ARTICLE | doi:10.20944/preprints202208.0534.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: Targeted Adenoviral Vectors (Ad), Streptavidin-Polylysine (STAVpLys), messenger Ribonucleic Acid (mRNA)
Online: 31 August 2022 (05:08:33 CEST)
Molecular therapies exploiting mRNA vectors embody enormous potential, as evidenced by the utility of this technology for the context of the COVID-19 pandemic. None-the-less, broad implementation of these promising strategies has been restricted by the limited repertoires of delivery vehicles capable of mRNA transport. On this basis, we explored a strategy based on exploiting the well characterized entry biology of adenovirus. To this end, we studied an adenovirus-polylysine (AdpL) that embodied “piggyback” transport of the mRNA on the capsid exterior of adenovirus. We hypothesized that the efficient steps of Ad binding, receptor-mediated entry, and capsid-mediated endosome escape could provide an effective pathway for transport of mRNA to the cellular cytosol for transgene expression. Our studies confirmed that AdpL could mediate effective gene transfer of mRNA vectors in vitro and in vivo. Facets of this method may offer key utilities to feasibilize the promise of mRNA-based therapeutics.
ARTICLE | doi:10.20944/preprints202007.0424.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: 4-Phenylbutyric acid; Colon-targeted drug delivery; Colitis; Prodrug; ER stress; Chemical chaperone
Online: 19 July 2020 (19:15:20 CEST)
An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for inflammatory bowel disease (IBD). To develop an ER stress attenuator that is effective against colitis, 4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with acidic amino acids to yield a 4-PBA-glutamic acid conjugate (PBA-GA) and a 4-PBA-aspartic acid conjugate (PBA-AA). The PBA derivatives were converted to 4-PBA in the cecal contents, where the conversion was greater with PBA-GA. After oral administration of PBA-GA (oral PBA-GA), millimolar levels of PBA were accumulated in the cecum, whereas 4-PBA was not detected in the blood, indicating the targeting of PBA-GA to the large intestine. At concentrations in the cecum achievable by oral PBA-GA, 4-PBA effectively attenuated ER stress in human colon epithelial cells. In 2,4-dinitrobenzenesulfonic acid-induced colitis in rats, oral PBA-GA alleviated the damage and inflammation in the colon. Moreover, oral PBA-GA substantially reduced the elevated levels of ER stress marker proteins in the inflamed colon. Moreover, PBA-GA was as effective as the currently used anti-IBD drug, sulfasalazine. In conclusion, PBA-GA is a colon-targeted prodrug of 4-PBA and is effective against rat colitis probably through the attenuation of ER stress in the inflamed colon.
ARTICLE | doi:10.20944/preprints202110.0196.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: star polymer; β-cyclodextrin; tumor-targeted; disulﬁde bond; theranostic nanoparticles
Online: 13 October 2021 (11:00:40 CEST)
β-cyclodextrin-based star polymers have attracted much interest because of their unique structures and potential biomedical and biological applications. Herein, we synthesized well-defined folic acid (FA)-conjugated and disulfide bond-linked star polymer ((FA-Dex-SS)-βCD-(PCL)14) acted as theranostic nanoparticles for tumor-targeted magnetic resonance imaging (MRI) and chemotherapy. Theranostic nanoparticles were obtained by loading doxorubicin (DOX) and superparamagnetic iron oxide particles (SPIO) were loaded into the star polymer nanoparticles to obtain ((FA-Dex-SS)-βCD-(PCL)14@DOX/SPIO) theranostic nanoparticles. In vitro drug release studies showed that approximately 100% of the DOX was released from disulfide bond-linked theranostic nanoparticles within 24 h under a reducing environment in the presence of 10.0 mM GSH. DOX and SPIO could be delivered into HepG2 cells efficiently, owing to folate receptor-mediated endocytosis process of the nanoparticles and GSH triggered disulfide-bonds cleaving.Moreover, (FA-Dex-SS)-βCD-(PCL)14@DOX/SPIO showed strong MRI contrast enhancement properties. In conclusion, folate-decorated reduction-sensitive star polymeric nanoparticles are a potential theranostic nanoparticle candidate for tumor-targeted MRI and chemotherapy.
REVIEW | doi:10.20944/preprints202103.0699.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Bismuth-213; Targeted Radionuclide Therapy; Targeted alpha Therapy; radiopharmaceutical; bifunctional chelator; vector molecule
Online: 29 March 2021 (14:43:57 CEST)
Besides external high-energy photon or proton beam therapy, targeted radionuclide therapy (TRNT) is an alternative approach to deliver radiation to cancer cells. TRNT is distributed within the body by the vascular system and allows targeted irradiation of a primary tumor and all its metastases, resulting in substantially less collateral damage to normal tissues as compared to ex-ternal beam radiotherapy (EBRT). It is a systemic cancer therapy, tackling systemic spread of the disease, which is the cause of death in most cancer patients. The α-emitting radionuclide bis-muth-213 (213Bi) has interesting properties and can be considered as a magic bullet for TRNT. The benefits and drawbacks of targeted alpha therapy with 213Bi are discussed in this review, covering the entire chain from radionuclide production to bedside. First, the radionuclide properties and production of 225Ac and its daughter 213Bi are discussed, followed by the fundamental chemical properties of bismuth. Next, an overview of available acyclic and macrocyclic bifunctional chelators for bismuth, and general considerations for designing a 213Bi-radiopharmaceutical are provided. Finally, we will provide an overview of preclinical and clinical studies involving 213Bi-radiopharmaceuticals, as well as the future perspectives of this promising cancer treatment option.
REVIEW | doi:10.20944/preprints202112.0315.v1
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: Nanotechnology; Niosomes; Targeted Drug Delivery
Online: 20 December 2021 (14:18:53 CET)
Nanotechnology is making significant transformation to our world, especially in healthcare and the treatment of diseases. It is widely used in different medical applications, such as in treatment and detection. Targeting diseased cell with nanomedicines is one of the numerous applications of nanotechnology. Targeted drug delivery systems for delivering various types of drugs to specific sites are such a dynamic area in pharmaceutical biotechnology and nanotechnology. Compared to conventional drugs, nanomedicines have a higher absorption and bioavailability rate, improving efficacy and minimizing side effects. There are several drug delivery systems including metallic nanoparticles, polymers, liposomes, and microspheres, but one of the most important is the niosomes, which are produced by nonionic surfactants. Because of the amphiphilic nature and structure, hydrophilic or hydrophobic drugs can be loaded into niosome structures. Other compounds, including cholesterol, can also be applied to the niosomes' backbone to rigidize the structure. Several variables such as the type of surfactant in niosome production, the preparation method, and the hydration temperature can affect the structure of the niosomes. Nevertheless, in-silico design of drug delivery formulations requires molecular dynamic simulation tools, molecular docking, and ADME (absorption; distribution; excretion; metabolism) properties, which evaluate physicochemical features of formulation and ADME attitudes before synthesis, investigating the interaction between nano-carriers and specific targets. Hence, experimenting in-vitro and in-vivo is essential. In this review, the basic aspects of niosomes are described including their structure, characterization, preparation methods, optimization with in-silico tools, factors affecting their formation, and limitations.
REVIEW | doi:10.20944/preprints202202.0242.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Colorectal cancer; Targeted therapy; Clinical trial
Online: 21 February 2022 (03:05:05 CET)
Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab were developed. The use of targeted drugs in clinical practice has significantly increased patients’ overall survival. To date, the emergence of several types of targeted drugs has opened new possibilities and revealed new prospects for mCRC treatment. Therapeutic strategies are continually being updated to select the most suitable targeted drugs based on the results of clinical trials that are currently underway. This review discusses the up-to date molecular evidence of targeted therapy for mCRC and summarizes the Food and Drug Administration-approved targeted drugs including the results of clinical trials. We also explain their mechanisms of action and how these affect the choice of a suitable targeted therapy.
REVIEW | doi:10.20944/preprints202109.0242.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: PDK1; breast cancer; survival; prognosis; targeted therapy
Online: 14 September 2021 (14:51:06 CEST)
Given that 3-Phosphoinositide-dependent kinase 1 (PDK1) plays a crucial role in malignant biological behaviors of a wide-range of cancers, we further review the influence of PDK1 in breast cancer (BC). First, we describe the power of PDK1 in cellular behaviors and extensively demonstrate the interacting networks of PDK1 via PI3K-dependent/ PI3K-independent pathway. Then we enlighten the roles of PDK1 in carcinogenesis, growth and survival, metastasis, and chemoresistance in BC cells. More important, we sort the current preclinical or clinical trials of PDK1 targeted therapy in BC and find that even though at present no selective PDK1 inhibitor is available for BC therapy, but the combination trials of PDK1 targeted therapy and other agents have demonstrated some benefit. Thus, there is increasing anticipations that PDK1 targeted therapy will have its space in future therapeutic concepts of BC, and we hope to feature PDK1 in BC to the clinic and bring the new promising to patients for targeted therapies.
ARTICLE | doi:10.20944/preprints202106.0460.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: melanoma; targeted therapy; elderly people; side effects
Online: 17 June 2021 (13:59:08 CEST)
Purpose: Melanoma’s incidence is increasing, and elderly people could be significantly impacted since the majority occurs in people over 65 years of age. Combined targeted therapies (TT) are current standard regimen for BRAF mutated metastatic melanoma (MM). Except for subgroups of pivotal trials, little data are available for TT in this population. Materials and Methods: Outcomes were explored in real life patients from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. Patients treated by BRAF TT and/or MEK TT combined or not, were included from 2013 to 2017 in 2 groups: group 1 <65-year-old (yo), group 2 >65 yo, analyzed for tolerance and efficacy. Results: 353 patients were included: 231 in group 1, 122 in group 2. Median follow-up was 12 months (M). Median time of treatment was 6.9 M. A total of 80% had at least one Adverse Effect (AE). Most frequent AE (all grades) were mainly skin and subcutaneous, general, and gastrointestinal disorders. A total of 31% of AE were grade 3–4: 28% in group 1 and 39% in group 2 (p = 0.05). No differences were observed in all AE grades proportion, dose modifications, interruptions, and discontinuations. For each group, median overall survival was 20.3 M (CI 95%: 15.5–27.9) and 16.3 M (CI: 14.5–26.9), respectively (p = 0.8). Median progression free survival was 7.8 M (6.4–9.9) and 7.7 M (CI: 5.8–11.3) (p = 0.4). Objective response rate was 59% and 50% (p = 0.6). Conclusion: This study on a large multicentric cohort is the first to assess that TT is well tolerated in elderly BRAF-mutated patients such as in patients younger than 65. Efficacy was similar between groups with outcomes reaching those from pivotal studies. There is thus no argument against using TT in elderly people, although an onco-geriatric opinion is welcome for the most vulnerable.
