk factor for the development of CR-POPF. To reduce the incidence of POPF, this ratio should be tried to be kept at an optimal level.
ARTICLE | doi:10.20944/preprints202112.0001.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: pancreatic ductal adenocarcinoma; deep-learning; early detection
Online: 1 December 2021 (10:14:14 CET)
Early detection improves prognosis in pancreatic ductal adenocarcinoma (PDAC) but is challenging as lesions are often small and poorly defined on contrast-enhanced computed tomography scans (CE-CT). Deep learning can facilitate PDAC diagnosis, however current models still fail to identify small (<2cm) lesions. In this study, state-of-the-art deep learning models were used to develop an automatic framework for PDAC detection, focusing on small lesions. Additionally, the impact of integrating surrounding anatomy was investigated. CE-CT scans from a cohort of 119 pathology-proven PDAC patients and a cohort of 123 patients without PDAC were used to train a nnUnet for automatic lesion detection and segmentation (nnUnet_T). Two additional nnUnets were trained to investigate the impact of anatomy integration: (1) segmenting the pancreas and tumor (nnUnet_TP), (2) segmenting the pancreas, tumor, and multiple surrounding anatomical structures (nnUnet_MS). An external, publicly available test set was used to compare the performance of the three networks. The nnUnet_MS achieved the best performance, with an area under the receiver operating characteristic curve of 0.91 for the whole test set and 0.88 for tumors <2cm, showing that state-of-the-art deep learning can detect small PDAC and benefits from anatomy information.
REVIEW | doi:10.20944/preprints202110.0187.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: pancreatic cancer; molecular markers; target therapy; nanomedicine
Online: 12 October 2021 (20:45:44 CEST)
Pancreatic cancer leads the most common lethal tumor in America. This lethality is related to limited treatment options. Conventional treatments involve a non-specific use of chemotherapeutical agents like 5-FU, capecitabine, gemcitabine, cisplatine, oxaliplatine, or irinotecan, that produce several side effects. This review we focus on the use of targeted nanoparticles as an alternative to the standard treatment for the pancreatic cancer. The principal objective of the use of nanoparticles is the reduction in side effects that conventional treatments produce, mostly because of their nonspecificity. Currently, several molecular markets of pancreatic cancer cells have been studied to target nanoparticles and improve the actual treatment. Therefore, properly functionalizated nanoparticles with specific aptamers or antibodies can be used to recognize pancreatic cancer cells and once cancer is recognized, these nanoparticles can attack the tumor by drug delivery, hyperthermia, or gene therapy.
REVIEW | doi:10.20944/preprints202106.0629.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: pancreatic cancer; epigenetics; metastasis; enhancer; DNA methylation
Online: 25 June 2021 (16:05:34 CEST)
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis.
ARTICLE | doi:10.20944/preprints202102.0085.v2
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: unresectable pancreatic ductal adenocarcinoma; conversion surgery; chemoradiotherapy
Online: 17 February 2021 (09:57:14 CET)
BackgroundUnresectable pancreatic ductal adenocarcinoma (UR-PDAC) has a poor prognosis. Conversion surgery is considered a promising strategy for improving the prognosis of UR-PDAC. This study aimed to investigate the clinical benefits of conversion surgery in patients with UR-PDAC.Methods: We retrospectively evaluated patients with PDAC who were referred to our department for possible surgical resection between January 2006 and December 2019. Conversion surgery was performed only in patients with UR-PDAC who could expect R0 resection. We analyzed the prognostic factors for overall survival among patients who underwent conversion surgery. Results: Overall, 638 patients with advanced pancreatic cancer were enrolled in this study. According to resectability, resectable cancer (R) was present in 180 patients, borderline resectable cancer (BR) in 60, unresectable locally advanced cancer (UR-LA) in 252, and unresectable cancer with distant metastasis (UR-M) in 146. Conversion surgery was performed in 20 of the 398 UR cases (5.1%). The median period between the initial therapy and conversion surgery was 15.5 months. According to the RECIST evaluation, the treatment response was CR in one patient, PR in 13, SD in five, and PD in one. Downstaging was pathologically determined in all cases. According to the Evans grading system, grade I was observed in four patients (20%), grade IIb in seven (35%), III in seven (35%), and IV in two (10%). We compared the overall survival period from initial treatment among patients undergoing conversion surgery; the median overall survival durations in the conversion surgery, R, BR, UR-LA, and UR-M groups were 73.7, 32.7, 22.7, 15.7, and 8.8 months, respectively. Multivariate analysis revealed that the presence or absence of CRT and the RECIST PR/CR for the main tumor were statistically significant prognostic factors for overall survival among patients undergoing conversion surgery (p = 0.004 and 0.03, respectively).Conclusion: In UR-PDAC, it is important to perform multidisciplinary treatment, including CRT with conversion surgery.
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Pancreatic cancer; Predictive diagnosis; Liquid biopsy; gemcitabine
Online: 21 October 2020 (11:53:07 CEST)
Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second cause of cancer death by 2022. For nearly 80% of patients, diagnosis occurs at an advanced, non-surgical stage, making such patients incurable. Gemcitabine is still an important component in PDAC treatment and is most often used as a backbone to test new targeted therapies and there is, to date, no routine biomarker to predict its efficacy. Samples from a phase III randomized trial were used to develop trough a large approach based on blood-based liquid biopsy, transcriptome profiling, and machine learning, a 9 gene predictive signature for gemcitabine sensitivity. Patients with a positive test (41.6%) had a significantly longer progression free survival (PFS) (3.8 months vs. 1.9 months p=0.03) and a longer overall survival (OS) (14.5 months vs. 5.1 p<0.0001). In multivariate analyses, this signature was independently associated with PFS (HR=0.5 (0.28-0.9) p=0.025) and OS (HR=0.39 (0.21-0.7) p=0.002).
ARTICLE | doi:10.20944/preprints201901.0155.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: EIF4GI; pancreatic ductal adenocarcinoma; prognosis; GEO; TCGA
Online: 16 January 2019 (07:54:33 CET)
Background: The advances of genomics have greatly improved the survival rate cancer patients. However, due to genetic heterogeneity, pancreatic ductal adenocarcinoma (PDAC) is still difficult to diagnose early and the survival rate is extremely low. Therefore, we identified biomarkers that predict the prognosis of PDAC patients by using independent cohort data. Methods: To develop a novel prognostic biomarker, we used gene expression and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). In Kaplan-Meier survival curve using median values of genes as cut off, the only statistically significant gene in the three cohorts was EIF4G1. We analyzed prognostic significance of EIF4G1 using the time-dependent area under the curve (AUC) of the Uno's C-index, the AUC value of the receiver operating characteristics (ROC) at 3 years, and multivariate cox analysis. Also, we compare EIF4G1 levels between tumor and matched non-tumor. Results: EIF4G1 is the only prognostic gene patients with PDAC which was selected by Kaplan-Meier survival analysis. Kaplan-Meier survival analysis showed that high expression of EIF4G1 was associated with poor prognosis of PDAC with good discriminative ability in 3 independent cohorts. Risk stratifying ability of EIF4G1 was demonstrated by analyzing C-indices and AUC values. Multivariate cox regression analysis confirmed its prognostic significance. EIF4G1 expression was significantly higher in the PDAC tissues than in the matched normal tissues. Conclusions: Herein, the novel prognostic biomarker EIF4G1 could be used as prognostic maker for PDAC and determining suitable treatment options.
ARTICLE | doi:10.20944/preprints201810.0375.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: endophytic fungi; sesterterpene; cytotoxic activity; pancreatic cancer
Online: 17 October 2018 (06:39:51 CEST)
As a part of our ongoing research on endophytic fungi, we have isolated a sesterterpene mycotoxin, fusaproliferin (FUS), from Fusarium solani strain associated with the plant Aglaonema hookerianum Schott. FUS showed rapid and sub-micromolar IC50 against pancreatic cancer cell lines. Time dependent survival analysis and microscopy imaging showed rapid morphological changes in cancer cell lines 4 hours after incubation with FUS. This provides a new chemical scaffold that can be further developed to obtain more potent synthetic agents against pancreatic cancer.
ARTICLE | doi:10.20944/preprints202308.1933.v1
Subject: Engineering, Electrical And Electronic Engineering Keywords: Pancreatic cancer; NIH PLCO dataset; feature selection; classification
Online: 29 August 2023 (10:11:39 CEST)
Background: Pancreatic cancer (PC) is a disease with poor prognosis and survival rate. There is a pertinent need to identify the risk factors of this disease. The purpose of this study is to identify a subset of factors (a.k.a. features) as predictors of PC from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer dataset consisting of responses to 65 questions about demographics, cancer and health history, medication usage, and smoking habits from 154,897 participants. Method: There are two challenges to selecting the subset of features that predict PC with highest probability: the problem is computationally intractable, and the PLCO dataset is highly imbalanced. We use an innovative method to use the dataset in a balanced way, without involving up- or down-sampling. We use nine feature selection methods to select the optimal subset of features from the preprocessed and balanced dataset. Results: Our preprocessed dataset consists of 32 risk factors (8 demographics, 5 cancer history, 13 health history, 2 medication usage, 4 smoking habits). Risk factors belonging to cancer and health history, followed by smoking habits, were consistently chosen by the feature selection methods. We also discuss findings in the medical sciences literature that corroborate our findings. Conclusions: The study found that risk factors belonging to cancer and health history are the most prominent ones for PC. In particular, previously diagnosed with PC is chosen as the most prominent risk factor by majority of methods. While most of our findings are consistent with the literature, some of our findings shed light on novel factors that may not have received their due attention by the research community.
ARTICLE | doi:10.20944/preprints202110.0400.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Orai3; Store Operated Calcium entry; Pancreatic Cancer; Metastasis
Online: 27 October 2021 (11:16:03 CEST)
Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca2+ influx into non-excitable cells. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in 6 PC cell lines and found that Orai3 forms a functional SOCE in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first time reports that Orai3 drives aggressive phenotypes of PC cells i.e. migration in vitro and metastasis in vivo. Considering that Orai3 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.
ARTICLE | doi:10.20944/preprints202105.0295.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Pancreaticoduodenectomy: pancreatic cancer; peri ampullary cancer; laparoscopic surgery
Online: 13 May 2021 (13:11:34 CEST)
Background: There is ongoing debate regarding the usefulness of laparoscopic pancreaticoduodenectomy. This study aimed to analyze all the randomized control trials published including the most recent one. Material and methods: The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and MOOSE guidelines. Heterogeneity was measured using Q tests and I2. The random-effects models were used to summarise the relative risks, odds ratios, and mean differences as appropriate.Results:4 RCTs were included consisting of 818 patients. 411 patients were in the laparoscopic group and 407 in the open pancreaticoduodenectomy group. Weighted baseline patient characteristics were similar except more patients with pancreatic adenocarcinoma and more males were there in the open pancreaticoduodenectomy group. There was no difference in-hospital stay,90 days complications rate, 90 days mortality, R1 resection, postoperative pancreatic fistula, delayed gastric emptying, post pancreatectomy hemorrhage, bile leak between the two groups. Operative time was more in the laparoscopic group. Blood loss [mean difference -132.12 ml (-172.60,-91.65)] and surgical site infection [Risk ratio 0.41 ( 0.17-1.0)] were significantly lesser in laparoscopic group.Conclusion:There was no benefit in-hospital stay or clinical outcomes after laparoscopic pancreaticoduodenectomy. Blood loss and surgical site infection were lesser in laparoscopic pancreaticoduodenectomy.
ARTICLE | doi:10.20944/preprints202011.0215.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Pancreatic Cancer; PLGA-PAA copolymer; Hydroxytyrosol; Curcumin; Apoptosis
Online: 5 November 2020 (14:51:15 CET)
Background and Aim: Pancreatic cancer (PC) is a highly aggressive malignancy associated with low survival rates. Many chemotherapeutic regimens have been investigated for advanced unresectable and metastatic PC, but with only minimal improvement in survival and prognosis. The present study aimed to investigate the anti-cancer function of free and nano-encapsulated hydroxytyrosol (Hyd) and curcumin (Cur), and its combinations (Hyd-Cur) on the PANC-1 cell line.Methods: The poly lactide-co-glycolide-co-polyacrylic acid (PLGA-co-PAA) nano-encapsulated Hyd and Cur were synthesized, and MTT assay was performed to evaluate cytotoxic effects of free and nano-encapsulated Hyd, Cur, and Hyd-Cur. Moreover, effects of free and nano-encapsulated Hyd, Cur, and Hyd-Cur were evaluated on viability, migration, morphological alterations, colony formation, and apoptosis on PANC-1 cell line. The mRNA expression levels of MMP2, MMP9, BAX, BCL-2, and Cas9 genes were assessed after treated PANC-1 cells with free and nano-encapsulated Hyd, Cur, and Hyd-Cur.Results: The obtained results showed that free and nano-encapsulated Hyd, Cur, and Hyd-Cur treatments significantly decreased the viability, migration, and colony formation in the PANC-1 cells. Furthermore, apoptosis rates in PANC-1 cells were increased in a concentration and time dependent manner in all of the treatment groups. Moreover, anti-proliferative activity of nano-encapsulated Hyd-Cur was significantly more than other treatments.Conclusion: According to our results, Hyd-Cur combination and nano-encapsulation therapy exerts more profound apoptotic and anti-proliferative effects on PANC-1 cell line than free Hyd or Hyd monotherapy.
REVIEW | doi:10.20944/preprints202009.0545.v1
Subject: Medicine And Pharmacology, Surgery Keywords: Meta-analysis; Procalcitonin; pancreatic surgery; pancreaticoduodenectomy; Infectious complications
Online: 23 September 2020 (08:07:40 CEST)
Aim of study:Aim of this meta-analysis is to evaluate post-operative procalcitonin as a marker to predict post- operative infectious complications after pancreatic surgeries.Material and Methods:Systemic literature search was performed using MEDLINE, EMBASE and to identify studies evaluating the diagnostic accuracy of Procalcitonin (PCT) as a predictor for detecting infectious complications on postoperative days (POD) 3 and 5 following pancreatic surgery. A meta-analysis was performed using random effect model and pooled predictive parameters for POD 3 and 5 were derived. Geometric means were calculated for PCT cut offs. Results:6 studies included day 3 PCT analysis, 2 studies included both day 3 and day 5 analysis. Total data of 471 patients were derived. 161 patients developed infectious complications. Pooled sensitivity, specificity, pooled area under curve, diagnostic odds ratio (DOR), positive and negative like hood ratio of day 3 PCT were 74%,79%,0.8453, 11.03,3.17 and 0.31 respectively. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive and negative like hood ratio of day 5 PCT were 83%,70%,12.91,2.91 and 0.25 respectively. Geometric means for PCT cut off for day 3 and 5 were 0.80 and 0.43. Conclusion:Postoperative procalcitonin particularly day 3 procalcitonin levels predict post-operative infectious complications following pancreatic surgeries.
ARTICLE | doi:10.20944/preprints202310.0611.v1
Subject: Medicine And Pharmacology, Surgery Keywords: lymph node dissection; nonfunctioning pancreatic neuroendocrine neoplasms; surgical resection
Online: 10 October 2023 (10:04:06 CEST)
This study aimed to evaluate the optimal extent of lymphadenectomy in patients with nonfunctioning pancreatic neuroendocrine neoplasms. We retrospectively analyzed the clinicopathological data of patients with nonfunctioning pancreatic neuroendocrine neoplasms who underwent surgical resection. We investigated the frequency of metastases at each lymph node station according to tumor location and analyzed the factors contributing to poor overall survival (OS) and disease-free survival (DFS). Overall, data of 84 patients were analyzed. For pancreatic head tumors, metastases at stations 8, 13, and 17 were found in one (3.1%), four (12.5%), and three (9.3%) patients, respectively. However, none of the other stations showed metastases. For pancreatic body and tail tumors, only metastases at station 11 were found in two (5.1%) patients. Additionally, multivariate DFS and OS analyses showed that lymph node metastasis was the only independent prognostic factor. Lymph node metastasis was found near the primary tumor and was the only independent factor of poor prognosis in patients with nonfunctioning pancreatic neuroendocrine neoplasms after undergoing curative surgery. Peri-pancreatic lymphadenectomy might be recommended for nonfunctioning pancreatic neuroendocrine neoplasms.
ARTICLE | doi:10.20944/preprints202308.0834.v1
Subject: Biology And Life Sciences, Life Sciences Keywords: SERCA activity; insulin release; pancreatic beta-cells; polyphenolic compounds
Online: 10 August 2023 (08:21:09 CEST)
Many redox diseases, including diabetes, are associated with an imbalance of calcium homeostasis, regulated mainly by a Ca2+-ATPase pump (SERCA). Dysfunction of this enzyme may be prevented by natural polyphenolic compounds, representing a possible supporting treatment. Compounds that increase SERCA activity/expression may be useful for the treatment of diabetic complications. Stimulation of SERCA1 activity was analyzed experimentally and by molecular modeling. SERCA1 activity under methylglyoxal- and palmitate-induced oxidative stress was evaluated. The viability of INS-1E cells and insulin secretion were determined. -Gingerol, resveratrol, and ellagic acid increased SERCA1 activity and exerted a protective effect under oxidative stress in the noncellular system. We found for the first time that the binding of polyphenols (-gingerol, resveratrol, ellagic acid) to Glu439 in the SERCA1 P-domain may be critical for the stimulation of its activity. Moreover, this binding may also be important in the protective effects against oxidative stress. Direct stimulation of SERCA1 activity by ellagic acid was observed for the first time. In INS-1E cells, these compounds increased insulin secretion.
ARTICLE | doi:10.20944/preprints202306.0482.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: cachexia; pancreatic cancer; ketogenic diet; gemcitabine; cancer-associated cachexia
Online: 7 June 2023 (03:53:16 CEST)
Cancer associated cachexia (CAC) is a critical contributor to pancreatic ductal adenocarcinoma (PDAC) mortality. Thus, there is an urgent need for new strategies to mitigate PDAC-associated cachexia; and the exploration of dietary interventions is a critical component. We previously observed that a ketogenic diet (KD) combined with gemcitabine enhances overall survival in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. In this study, we investigated the effect and cellular mechanisms of a KD in combination with gemcitabine on the maintenance of skeletal muscle mass in KPC mice. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD), a KD, a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. We observed that a KD or a KG mitigated muscle strength decline over time and presented higher gastrocnemius weights compared CD-fed mice. Mechanistically, we observed sex-dependent effects of KG treatment, including the inhibition of autophagy, and increased phosphorylation levels of eIF2α in KG-treated KPC mice when compared to CG-treated mice. Our data suggests that a KG results in preservation of skeletal muscle mass. Additional research is warranted to explore whether this diet-treatment combination can be clinically effective in combating CAC in PDAC patients.
ARTICLE | doi:10.20944/preprints202306.0031.v1
Subject: Biology And Life Sciences, Life Sciences Keywords: cancer; pancreatic cancer; CWA; APTT; sTF/FIXa; thrombin time
Online: 1 June 2023 (04:53:42 CEST)
Background: The patients with cancer, especially pancreas cancer, are frequently associated with thrombosis which is one of causes for poor outcome, and hypercoagulability exists in cancer patients. Hypercoagulability is considered to be caused by thrombin burst. Methods: Activated partial thromboplastin time (APTT), small amount of tissue factor induced FIX activation (sTF/FIXa) assays and thrombin time (TT) using clot waveform analysis (CWA) were performed in 138 patients with malignant neoplasm including pancreas cancer and 66 non-cancer patients. Results: Thrombosis was frequently associated in pancreas cancer and was observed in stage I. CWA-APTT showed that the peak times and heights were markedly long and heigh, respectively, in cancer patients, and the peak times were significantly longer in pancreas cancer patients than benign pancreas diseases, and the 1st DPH was significantly higher in pancreas cancers than other cancers or benign pancreas diseases. CWA-sTF/FIXa showed that the peak times and heights were longer and higher, respectively, in patients with cancer than those without cancers, and that the 1st DPH was significantly higher in pancreas cancers than in other cancers. CWA-TT showed that the peak times were significantly shorter in cancer patients than in healthy volunteers and that the peak heights were significantly higher in cancer than in benign pancreas diseases. Conclusions: Cancer patients including pancreas cancer were frequently associated with thrombosis due to hypercoagulability with thrombin burst detected by CWA.
REVIEW | doi:10.20944/preprints202305.0914.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: pancreatic cancer; KRAS; KRAS inhibitors; KRAS-dependency; resistance; escaping.
Online: 12 May 2023 (09:33:30 CEST)
Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in Oncology be-cause of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein ex-tremely difficult. KRAS regulates development, cell growth, Epigenetically-dysregulated differ-entiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indirect inhibitors of KRAS signaling. Therefore, KRAS dependency is so essential in KRASmu PDAC that cancer cells have secured several compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors, such as activation of MEK/ERK signaling or YAP1 upregulation. This review will provide insights into KRAS dependency in PDAC and analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms.
ARTICLE | doi:10.20944/preprints202304.0658.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: acute pancreatitis; coumarins; warfarin; inflammation; coagulation; pancreatic blood flow.
Online: 21 April 2023 (02:38:22 CEST)
Acute pancreatitis (AP) is the most common gastrointestinal disease leading to hospitalizations. The development of AP leads to damage of the pancreatic microcirculation with a cascade of subsequent events resulting, among others, in coagulopathy. Previous research showed that anticoagulants can be an important therapeutic agent. Heparin and acenocoumarol can alleviate the course of AP, as well as accelerate healing and post-inflammatory regeneration of the pancreas. The aim of this study was to check whether warfarin, a drug with more stable effects than acenocoumarol, affects the healing and regeneration of the pancreas in the cerulein-induced AP. AP was evoked in Wistar male rats by intraperitoneal administration of cerulein. The first dose of warfarin (45, 90 or 180 µg/kg/dose) was administered 24 hours after the first dose of cerulein and the doses of warfarin were repeated once a day in subsequent 10 days. The severity of acute pancreatitis was assessed immediately after the last dose of cerulein, as well as 1, 2, 3, 5, and 10 days after AP induction. Treatment with warfarin dose-dependently increased interna-tional normalized ratio (INR) and attenuated the severity of pancreatitis in histological ex-amination and accelerated pancreatic recovery. Those effects were accompanied with a faster reduction in the pancreatitis-evoked increase in serum activity of amylase and lipase, serum concentration of pro-inflammatory interleukin-1β, and plasma level of D-Dimer. In addition, treatment with warfarin decreased pancreatic weight and improved pancreatic blood flow in rats with AP. The therapeutic effect was particularly pronounced after the administration of warfarin at a dose of 90 µg/kg/dose. Conclusion: Administration of warfarin accelerates re-generation of the pancreas and recovery in the course of cerulein-induced mild-edematous acute pancreatitis.