ARTICLE | doi:10.20944/preprints202009.0510.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: Hydrogel; pH-responsive; colon; targeted delivery; methotrexate
Online: 22 September 2020 (08:17:48 CEST)
The purpose of current research work was to formulate and typify gelatin and poly(vinyl) alcohol (Gel/PVA) hydrogel which would be highly pH-responsive and can able to accomplish targeted delivery of methotrexate in order to treat the colo-rectal pathologies. The primed gel/pva hydrogel discs were subjected to various physicochemical techniques i.e. swelling, diffusion co-efficient, sol-gel analysis and porosity using three altered sorts of pH (1.2, 6.8 & 7.4) phosphate buffer solutions for assessment/evaluation, and their characterization was done through Fourier transform infrared spectroscopy (FTIR) and thermal gravimetric analysis (TGA). Shape alteration and controlled methotrexate of release of Gel/PVA hydrogel have been done using three type of pH (1.2, 6.8 & 7.4) phosphate buffer mediums. Methotrexate was loaded through in-situ drug loading method due to hydrophobicity. Different kinetic models (first order & zero order kinetic), Higuchi model and Krosmere peppas model/Power law were applied to manipulate the drug release data. Physicochemical evaluation tests and drug release profile results were found insignificant (p< 0.05) in various pH mediums and dependent upon polymers concentration pH of medium and cross-linker amount. Kinetic model disclosed that release of methotrexate from Gel/PVA hydrogel follow non-Fickian diffusion method. It became concluded from this research work that release of methotrexate Gel/PVA hydrogel in targeted colon area can be achieved for treating colo-rectal disorders.
ARTICLE | doi:10.20944/preprints202209.0126.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: liposome; tumor-targeted; radiation; tumor; drug delivery; chemotherapy
Online: 8 September 2022 (14:06:26 CEST)
Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg PE, DSPC, cholesterol, and DSPE-PEG-2000, and the mean size of the RTL was in the range of 114 to 133 nm, as measured by NTA. The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three i.v. injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone.
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Pediatric Acute Lymphoblastic Leukemia; Genomics; Epigenetics; Targeted Therapy
Online: 1 October 2021 (12:23:33 CEST)
Acute lymphoblastic leukemia is the most common malignancy in children and is characterized by numerous genetic and epigenetic abnormalities. Epigenetic mechanisms, which involve DNA methylations and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. Emerging studies are increasing our understanding of the epigenetic role of leukemogenesis and have demonstrated the potential of DNA methylations and histone modifications as a biomarker for lineage and subtypes classification, predicting relapse, and disease progression in ALL. Epigenetic abnormalities are relatively reversible when treated with some small molecule-based agents compared to genetic alterations. In this review, we conclude the genetic and epigenetic characteristics in ALL and discuss the future role of DNA methylation and histone modifications in predicting relapse, finally focus on the individual and precision therapy targeting epigenetic alterations.
ARTICLE | doi:10.20944/preprints202107.0281.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Glioblastoma; Precision Medicine; Targeted Therapy; Genomics; Neuro-Oncology
Online: 13 July 2021 (09:28:35 CEST)
BACKGROUND: Glioblastoma (GBM) is driven by various genomic alterations. Next generation sequencing (NGS) could yield targetable alterations that may impact outcomes. The goal of this study was to describe how NGS can inform targeted therapy (TT) in this patient population. METHODS: The medical records of patients (pts) with a diagnosis of GBM from 2017-2019 were reviewed. Records of patients with recurrent GBM and genomic alterations were evaluated. Objective response rates and disease control rates were deter-mined. RESULTS: A total of 87 pts with GBM underwent NGS. Forty percent (n = 35) were considered to have actionable alterations. Of the 35, 40% (n=14) pts had their treatment changed due to an alteration. The objective response rate (ORR) of this population was 43%. The disease control rate (DCR) was 100%. The absolute mean decrease in contrast enhancing disease was 50.7% (95% CI 34.8 – 66.6). CONCLUSION: NGS for GBM, particularly in the recurrent setting, yields a high rate of actionable alterations. We observed a high ORR and DCR, reflecting the value of NGS in deciding on TT to match alterations that are likely to respond. In conclusion, patient selection and availability of NGS may impact outcomes in select pts with recurrent GBM.
REVIEW | doi:10.20944/preprints202011.0061.v1
Subject: Biology And Life Sciences, Anatomy And Physiology Keywords: Targeted Protein Silencing (TPS); Targeted Protein Degradation (TPD); dTAG; FKBP12; von Hippel-Lindau (VHL); degron; deGradFP; Anchor-Away; Nanobody; Nano-Grad
Online: 2 November 2020 (15:59:46 CET)
Targeted Protein Silencing (TPS) is an elegant approach to investigate protein function and its role in the cellular landscape, overcoming limitations of genetic perturbation strategies. In contrast to CRISPR/Cas9 and RNA interference, these systems act in a reversible manner and reduce off-target effects. Several TPS have been developed and wisely improved, including compartment delocalization tools and protein degradation systems. In this review, we focus on Anchor-Away, deGradFP, auxin inducible degron (AID) and dTAG technologies, and discuss their recent applications and advances. Finally, we propose Nano-Grad, a novel nanobody-based protein degradation tool to specifically proteolyze endogenous tag-free target protein.
ARTICLE | doi:10.20944/preprints202103.0687.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: gold nanorods; targeted; EGFR; HNSCC; uptake; NIR-II window
Online: 29 March 2021 (12:11:26 CEST)
Gold nanoparticles have been indicated for use in a diagnostic and/or therapeutic role in several cancer types. The use of gold nanorods (AuNRs) with a surface plasmon resonance (SPR) in the second Near-Infrared II (NIR-II) optical window promises deeper anatomical penetration through increased maximum permissible exposure and lower optical attenuation. In this study, the targeting efficiency of anti-epidermal growth factor receptor (EGFR) antibody functionalised AuNRs with an SPR at 1064 nm was evaluated in vitro. Four cell lines, KYSE-30, CAL-27, Hep-G2 and MCF-7 that either over or under expressed EGFR were used. This expression was confirmed by flow cytometry and immunofluorescence. Cytotoxicity assays showed no AuNRs toxicity to both EGFR positive and EGFR negative cell lines up to a concentrations of 19 µg/ml. Optical microscopy demonstrated a significant difference (p<0.0001) between targeted AuNRs (tAuNRs) and untargeted AuNRs (uAuNRs) in all four cancer cell lines. This study demonstrates that anti-EGFR functionalisation significantly increased the number of tAuNRs associated with each EGFR positive cancer cell. This successful targeting highlights the use of tAuNRs for molecular photoacoustic imaging or tumour treatment through plasmonic photothermal therapy.
REVIEW | doi:10.20944/preprints202012.0062.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Trop 2; targeted therapy; antibody-drug conjugate; solid tumors
Online: 2 December 2020 (12:35:36 CET)
Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline expression in most of normal tissues. Its overexpression is associated with tumor growth and poor prognosis; Trop 2 is therefore, an ideal therapeutic target for epithelial cancers. Several Trop 2 targeted therapeutics have recently been developed for the treatment of cancers, such as anti-Trop 2 antibodies and antibody-drug conjugates (ADCs), as well as Trop 2-specific cell therapy. In particular, the safety and clinical benefit of Trop 2-based ADCs have been demonstrated in clinical trials across multiple tumor types, including those with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and heavily pretreated non-small cell lung cancer. In this review, we elaborate on recent advances in Trop 2 targeted modalities and provide an overview of novel insights for future developments in this field.
REVIEW | doi:10.20944/preprints202305.0620.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: ALL; immunotherapy; antibody-drug conjugate; CAR-based therapies, targeted therapies
Online: 9 May 2023 (09:03:11 CEST)
Acute lymphoblastic leukemia (ALL) is a blood cancer that primarily affects children but also adults. It is due to the malignant proliferation of lymphoid precursor cells that invade the bone marrow and can spread to extramedullary sites. ALL is divided into B cell (85%) and T cell lineages (10 to 15%); rare cases are associated with the natural killer (NK) cell lineage (<1%). To date, the survival rate in children with ALL is excellent while in adults continues to be poor. Despite the therapeutic progress, there are subsets of patients that still have high relapse rates after chemotherapy or hematopoietic stem cell transplantation (HSCT) and an unsatisfactory cure rate. Hence, the identification of more effective and safer therapy choices represents a primary issue. In this review, we will discuss novel therapeutic options including bispecific antibodies, antibody-drug conjugates,chimeric antigen receptor (CAR)-based therapies, and other promising treatments for both pediatric and adult patients.
REVIEW | doi:10.20944/preprints202304.0677.v1
Subject: Biology And Life Sciences, Other Keywords: Metabolomics; Simultaneous Quantitation and Discovery (SQUAD); Targeted Metabolomics; Untargeted Metabolomics
Online: 21 April 2023 (07:29:13 CEST)
Untargeted and targeted approaches are the traditional metabolomics workflows acquired for a wider understanding of the metabolome under focus. Both approaches have their strengths and weaknesses. The untargeted, for example, is maximizing the detection and accurate identification of thousands of metabolites, while the targeted is maximizing the linear dynamic range and quantification sensitivity. These workflows, however, are acquired separately, so researchers compromise either a low-accuracy overview of total molecular changes (i.e., untargeted analysis) or a detailed yet blinkered snapshot of a selected group of metabolites (i.e., targeted analysis) by selecting one of the workflows over the other. In this review, we present a novel single injection simultaneous quantitation and discovery (SQUAD) metabolomics that combines targeted and untargeted workflows. It is used to identify and accurately quantify a targeted set of metabolites. It also allows data retro-mining to look for global metabolic changes that were not part of the original focus. This offers a way to strike the balance between targeted and untargeted approaches in one single experiment and address the two’s limitations. This simultaneous acquisition of hypothesis-led and discovery-led datasets allows scientists to gain more knowledge about biological systems in a single experiment.
ARTICLE | doi:10.20944/preprints202202.0222.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: hepatocellular carcinoma; lenvatinib; molecular targeted agents; complete response; CT value
Online: 18 February 2022 (04:05:18 CET)
Purpose: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. Method: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e. the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. Results: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (>30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (<30.6%) N30-CTav group (P<0.001, 61.5% at 1 year). Conclusion: The cut-off value of 30.2 HU for CTav (N30-CTav) might be appropriate for identifying post-lenvatinib necrosis in HCC, and an N30-CTav occupancy rate of >30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.
REVIEW | doi:10.20944/preprints202105.0513.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Cell penetrating peptides; protein transduction domains; tumor imaging; targeted therapies.