ARTICLE | doi:10.20944/preprints202210.0296.v2
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pancreatic Ductal Adenocarcinoma; K-Ras; N-Ras; G2 cyclins
Online: 16 February 2023 (03:22:47 CET)
Development of K-Ras independence may explain failure of targeted therapy for pancreatic cancer (PC). In this paper active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. Knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism but only K-Ras depletion caused a decrease in G2 cyclins, proteasome inhibition reversed this and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from G2 phase to slow relative to completion of S-phase, suggesting mutant K-Ras may inhibit APC/c prior to anaphase but stabilizes G2 cyclins independently of this. We propose that during tumorigenesis, cancer cells expressing wild type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of cell cycle independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division even in cells where K-Ras is inhibited. Keywords: Pancreatic Ductal Adenocarcinoma, K-Ras, N-Ras, G2 cyclins.
ARTICLE | doi:10.20944/preprints202207.0178.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Biomarkers; Pancreatic Cancer; CTC; Surfaceome; Protemics; Flow Cytometry; ALCAM
Online: 12 July 2022 (09:11:05 CEST)
Background: Current strategies in circulating tumor cell (CTC) isolation in pancreatic cancer heavily rely on the EpCAM and cytokeratin cell status. EpCAM is generally not considered as a good marker given its transitory change during Epithelial to Mesenchymal Transition (EMT) or reverse EMT. There is a need to identify other surface markers to capture the complete repertoire of PDAC CTCs. The primary objective of the study is to characterize alternate surface bi-omarkers to EpCAM on CTCs that express low or negligible levels of surface EpCAM in pancre-atic cancer patients. Methods: Flow cytometry and surface mass spectrometry were used to iden-tify proteins expressed on the surface of PDAC CTCs in culture. CTCs were grown under condi-tions of attachment and in co-culture with naïve neutrophils. Putative biomarkers were then validated in GEMMs and patient samples. Results: Surface proteomic profiling of CTCs identi-fied several novel protein biomarkers. ALCAM was identified as a novel robust marker in GEMM models and in patient samples. Conclusions: We identified several novel surface bi-omarkers on CTCs expressed under differing conditions of culture. ALCAM was validated and identified as a novel alternate surface marker on EpCAMlow CTCs.
REVIEW | doi:10.20944/preprints202007.0029.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: Gambogic acid; phytochemical; breast cancer; pancreatic cancer; glioma cancer
Online: 3 July 2020 (09:05:13 CEST)
Gambogic acid, a common traditional Chinese medicine and widely distributed throughout South China, Vietnam, Cambodia, and Thailand. It is prenylated xanthone which is the significant bioactive compound of gamboge. Gambogic acid is known as a strong apoptotic inducer in cancer cells. It has been found as strong anticancer agent against various types of cancer cells lines such as breast cancer, pancreatic, and cervical cancer. It induces apoptosis, down regulates the anti-apoptotic proteins (survivin and BCL2,) and down regulates the activities of P-glycoprotein in drug sensitive human breast MCF-7 and drug-resistant MCF-7/ADR cells. Similarly, it also exerts alteration in P13K, AKT, p21, MMP-2 &-9, and phosphorylated-AKT expressions. The current review highlights the anticancer and chemo-preventive perspectives of gambogic acid and its mechanistic role against human and animal cancers.
ARTICLE | doi:10.20944/preprints201909.0189.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: miR-139-5p; SLC7A11; proliferation; migration; pancreatic cancer (PANC)
Online: 17 September 2019 (12:42:14 CEST)
Objective: Pancreatic carcinoma (PANC) is one of the important aggressive cancers, with deficiency in effective therapeutics. Studies have unveiled that miR-139-5p expression is significantly downregulated in other types of cancers. However, the functions and mechanisms of miR-139-5p in PANC remain unclear. Methods: Bioinformatic analysis was performed to analyze the differentially expressed genes in the TCGA database. PANC cell line with overexpressed miR-139-5p and Solute Carrier Family 7, Member 11 (SLC7A11) was established, and has been used to detect cell proliferation, migration, invasion and colony formation in PANC. Subsequently, bioinformatic analysis and luciferase assay were performed to confirm that SLC7A11 was a target gene of miR-139-5p. Xenograft mouse model was used to investigate the role of miR-139-5p in PANC tumorigenicity. Results: Through bioinformatic analysis, miR-139-5p was predicted to regulate phosphatidylinositol signaling pathway by targeting SLC7A11. MiR-139-5p was found to be lowly expressed in PANC tissues, while SLC7A11 was highly expressed. Low expression of miR-139-5p and high expression of SLC7A11 were positively associated with poor clinical outcomes. PANC cell proliferation, migration, and invasion could be inhibited by miR-139-5p overexpression and could be promoted by SLC7A11 overexpression. MiR-139-5p could regulate the protein expression level of PI3K and Akt associated with phosphatidylinositol signaling pathway could be by inhibiting the expression of SLC7A11. MiR-139-5p overexpression could suppress PANC tumor growth and the expression of SLC7A11, p-PI3K, p-Akt in tumor tissues. Therefore, the inhibiting effect of miR-139-5p to PANC cell proliferation, invasion and migration, at least, was partly due to its inhibiting effect on SLC7A11 expression. Conclusion: These results demonstrated a novel role of miR-139-5p/SLC7A11 in PANC and provided potential prognostic predictors for PANC patients.
REVIEW | doi:10.20944/preprints201905.0239.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: oligonucleotide therapeutics; RNA interference; antisense; aptamer; decoy; pancreatic cancer
Online: 20 May 2019 (10:12:46 CEST)
Although there is a several array of diagnostic and therapeutic choices for pancreatic cancer in recent years, a crucial medical approach for the refractory disease is still needed. Oligonucleotide therapeutics, such as those based on antisense RNAs, RNA interference, aptamers and decoys, are promising agents against pancreatic cancer because they identify a specific nucleotide sequence or protein and interfere with gene expression as molecular-targeted agents. Within just the past quarter-century, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Actually, there have been several clinical and preclinical studies of oligonucleotides for patients with pancreatic cancer so far. To support the discovery of effective diagnostic or therapeutic options by using oligonucleotide-based strategies in the absence of satisfactory therapies for long-term survival and the rising trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients with underlying preclinical or scientific data and focus on the possibility of oligonucleotides to target pancreatic cancer in clinical implications.
REVIEW | doi:10.20944/preprints201712.0014.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: pancreatic cancer; immune surveillance; galectins; immunotherapy; immune checkpoints; stroma
Online: 4 December 2017 (05:17:15 CET)
Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, is one of the main unfinished businesses in the biomedical and clinical fields, with still discouraging 5 year survival rates and poor therapy efficiency. PDA abundant desmoplasia has for long played the lead in the mechanisms involved in poor drug performance, being the main source of cytokines and chemokines orchestrating rapid and silent tumor progression and guilty of isolating tumor cells into a extense fibrotic reaction resulting in inefficient drug delivery. However, since immunotherapy was proclaimed the breakthrough of the year back to 2013, the focus in the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play part in the strong immune evasion that characterizes PDA. PDA microenvironment is highly immune-suppressive, being basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressive cells (MDSCs), which boycott CD8+ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways inhibiting the immune attack as the key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.
ARTICLE | doi:10.20944/preprints201703.0149.v1
Subject: Medicine And Pharmacology, Dietetics And Nutrition Keywords: pancreatic cancer; alcohol intake; folate intake; case-control study
Online: 20 March 2017 (08:29:00 CET)
Pancreatic cancer is one of the most fatal common cancers affecting both men and women, representing about 3 percent of all new cancer cases in the United States. In this study, we aimed to investigate the association of pancreatic cancer risk with alcohol consumption as well as folate intake. We performed a case-control study of 384 patients diagnosed with pancreatic cancer from May 2004 to December 2009 and 983 primary care healthy controls. Our findings showed no significant association between risk of pancreatic cancer and either overall alcohol consumption or type of alcohol consumed (drinks/day). Our study showed dietary folate intake was modestly but significantly inversely associated with pancreatic cancer (OR=0.99, P <.0001). The current study supports the hypothesis that pancreatic cancer risk is reduced with higher food-based folate intake.
ARTICLE | doi:10.20944/preprints202310.1348.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: podocalyxin; PODXL; cancer-specific monoclonal antibody; defucosylated antibody; pancreatic cancer
Online: 20 October 2023 (11:46:59 CEST)
Podocalyxin (PODXL) overexpression is associated with poor clinical outcomes in various tumors. PODXL is involved in tumor malignant progression through the promotion of invasiveness and metastasis. Therefore, PODXL has been considered as a promising target of monoclonal antibody (mAb)-based therapy. However, PODXL also plays an essential role in normal cells such as vascular and lymphatic endothelial cells.Therefore, cancer-specificity or selectivity is required for the reduction of adverse effects on normal cells. Here, we developed an anti-PODXL cancer-specific mAb (CasMab), PcMab-6 (IgG1, kappa), by immunizing mice with soluble PODXL ectodomain derived from a glioblastoma LN229 cell.PcMab-6 reacted with the PODXL-positive LN229 cells, but not with PODXL-knockout LN229 cells in flow cytometry. Importantly, PcMab-6 recognized pancreatic ductal adenocarcinoma (PDAC) cell lines (MIA PaCa-2, Capan-2, and PK-45H), but did not react with normal lymphatic endothelial cells (LECs). In contrast, one of the non-CasMabs, PcMab-47 showed high reactivity to both the PDAC cell lines and LECs. Next, we engineered PcMab-6 into a mouse IgG2a type (PcMab-6-mG2a) and a humanized IgG1-type (humPcMab-6) mAbs, and further produced the core fucose-deficient types (PcMab-6-mG2a-f and humPcMab-6-f, respectively) to potentiate the antibody-dependent cellular cytotoxicity (ADCC). Both PcMab-6-mG2a-f and humPcMab-6-f exerted ADCC and complement-dependent cellular cytotoxicity in the presence of effector cells and complements, respectively. In the PDAC xenograft model, both PcMab-6-mG2a-f and humPcMab-6-f exhibited potent antitumor effects. These results indicated that humPcMab-6-f could apply to antibody-based therapy against PODXL-expressing pancreatic cancers.
ARTICLE | doi:10.20944/preprints202310.1343.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pancreatic cancer; Cancer metabolism; Alkalization therapy; Tumor microenvironment; Urine pH
Online: 20 October 2023 (11:44:36 CEST)
Current treatments in patients with pancreatic cancer offer limited benefits. In this report, we applied “alkalization therapy”, which was efficacious for other solid tumors at our clinic, to stage 4 pancreatic cancer patients, and investigated its effect on disease prognosis. Patients with metastatic pancreatic cancer who were treated at Karasuma Wada Clinic in Kyoto, Japan, between 2011 and 2022 were included in the study. All patients received alkalization therapy (combination of an alkaline diet, bicarbonate, and citric acid administration), alongside standard chemotherapy. Urine samples were collected to assess urine pH as a marker for whole-body alkalization. In the 98 patients analyzed, the median overall survival (OS) from the time of diagnosis was 13.2 months. Patients with a mean urine pH of 7.5 or greater had a median OS of 29.9 months, compared with 15.2 months for those with a mean urine pH of 6.5 to 7.5, and 8.0 months for those with a mean urine pH of less than 6.5, which suggests a trend of a longer OS in patients with a higher urine pH. Conclusions: Alkalization therapy may offer a viable approach to enhance the survival of stage 4 pancreatic cancer patients, who typically have an unfavorable prognosis.