Online: 21 May 2021 (09:44:48 CEST)
Since their identification over twenty-five years ago, the plethora of cell penetrating peptides (CPP) and their applications has skyrocketed. These 5 to 30 amino acid long peptides have the unique property of breaching the cell membrane barrier while carrying cargoes larger then themselves into cells in an intact, functional form. CPPs can be conjugated to fluorophores, activatable probes, radioisotopes or contrast agents for imaging tissues, such as tumors. There is no singular mechanism for translocation of CPPs into a cell, and therefore, many CPPs are taken up by a multitude of cell types, creating the challenge of tumor specific translocation and hindering clinical effectiveness. Varying strategies have been developed to combat this issue and enhance their diagnostic potential by derivatizing CPPs for better targeting by constructing specific cell activated forms. These methods are currently being used to image integrin expressing tumors, breast cancer cells, human histiocytic lymphoma and protease secreting fibrosarcoma cells, to name a few. Additionally, identifying safe, effective therapeutics for malignant tumors has long been an active area of research. CPPs can circumvent many of the complications found in treating cancer with conventional therapeutics by targeted delivery of drugs into tumors, thereby decreasing off-target side effects, a feat not achievable by currently employed conventional chemotherapeutics. Myriad types of chemotherapeutics such as tyrosine kinase inhibitors, anti-tumor antibodies and nanoparticles can be functionally attached to these peptides leading to the possibility of delivering established and novel cancer therapeutics directly to tumor tissue. While much research is needed to overcome potential issues with these peptides, they offer a significant advancement over current mechanisms to treat cancer. In this review, we present a brief overview of the research leading to identification of CPPs with a comprehensive state of the art review on the role of these novel peptides in both cancer diagnostics as well as therapeutics.
REVIEW | doi:10.20944/preprints202103.0095.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: doxorubicin; drug delivery; polymers; targeted therapy; anticancer treatment; controlled release
Online: 2 March 2021 (14:14:38 CET)
Doxorubicin, a member of the anthracycline family, is a common anticancer agent often used as a first line treatment for the wide spectrum of cancers. Doxorubicin-based chemotherapy, although effective, is associated with serious side effects, such as irreversible cardiotoxicity or nephrotoxicity. Those often life-threatening adverse risks, responsible for the elongation of the patients' recuperation period and increasing medical expenses, have prompted the need for creating novel and safer drug delivery systems. Among many proposed concepts, polymeric nanocarriers are shown to be a promising approach, allowing for controlled and selective drug delivery simultaneously enhancing its activity towards cancerous cells and reducing toxic effects on healthy tissues. This article is a chronological examination of the history of the work progress on polymeric nanostructures, designed as efficient doxorubicin nanocarriers, with the emphasis on the main achievements of 2010-2020. Numerous publications have been reviewed to provide an essential summation of the nanopolymer types and their essential properties, mechanisms towards efficient drug delivery, as well as active targeting stimuli-responsive strategies that are currently utilized in the doxorubicin transportation field.
REVIEW | doi:10.20944/preprints202002.0382.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: metastatic breast cancer; targeted therapies; fibroblast growth factors receptors drugs
Online: 26 February 2020 (01:41:54 CET)
Breast cancer (BC) is the most frequent form of malignancy and the second only to lung cancer as common cause of cancer-causing deaths in women. Notwithstanding many progresses in the field, metastatic BC has a very poor prognosis. As therapies are becoming more personalized to meet patients‘ needs, a better knowledge of the molecular biology leading to the disease unfolds the possibility to project more precise compounds or antibodies targeting definite alteration at the molecular level expressed in cancer cells of patients or as antigens on the surface of cell membranes. Fibroblast growth factor receptor (FGFR) is a druggable target -which is activated by its own ligands -namely the Fibroblast Growth Factors (FGFs). This pathway provides a vast range of interesting molecular targets pursued at different levels of clinical investigation. Herein we provide an update on the knowledge on genetic alterations of the receptors in breast cancer, their role in tumorigenesis and the most recent drugs against this particular receptor to treat the disease.
REVIEW | doi:10.20944/preprints201909.0026.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: antiandrogen; bisphosphonates; bone niche; immune system; osteoimmunology; RankL; targeted therapy
Online: 2 September 2019 (16:34:22 CEST)
Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.
REVIEW | doi:10.20944/preprints202109.0453.v3
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: BNCT; targeted therapy; biological dosimetry; boron imaging; personalized oncology; personalized medicine
Online: 16 May 2022 (15:22:13 CEST)
Boron Neutron Capture Therapy (BNCT) is a promising binary disease-targeted therapy, as neutrons preferentially kill cells labeled with boron (10B), which makes it a precision medicine treatment modality that provides a therapeutic effect exclusively on patient-specific tumor spread. Contrary to what is usual in radiotherapy, BNCT proposes cell-tailored treatment planning rather than to the tumor mass. The success of BNCT depends mainly on the sufficient spatial biodistribution of 10B located around or within neoplastic cells to produce a high-dose gradient between the tumor and healthy tissue. However, it is not yet possible to precisely determine the concentration of 10B in a specific tissue in real-time using noninvasive methods. Critical issues remain to be resolved if BNCT is to become a valuable, minimally invasive, and efficient treatment. Moreover, functional imaging technologies such as PET can be applied to determine biological information that can be used for the combined-modality radiotherapy protocol for each specific patient. Anyway, not only imaging methods but also proteomics and gene expression methods will facilitate BNCT becoming a modality of personalized medicine. This work provides an overview of the fundamental principles, recent advances, and future directions of BNCT as cell-targeted cancer therapy for personalized radiation treatment.
REVIEW | doi:10.20944/preprints202111.0504.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: NSCLC 1; KRAS G12C mutation 2; targeted therapy 3; immunotherapy 4
Online: 26 November 2021 (11:34:27 CET)
The KRAS mutant population has been undruggable for 40 years. G12C inhibitors and immunotherapy are the beginning of success. It is necessary to summarize the successful experience of the existing treatment model and explore the direction of the next treatment. In this review, we discuss the latest developments in targeted therapy and immunotherapy for KRAS-mutation NSCLC, aiming to provide direction or enlightenment for future treatment strategies.
REVIEW | doi:10.20944/preprints202110.0013.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: uveal melanoma; tumorigenesis; molecular classification; targeted therapy; immune checkpoint; tumor heterogeneity
Online: 1 October 2021 (11:54:23 CEST)
Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovate therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of MEK-inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM) show only marginal effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers and YAP/TAZ specific drugs give new hope to repeat the success of innovative therapy obtained for CM.
ARTICLE | doi:10.20944/preprints202105.0772.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Immune checkpoint inhibitors; immune-related endocrine dysfunction; hypothyroidism; targeted therapy; malignancy
Online: 31 May 2021 (12:49:40 CEST)
Abstract Background The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) combinations using different modalities of anti-cancer treatment. Method A retrospective analysis was conducted on consecutive patients >18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a Hong Kong university hospital. Patients were reviewed for up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis. Result A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) received ICIs during the study period. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo+ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted+ICI). A significantly higher proportion of patients using targeted+ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (>65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. Conclusions This large, real-world cohort demonstrates that combining ICI with targeted therapy has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is needed in older populations.
ARTICLE | doi:10.20944/preprints202105.0671.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Folate-targeted nanoparticles; BSA/Alginate nanocarriers; paclitaxel; cellular uptake; cell viability.
Online: 27 May 2021 (13:55:13 CEST)
Among the different ways to reduce the secondary effects of antineoplastic drugs in cancer treatment, the use of nanoparticles has demonstrated good results due to the protection of the drug and the possibility of releasing compounds to a specific therapeutic target. The α-isoform of folate receptor (FR) is overexpressed on a significant number of human cancers; therefore, folate-targeted crosslinked nanoparticles based on BSA and alginate mixtures and loaded with paclitaxel (PTX) have been prepared to maximizing the proven antineoplastic activity of the drug against solid tumors. Nanometric-range sized particles (169 ± 28nm - 296 ± 57nm), with negative Z-potential values (between -0.12 ± 0.04 and -94.1± 0.4), were synthesized. The loaded PTX (2.63±0.19 - 3.56 ±0.13 µg PTX/mg Np) was sustainably released along 23 and 27h. Three cell lines (MCF-7, MDA-MB-231 and HeLa) were selected to test the efficacy of the folate-targeted PTX-loaded BSA/ALG nanocarriers. The presence of FR on cell membrane led to a significant larger uptake of BSA/ALG-Fol nanoparticles regarding to the equivalent nanoparticles without folic acid on its surface. The cell viability results demonstrated a cytocompatibility of unloaded nanoparticle-Fol and a gradual decrease in cell viability after treatment with PTX-loaded nanoparticles-Fol due to the sustainable PTX release.
REVIEW | doi:10.20944/preprints201806.0105.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: fibroblast growth factor; fibroblast growth factor receptor; targeted treatments; breast cancer
Online: 7 June 2018 (07:50:30 CEST)
Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, the metastatic breast cancer leaves a poor prognosis. In an era of personalized medicine, there is an urgent need for a better knowledge of the biology leading to the disease, which can lead to the design of always more accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the Fibroblast Growth Factor Receptor (FGFR) pathway, triggered by specific ligands. The FGFRs/FGFs axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of the FGFRs mutations leading to tumour formation and summarizes the state-of-the-art of therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.
ARTICLE | doi:10.20944/preprints202301.0512.v1
Subject: Biology And Life Sciences, Food Science And Technology Keywords: micronutrient deficiencies; rational food design; adolescents; biscuits; texture; chickpea flour; targeted nutrition
Online: 28 January 2023 (03:06:52 CET)
"Hidden hunger", the deficiency of important mineral micronutrients, affects more than 2 billion people globally. Adolescence is unquestionably a period of nutritional risk, given the high nutritional requirements for growth and development, erratic or capricious diets and the increased consumption of snacks. This study applied the rational food design approach to obtain micronutrient-dense biscuits by combining chickpea and rice flours to achieve an optimal nutritional profile, crunchy texture and appealing flavour. The perception of 33 adolescents of the suitability of such biscuits as a mid-morning snack was examined. Four biscuits were formulated, with different ratios of chickpea and rice flours (CF:RF): G100:0, G75:25, G50:50 and G25:75. Nutritional content, baking loss, acoustic-texture and sensory analyses were carried out. On average, the mineral content of biscuits with the CF:RF ratio of 100:0 doubled compared with the 25:75 formula. The dietary reference values for iron, potassium and zinc reached 100% in the biscuits with CF:RF ratios of 50:50, 75:25 and 100:0, respectively. The analysis of mechanical properties revealed that samples G100:0 and G75:25 were harder than the others. Sample G100:0 showed the highest sound pressure level (Smax). Sensory analysis showed that increasing the proportion of CF in the formulation augments the grittiness, hardness, chewiness and crunchiness. Most of the adolescents (72.7%) were habitual snack consumers; 52% awarded scores ≥ 6 to biscuit G50:50 for its overall quality, 24% described its flavour as "biscuit" and 12% as "nutty". However, 55% of the participants could not pinpoint any dominant flavour. In conclusion, it is possible to design nutrient-dense snacks that meet the micronutrient requirements and sensory expectations of adolescents by combining flours naturally rich in micronutrients.