ARTICLE | doi:10.20944/preprints202304.0668.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Quality-of-life; pancreatic cancer, physicians; VAS; cTTO; EQ-5D
Online: 21 April 2023 (03:51:46 CEST)
Quality-of-life (QOL) is important for cancer patients with poor prognosis. However, QOL survey is difficult using patients. We created cancer scenarios and investigated QOL utility values among the general public using vignette-based methods. On the other hand, some scenarios may have been difficult for the general public to image and understand. Therefore, we conducted a QOL survey among physicians. This survey was conducted by interviewing physicians adminis-tering chemotherapy to patients for recurrent/metastatic pancreatic cancer. Responses were eval-uated using Composite Time Trade-Off (cTTO) and Visual Analog Scale (VAS) for 11 pancreatic cancer status scenarios to be evaluated (survey scenarios). Survey scenarios consisted of health state, type and Grade of adverse events. Health status was classified into two categories: Stable disease (SD) and Progressive disease (PD). Twenty responders answered in this survey, however two responses were excluded because of inconsistent responses. The stable disease had the highest QOL value for both assessment method. Whereas progression disease (PD) had the lowest QOL value. The physicians scored higher QOL values on VAS and cTTO than the general public in all survey scenarios. The QOL values obtained by physicians were consistent with the degree of sta-tus in any assessment scenarios.
REVIEW | doi:10.20944/preprints202011.0745.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Pancreatic Cancer; Adjuvant therapy; neoadjuvant therapy; biomarkers; Precision medicine; timing
Online: 30 November 2020 (16:45:30 CET)
Adjuvant chemotherapy is currently used in all patients with resected pancreatic cancer who are able to begin treatment within 3 months after surgery. Since the recent publication of the PRODIGE 24 trial results, modified FOLFIRINOX has become the standard-of-care in the non-Asian population with localized pancreatic adenocarcinoma following surgery. Nevertheless, there is still a risk of toxicity, and feasibility may be limited in heavily pre-treated patients. In more frail patients, gemcitabine-based chemotherapy remains a suitable option, for example gemcitabine or 5FU in monotherapy. In Asia, although S1-based chemotherapy is the standard of care it is not readily available outside Asia and data are lacking in non-Asiatic patients. In patients in whom resection is not initially possible, intensified schemes such as FOLFIRINOX or Gemcitabine-Nabpaclitaxel have been confirmed as options to enhance the response rate and resectability, promoting research in adjuvant therapy. In particular, should oncologists prescribe adjuvant treatment after a long sequence of chemotherapy +/- chemoradiotherapy and surgery? Should oncologists consider the response rate, the R0 resection rate alone, or the initial chemotherapy regimen? And finally, should they take into consideration the duration of the entire sequence, or the presence of limited toxicities of induction treatment? The aim of this review is to summarize adjuvant management of resected pancreatic cancer and to raise current and future concerns, especially the need for biomarkers and the best holistic care for patients.
CASE REPORT | doi:10.20944/preprints201908.0278.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: FOLFIRINOX; pancreatic ductal adenocarcinoma; surgery; liver metastases; long term survival
Online: 27 August 2019 (05:16:03 CEST)
Metastatic pancreatic ductal adenocarcinoma pancreatic (PDAC) is characterized by poor prognosis and short survival. Today, the use of new polytherapeutic regimens increases clinical outcome of these patients opening new clinical scenario. A crucial issue related to the actual improvement achieved with these new regimens is represented by the occasional possibility to observe a radiological complete response of metastatic lesions in patients with synchronous primary tumor. What could be the best therapeutic management of these patients? Could surgery represent an indication? Herein we reported a case of a patient with a PDAC of the head with multiple liver metastasis, who underwent first line chemotherapy with mFOLFIRINOX. After 10 cycles, he achieved a complete radiological response of liver metastases and a partial response of pancreatic lesion. A, duodenocephalopancreasectomy was performed. Due to liver a lung metastases after 8 months from surgery, a second line therapy was started with a disease free survival and overall survival of 8 months and 45 months, respectively. Improvement in the molecular characterization of PDAC could help in the selection of patients suitable for multimodal treatments.
REVIEW | doi:10.20944/preprints202308.0190.v2
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Savolitinib; MET-TKI; NSCLC; gastric cancer; renal cell carcinoma; pancreatic cancer
Online: 7 August 2023 (10:03:49 CEST)
Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations, and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.
ARTICLE | doi:10.20944/preprints202306.0091.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: Collagen; hydrogel; interpenetrating network; beta pancreatic cells; vascular endothelial factor; biomaterial
Online: 1 June 2023 (12:48:03 CEST)
Three-dimensional matrices are a new strategy used to tackle type I diabetes; a chronic metabolic disease characterized by the destruction of beta pancreatic cells. Type I collagen is an abundant extracellular matrix (ECM), component that has been used to support cell growth. However, pure collagen possesses some difficulties including low stiffness and strength, and high susceptibility to cell-mediated contraction. Therefore, we developed a collagen hydrogel with a poly(ethylene glycol) diacrylate (PEGDA) interpenetrating network (IPN), functionalized with vascular endothelial growth factor (VEGF) to mimic the pancreatic environment for the sustenance of beta-pancreatic cells. We analyzed the physicochemical characteristic of the hydrogels and found that they were successfully synthesized. The mechanical behavior of the hydrogels improved with the addition of VEGF, and the swelling degree and the degradation were stable over time. In addition, it was found that 5 ng/mL VEGF-functionalized collagen/PEGDA IPN hydrogels sustained and enhanced viability, proliferation, respiratory capacity and functionality of beta pancreatic cells. Hence, this is a potential candidate for future preclinical evaluation, which may be favorable for diabetes treatment.
ARTICLE | doi:10.20944/preprints202209.0023.v1
Subject: Computer Science And Mathematics, Applied Mathematics Keywords: Pancreatic cancer; cancer evolution; tumour microenvironment; mathematical model; open quasispecies model
Online: 1 September 2022 (10:52:10 CEST)
Pancreatic cancer represents one of the difficult problems of contemporary medicine. The development illness evolves very slowly, takes place in special sake (stroma) and manifests clinically close to a final stage. Another feature of this pathology is a coexistence (symbiotic) effect between cancer cells and normal cells inside stroma. All these aspects make it difficult to understand the pathogenesis of pancreatic cancer and develop a proper therapy. The emergence of pancreatic pre-cancer and cancer cells represents a branching stochastic process engaging populations of 64 cells differing in the number of acquired mutations. In this study we formulate and calibrate the mathematical model of pancreatic cancer using the quasispecies framework. The mathematical model incorporates the mutation matrix, fineness landscape matrix and the death rates. Each element of the mutation matrix presents the probability of appearing a specific mutation in the branching sequence of cells representing the accumulation of mutations. The model incorporates the cancer cell elimination by effect CD8 T cells (CTL). The down-regulation of the effector function of CTLs and exhaustion are parameterized. The symbiotic effect of coexistence of normal and cancer cells is considered. The computational predictions obtained with the model are consistent with empirical data. The modelling approach can be used to investigate other types of cancers and examine various treatment procedures.
ARTICLE | doi:10.20944/preprints202108.0235.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Pancreatic Ductal Adenocarcinoma; metabolites; cholestatic (obstructive) jaundice; lipoprotein; inflammation; tumour stages
Online: 10 August 2021 (14:08:27 CEST)
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman’s correlation and Kapan Meier tests were conducted for correlation and survival analyses respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose, lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used in predicting patient survival and in informing treatment intervention.
REVIEW | doi:10.20944/preprints202001.0296.v1
Subject: Engineering, Bioengineering Keywords: stem cells; organoids; hepatocytes; pancreatic islets; cholangiocytes; organoid morphogenesis; organoid imaging
Online: 25 January 2020 (15:32:27 CET)
Organoid engineering promises to revolutionize medicine with wide ranging applications of scientific, engineering, and clinical interest, including precision and personalized medicine, gene editing, drug development, disease modeling, cellular therapy, and a basic understanding of human development. Organoids are a three-dimensional (3D), miniature, caricature of a target organ, are initiated with stem/progenitor cells, and are extremely promising tools to model organ function. The biological basis for organoids is that they foster stem cell-self renewal, differentiation, and self-organization, recapitulating tissue structure or function better than 2D systems. In this review, we first discuss the importance of epithelial organs and the general properties of epithelial cells to provide context for the liver, pancreas, and gall bladder and rationale for organoid cultures. Next, we develop a general framework to understand self-organization, tissue hierarchy, and organoid cultivation. For each of these areas, we provide historical context, and review both a wide range of biological and/or biophysical/mathematic perspectives that enhances understanding of organoids. Next, we review existing techniques and progress in hepatobiliary and pancreatic organoid engineering. To do this, we review organoids from both primary tissues, cell lines, and stem cells, and introduce engineering studies when applicable. Noninvasive assessment of 1 organoids can reveal underlying biology and enable improved assays for growth, metabolism, and function. Applications of organoid for cell therapy are also discussed. Taken together, we establish a broad strong scientific foundation for organoids and provide an in-depth review of hepatic, biliary and pancreatic organoids.
REVIEW | doi:10.20944/preprints202001.0063.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: hPSCs; hyperglycemia; insulin-secreting cells; β-cell precursors; pancreatic islets; transplantation.
Online: 8 January 2020 (05:30:34 CET)
Diabetes mellitus (DM) is one of the most prevalent metabolic disorders. In order to replace the function of the destroyed pancreatic beta cells in diabetes, islet transplantation is the widely practiced treatment; however, it has several limitations. As an alternative approach, human pluripotent stem cells (hPSCs) can provide an unlimited source of pancreatic cells that have the ability to secrete insulin in response to high blood glucose level. However, determination of the appropriate pancreatic lineage candidate for the purpose of cell therapy for treatment of diabetes is still debated upon. While hPSC-derived beta cells are perceived as the ultimate candidate, the efficiency needs further improvement in order to obtain a sufficient number of glucose responsive β-cells for transplantation therapy. On the other hand, hPSC-derived pancreatic progenitors can be efficiently generated in vitro and can further mature into glucose responsive beta cells in vivo after transplantation. Herein, we discuss the advantages and predicted challenges associated with the use of each of the two pancreatic lineage products for diabetes cell therapy. Furthermore, we address co-generation of functionally relevant islet cell subpopulations and structural properties contributing to glucose responsiveness of beta cells, as well as the available encapsulation technology for these cells.
ARTICLE | doi:10.20944/preprints201809.0322.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: p21-activated kinase (PAK); Pancreatic ductal adenocarcinoma (PDA); PF-3758309; gemcitabine
Online: 17 September 2018 (15:28:54 CEST)
Pancreatic ductal adenocarcinoma (PDA) remains the most lethal malignancy due to lack of an effective treatment. P21-activated kinases (PAKs) play key roles in PDA growth, and the PAK inhibitor PF-3758309 synergistically reduced PDA growth with gemcitabine. The aim of this study was to determine the effect of PF-3758309 with multiple chemotherapeutic reagents on a panel of patient-derived PDA cell lines. Cells were treated with PF-3758309 plus or minus gemcitabine, 5-fluorouracil (5-FU) or abraxane, and cell proliferation was determined. Protein expression profiles were measured by Western blot. PDA cells were subcutaneously injected into the flanks of SCID mice which were then treated with PF-3758309, gemcitabine, PF-3758309 plus gemcitabine, or gemcitabine plus abraxane. Tumour growth was measured by volume and weight. PF-3758309 enhanced the inhibitory effects of 5-FU, gemcitabine and abraxane on a panel of patient-derived PDA cells, inhibited HIF-1 protein expression and reduced the protein levels of palladin and -SMA in these cells. The combination of PF-3758309 with gemcitabine maximally inhibited PDA growth in vivo, which was comparable to the combination of gemcitabine with abraxane. PF-3758309 enhanced the suppressive effects of multiple chemotherapeutic reagents on the growth of a panel of patient-derived PDA cell lines. The combination of PF-3758309 with gemcitabine provides a potential treatment option with less toxicity than gemcitabine plus abraxane.
ARTICLE | doi:10.20944/preprints201802.0013.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: pancreatic cancer; proteomics; PI3K pathway; precision medicine; predictor of therapeutic response
Online: 2 February 2018 (06:57:47 CET)
In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context.
REVIEW | doi:10.20944/preprints201802.0011.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pancreatic cancer, proteomics, PI3K pathway, precision medicine, predictor of therapeutic response
Online: 1 February 2018 (17:16:04 CET)
In metastatic pancreatic cancer patients non eligible to surgery, signal-targeted therapies so far failed to show a significant amelioration of survival. These therapeutic options were tested in Phase II/III clinical trials mostly in combination with the reference treatment Gemcitabine. These innovative therapies aim at annihilating the oncogene dependency; they also aim at renormalizing the tumoral stroma to allow immune cell function or re-vascularisation. Transcriptomics and genomics large scale analysis show the great heterogeneity of pancreatic cancers and failed to clearly delineate specific oncogene dependency besides oncogenic Kras. In this review, we will describe the most recent proteomic data in pancreatic tumors and its metastasis, which could help at identifying their major signalling dependencies, as well as explain why they are intrinsically resistant to signal-targeted therapies. We will also discuss why PI3K signalling, as a paradigm of pro-tumorigenic cell signalling and of tumoral adaptative resistance to drugs, is a relevant target in this context.
REVIEW | doi:10.20944/preprints202308.0710.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: diabetes; mitochondrial dynamics; glucose-stimulated insulin secretion; pancreatic beta cell; fusion; fission
Online: 9 August 2023 (08:22:26 CEST)
Mitochondria are involved in the regulation of cellular energy metabolism, calcium homeostasis, and apoptosis. For mitochondrial quality control, dynamic processes, such as mitochondrial fission and fusion, are necessary to maintain shape and function. Disturbances of mitochondrial dynamics lead to dysfunctional mitochondria which contribute to the development and progression of numerous diseases, including Type 2 Diabetes (T2D). Compelling evidence put forward that mitochondrial dynamics play a significant role in the metabolism-secretion coupling of pancreatic β cells. The disruption of mitochondrial dynamics is linked with defects in energy production and increased apoptosis, ultimately impairing insulin secretion and β cell death. This review provides an overview of altered mitochondrial dynamics in pancreatic β cells using ge-netic/pharmacologic approaches, and how these affect insulin secretion.
REVIEW | doi:10.20944/preprints202308.0567.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: Pancreatic Ductal Adenocarcinoma; secretome; cell signaling; tumor microenvironment; small molecules; monoclonal antibodies.
Online: 7 August 2023 (12:12:00 CEST)
Pancreatic ductal adenocarcinoma (PDAC) is a ravaging disease whose poor prognosis requires a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggested to rather focus on the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer secreted proteins in the complex TME tumor-stroma crosstalk, to sched lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.
ARTICLE | doi:10.20944/preprints202212.0083.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Irreversible electroporation; Cytokine-induced killer cells; Combination therapy; Pancreatic cancer; Chemokine receptors
Online: 6 December 2022 (01:31:32 CET)
The current study aimed to investigate the antitumor effects and potent mechanism of cytokine-induced killer (CIK) cells combined with irreversible electroporation (IRE) via an in vitro function assay in an in vivo Panc02 cell–bearing mouse model. We established an in vitro culture assay for CIK cells and determined the proportions of different peripheral lymphocytes. The antitumor effect of the combination of IRE and CIK cells in a Panc02 pancreatic-cancer (PC) subcutaneous-xenograft model was investigated; tumor size and mouse survival rates were recorded. We used flow cytometry (FCM) to analyze the proportion of intratumoral lymphocytes, the expression of chemokine receptors, and the proliferative activity of CIK cells. The proportion of cells that were positive for clusters of differentiation 3 and 8 (CD3+CD8+) and the proportion of CD3+CD56+ cells were both significantly increased after 21 days of in vitro culture. Combined IRE/CIK cell treatment significantly inhibited tumor growth and increased the survival rate of Panc02 cell–bearing mice. Furthermore, infiltration of lymphocytes into tumor tissue was significantly increased by this combination therapy compared with the untreated group or monotherapy group. In addition, IRE significantly enhanced the expression of chemokine receptors elicited by, and the proliferative activity of, CIK cells. In conclusion, IRE combined with CIK cells showed superior antitumor efficacy in a PC subcutaneous-xenograft model, which we attributed to the promotion of lymphocytic infiltration, as well as to upregulation of chemokine receptor expression and of regulators of CIK cell proliferation.
ARTICLE | doi:10.20944/preprints202012.0556.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Pancreatic cancer; recurrence; metastasis; surgical resection; circulating tumour cells; CTC; CellSearch; prognostication
Online: 22 December 2020 (12:02:41 CET)
In patients with presumed pancreatic ductal adenocarcinoma (PDAC), biomarkers that may open for personalised, risk-adapted treatment are lacking. The study analysed the impact of circulating tumour cells (CTCs) on the patterns of recurrence and survival in 98 patients resected for PDAC with 5-10 years of follow-up. Preoperative samples were analysed by the CellSearch® system for EpCAM+/DAPI+/CK+/CD45- CTCs. CTCs were detected in 7 of the 98 patients. CTCs predicted a significantly shorter median DFS of 3.3 vs. 9.2 months and a median CSS of 6.3 vs. 18.5 months. Relapse status was confirmed by imaging for 87 patients. Of these, 58 developed distant metastases (DM) and 29 cases isolated local recurrence (ILR) as first event. All patients with CTCs experienced DM. pN-status and histological grade >2 were other independent risk factors for DM, but only CTCs predicted significantly shorter cancer-specific, disease-free and post-recurrence survival. We conclude that CTC presence in resected PDAC patients predicted early distant metastasis and impaired survival. The impact of CTCs was comparable to that of histopathological risk factors and exceeded the effect size of other preoperative parameters. Thus, preoperative CTCs alone or in combination with histopathological factors may guide initial treatment decisions in patients with resectable PDAC in the future.
REVIEW | doi:10.20944/preprints202304.1189.v1
Subject: Biology And Life Sciences, Endocrinology And Metabolism Keywords: Functional role of GABA in insulin secretion stimulation; GABA metabolism in pancreatic islets; GABA and insulin secretion; interaction of glucose and GABA metabolism in pancreatic islets; GABA shunt
Online: 29 April 2023 (02:51:09 CEST)
The stimulus-secretion coupling of glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that closes the ATP-dependent K+-channel at the plasma membrane by the interaction of ATP with the regulatory Kir6.2 channel subunit The resultant depolarization of the β-cells opens voltage-dependent Ca2+-channels at the plasma membrane that allow an increase of the cytosolic cation concentration that triggers the exocytosis of insulin secretory granules. The resultant secretory response evolves in time as a biphasic secretion with a first and transient peak of approximately 10 minutes duration followed by a sustained phase of secretion lasting as long as the stimulus. Whereas the first transient peak can be reproduced by a simple depolarization of β-cells with high extracellular KCl maintaining the KATP-channels open with diazoxide, the sustained phase is agreed to depend on the participation of some metabolic signal that remains to be determined Our group has been investigating for several years the participation of β-cell GABA metabolism, together with that of glucose (the β-cell “specific” nutrient secretagogue) and some other “metabolic” secretagogues (branched-chain alpha-ketoacids and a mixture of L-Leucine + L-glutamine, at supraphysiological concentrations) in their mechanism of stimulation of insulin secretion. All three types of stimuli promote the flux in the GABA shunt of rat islets by different metabolic pathways that end in the production of α-ketoglutarate. This citric acid cycle intermediary is preferentially derived to the GABA shunt instead of its continuous oxidation in the citric acid cycle. Islet content of GABA is significantly suppressed by all the stimuli and blocking the GABA shunt with gabaculine, or ϒ-vinyl-GABA (GABAT inhibitors), diminish the insulin secretory responses as well as total ATP and the ATP/ADP ratio. It is concluded that GABA metabolism is increased in parallel to glucose metabolism and is significantly contributing to the magnitude of the insulin secretory response. Its possible implication in β-cells degradation in type-2 (perhaps also in type 1) diabetes is suggested.
ARTICLE | doi:10.20944/preprints202310.0666.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: inflammatory bowel disease; anti-pancreatic antibodies; cell based assay; Crohn’s disease; diagnostic biomarker
Online: 11 October 2023 (14:23:46 CEST)
Introduction: The serological support to early diagnosis and differential diagnosis of inflammatory bowel diseases (IBD) is actually very limited. In this study we evaluated the performance of a promising multiparametric method including either well established and newly developed biomarkers. Methods: This multicenter retrospective observational study finally enrolled 156 patients with IBD, 100 affected by Crohn’s disease (CD) and 56 by ulcerative colitis (UC) recruited at the Gastroenterology Units of Udine (Italy), Rijeka (Croatia) and Belgrade (Serbia). Twently age-sex matched blood donors (BD) were included as controls. Autoantibody profiles were determined using a mosaic cell and tissue-based indirect immunofluorescence (IIF) method simultaneously investigating: anti-saccharomyces cerevisiae antibodies (ASCA), anti-atypical perinuclear neutrophilic antibodies (P-ANCA), anti-pancreatic antigens antibodies (PAB) and anti-goblet cells antibodies (GAB). Results: PAB (anti-CUZD1 and/or anti-GP2 antibodies) were present in 24 CD patients versus none of UC patients or BD (24% sensitivity, 100% specificity). As regards CD patients, combined positivity of PAB and ASCA (sensitivity 84%, specificity 71.4%) performed better than ASCA alone. Colon involvement (87.5% vs. 60.5%; p=0.014), deep mucosal lesions (58.3% vs. 25.0%; p=0.002) and need for biologic therapies (79.2% vs. 46.1%; p=0.005) were significantly more prevalent in PAB-positive than in PAB-negative CD patients. Multivariate analysis identified PAB positivity (OR=3.67; 95%CI=1.29-10.46) and anti-CUZD1 in particular (OR=3.54; 95%CI=1.08-11.63) as significant risk factors for deep mucosal lesions development in CD. Conclusion: A multiparametric diagnostic approach appears very useful to better characterize IBD patients. PAB, isolated or combined with other autoantibodies, may support both differential diagnosis and selection of CD patients at risk for more severe disease.