REVIEW | doi:10.20944/preprints202202.0052.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: cervical cancer; endometrial cancer; ovarian cancer; 2021 update; novel targeted therapies; immunotherapy
Online: 3 February 2022 (13:02:11 CET)
This review of the meaningful data from 2021 on cervical, endometrial, and ovarian cancers aims to provide an update of the most clinically relevant studies presented at important oncologic congresses during the year [the American Society of Clinical Oncology (ASCO) Annual Meeting, the European Society for Medical Oncology (ESMO) Congress and the Society of Gynecologic Oncology (SGO) Annual Meeting]. Despite the underlying existence of the COVID-19 pandemic, the last year has been notable in terms of research, with significant and promising advances in gynecologic malignancies. Several major studies reporting the effects of innovative therapies for patients with cervical, endometrial, and ovarian cancers might change the medical practice in the future.
ARTICLE | doi:10.20944/preprints202105.0333.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: genome editing; CRISPR; protoplast; , targeted mutagenesis; TREX2; construct validation; transi-ent expression
Online: 14 May 2021 (13:44:26 CEST)
Cas endonuclease-mediated genome editing provides a long-awaited molecular biological approach to the modification of predefined genomic target sequences in living organisms. Although cas9/guide (g)RNA constructs are straightforward to assemble and can be customized to target virtually any site in the plant genome, the implementation of this technology can be cumbersome, especially in species like Triticale that are difficult to transform, for which only limited genome information is available and/or which carry comparatively large genomes. To cope with these challenges, we have pre-validated cas9/gRNA constructs (1) by frameshift restitution of a reporter gene co-introduced by ballistic DNA transfer to barley epidermis cells, and (2) via transfection in Triticale protoplasts followed by either a T7E1-based cleavage assay or by deep-sequencing of target-specific PCR amplicons. For exemplification, we addressed the Triticale ABA 8’-hydroxylase 1 gene, one of the putative determinants of pre-harvest sprouting of grains. We further show that in-del induction frequency in Triticale can be increased by TREX2 nuclease activity, which holds true for both well- and poorly performing gRNAs. The presented results constitute a sound basis for the targeted induction of heritable modifications in Triticale genes.
Subject: Environmental And Earth Sciences, Sustainable Science And Technology Keywords: Straw Hat University; Farmer's Professor; Rural Transformation; Targeted poverty alleviation in China
Online: 7 April 2021 (17:40:08 CEST)
China is out of extreme poverty in 2020 on schedule and one decade in advance to fulfill the UN 2030 Agenda for Sustainable Development Goals (SDGs), and became the first developing country to alleviate poverty in half century. Therefore, a large numbers of effective approaches are emerging, and the intellectual’s technology-led poverty reduction, which locally known as the “Straw Hat University”initiated by “Farmer's professor”mode, is the most tried and tested approach motivated by the intellectual’s “Serve the people” tradition and supported by the all nation. This research conduct case analysis with three most remarkable organic intellectuals as Agronomist Yuan longping, Mycologist Lin Zhanxi and Plant pathologist Zhu Youyong with their bridging gaps in food security, regional imbalance and ethnic disparity respectively to sort out the sustainable modules and universal experiences. The conclusion indicates that“Farmer's Professor” Initiated “Straw Hat University” is an effective approach to solve human beings’ development problems and benefit the livelihoods, especially in the under development regions; and the authentic down to earth experiments into productivity as well as the Intellectual property transformation is the perfect path to deploy offline and online resources building the effective production and supply chain to integrate industries by intellectual’s critical innovation.
REVIEW | doi:10.20944/preprints202007.0523.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: discovery proteomics; targeted proteomics; mass spectrometry; fish allergens; crustacean allergens; mollusk allergens
Online: 22 July 2020 (11:23:40 CEST)
Seafood is considered one of the main food allergen sources by the European Food Safety Authority (EFSA). It comprises several distinct groups of edible aquatic animals including fish and shellfish such as crustacean and mollusks. Recently the EFSA recognized the high risk of food allergy over the world and established the necessity of developing new methodologies for its control. Consequently, accurate, sensitive and fast detection methods for seafood allergy control and detection in food products are highly recommendable. In this work, we present a comprehensive review of the applications of the proteomics methodologies for the detection and quantification of seafood allergens. For that, two consecutive proteomics strategies (Discovery and Targeted Proteomics) applied for the study and control of seafood allergy are reviewed in detail. In addition, future directions and new perspectives were also provided.
REVIEW | doi:10.20944/preprints201909.0140.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: hepatocellular carcinoma; immune checkpoint inhibitors; HCC; pembrolizumab; nivolumab; immune microenvironment; targeted therapies
Online: 14 September 2019 (18:37:29 CEST)
Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib has been the standard of care for almost a decade until 2018 when FDA approved an alternative first-line agent namely lenvatinib. Whereas FOLFOX4 results an alternative first-line treatment for the chinese clinical oncology guidelines. In addition to cabozantinib, regorafenib, and ramucirumab, two therapeutics against the PD-L1/PD1 axis have been recently approved for subsequent-line therapy, as nivolumab and pembrolizumab. However, similar to other solid tumors, the response rate of single-agent targeting PD-L1/PD1 axis is low. Therefore a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors, the addition of immune checkpoint inhibitors after resection or during locoregional therapy, immune checkpoint inhibitors in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with an attent evaluation of new ICIs based combinatory approaches.
REVIEW | doi:10.20944/preprints201904.0127.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: PTEN; PI3K; cancer predisposition syndromes; targeted therapies; mouse models of human cancer
Online: 10 April 2019 (10:37:43 CEST)
The PI3K-AKT-mTOR signal transduction pathway regulates a variety of biological processes including cell growth, cell cycle progression and proliferation, cellular metabolism and cytoskeleton reorganization. Fine-tuning of the PI3K pathway signaling output is essential for the maintenance of tissue homeostasis and uncontrolled activation of this cascade leads to a number of human pathologies including cancer. Inactivation of the tumour suppressor phosphatase PTEN and/or activating mutations in the proto-typical lipid kinase PI3K have emerged as some of the most frequent events associated with human cancer and as a result the PI3K pathway has become a highly sought-after target for cancer therapies. In this review we summarize the essential role of the PTEN-PI3K axis in controlling cellular behaviors by modulating activation of key proto-oncogenic molecular nodes and functional targets. Further, we highlight important functional redundancies and peculiarities of these two critical enzymes that over the last few decades have become a central part of the cancer research field and have instructed hundreds of pre-clinical and clinical trials to better cancer treatments.
ARTICLE | doi:10.20944/preprints201807.0459.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: Superparamagnetic iron oxide; Magnetic resonance imaging; Solid lipid nanoparticles; Galactose; Liver-targeted
Online: 24 July 2018 (14:01:51 CEST)
The aim of this study was to develop a novel nanostructured lipid carriers (NLCs) with hepatocytes targeting as carriers for the magnetic resonance imaging (MRI) contrast agent (i.e., magnetic nanostructured lipid carriers, MNLCs), and to evaluate the targeting ability of the MNLCs with T2-weighted MRI both in vitro and in vivo. Here, the galactose-octadecylamine (Gal-ODA) conjugates were synthesized by chemical coupling reaction between lactose acid (LA) and octadecylamine (ODA). Then the superparamagnetic iron oxide (SPIO) loaded nanostructured lipid carrier (conjugated by Gal-ODA, Gal-NLC-SPIO) was prepared by emulsification-ultrasonic method using monoglyceride as lipid materials. The Gal-NLC-SPIO with a diameter of about 50 nm could specifically internalize into LO2 (human hepatic cell line) cells. In vitro MRI results also proved the specific targeting ability of Gal-NLC-SPIO to LO2 cells. The in vivo MR imaging experiments using an orthotopic intrahepatic xenograft tumor model further validated the hepatocytes targeted effect of Gal-NLC-SPIO. The results of this study suggested that Gal-NLC-SPIO can be used as a contrast agent to aid in the diagnosis of hepatic diseases.
ARTICLE | doi:10.20944/preprints202305.0400.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: transcriptionally targeted oncolytic adenovirus; gynecologic cancer; human samples; cytokines; ovarian cancer; tumor stroma
Online: 6 May 2023 (09:25:49 CEST)
More than 1 million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at late stage, either because lack of symptoms such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV) whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer. uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404) a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.
ARTICLE | doi:10.20944/preprints202302.0343.v1
Subject: Chemistry And Materials Science, Medicinal Chemistry Keywords: targeted alpha therapy; alpha-emitter; thorium-226; uranium-230; isotope generator; extraction chromatography
Online: 20 February 2023 (14:17:58 CET)
A unique two-column 230U/226Th generator has been developed. The focus was hold on obtaining 226Th of high purity in a solution amenable to further labeling. The first column of the proposed generator filled with TEVA Resin held 230U, from which 226Th was eluted with 7 M HCl solution. UTEVA Resin pretreated with nitric acid solution was used as a sorbent for the second column for thorium retention. 226Th was extracted with 0.01-0.05 M citric buffer solution. One cycle of generator milking took 5-7 minutes and produced > 90% of 226Th in 1.5 ml of eluate, pH 4.5-5.0. The proposed two-column 230U/226Th generator was tested over two months including a second loading of 230U additionally accumulated from 230Pa. The 230U impurity in 226Th eluate was less than 0.01% allowing to use it directly in synthesis of radiopharmaceutical compounds.
REVIEW | doi:10.20944/preprints202210.0362.v1
Subject: Biology And Life Sciences, Food Science And Technology Keywords: gut microbiome; time-restricted feeding; intermittent fasting; targeted approach; hormonal signaling; metabolic regulators
Online: 24 October 2022 (12:00:48 CEST)
Each individual has a unique gut microbiota; therefore the genes in our microbiome outnumber the genes in our genome by about 150 to 1. Perturbation in host nutritional status influences gut microbiome composition and vice versa. The gut microbiome can help in producing vitamins, hormones, and other active metabolites that support the immune system; harvest energy from food; aid in digestion; protect against pathogens; improve gut transit and function; send signals to the brain and other organs, oscillating the circadian rhythm and coordinate with host metabolism through multiple cellular pathways. Gut microbiota can be influenced by host genetics, medications, diet, and lifestyle factors from preterm to aging. So before prescribing a customized treatment, it is crucial to monitor and count the gut flora as a focused biomarker. Many nutritional approaches that have been developed help in maintaining and restoring an optimal microbiome such as specific diet therapy, nutrition interventions and customized eating patterns. One of these approaches is time-restricted feeding/eating (TRF/E), a type of intermittent fasting (IF) in which a subject abstains from food intake for a specific time window. Such a dietary modification might alter and restore the gut microbiome for proper alignment of cellular and molecular pathways throughout the lifespan. In this review, we have highlighted that gut microbiota would be a targeted biomarker and TRF/E would be a targeted approach for restoring the gut microbiome associated molecular pathways like hormonal signaling, the circadian system, metabolic regulators, neural responses, and immune-inflammatory pathways. Consequently, modulation of gut microbiota through TRF/E could contribute in proper utilization and availability of the nutrients and in this way confer protection against diseases for harnessing personalized nutrition approaches to improve human health.
REVIEW | doi:10.20944/preprints202206.0160.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: breast cancer; HER2-positive; estrogen receptor positive; triple-positive; HER2-targeted therapy; immunotherapy
Online: 10 June 2022 (11:03:05 CEST)
Up to 25% of early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients will relapse despite the improvement achieved by the introduction of HER2-targeted therapy. Beyond trastuzumab, other agents approved for early HER2+ BC include the monoclonal antibody pertuzumab, the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) and the reversible HER2 inhibitor lapatinib. New agents, such as trastuzumab-deruxtecan or tucatinib in combination with capecitabine and trastuzumab, have also shown an improvement in the metastatic setting. Other therapeutic strategies to overcome treatment resistance have been explored in HER2+ BC, mainly in HER2+ that also overexpress estrogen receptors (ER+). One strategy has been to target the cyclin-dependent kinases 4/6 (CDK4/6) as they are downstream of HER2 and many of the cellular pathways associated with resistance to HER2-targeted therapies play a key role in cell cycle and proliferation. Different trials have explored these strategies with encouraging results, but definitive results are needed. In addition, HER2+ BC is known to be more immunogenic than other BC subgroups, with high variability between tumors. Different immunotherapeutic agents have been investigated in this setting, with promising but controversial results obtained to date.
ARTICLE | doi:10.20944/preprints202111.0257.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: metastatic melanoma; targeted therapy; immune checkpoint inhibitor therapy; survival; statutory health insurance data
Online: 15 November 2021 (11:50:07 CET)
(1) Background: Targeted (TT) and immune checkpoint inhibitor (ICI) therapies have become available in the routine care of metastatic melanoma in recent years. (2) Objective: We compared mortality in patients with metastatic melanoma and different systemic therapies. (3) Methods: A retrospective cohort study, based on pseudonymized health insurance data of about 2 million individuals from Saxony, Germany, was conducted for the years 2010 to 2020. Only patients with an advanced stage, i.e. distant metastases were considered for the main analysis. Relative survival since metastasis and predicted survivor curves derived from a Cox model were used to assess potential differences in mortality. (4) Results: Relative survival was highest in the subgroup with sequential use of ICI and TT. All treatments except interferon had significant hazard ratios (HR) in the Cox model with time-dependent effects indicating a protective effect after treatment initiation (HR 0.01-0.146) but decreasing over time (HR 1.351-2.310). The predicted survivor curves revealed best survival under ICI-TT treatment and worst survival under TT treatment alone. (5) Conclusions: We found real-world evidence for survival benefits of patients with metastatic melanoma who received sequential ICI and TT treatment. It is conceivable that the observed high survival differences were overestimated due to bias, such as confounding by indication.
ARTICLE | doi:10.20944/preprints202109.0289.v1
Subject: Medicine And Pharmacology, Urology And Nephrology Keywords: BRD9; Prostate Cancer; SWI/SNF; Survival; pathways; signal transduction; human cohorts; targeted therapy
Online: 16 September 2021 (13:51:57 CEST)
Background and aims: Despite recent advances in advanced prostate cancer treatments, there are no clinically useful biomarkers or treatments for men with such cancers. Targeted therapies have shown promise, but there remain fewer actionable targets in prostate cancer than in other cancers. This work aims to characterize BRD9, currently understudied in prostate cancer, and investigate its co-expression with other genes to assess its potential as a biomarker and therapeutic target in human prostate cancer. Materials and methods: Omics data from a total of 2053 prostate cancer patients across 11 independent datasets were accessed via Cancertool and cBioPortal. mRNA expression and co-expression, mutations, amplifications, and deletions were assessed with respect to key clinical parameters including survival, Gleason grade, stage, progression and treatment. Network and pathway analysis was carried out using Genemania, and heatmaps were constructed using Morpheus. Results: BRD9 is overexpressed in prostate cancer patients, especially those with metastatic disease. BRD9 expression did not differ in patients treated with second generation antiandrogens versus those who were not. BRD9 is co-expressed with many genes in the SWI/SNF and BET complexes, as well as those in common signaling pathways in prostate cancer. Summary and conclusions: BRD9 has potential as a diagnostic and prognostic biomarker in prostate cancer. BRD9 also shows promise as a therapeutic target, particularly in advanced prostate cancer, and as a co-target alongside other genes in the SWI/SNF and BET complexes, and those in common prostate cancer signalling pathways. These promising results highlight the need for wider experimental inhibition and co-targeted inhibition of BRD9 in vitro and in vivo, to build on the limited inhibition data available.
ARTICLE | doi:10.20944/preprints202303.0315.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Type I nitroreductase; NfsB; Crystal structure; Prodrug; Metronidazole; Targeted cellular ablation; Tinidazole; CB1954; Dinitrotoluene
Online: 17 March 2023 (03:22:59 CET)
Bacterial nitroreductase enzymes that convert prodrugs to cytotoxins are valuable tools for creating transgenic targeted ablation models to study cellular function and cell-specific regeneration paradigms. We recently engineered a nitroreductase (“NTR 2.0”) for substantially enhanced reduction of the prodrug metronidazole, which permits faster cell ablation kinetics, cleaner interrogations of cell function, ablation of previously recalcitrant cell types, and extended ablation paradigms useful for modelling chronic diseases. To provide insight into the enhanced enzymatic mechanism of NTR 2.0, we have solved the X-ray crystal structure at 1.85 Angstroms resolution and compared it to the parental enzyme, NfsB from Vibrio vulnificus. We additionally present a survey of reductive activity with eight alternative nitroaromatic substrates, to provide access to alternative ablation prodrugs, and explore applications such as remediation of dinitrotoluene pollutants. The predicted binding modes of four key substrates were investigated using molecular modelling.
ARTICLE | doi:10.20944/preprints202212.0214.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Breast; Targeted Radiotherapy; Lung injury; Heart injuries; Health-Related Quality Of Life; Irradiation toxicity.
Online: 13 December 2022 (01:17:52 CET)
TomoBreast hypothesized that hypofractionated 15 fractions/3 weeks image-guided radiation therapy (H-IGRT) can reduce lung-heart toxicity, as compared with normofractionated 25-33 fractions/5-7 weeks conventional radiation therapy (CRT). 123 women with stage I-II operated breast cancer were randomized to receive CRT (N=64) or H-IGRT (N=59). The primary endpoint used a four-items measure of the time to 10% alteration in any of patient self-reported measure, physician clinical evaluation, echocardiography or lung function tests, analyzed by intention-to-treat without exclusion. Results found comparable survivals, but H-IGRT significantly reduced the toxicity measured by lung diffusion capacity and alveolar volume as compared with CRT, G1 in 53% (31/59) versus 72% (44/61) patients, P=0.006; G2, 29% versus 48%, P=0.020. H-IGRT significantly reduced the risk of composite cardio-pulmonary alteration at 5 years, 10.2% versus 26.7%, P=0.024. In conclusion, TomoBreast is a proof-of-concept that image-guided radiation-therapy can improve the overall balance of lung-heart outcomes in breast cancer adjuvant therapy. Furthermore, the significance of the findings supports the efficacy of a small trial size design, which can be critical when clinical research resources are limited.
COMMUNICATION | doi:10.20944/preprints202112.0420.v3
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: Non-targeted methods; method validation; food fraud; food authenticity; mass spectrometry; spectroscopy; NGS; NMR
Online: 23 May 2022 (11:10:00 CEST)
Through its suggestive name, non-targeted methods (NTMs) do not aim at a predefined "needle in the haystack". Instead, they exploit all the constituents of the haystack. This new form of analytical methods is increasingly finding applications in food and feed testing. However, the concepts, terms, and considerations related to this burgeoning field of analytical testing needs to be propagated for the benefit of ones associated in academic research, commercial development, and official control. This paper addresses the frequently asked questions around notations and terminologies surrounding NTMs. The widespread development and adoption of these methods also necessitates the need to develop approaches to NTM validation, i.e., evaluating the performance characteristics of a method to determine if it is fit-for-purpose. This work aims to provide a roadmap to approaching NTM validation. In doing so, the paper deliberates on the different considerations that influence the approach to validation and provides suggestions thereof.
ARTICLE | doi:10.20944/preprints202104.0724.v1
Subject: Chemistry And Materials Science, Biomaterials Keywords: TNBC; dasatinib; poly(styrene-co-maleic acid) micelles; nanoformulation; metabolism; EPR; nanomedicine; targeted therapy.
Online: 27 April 2021 (13:56:12 CEST)
Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.
Subject: Medicine And Pharmacology, Obstetrics And Gynaecology Keywords: HBOC; statewide random sampling; cancer survivorship; targeted intervention; tailored intervention; black participants; family recruitment
Online: 5 September 2019 (16:16:34 CEST)
We compared the efficacy of a tailored and a targeted intervention designed to increase clinical breast exam (CBE), mammography, and genetic services/testing among young breast cancer survivors (YBCS) (diagnosed <45 years old) and their blood relatives. A two-arm cluster randomized trial recruited a random sample of YBCS from the Michigan cancer registry and up to two of their blood relatives. Participants were stratified according to race and randomly assigned as family units to the tailored (n=637) or the targeted (n=595) intervention. Approximately 40% of participants were Black; 12% YBCS and 27% relatives were living in more than 20 different U.S. States. Higher screening rates were reported by YBCS (CBE p=0.05; mammography p=0.04) and relatives (CBE p<0.01; mammography p=0.04) in the tailored arm, and by White/Other YBCS (CBE p=0.02) and relatives (CBE p<0.01; mammography p=0.03). YBCS genetic testing rates increased from 22% to 26% (p=0.11). Black YBCS and relatives reported higher self-efficacy and intention for genetic testing, and higher satisfaction and intervention acceptance. The tailored intervention improved CBE and mammography uptake - despite having minimal contact with participants. Professional referrals will improve genetic testing uptake. Intervention materials increased self-efficacy and satisfaction for Black women but could not overcome multiple access barriers.
REVIEW | doi:10.20944/preprints201902.0245.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: cyclin-dependent kinases; cyclin-dependent kinase 4 and 6 inhibitors; targeted therapies; breast cancer
Online: 27 February 2019 (04:48:54 CET)
Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in the last decades improving life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the INK4 protein family specifically inhibit the CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in the other BC subtypes. In HER2-positive BC, combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, CDK4/6 inhibitors efficacy has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions of ongoing clinical trials and predictive biomarkers will be further debated.