REVIEW | doi:10.20944/preprints202309.2083.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Cystic Fibrosis; transition of care; pediatrics; Gastrointestinal care; Pancreatic enzyme; highly effective modulators
Online: 29 September 2023 (10:43:47 CEST)
Cystic Fibrosis is a chronic disease affecting multiple systems including the GI tract. Clinical manifestation in patients can start as early as infancy and vary across different age groups. With the advent of new highly effective modulators, the life expectancy of PwCF has improved significantly. Various GI aspects of CF care such as nutrition are linked to the overall improvement in morbidity, lung function, and quality of life of PwCF. The variable clinical presentations and management of GI diseases in pediatrics and adults CF should be recognized. Therefore, it is necessary to ensure efficient transfer of information between pediatric and adult providers for proper continuity of management and coordination of care at the time of transition. The transition of care is a challenging process for both patients and providers and currently, there are no specific tools for GI providers to help ensure smooth transition. In this review, we aim to highlight the crucial features of GI care at the time of transition and provide a checklist that can assist in ensuring an effective transition and ease the challenges associated with it.
REVIEW | doi:10.20944/preprints202006.0277.v2
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: Diabetes; transcription factor; β-cell mass; pluripotent stem cells; pancreatic progenitors; cell therapy
Online: 19 October 2020 (16:04:27 CEST)
Understanding the biology underlying the mechanisms and pathways regulating pancreatic β-cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin producing β-cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β-cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β-cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive toβ-cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β-cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1-) results in an undesirable generation of non-functional polyhormonal β-cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β-cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a mean to increase β-cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β-cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.
ARTICLE | doi:10.20944/preprints201903.0042.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: pancreatic cancer, T cells, cancer stem cells, CD8, PD-L1, CD44, CD133, immunotherapy
Online: 4 March 2019 (13:28:43 CET)
Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effect to evade the immune recognition. However, clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, CD8+ T cells infiltration could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.
SHORT NOTE | doi:10.20944/preprints201806.0454.v1
Subject: Chemistry And Materials Science, Organic Chemistry Keywords: Pancreatic Porcine Lipase, Regio-selectivity; Quercetin derivatives, Oleic acid, ecofriendly reaction, scalable process.
Online: 27 June 2018 (16:01:26 CEST)
Polyphenols are well-known health promoting agents, but they have some limitations due to their spontaneous oxidation. This evidence has limited their use as drugs in the last years. In this field, several chemical modifications have been proposed to overcome these restrictions; among these, the esterification seems to be the preferred. Ester derivatives could be able to reduce the bioavailability problems connected to polyphenols. On the other hand, the presence of the esterase enzymes in the body guarantees the ester hydrolysis, which in turn frees the two molecules that make it up. Lipase-catalyzed esterifications afforded several derivatives of flavonoids glycosides, in green conditions. In this short note, pancreatic porcine lipase was firstly used as a cheap bio-catalyst, to synthesize oleoyl derivatives of quercetin in aglycone form. Results demonstrated how the enzyme acyl regioselective in position C-3, with high yields and easy purification processes
ARTICLE | doi:10.20944/preprints202310.1360.v1
Subject: Public Health And Healthcare, Primary Health Care Keywords: artificial intelligence; holistic health records; pancreatic cancer; real-time monitoring; primary and secondary data
Online: 20 October 2023 (16:12:43 CEST)
The healthcare domain is increasingly adopting IoT and Electronic Health Record (EHR) systems, generating vast volumes of healthcare data. This shift is driven by the growing need of delivering the right information to the right individuals, at the right time. The latter underscores the importance of adopting a comprehensive strategy for efficiently collecting, utilizing, and analyzing health-related data to not only enhance overall healthcare management but also for the provision of timely and personalized prevention strategies. The latter is of highest importance especially in scenarios where lack of effective treatments or poor survival rates (such in pancreatic cancer) renders typical healthcare strategies ineffective. In this article, we introduce an innovative and integrated platform that is specifically designed and developed for accessing, processing, and analyzing data in challenging healthcare scenarios, such as dealing with pancreatic cancer. This platform, called iHelp, combines multidisciplinary technologies and provides healthcare professionals reliable risk modelling, analysis, and prediction techniques so that individuals (at risk of developing pancreatic cancer) can be provided with timely, reliable, and personalized prevention and intervention measures. A key innovation in the iHelp platform is the standardized data management approach called Holistic Health Records (HHRs) that facilitate the capturing of all health determinants in a standardized and well-structured way for processing towards the provision of health risk detection and personalized healthcare decision support. In the development of iHelp platform, the HHRs are evaluated through different real-world healthcare datasets, including datasets coming from hospital systems, data from wearables, questionnaires, and mobile applications.
CASE REPORT | doi:10.20944/preprints202308.1058.v2
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: neuroendocrine tumors; NETs; pancreatic neuroendocrine tumors; P-NETs; endoscopic ultrasonography; EUS-FNA; EUS-FNB
Online: 18 September 2023 (13:31:36 CEST)
Pancreatic neuroendocrine tumor (P-NET) is a rare neoplasm originating in the neuroendocrine system. Carcinoid syndrome occurs in approximately 19% of patients with functional P-NETs, typically when liver metastases occur. NETs diagnosis is frequently late, along with symptoms related to hormone hypersecretion. We described the case of a patient with a low-grade non-functional P-NET, but with a typical clinical presentation of a carcinoid syndrome; moreover, we reviewed the literature regarding this topic. An 81-year-old male was admitted to our Department of Internal Medicine at Cannizzaro Hospital (Catania, Italy) because of the onset of abdominal pain with nausea, loose stools and episodic flushing. Firstly, an abdominal contrast-enhanced CT scan showed a small pancreatic hypervascular mass; then a gallium-68 DOTATOC integrated PET/CT revealed an elevated expression of SSTR receptors. Serum Chromogranin A and urinary 5-HIAA measurements resulted negative. Given the small size of the lesion (8 mm), we preferred to perform an endoscopic ultrasonography (EUS) with fine-needle biopsy (EUS-FNB), allowing the diagnosis of low-grade (G1) non-functional P-NET (NF-P-NET). Surgery was waived, while a follow-up strategy was chosen. Early recognition of P-NETs, although rare, is necessary to improve patient’s survival. EUS-FNB should be the protocol of choice for an early characterization of these tumors.
REVIEW | doi:10.20944/preprints202308.1657.v1
Subject: Medicine And Pharmacology, Internal Medicine Keywords: Mucinous breast carcinoma; pancreatic cancer; diabetes mellitus type 2; obesity; metabolic syndrome; postmenopausal women
Online: 23 August 2023 (11:22:36 CEST)
Mucinous breast carcinoma is a rare subtype of mammary neoplasm encountered in medical practice. It represents approximately 1-6% of all breast cancers and is more common in postmenopausal women. There are two subtypes of mucinous breast carcinoma: pure and mixed. We report the case of a 73-year-old Caucasian woman diagnosed with mucinous pancreatic cystadenoma in 2007. She underwent a surgical procedure involving pancreatectomy of the body and tail, along with multiple known cardiovascular and metabolic comorbidities. In November 2019, during a clinical-biological evaluation for associated diseases, a mucinous carcinoma of the right breast was accidentally detected and later confirmed through further investigations. For treatment, a surgical procedure was performed involving lower right quadrantectomy with right axillary lymph node dissection. The postoperative clinical course was favorable. In conclusion, we present the case of a patient diagnosed with mixed mucinous breast carcinoma, without axillary lymph node invasion. Postmenopausal women with diabetes, overweight, and obesity have an increased susceptibility to breast cancer, with our patient having all these risk factors. To date, no study has demonstrated the genetic or radiation implication in the occurrence of mucinous carcinomas, nor the possible development of mucinous carcinomas in series in the same patient. Current data are insufficient to provide recommendations for the screening of malignant mucinous tumors in subjects with significant cardiometabolic risk factors.
ARTICLE | doi:10.20944/preprints202201.0312.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: cancer-associated fibroblasts; tumor microenvironment; pancreatic cancer; intracellular metabolism; glycolysis; oxidative phosphorylation; cell differentiation
Online: 20 January 2022 (19:42:29 CET)
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment perform glycolysis to produce energy, i.e., ATP. Since the origin of CAFs is unidentified, it is not determined whether the intracellular metabolism transitions from oxidative phosphorylation (OXPHOS) to glycolysis when normal tissue fibroblasts differentiate into CAFs. In this study, we established an experimental system and induced the in vitro differentiation of mesenchymal stem cells (MSCs) to CAFs. Additionally, we performed metabolomic and RNA-sequencing analyses before and after differentiation to investigate changes in the intracellular metabolism. Consequently, we discovered that OXPHOS, which was the primary intracellular metabolism in MSCs, was reprogrammed to glycolysis. In addition, we identified CAF-specific metabolites that were expressed during this reprogramming and determined their presence in the pancreatic tumor tissues of mouse models. Thus, we conclude that normal tissue fibroblasts that differentiate into CAFs undergo a metabolic reprogramming from OXPHOS to glycolysis. Moreover, we identified the CAF-specific metabolites expressed during metabolic reprogramming as potential future biomarkers for pancreatic cancer.
REVIEW | doi:10.20944/preprints202107.0064.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: virotherapy; oncolytic viruses; gliomas; pancreatic cancer; adenoviruses; parvoviruses; enteroviruses; blood-brain barrier; tropism; transgene
Online: 2 July 2021 (14:23:22 CEST)
The idea of using the lytic power of viruses against the malignant cells has been entertained for many decades. However, oncolytic viruses (OV) gained broad attention as an emerging anti-cancer therapy only recently with the successful implementation of the oncolytic herpesvirus to treat advanced melanoma. OVs offer an attractive therapeutic combination of tumor-specific cell lysis together with immune stimulation, yet the latter effect is less well studied. Nevertheless, OVs can be envisaged as potential in situ tumor vaccines. The therapeutic potential of OVs can be instigated further by using the molecular biological and biotechnological tools to modify the existing viruses for their optimal tumor selectivity and enhanced immune stimulation. Furthermore, OVs can be readily combined with other therapeutic agents to increase the efficacy of the existing therapeutic schemes. In this review, we discuss biotechnological advances in the development of therapeutic applications of OVs in Russia. Particular emphasis is made on the OV-mediated treatment of glioblastoma. In addition, we highlight the challenges of oncolytic virotherapy, and describe the strategies to optimize current approaches to improve clinical outcomes.
REVIEW | doi:10.20944/preprints202008.0216.v1
Subject: Biology And Life Sciences, Cell And Developmental Biology Keywords: pancreas; pancreatic cancer; acinar-to-ductal metaplasia; organotypic culture; KRAS; metabolic reprogramming; epigenetic reprogramming
Online: 8 August 2020 (18:24:28 CEST)
Multi-step evolution characterizes the carcinogenesis of GI malignancies, where the disease progresses through the accrual of genetic mutations, co-option of multiple host cellular factors and the acquisition of increasingly aggressive pathological features. Ensuing cancer complexity and plasticity are challenges for therapeutic approaches. On the other hand, disease inception is often triggered by a defined oncogenic event, which leads to escalating effects on gene expression, cellular metabolism, chromatin organization and ultimately cell identity. Decoding this molecular cascade of events is crucial to design strategies for early diagnosis as well as to tackle tumor onset. To this aim, the in vitro culture of non-transformed epithelial cells represents a major technical challenge. Genetic studies, combined with lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a specialized cell type in the pancreatic epithelium, following mutations of the KRAS oncogene. Ex vivo culture of pancreatic acinar cells has allowed the identification of early mutant KRAS-driven alterations. Primary acinar cells survive in vitro in organoid-like 3D spheroids, which can recapitulate histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary mouse pancreatic acinar cells, providing and historical and technical perspective. Impact for pancreatic cancer research will also be debated; in particular we will dissect the role of KRAS signaling in driving oncogenic transformation and highlight differences with canonical 2D culture of established cancer cell lines.
ARTICLE | doi:10.20944/preprints201806.0096.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: long noncoding RNA; MALAT1; UCA1; NRON; Z probe; colorectal cancer; pancreatic cancer; breast cancer
Online: 6 June 2018 (13:05:30 CEST)
Formalin-Fixed Paraffin Embedded (FFPE) tissues are a valuable resource in studying different markers and mechanistic molecules (protein, DNA and RNA) in order to understand the etiology of different cancers as well as many other diseases. Degradation and modification of RNA is the major challenge in utilizing FFPE tissue samples in medical research. Recently, non-protein coding transcripts long non-coding RNAs (lncRNAs), have gained significant attention due to their important biological actions and potential involvement in cancer. There is no validated method except qRTPCR or RNAseq to evaluate and study lncRNA expression. We have standardized and are reporting a sensitive Z probe based in situ hybridization method to identify, localize and quantitate lncRNA in FFPE tissues. This assay is sensitive to single transcript and localizes lncRNA in individual cells within tumor. We have characterized a tumor suppressor lncRNA-NRON (non coding repressor of NFAT), which is scarcely expressed, a moderately expressed oncogeneic lncRNA UCA1 (urothelial cancer associated 1), and a highly studied and expressed lncRNA MALAT1 (metastasis associated lung adenocarcinoma transcript1) in different cancers. High MALAT1 staining was found in colorectal, breast and pancreatic cancer. MALAT1 expression increased with the progression of the stage in colorectal cancer and invasiveness in breast cancer.
ARTICLE | doi:10.20944/preprints202211.0121.v1
Subject: Medicine And Pharmacology, Endocrinology And Metabolism Keywords: Antigen mimicry; Autoimmune diseases; SARS-CoV-2; Human Coronaviruses; Thyroid gland; Pancreatic islets; Adrenals; Pituitary
Online: 7 November 2022 (11:32:33 CET)
The article is devoted to the problem of autoimmune diseases provocation by coronavirus infection and the role of molecular mimicry in this phenomenon. SARS-CoV-2 can disguise its proteins as human ones in order to avoid immune attack. A bioinformatics analysis of the probable pentapeptide sharing between human autoantigens of endocrinocytes and SARS-CoV-2 spike protein, membrane protein and nucleocapsid protein was performed. Antigen mimicry between S-proteins of all other known human Coronaviruses and typical target autoantigens of endocrinocytes was also explored. Six human-identical regions were found in the SARS-CoV-2 membrane and nucleocapsid proteins, all of them in their immunodominant epitopes. All shared epitopes belong to antigens of endocrine cells commonly targeted during autoimmune endocrinopathies. Moreover, samples of the pituitary, adrenal and thyroid from patients who died from coronovirus infection (COVID-19) were studied morphologically using histochemical methods. A high frequency of SARS-CoV-2 caused inflammation of the studied endocrine organs was found in patients who died from severe COVID-19. At the same time, the abundant expression of virus antigens by the cells of the adenohypophysis was combined with the complete absence of its expression by the cells of the neurohypophysis. SARS-CoV-2 infected cells apparently perished by non-apoptotic pathway. The foci of lesions in endocrine organs contained abundant lymphocytic infiltrates which may witness for the impact of autoimmune processes. The facts revealed emphasize the need of endocrinological diagnostic alertness of a physician while observing patients with post-vaccination and post-COVID-19 health disorders. [3 figures, 6 tables, bibliography: 45 references].
ARTICLE | doi:10.20944/preprints202209.0242.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: pancreatic cancer (PC); abdominal ultrasonography (US); surveillance; prognosis; medical checkup; 5-year survival; cancer screening
Online: 16 September 2022 (08:08:33 CEST)
Recent advancements in surgical and anti-cancer therapies have provided significant hope of long survival in patients with pancreatic cancer (PC). To realize this hope, routine medical checkups of asymptomatic people should be performed to identify operable PCs. In this study, we evaluated the efficacy of medical checkups using abdominal ultrasonography (US). We retrospectively analyzed 374 patients with PC at our institute between 2010 and 2021. We divided these patients into several groups according to the diagnostic approach and compared their background and prognosis. These groups comprised PCs diagnosed through (a) symptoms, 242 cases; (b) US during medical checkup for asymptomatic individuals, 17; and other means. Of the 375 patients, 192 were men (51.3%), and the median age was 74 years (34–105). Tumors were located in the pancreatic tail in 67 patients (17.9%). Excision ratio and 5-year survival rate were significantly better in group (b) than in (a) (58.8% vs. 23.1%, P<0.01 and 42.2% vs. 9.4%, P<0.001, respectively). The prognosis of patients diagnosed using US during medical checkup was better than that of patients identified through symptomatic presentation of PC. US for asymptomatic individuals with PC might be useful for promoting better prognosis of PCs.
ARTICLE | doi:10.20944/preprints202106.0638.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: pancreatic ductal adenocarcinoma; targeted therapies; therapeutic resistance; tumor microenvironment; desmoplasia; collagen; collagenase; attenuated Salmonella typhimurium
Online: 28 June 2021 (10:36:31 CEST)
Therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) can be attributed, in part, to a dense extracellular matrix containing excessive collagen deposition. Here, we describe a novel Salmonella typhimurium (ST) vector expressing the bacterial collagenase Streptomyces omiyaensis trypsin (SOT), a serine protease known to hydrolyze collagens I and IV, which are predominantly found in PDAC. Utilizing aggressive models of PDAC, we show that ST-SOT selectively degrades intratumoral collagen leading to enhancement of immune checkpoint blockade (ICB) therapy in tumor-bearing mice. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment more conducive to ICB.
CASE REPORT | doi:10.20944/preprints201905.0173.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pancreatic ductal adenocarcinoma; non small cell lung cancer; double primary cancers; B7-H3; gefitinib; chemotherapy
Online: 14 May 2019 (13:04:44 CEST)
Management of multiple primary cancers, a not so infrequent event in oncology practice, is a critical issue due to the lack of literature . In this study, we reported the case of a patient with metachronous double metastatic non small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) who received gefitinib in combination with gemcitabine plus nab-paclitaxel and with mFOLFOX6 in first and second line, respectively. She achieved a progression free survival and an overall survival (OS) of 28 months for NSCLC and PFS-1 and OS of 20 and 13 months, respectively for PDAC. Moreover, the combination of gefitinib and chemotherapies treatments displayed a good safety profile. Given the insignificant frequency of this case, we performed a molecular characterization of both neoplasms with the aim to investigate the existence of particular activated pathways and/or similar immunological mutations. it is interesting to note that two neoplasms shared a commune mutation of B7-H3 gene, with the consecutive impairment of its expressed protein. In both PDAC and NSCLC, the expression of this protein was associated with a worse survival. Since B7-H3 is an anti-apoptotic protein, the reduction of its expression or function should justify a pro-apoptotic activity with a putative justification of the long survival of the patient considered in this report.
ARTICLE | doi:10.20944/preprints202311.1083.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pancreatic adenocarcinoma, PDAC, cancer stem cells, EMT, Epithelial-Mesenchymal-Transition, Heterogeneity, Plasticity, Adhesion, Migration, Invasion, Metastasis
Online: 16 November 2023 (11:36:00 CET)
Pancreatic ductal adenocarcinoma (PDAC) is mostly diagnosed at advanced or even metastasized stages limiting patient´s prognosis. Metastasis requires high tumor cell plasticity implying phenotypic switching in response to changing environments. Here, Epithelial-Mesenchymal-Transition (EMT), being associated with the gain of cancer stem cell (CSC) properties, and its reversion are important. Since it is poorly understood whether different CSC-phenotypes exist along the EMT-axis and how these impact malignancy-associated properties, we aimed to characterize CSC-populations of epithelial and mesenchymal PDAC cells. Single-cell cloning revealed CSC (Holoclone) and non-CSC (Paraclone) clones from the PDAC cell lines Panc1 and Panc89. Panc1 Holoclone cells showed a mesenchymal phenotype dominated by high expression of the stemness marker Nestin, while Panc89 Holoclone cells exhibited a SOX2-dominated epithelial phenotype. Panc89 Holoclone cells showed enhanced cell growth and self-renewal capacity but slow cluster-like invasion. Contrarily, Panc1 Holoclone cells showed slower cell growth and self-renewal ability but were highly invasive. Moreover, cell variants differentially responded to chemotherapy. In vivo, Panc1 and Panc89 cell variants significantly differed regarding number and size of metastases as well as organ manifestation leading to different survival outcomes. Overall, these data support the existence of different CSC-phenotypes along the EMT-axis in PDAC manifesting in different metastatic propensities.
ARTICLE | doi:10.20944/preprints202307.1251.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: ascorbic acid; pharmacologic ascorbate; pancreatic cancer; epigenetics; DNA methyltransferase (DNMT); ten-eleven translocation (TET) methylcytosine dioxygenase
Online: 18 July 2023 (13:51:14 CEST)
Recent studies have demonstrated an important role for vitamin C in the epigenetic regulation of cancer-related genes via DNA demethylation by the ten-eleven translocation (TET) methylcytosine dioxygenase enzymes. DNA methyltransferase (DNMT) reverses this, increasing DNA methylation and decreasing gene expression. Dual oxidase (DUOX) enzymes produce hydrogen peroxide (H2O2) in normal pancreatic tissue but are silenced in pancreatic cancer (PDAC). Treatment of PDAC with pharmacologic ascorbate (P-AscH-, intravenous, high dose vitamin C) increases DUOX expression. We hypothesized that inhibiting DNMT may act synergistically with P-AscH- to further increase DUOX expression and cytotoxicity of PDAC. PDAC cells demonstrated dose-dependent increases in DUOX mRNA and protein expression when treated with DNMT inhibitors. PDAC cells treated with P-AscH- + DNMT inhibitors demonstrated increased DUOX expression, increased intracellular oxidation, and increased cytotoxicity in vitro and in vivo compared to either treatment alone. These findings suggest a potential therapeutic, epigenetic mechanism to treat PDAC.
ARTICLE | doi:10.20944/preprints202304.0457.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: Peptide nucleic acid; microRNA detection; duplex specific nuclease; Early diagnosis of pancreatic cancer; Lateral flow biosensor
Online: 18 April 2023 (02:48:27 CEST)
Malignancy is a fatal disease with an increasing incidence with each passing year, and the early diagnosis of malignancy can significantly improve the cure rate of patients, which has profound implications for saving patients' lives. The changes of miRNA are closely related to the occurrence of malignant tumors. The expression of miRNA in many malignant tumors is obviously different and unique from that in normal tissues. In this study, a strategy for amplifying microRNA (miRNA) signal was designed using duplex specific nuclease (DSN), which was then combined with Peptide nucleic acid (PNA) probe hybridization technology to prepare a sensitive and efficient paper-based lateral flow biosensor (LFB) for the detection of pancreatic cancer (PC) associated microRNA-10b. The performance evaluation results of the LFB showed that the detection limit of miR-NA-10b is 5 nM/mL, and carries demonstrated well specificity, stability, reproducibility. The biosensor prepared in this paper can provide accurate and rapid detection of miRNA-10b. The detection results play a guiding role in the early diagnosis of PC. Meeting the clinical need for largescale screening of individuals at high risk of PC. Providing new avenues to achieve early mass screening in individuals at high risk of PC.