ARTICLE | doi:10.20944/preprints201609.0024.v1
Subject: Medicine And Pharmacology, Neuroscience And Neurology Keywords: neurofibromatosis type 1; congenital pseudarthrosis of the tibia; whole-exome sequencing; targeted sequencing; BCOR
Online: 7 September 2016 (11:19:00 CEST)
Neurofibromatosis type1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1gene. Although congenital pseudarthrosis of the tibia (CPT) has frequently been associated with NF1, the underlying molecular mechanism of CPT in these NF1 patients is yet ill-understood. The aim of the present study was to detect NF1 mutations from genomic DNA and to harbor variants associated with CPT in NF1 patients. Whole-exome sequencing was first carried out with samples from two patients with CPT in one NF1 family, and a novel mutation c.2324A>G (p.E775G) in NF1 gene was identified. Additionally, a missense variant c.455C>T (p.P152L) in BCOR gene completely co-segregated with the CPT phenotype within this family. Subsequently, NF1 and NF2 genes in four other unrelated patients with both NF1 and CPT were screened using targeted sequencing. Four mutations in NF1 gene, including two known mutations (c.2288T>C/p.L763P, c.574 C>T/p.R192*) and two novel mutations (c.768delT/p.F256Lfs*25, c.2229_2230delTG/ p.V744Qfs*23) were detected. Further study confirmed that CPT was present in NF1 families, and NF1 mutations were closely associated with these complex phenotypes. Moreover, the data from the current study indicated that male gender might be a susceptibility factor for CPT in NF1. Therefore, we speculated that BCOR variants might be related to CPT phenotype among male NF1 patients.
REVIEW | doi:10.20944/preprints202210.0450.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Tumor microenvironment; stromal cells; immune cells; ECM; cancer hallmarks; hypoxia; exosomes; drug resistance; targeted therapy
Online: 28 October 2022 (09:57:34 CEST)
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.
REVIEW | doi:10.20944/preprints202208.0220.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Molecular switches; oncolytic vectors; patient-specific ubiquitous mutations; targeted therapy; multi-region sequencing; molecular biology
Online: 11 August 2022 (11:50:12 CEST)
Most existing cancer therapies negatively affect normal tissue as well as cancerous tissue. A potentially effective strategy for treating cancer that precludes off-target damage and could be an option for most patients would involve targeting one or more mutations that are ubiquitous in the given patient’s tumor(s). To effect this strategy, one would employ multi-region sequencing of a patient’s primary tumor and metastases to seek out mutations that are shared between all or at least most regions. Once the target or targets are known, one would ideally rapidly generate a molecular switch for at least one of said ubiquitous mutations that can distinguish the mutated DNA, RNA, or protein from the wild-type version and subsequently trigger a therapeutic response. I propose that the therapeutic response involve the replication of an oncolytic virus or intracellular bacterium, as any mutation can theoretically be detected by a vector that enters the cell - and automatic propagation could be very helpful. Moreover, the mutation “signal” can be easily enhanced through transcriptional and translational (if the target is an intracellular protein) enhancement. Importantly, RNA may make the best target for the molecular switches in terms of amplification of the signal and ease of targeting.
ARTICLE | doi:10.20944/preprints202204.0137.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: Taihe silky fowl; metabolic components; un-targeted metabolome; breed and feed; biosynthesis of amino acids
Online: 15 April 2022 (05:47:06 CEST)
Chinese Taihe Black-bone silky fowl (TBsf) is the homology of medicine and food and has high nutritional and medical value all over the world. However, the nutritional compositions and specific metabolite advantages of Taihe silky fowl muscle are still poorly understood. In this study, we investigated the differences of nutritional components between TBsf and another similar breed (Black Feathered chicken and laid green-shelled eggs, BF-gsc). Meanwhile, we also explored the divergences in muscle characteristics of Taihe silky fowl fed with two different diets, that is normal chicken feed (TBsf-ncf) and Broussonetia papyrifera-fermented feed (TBsf-bpf). Firstly, the growth performance and biochemical index of Taihe silky fowl was significantly different compared with black-feathered chicken. Secondly, we identified the metabolic alterations in Taihe silky fowl by performing an un-targeted UHPLC-Q-TOF-MS/MS analysis. Our results suggested that the whole metabonomic characteristics had obvious separation between TBsf-ncf, TBsf-bpf and BF-gsc groups both in the positive and negative ion mode by PCA analysis. Next, OPLS-DA multivariate analysis revealed that 57 metabolites (in positive mode) and 49 metabolites (in negative mode) were identified as differential metabolites between TBsf-ncf and BF-gsc group. These differential metabolites were mainly enriched to ABC transporters, biosynthesis of amino acids and aminoacyl-tRNA biosynthesis. Besides, there were 47 metabolites (in positive) and 13 metabolites (in negative) were differentially regulated between TBsf-ncf and TBsf-bpf group, which were majorly involved in histidine metabolism and linoleic metabolism. Furthermore, the integrated network analysis suggested that DL-arginine, DL-isoleucine, linoleoylcarnitine, stearoylcarnitine (positive) and ricionleic acid, D-proline, uric acid (negative) were the significantly metabolic biomarkers in Taihe silky fowl. Moreover, the metabolites of primaquine, ticlpoidine, riboflavin, acetylcarnitine (positive) and salicylic acid, acetaminophen sulfate, glutamic acid (negative) were markedly changed in the Taihe silky fowl fed with BP-fermented feed. In summary, a global survey of the nutritional components and metabolite differences were performed in muscle tissues of Taihe silky fowl between various breeds and feeds. The comprehensive expression profiles of the metabolites in Taihe silky fowl affected by genetic and environmental factors were acquired. This study provided valuable evidence fo breed and feed-induced putative biomarkers as well as improved the economic value of Taihe silky fowl through targeted metabolite regulation.
ARTICLE | doi:10.20944/preprints202109.0300.v1
Subject: Computer Science And Mathematics, Applied Mathematics Keywords: CAR T; Targeted Radionuclide Therapy; TRT; Mathematical Model; Multiple Myeloma; Immunotherapy; Daratumumab; CS1; Combination Therapy
Online: 17 September 2021 (09:32:33 CEST)
Targeted radionuclide therapy (TRT) has recently seen a surge in popularity, with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results – an example being chimeric antigen receptor (CAR) T-cells therapy in hematologic malignancies. Moreover, TRT and CAR T therapies possess unique features that require special consideration when determining how to dose, time, and sequence combination treatments, including the distribution of TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate additive or synergistic effects of combination therapies and warrant a mathematical treatment which includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here we combine two previously published mathematical models in a multiple myeloma setting to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell based therapies. We find that for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR T therapies.
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.
ARTICLE | doi:10.20944/preprints202104.0692.v1
Subject: Biology And Life Sciences, Virology Keywords: RACK1; HIV-1; IRES; Hepatitis C; HCV; AZT; HTA; Host-targeted antiviral; HEK293T; SD29-14
Online: 26 April 2021 (20:35:00 CEST)
Host ribosome-associated scaffold protein Receptor for Activated C Kinase 1 (RACK1) is utilized by a diverse group of human viruses for Internal Ribosomal Entry Sites (IRES) – mediated translation of viral mRNAs. We recently reported inhibition of herpes virus by small molecules targeting the RACK1 functional site. Here, we tested these molecules against HIV-1 and HCV, as HIV-1 contains two potential IRES sites and HCV translation occurs exclusively through IRES. Compounds significantly downregulated activities of HIV-1- and HCV-related dicistronic reporter constructs in transfected HEK293T cells. The compounds also strongly downregulated production of the HIV-1 capsid protein p24 in HIV-infected cells, as well as production of HIV-1 Gag precursor p55 and p55-derived proteins p24 and p17 in cells infected with the HIV-1 virus. Hepatitis C virus (HCV) IRES activities were also significantly inhibited by RACK1 inhibitor compounds. Since a number of human and plant pathogenic viruses are reported to use IRES, the RACK1 compounds can be established as broad host-targeted antivirals.
COMMENTARY | doi:10.3390/sci2030070
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: small molecule inhibitor; personalized medicine; precision medicine; oncology; targeted therapy; drug delivery; drug screening; chemotherapy
Online: 8 September 2020 (00:00:00 CEST)
The development of targeted therapeutics for cancer continues to receive intense research attention as laboratories and pharmaceutical companies seek to develop drugs and technologies that improve treatment efficacy and mitigate harmful side effects. In the aftermath of World War I, it was discovered that mustard gas destroys rapidly dividing cells and could be used to treat cancer. Since then, chemotherapy has remained a predominant treatment for cancer; however, the destruction of dividing cells throughout the body yields devastating side effects including off-target damage of the digestive tract, bone marrow, skin, and reproductive tract. Furthermore, the high mutation rate of cancerous cells often renders chemotherapy ineffective long-term. Therapies with improved specificity, localization, and efficacy are redefining cancer treatment. Herein, we define and summarize the principal advancements in targeted cancer treatment and briefly comment on the march towards personalized medicine in the treatment of human cancer.
REVIEW | doi:10.20944/preprints202103.0143.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: antioxidants; alcohol metabolism; hepatoprotective; anti-ALD; mitochondrial dysfunction; mitochondria-targeted; oxidative stress; and cytochrome P450 2E1
Online: 4 March 2021 (09:13:05 CET)
Oxidative stress initiates and facilitates the disruption of the structural integrity of hepatic mitochondria, which leads to steatosis, steatohepatitis, fibrosis, and cirrhosis. It is now evident that mitochondrial dysfunction could be responsible for alcoholic liver disease (ALD). The challenge in treating ALD has been the limited availability of hepatoprotective agents and the lack of highly efficient delivery systems. Recent studies have shown that mitochondria-targeted therapies could address mitochondrial dysfunction (MD), which may greatly improve hepatoprotection and ALD treatment. This mini-review discusses the potential role of mitochondria-targeted antioxidants (MTAs) in the maintenance of hepatocellular integrity. This report also considers the mechanism of liver injury induced by alcohol and the progression of ALD from a mitochondrial oxidative damage perspective as well as the possible mechanistic actions of hepatoprotective antioxidants. Preliminary studies suggest the prospect of MTAs as anti-ALD and hepatoprotective agents.
REVIEW | doi:10.20944/preprints201811.0143.v1
Subject: Medicine And Pharmacology, Urology And Nephrology Keywords: clear cell renal cell carcinoma; tumor evolution; tumor ecology; intratumor heterogeneity; multisite tumor sampling; targeted therapy
Online: 6 November 2018 (13:30:54 CET)
Malignant tumors behave dynamically as cell communities governed by ecological principles. Massive sequencing tools are unveiling the true dimension of the heterogeneity of these communities along their evolution in most human neoplasms, clear cell renal cell carcinomas (CCRCC) included. Although initially thought to be purely stochastic processes, very recent genomic analyses have shown that temporal tumor evolution in CCRCC may follow some deterministic pathways that give rise to different clones and sub-clones randomly spatially distributed across the tumor. This fact makes each case unique, unrepeatable and unpredictable. Precise and complete molecular information is crucial for patients with cancer since it may help in establishing a personalized therapy. Intratumor heterogeneity (ITH) detection relies on the correctness of tumor sampling and this is part of the pathologist’s daily work. International protocols for tumor sampling are insufficient today. They were conceived decades ago, when ITH was not an issue, and have remained unchanged until now. Noteworthy, an alternative and more efficient sampling method for detecting ITH has been developed recently. This new method, called multisite tumor sampling (MSTS), is specifically addressed to large tumors that are impossible to be totally sampled, and represent an opportunity to improve ITH detection without extra costs.
ARTICLE | doi:10.20944/preprints201804.0307.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: gastric cancer; ramucirumab; paclitaxel; second line therapy; vascular endothelial growth factor receptor 2; targeted therapy; nutrition
Online: 24 April 2018 (06:01:56 CEST)
The RAINBOW Phase III study established the efficacy of the combination of paclitaxel and ramucirumab, a monoclonal antibody targeting VEGF receptor-2 (VEGF-R2), as second-line therapy. We retrospectively analyzed the data of patients treated with ramucirumab plus paclitaxel at our Institution to evaluate the impact of clinical heterogeneous figures on the efficacy and safety of this combination paclitaxel/ramucirumab in a real- life cohort of patients. After a median follow-up of 10.74 months, the median progression-free survival (PFS) was 5.8 months (95% CI: 3.04 - 5,63). Disease control rate (DCR) was 61% and the median duration of response (DOR) was 5.8 months. Median overall survival (OS) was 8.3 months. A trend toward better outcome was observed in HER2 positive patients. In multivariate analysis, nutritional status (p = 0.0001) and number of metastatic sites (p = 0.0266) resulted significantly related with longer PFS. Our analysis confirmed the efficacy and safety of the combination of ramucirumab with paclitaxel also in the real-life practice and the median PFS is significantly longer than that reported for Western population in previous studies. Subgroup analysis confirms the key-role of nutritional status as prognostic factor and suggests a possible interaction between EGF and angiogenesis pathways that deserves further investigations.
ARTICLE | doi:10.20944/preprints202105.0546.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: triple negative breast cancer; Pembrolizumab; Atezolizumab; chemotherapy; anti-PD-L1; biomarkers; targeted therapies; development of novel drugs
Online: 24 May 2021 (09:23:50 CEST)
Triple negative breast cancer (TNBC) has a higher mRNA expression of programmed cell death ligand 1 (PD-L1) which is a ligand to programmed cell death protein 1 (PD-1). The binding of the ligand leads to suppressed activity of T-cell-mediated immune response against cancer cells. The approval of anti-PD-L1 drugs including pembrolizumab and atezolizumab in subgroups of TNBC offer potential improvement to the current treatment regimens available for TNBC. We conducted a meta-analysis to review the efficacy of pembrolizumab and atezolizumab for the treatment of TNBC in both adjuvant and neo-adjuvant settings. A systematic strategy was used as per the PRISMA 2020 statement. All statistical analyses were conducted using Review Manager 5.4. Outcome measures included objective response rate, progression free survival, overall survival in adjuvant therapy groups, and pathological complete response rates in neoadjuvant groups. Six clinical trials were included. For adjuvant therapies, the ORR (OR=1.26, P = 0.04) of Atezolizumab/Pembrolizumab plus chemotherapy was higher in intention to treat (ITT) arms than the placebo groups in TNBC. A positive effect size was found for PFS in the ITT arms (Cohen’s d = 1.55, P<0.001). The Atezolizumab plus chemotherapy group had a positive effect size for OS compared to the control groups (Cohen’s d = 0.52, P<0.001). In the neo-adjuvant setting, patients in ITT arms had higher pCR rates as compared to the control groups (OR= 1.61, P = 0.001). Our findings collate evidence of pembrolizumab and atezolizumab as a viable treatment option among patients with TNBC with PDL1+ subgroups deriving benefits.
REVIEW | doi:10.20944/preprints202001.0030.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: histone deacetylase 6 inhibitor; personalized treatment; heat shock protein 90α; leukemia stem cells; imatinib resistance; targeted therapy
Online: 4 January 2020 (06:18:22 CET)
Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.
ARTICLE | doi:10.20944/preprints201905.0370.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Targeted drug delivery, VX2 tumor, breast cancer, cryoablation, cryo-assisted injection, cryo-assisted resection, blue dye, epirubicin.
Online: 30 May 2019 (13:44:41 CEST)
Background: We assess locoregional drug targeting effectiveness of intraoperative (IO) cryoprobe-assisted injection of blue dye (BD) and cytotoxic-tracer mixture (TTM), in VX2 tumor model, and its translational value to cryo-assisted breast tumor surgery with BD alone. Methods: Under computed tomography (CT) guidance, we injected two ml TTM in five aliquots in the margin of 16 frozen or normothermic VX2 tumors. We evaluated the IO and post-operative drug targeting and therapeutic efficacy in tumor-host interface (T-HI) by CT, gross examination, and histopathology. In twenty-six T1 to T4 primary breast cancer (BRCA) we performed ultrasound-guided (US) cryoprobe-assisted tumor freezing, BD guided lymphatic mapping, and surgery. We evaluated, IO and in freshly resected specimen, BD distribution pattern in T-HI, lymph node(s), breast parenchyma, and resection cavity. Results: Fluids-impervious frozen VX2 or breast tumor transported drug(s) an arc-like pattern at T-HI regardless of freeze dose, number of freeze-thaw cycles, drug dose fractionation, tumor characteristics or dimensions. During melting, TTM spread within fifty percent VX2 tumor mirrored that of T-HI; it was massive in normothermia. In VX2 twenty percent focal margin necrosis at pathology coincided with CT gap; in both studies, BD dose-staining spread in T-HI and tumor was linear. Eighty-four patients had one to twelve stained axillary lymph nodes; sixty-nine percent and all respectively, had another quadrant and resection cavity stained. Conclusion: Intraoperative freezing-assisted drug delivery and targeting techniques during cryoablation of VX2 tumor translate successfully to locoregional BD targeting, lymphatic mapping during cryo-assisted surgery of breast cancer.
REVIEW | doi:10.20944/preprints202301.0053.v1
Subject: Chemistry And Materials Science, Nanotechnology Keywords: gastrin releasing peptide receptor; GRPR; bombesin receptor subtype 2; BB2; bombesin; targeted therapy; molecular imaging; theranostics; nanotechnology; nanoparticle; nanomedicine
Online: 4 January 2023 (03:19:26 CET)
Advances in nanomedicine bring the attention of researchers to the molecular targets which can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide on the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby the recent advances in the field of applications of various nanoplatforms which are able to reach the GRPR expressing cells are reviewed.
ARTICLE | doi:10.20944/preprints202104.0553.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Raman biosensor; Au-coated nanoparticles; hot-spot SERS substrate; anticancer drug nanocarriers; targeted drug delivery sensing; magneto-plasmonic nanoparticles.
Online: 20 April 2021 (17:43:09 CEST)
Safe administration of highly cytotoxic chemotherapeutic drugs is a challenging problem in cancer treatment due to the adverse side effects and collateral damage to non-tumorigenic cells. To mitigate these problems, new promising approaches, based on the paradigm of controlled targeted drug delivery (TDD), utilizing drug nanocarriers with biorecognition ability to selectively target neoplastic cells, are being considered in cancer therapy. Herein, we report on the design and testing of a nanoparticle-grid based biosensing platform to aid in the development of new targeted drug nanocarriers. The proposed sensor grid consists of superparamagnetic gold-coated core-shell Fe2Ni@Au nanoparticles, further functionalized with folic acid targeting ligand, model thiolated chemotherapeutic drug doxorubicin (DOX), and a biocompatibility agent, 3,6,-dioxa-octanethiol (DOOT). The employed dual transduction based on electrochemical and enhanced Raman scattering detection have enabled efficient monitoring of the drug loading onto the nanocarriers, attached to the sensor surface, as well as the drug release under simulated intracellular conditions. The grid’s nanoparticles serve here as the model nanocarriers for new TDD systems under design and optimization. The superparamagnetic properties of the Fe2Ni@Au NPs aid in nanoparticles’ handling and constructing a dense sensor grid with high plasmonic enhancement of the Raman signals due to the minimal interparticle distance.
REVIEW | doi:10.20944/preprints202305.0720.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Prostate cancer; androgen receptor; AR signaling pathway; disease progression; therapeutic re-sistance; personalized treatment; androgen deprivation therapy; AR-targeted therapies
Online: 10 May 2023 (09:09:13 CEST)
Prostate cancer (PCa) is a significant cause of cancer-related deaths globally, with an increasing incidence over the years. Our review article aims to unlock the secrets of androgen receptors in prostate cancer susceptibility, progression, and treatment by analyzing recent literature. Androgen receptor (AR) plays a crucial role in male development and maintains masculine characteristics. However, in prostate cancer, AR signaling pathway aberrations can lead to disease progression and treatment resistance. Understanding AR regulation and function in healthy and diseased states is essential for developing effective treatment strategies to combat this disease and improve patient outcomes. Our findings have significant implications for developing new treatments and identifying biomarkers for early detection and personalized treatment targeting the AR signalling pathway.
REVIEW | doi:10.20944/preprints201810.0204.v2
Subject: Biology And Life Sciences, Biology And Biotechnology Keywords: DNA origami; aptamer; DNA nanotechnology; protein nano array; biosensor; logic gate; enzyme cascade; drug delivery system; targeted therapy; molecular robotics
Online: 22 October 2018 (10:57:21 CEST)
DNA origami has emerged in recent years as a powerful technique for designing and building 2D and 3D nanostructures. While the breadth of structures that have been produced is impressive, one of the remaining challenges, especially for DNA origami structures intended to carry out useful biomedical tasks in vivo, is to endow them with the ability to detect and respond to molecules of interest. Target molecules may be disease indicators or cell surface receptors, and the responses may include conformational changes leading to release of therapeutically relevant cargo. Nucleic acid aptamers are ideally suited to this task and are beginning to be used in DNA origami designs. In this review we consider examples of uses of DNA aptamers in DNA origami structures and summarise what is currently understood regarding aptamer-origami integration. We review three major roles for aptamers in such applications: protein immobilisation, triggering of structural transformation, and cell targeting. Finally, we consider future perspectives for DNA aptamer integration with DNA origami.
REVIEW | doi:10.20944/preprints201807.0052.v1
Subject: Biology And Life Sciences, Agricultural Science And Agronomy Keywords: Plant stress, abiotic stress, biotic stress, metabolomics, phytometabolomics, sensomics, phytohormonics, LC-MS/MS, NMR, targeted metabolomics, untargeted metabolomics, functional food.