ARTICLE | doi:10.20944/preprints202301.0575.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: Directed endoscopic necrosectomy; endoscopic step-up approach; endoscopic transluminal drainage; percutaneous drainage; walled-off pancreatic necrosis
Online: 31 January 2023 (06:25:40 CET)
Abstract: Background and objectives: Symptomatic walled-off pancreatic necrosis is a serious local complication of acute necrotising pancreatitis. The endoscopic step-up approach is the standard treatment for symptomatic walled-off pancreatic necrosis; however, adjunctive radiologic percu-taneous drainage for this condition is controversial. This study compared the clinical and radio-logic resolution of walled-off pancreatic necrosis achieved with the endoscopic step-up approach with or without radiology-guided percutaneous drainage. Material and Methods: This retrospective, single-center cohort study enrolled patients with symp-tomatic walled-off pancreatic necrosis who underwent endoscopic transmural drainage (ETD) followed by directed endoscopic necrosectomy (DEN) with or without radiology-guided drainage. A total of 34 patients (endoscopic approach, n=22; combined modality approach, n=12) underwent the endoscopic step-up approach (ETD followed by DEN). Baseline characteristics, clinical success, and resolution of necrosis were compared between groups. Results: All patients achieved symptom resolution from walled-off pancreatic necrosis. The mean patient age was 58.4 years, and 21 (61.8%) were men. After treatment with the endoscopic approach and combined modality approach, clinical success was achieved in 90.9% of patients within 11.5 days, and 66.7% of patients within 16.5 days, respectively. Both the total hospital stay (55 days vs 71 days; p=0.071) and time to complete radiologic resolution were shorter (93 days vs 124 days; p=0.23) in the endoscopic approach group. Conclusion: The endoscopic step-up approach resulted in the clinical resolution of symptomatic walled-off pancreatic necrosis comparable to that of the combined modality drainage. However, the endoscopic approach alone allows higher clinical success, early clinical and radiologic resolution, and a shorter hospital stay.
ARTICLE | doi:10.20944/preprints202108.0368.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: pancreatic cancer; cancer subtype identification; somatic point mutations; genotype and phenotype characterization; therapeutic targets; personalized medicine
Online: 17 August 2021 (22:24:57 CEST)
It has now known that at least 10% of samples with pancreatic cancers (PC) contain a causative mutation in the known susceptibility genes, suggesting the importance of identifying cancer-associated genes that carry the causative mutations in high-risk individuals for early detection of PC. In this study, we develop a statistical pipeline using a new concept, called gene-motif, that utilizes both mutated genes and mutational processes to identify 4,211 3-nucleotide PC-associated gene-motifs within 203 significantly mutated genes in PC. Using these gene-motifs as distinguishable features for pancreatic cancer subtyping results in identifying five PC subtypes with distinguishable phenotypes and genotypes. Our comprehensive biological characterization reveals that these PC subtypes are associated with different molecular mechanisms including unique cancer related signaling pathways, in which for most of the subtypes targeted treatment options are currently available. Some of the pathways we identified in all five PC subtypes, including cell cycle and the Axon guidance pathway are frequently seen and mutated in cancer. We also identified Protein kinase C, EGFR (epidermal growth factor receptor) signaling pathway and P53 signaling pathways as potential targets for treatment of the PC subtypes. Altogether, our results uncover the importance of considering both the mutation type and mutated genes in the identification of cancer subtypes and biomarkers.
ARTICLE | doi:10.20944/preprints201906.0228.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: pancreatic cancer; PDAC; lymph node metastases; WNT; dendritic cells; M2 macrophages; XAV-939; tumour immune-microenvironment
Online: 22 June 2019 (16:50:32 CEST)
Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene-expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window.To this end, we provide an original bioinformatic dissection of the gene-expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient’s derived samples indicated that WNT increased activation and a peculiar immune-microenvironment identify subjects with nodal involvement.In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939, a specific WNT pathway inhibitor, has in re-educating a tumour permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in nodes-positive disease.
ARTICLE | doi:10.20944/preprints201809.0540.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Modified FOLFIRINOX; Severe neutropenia; Overall survival; Overall response rate; Time to treatment failure; Advanced pancreatic cancer
Online: 27 September 2018 (10:12:08 CEST)
Modified FOLFIRINOX is effective for advanced pancreatic cancer but frequently causes severe neutropenia. The present study was designed to investigate the influence of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients receiving modified FOLFIRINOX. Fifty-one advanced pancreatic cancer patients who received modified FOLFIRINOX during January 2014 and May 2018 were subjects of the present study. Adverse events, including neutropenia, were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Median overall survival (OS) was determined as the primary endpoint, while median time to treatment failure (TTF), overall response rate (ORR), and the incidence of other adverse events were measured as secondary endpoints. Severe neutropenia (grade≥3) occurred in 39 patients (76.4%), in which high level of total bilirubin (>0.6mg/dL) was a significant risk as assessed by a multivariate logistic regression analysis. Median duration of OS was significantly longer in patients with severe neutropenia than in those without it (15.2 months versus 7.2 months, P=0.032). Moreover, there was a significant correlation between OS and the grade of neutropenia (R=0.306, P=0.029). ORR tended to be higher, though not significantly, in patients with severe neutropenia. In contrast, the incidence rates of other adverse events were not different between the two groups. Severe neutropenia is an independent predictor of prognosis in advanced pancreatic cancer patients received modified FOLFIRNOX therapy.
REVIEW | doi:10.20944/preprints201805.0129.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: BET inhibitors; HDAC inhibitors; pancreatic cancer; aberrant transcription; enhancers; transcription factors; distal regulatory elements; MYC; FOXA1; BRD4
Online: 8 May 2018 (10:47:27 CEST)
While the mortality rates of cancer are generally declining, pancreatic cancer persists to be an exception with a 5-year-survival rate of less than 7%. Late diagnosis and resistance to conventional therapies contribute to high mortality rates in spite of the remarkable recent advances in cancer management and research. Consequently, there is an urgent need to find new and unconventional therapeutic targets to improve prognosis and survival of pancreatic cancer patients. In this review, we discuss the transcriptional effects of the most widely used epigenetic inhibitors in pancreatic cancer focusing on Bromodomain and Extraterminal domain (BET) and Histone Deacetylase (HDAC) inhibitors, which are currently highly promising therapeutic options. We suggest that these inhibitors can be better utilized at lower doses which exploit their transcriptional modulatory effects on pancreatic cancer transcriptional programs directed by specific factors such as MYC and FOXA1, rather than simply based on their anti-proliferative effects. This approach can potentially help avoid the intolerable adverse events frequently elicited by the use of these treatments at higher doses. In particular, we underscore the crucial role of distal regulatory elements in mediating the specific effects of these epigenetic inhibitors and propose using them in a more selective and prudent manner.
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Neuroendocrine Neoplasms; NOTCH; cancer driven genes; mutational mechanism; germline mutations.; small cell lung carcinoma; pancreatic NET; small bowel NET; medullary thyroid carcinoma; malignant castration-resistant prostatic cells
Online: 23 July 2019 (10:34:50 CEST)
Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies mainly originated from hormones secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout MEN-1 gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signaling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally, act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the roles and the potential therapeutic implications of gene mutations and NOTCH signaling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential roles across all NEN subtypes is required.
ARTICLE | doi:10.20944/preprints202304.0625.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: adverse drug reaction; cisplatin liposomes; circulating tumor cells; enhanced permeability and retention effect; nephrotoxicity; pulmonary metastasis of pancreatic cancer; quality of life; recurrent liver metastases from primary nasal cancer
Online: 20 April 2023 (07:52:10 CEST)
Cisplatin (CDDP) is a platinum-based drug effective against various cancers, including lung, bladder, prostate, ovarian, esophageal, stomach, and cervical cancer and malignant lymphoma. It plays a central role as the first choice in current anticancer therapy. However, CDDP causes serious side effects, such as neurological disorders, myelosuppression, and renal damage, because it is a small molecule indiscriminately distributed in normal tissues. Therefore, it is very important to prevent or attenuate CDDP toxicity. We hypothesized that liposomalization of CDDP could alleviate serious side effects. Therefore, this study aimed to evaluate the safety and efficacy of CDDP liposomes. A patient with multiple recurrent liver metastases from metastatic nasal carcinoma was administered CDDP liposomes with consent. Magnetic resonance imaging showed that the patient remained stable-diseased; however, no apparent side effects were observed, and blood draw data showed no worsening of renal function. Patients undergoing partial pancreatectomy and jejunoileal biliary anastomosis for biliary tract cancer who consented to receive CDDP liposomes demonstrated a partial response on angiographic computed tomography; however, they showed slight fatigue. To our knowledge, the present study is the first in Japan to suggest that liposomalization of CDDP may have anticancer effects while alleviating renal damage and bone marrow suppression.
INTERESTING IMAGES | doi:10.20944/preprints202309.0462.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: claudin-18; cytopathology; colloid carcinoma (CC) of the pancreas; intraductal papillary mucinous neoplasm with high-grade dysplasia (IPMNHGD) of the pancreas; signet-ring cell; serial pancreatic juice aspiration cytological examination (SPACE)
Online: 7 September 2023 (10:45:29 CEST)
We report a case of colloid carcinoma (CC) arising from an intestinal-type intraductal papillary mucinous neoplasm with high-grade dysplasia (IPMNHGD) of the pancreas, diagnosed with serial pancreatic juice aspiration cytological examination (SPACE). A rapidly growing intraductal papillary mucinous neoplasm (IPMN) in a 71-year-old Japanese man accelerated his hospitalization in our institute. Clinically, a large, ruptured pancreatic cyst was suspected. Cytologically, several mucin-positive signet-ring cells were scattered in the inflammatory, necrotic, or mucinous background. Signet-ring cells in cell block specimens were immunoreactive for MUC2, MUC5AC, maspin, S100P, and claudin-18. The final cytologic diagnosis was CC arising in an intestinal-type IPMNHGD with intraperitoneal penetration. The patient died two months postoperatively. The cytologic diagnosis was achieved through SPACE, and the presence of signet-ring cells was characteristic. Anti-claudin-18.2-specific monoclonal antibody therapy will likely be used to treat patients with IPMNHGD in the future. To our knowledge, this is the first report in English on mucin-positive signet-ring cells of CC arising in an intestinal-type IPMNHGD evaluated by SPACE cytology.
REVIEW | doi:10.20944/preprints202010.0578.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Type 1 diabetes; insulin therapy; C-peptide; islet transplantation, mesenchymal stem cells; induced pluripotent stem cells; pancreatic β cell; gene therapy; β-cell regeneration and reprogramming, type 1 diabetes precision medicine, diabetes personalized care.
Online: 28 October 2020 (10:02:34 CET)
Type 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The present standard-of-care for type 1 diabetes is exogenic insulin substitutional therapy. The most advanced stretegies in this area is the development of hybrid-closed loop system and the producing of long-acting insulins. Progresses in stem cell therapies have started to revolutionize the care of patients with type 1 diabetes; however, significant challenges remain including the limited islets availability, difficulties in maintaining the viability, the heterogeneity within a complex pathology and in patients’ responses to treatment. On the way, a considerable amount of efforts in maximizing the islet transplantation effectiveness by controlling the advantageous of different stem cell approaches. With the availability and the use of big data, the concept of precision medicine is gaining wide attention worldwide and could bring the dream of “presonlaized” therapies as a reality in the near future. Here we review the current range of treatments available as well as recent pre-clinical breakthroughs in the field of personlaized medicine for type 1 diabetes.