Online: 3 July 2018 (14:18:19 CEST)
The breeding of stress-tolerant cultivated plants that would allow for a reduction in harvest losses and undesirable decrease in quality attributes requires a new quality of knowledge on molecular markers associated with relevant agronomic traits, on quantitative metabolic responses of plants on stress challenges, and on the mechanisms controlling the biosynthesis of these molecules. By combining metabolomics with genomics, transcriptomics and proteomics datasets a more comprehensive knowledge of the composition of crop plants used for food or animal feed is possible. In order to optimize crop trait developments, to enhance crop yields and quality, as well as to guarantee nutritional and health factors, that provides the possibility to create functional food or feedstuffs, the knowledge about the plants’ metabolome is crucial. Next to classical metabolomics studies, this review focusses on several metabolomics based working techniques, such as sensomics, lipidomics, hormonomics and phytometabolomics, which were used to characterize metabolome alterations during abiotic and biotic stress, to find resistant food crops with a preferred quality or at least to produce functional food crops are highlighted.
REVIEW | doi:10.20944/preprints201608.0115.v2
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: oncogenes; oncogene addiction; carcinogenesis; transcription factor; cancer genome; gene fusion; cancer genetics; cancer stem cell; targeted cancer therapy; personalized medicine
Online: 14 September 2016 (08:30:41 CEST)
It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis.
REVIEW | doi:10.20944/preprints202305.2222.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Psychedelic renaissance; Mental health; Therapeutic potential; Gut microbiome; Psychedelic substances; Personalized medicine; Gut-brain axis; Mood regulation; Microbiome-targeted interventions; Psychopharmacology
Online: 31 May 2023 (10:32:05 CEST)
The psychedelic renaissance has reignited interest in the therapeutic potential of psychedelics for mental health and well-being. An emerging area of interest is the potential modulation of psychedelic effects by the gut microbiome - the ecosystem of microorganisms residing in our digestive tract. This review explores the intersection of the gut microbiome and psychedelic therapy, underlining potential implications for personalized medicine and mental health. We delve into the current understanding of the gut-brain axis, its influence on mood, cognition, and behavior, and how the microbiome may affect the metabolism and bioavailability of psychedelic substances. We also discuss the role of microbiome variations in shaping individual responses to psychedelics, along with potential risks and benefits. Moreover, we consider the prospect of microbiome-targeted interventions as a fresh approach to boost or modulate psychedelic therapy's effectiveness. By synthesizing insights from the fields of psychopharmacology, microbiology, and neuroscience, our objective is to advance knowledge about the intricate relationship between the microbiome and psychedelic substances, thereby paving the way for novel strategies to optimize mental health outcomes amid the ongoing psychedelic renaissance.
ARTICLE | doi:10.20944/preprints202208.0144.v1
Subject: Medicine And Pharmacology, Pharmacology And Toxicology Keywords: mucosal immunization; mucosal vaccine; vaccine delivery; administration volume; targeted vaccines; M cell targeting; dendritic cell targeting; C5aR1; C5a1R; CD88; EP54; EP67
Online: 8 August 2022 (10:17:30 CEST)
Generating long-lived mucosal and systemic antibodies through respiratory immunization with protective antigens encapsulated in nanoscale biodegradable particles could potentially decrease or eliminate the incidence of many infectious diseases but requires incorporation of a suitable mucosal immunostimulant. We previously found that respiratory immunization with a model protein antigen (LPS-free OVA) encapsulated in PLGA 50:50 nanoparticles (~380 nm diameter) surface modified with complement peptide-derived immunostimulant 02 (CPDI-02; formerly EP67) through 2kDa PEG linkers increases mucosal and systemic OVA-specific memory T-cells with long-lived surface phenotypes in young, naïve female C57BL/6 mice. Here, we determined if respiratory immunization with LPS-free OVA encapsulated in similar PLGA 50:50 microparticles (~1 μm diameter) surface modified with CPDI-02 (CPDI-02-MP) increases long-term OVA-specific mucosal and systemic antibodies. We found that, compared to MP surface modified with inactive, scrambled scCPDI-02 (scCPDI-02-MP), intranasal administration of CPDI-02-MP in 50 μL sterile PBS greatly increased titers of short-term (14 days post-immunization) and long-term (90 days post-immunization) antibodies against encapsulated LPS-free OVA in nasal lavage fluids, bronchoalveolar lavage fluids, and sera of young, naïve female C57BL/6 mice. Thus, surface modification of biodegradable microparticles with CPDI-02 is likely to increase long-term mucosal and systemic antibodies against encapsulated protein antigen after respiratory and possibly other routes of mucosal immunization.
ARTICLE | doi:10.20944/preprints202201.0380.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: Therapeutic biomarkers; circulating tumor cells; Immunocytochemistry; targeted therapy; Fluorescence in situ hybridization (FISH); Immune Checkpoint Inhibitors; Liquid Biopsy; Hormonal Treatments; Breast Cancer; Lung Cancer
Online: 25 January 2022 (11:31:05 CET)
Biomarker directed selection of targeted anti-neoplastic agents such as immune check-point inhibitors, small molecule inhibitors and monoclonal antibodies form an important aspect of cancer treatment. Immunohistochemistry (IHC) analysis of the tumor tissue is the method of choice to evaluate the presence of these biomarkers. However, a significant barrier to biomarker testing on tissue is the availability of an adequate amount of tissue and need for repetitive sampling due to tumor evolution. Also, tumor tissue testing is not immune to inter- and intra-tumor heterogeneity. We describe the analytical and clinical validation of a Circulating Tumor Cell (CTC) assay to accurately assess the presence of PD-L1 22C3 and PD-L1 28.8, ER, PR and HER2, from patients with solid tumors to guide the choice of suitable targeted therapies. Analytically, the test has high sensitivity, specificity, linearity and precision. Based on a blinded case control study, the clinical sensitivity and specificity for PD-L1 (22C3 and 28.8) was determined to be 90% and 100% respectively. The clinical sensitivity and specificity was 83% and 89% for ER; 80% and 94% for PR; 63% and 89% for HER2 (by ICC); and 100% and 92% for HER2 (by FISH), respectively. The performance characteristics of the test support its suitability and adaptability for routine clinical use.
ARTICLE | doi:10.20944/preprints202301.0500.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Alzheimer’s Disease (AD) mitochondria; endoplasmic reticulum (ER); serial block-face scanning electron microscopy (SBFSEM); three-dimensional electron microscopy (3D EM); small molecule mitochondria targeted therapeutics
Online: 27 January 2023 (10:08:59 CET)
Alzheimer’s Disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induces adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that mitochondria in AD dendrites exist primarily as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple mitochondria-ER contact sites (MERCS) known to contribute to abnormal lipid and calcium homeostasis. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis. These data provide novel information on the role MOAS play in AD and additional support for further development of partial MCI inhibitors as disease modifying strategy for AD.
ARTICLE | doi:10.20944/preprints202212.0542.v2
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: safety analysis; targeted therapy; monoclonal antibody therapy; immune checkpoint inhibibitors; tyrosine kinase inhibitors; breast cancer; gynecological cancer; Helixor; Viscum album L.; PARP inhibitors; CDK 4/6 inhibitors
Online: 30 December 2022 (12:00:35 CET)
Background: Newer personalized medicine including targeted therapies such as PARP inhibitors and CDK 4/6 inhibitors have shown to improve survival of breast and gynaecological cancer patients. However, efficacy outcomes may be hampered by treatment discontinuation due to targeted therapy-related adverse drug reactions or resistance. Studies suggest that add-on mistletoe (Viscum album L., VA) improves quality of life and ameliorates cytotoxic side effects of standard oncological therapy in cancer patients. The primary objective of this real-world data study was to determine the safety profile of targeted therapy in combination with add-on Helixor® VA therapy in breast and gynecological cancer patients. Methods: The present study is a real-world data study utilizing demographic and treatment data from the accredited national Network Oncology (NO) registry. The study has received ethics approval. The safety profile of targeted with or without Helixor® VA therapy as well as safety - associated variables were evaluated by univariate and adjusted multivariable regression analyses. Results: All stage breast or gynecological cancer patients (n = 242) were on average 54.5±14.2 years old. One hundred and sixty patients (66.1%) were in the control (CTRL, targeted therapy) and 82 patients (33.9%) in the combinational (COMB, targeted plus Helixor® VA therapy) group. The addition of Helixor® VA did not hamper the safety profile (χ2 = 0.107, p-value = 0.99) of targeted therapy. Furthermore, no adverse events and a trend towards an improved targeted therapy adherence were observed in the COMB group. Conclusions: The present study is the first of its kind showing the applicability of Helixor® VA in combination with targeted therapies. The results indicate that add-on Helixor® VA does not negatively alter the safety profile of targeted therapies in breast and gynaecological cancer patients.
REVIEW | doi:10.20944/preprints201912.0135.v1
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: vascular homing peptide; cell penetrating peptide; angiogenesis; vascular heterogeneity; fibrosis; targeted delivery; decorin; transforming growth factor-β (tgf-β), bystander effect, cendr peptide; tissue regeneration; regenerative medicine
Online: 10 December 2019 (15:02:39 CET)
Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic vasculature forming in the regenerating tissues has a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine
REVIEW | doi:10.3390/sci2030068
Subject: Medicine And Pharmacology, Tropical Medicine Keywords: COVID-19; pooling clinical trials; hyperinfection; steroids; treatment; targeted healthcare; population health management; cancer treatment; clinical research; clinical trials; developing vaccines; ranking and rating hospital quality; school closures; interventions for delirium; assessments of COVID-19 death inequities; regulatory safeguards; preventing child abuse and maltreatment; prevalence of health care worker burnout; nursing home ratings; challenging oncology practice; addressing racial; ethnic; social and economic divides; violence against sexual minority adolescents; primary tumors; metastasis; stages of cancer; reforming cancer clinical trials; supporting carers; protection and prevention; benign and malignant tumors; reforming cancer clinical trials; protection of healthcare personnel; comparing excess deaths in NYC; 1918 influenza pandemic; the possibility of full recovery from COVID-19; mental health impact of COVID-19 on young adults; ranking and rating nursing home quali
Online: 21 August 2020 (00:00:00 CEST)
The SARS-CoV-2 virus that causes the COVID-19 disease has wreaked havoc on the world community in terms of every imaginable parameter. The research output on COVID-19 has been nothing short of phenomenal, especially in the medical and biomedical sciences, where the search for a potential vaccine is being conducted in earnest. Much of the advanced research has been distributed in the leading medical journals, including the Journal of the American Medical Association (JAMA), where the latest research is distributed on a daily basis. The purpose of this paper is to provide some perspectives on 44 interesting and highly topical research papers that have been published in JAMA, at the time of writing, within the past two weeks. The diverse topics include public health, general medicine, internal medicine, oncology, paediatrics, geriatrics, and biostatistics.