Studies in animal models have suggested that the ketogenic diet may be effective in the treatment of cancer. However, human cohort studies on the ketogenic diet have, thus far, failed to show benefits in cancer survival or in any other hard clinical endpoints of the disease. This paper presents a case report of a patient with glioblastoma multiforme. The patient had initially been treated with standard oncotherapy including surgery, radiotherapy and chemotherapy. Despite standard treatment, the patient experienced a recurrence of the glioblastoma seven months later. Subsequently, the patient refused radiotherapy and chemotherapy and opted to use the paleolithic ketogenic diet (PKD) as a stand-alone therapy. Following the adoption of the PKD, progression of the disease has been completely halted. At the time of writing, the patient has remained in remission for 48 months, is without side-effects and experiences an excellent quality of life without the use of any drugs.

Carcinoembriogenic antigen (CEA) is a routine marker for follow-up of colo-rectal cancers. We aimed to determine whether a CEA increase within the normal range can be linked to a recurrence risk. We included 78 consecutive patients with colo-rectal cancer, who underwent curative surgical treatment with or without chemo- or radiotherapy. As reference, we used the smallest value of the CEA during follow-up. A total of 34/78 patients (43.6%) had fluctuations of CEA of at least 1.1 ng/ml, with or without increases above 5 ng/ml. In 27/34 patients (79.4%) increases of CEA were explained either by recurrence (15/34 patients, 44.1%), adjuvant chemotherapy (7/34 patients, 20.6%) or benign pathology (5/34 patients, 14.7%). In 5 of 22 recurrences (23%) a CEA increase of at least 1.1 ng/ml, but below 5 ng/ml preceded the clinical relapse by a median of 8 months (range 3-22 months). The 4-year disease-free survival was 89% in patients with postoperative CEA <2.5 ng/ml, and 55% in patients with CEA >2.5 ng/ml. CEA increase by at least 1.1 ng/ml within the normal range, after curative treatment of colorectal cancer can be either an early sign of relapse or can be usually explained by other pathological processes.

Long gone was the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues and immune cells in their environment, which is now known as the tumor microenvironment (TME). It is found that the interactions between tumors and their surrounding promote tumor growth, invasion and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME. This review explores how different factors in the TME supply tumors with the required growth factors and signaling molecules to proliferate, invade and metastasis. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis and anticancer drug delivery system. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (PET and SPECT).

MicroRNAs (miRNAs) are a kind of conserved small non-coding RNAs that participate in regulating gene expression by targeting multiple molecules. Early studies have shown that the expression of miRNAs changes significantly in different tumor tissues and cancer cell lines. It is well acknowledged that such variation is involved in almost all biological processes, including cell proliferation, mobility, survival and differentiation. Increasing experimental data indicate that miRNA dysregulation is a biomarker of several pathological conditions including cancer, and that miRNA can exert a causal role, as oncogenes or tumor suppressor genes, in different steps of the tumorigenic process. Anticancer therapies based on miRNAs are currently being developed with a goal to improve outcomes of cancer treatment. In our present study, we review the function of miRNAs in tumorigenesis and development, and discuss the latest clinical applications and strategies of therapy targeting miRNAs in cancer.

QSO B0218+357 is a blazar located at a cosmological redshift of 0.944. The source is gravitationally lensed by a spiral galaxy located at the redshift of 0.68. Strong gravitational lensing splits the signals emitted by the source into two components separated by 10-12 days, as observed in radio and gamma-ray bands. In July 2014 a GeV flare was observed by Fermi-LAT, triggering follow-up observations with the MAGIC telescopes at energies above 100 GeV. The expected time delay between the components allowed us to plan broad band MWL observations before, during and after the trailing component of the emission. The MAGIC observations at the expected time of arrival of the trailing component resulted in the first detection of QSO B0218+357 in Very-High-Energy (VHE, >100 GeV) gamma rays. It is both the farthest known VHE object and one of only a few Flat Spectrum Radio Quasars detected in this energy range. We report here the observed multiwavelength spectral and temporal properties of the emission during the 2014 flare.

Circulating tumor cells (CTC) have shown to be prognostic in advanced colorectal cancer (advCRC), but their value for predicting response to treatment or as a source of molecular data is debated. We compared CellSearch® (Janssen Diagnostics, LLC) and IsoFlux^TM (Fluxion Biosciences Inc, South San Francisco, CA) systems for the enumeration of CTC in patients with newly diagnosed advCRC (group 1; n=34). Using castPCR^TM we studied KRAS status in CTC isolated with IsoFlux^TM and compared it with that of the primary tumor in patients from group 1 and in KRAS wild-type (KRAS^WT) patients with progressive disease (group 2; n=22). Median number of CTC detected with CellSearch® (groups 1 and 2) was 1 (range: 0-78) and with IsoFlux^TM (group 1) was 8 (range: 0-419), showing a modest correlation (r=0.345, P=0.036), which improved if lung metastases (r=0.805, P=0.016) or if lung and liver metastases were present (r=0.812, P=0.05). A Bland-Altman plot showed that the higher the number of CTC detected the larger the difference between both methods in favor of IsoFlux^TM. After a median follow-up since CTC collection of 16 months (range: 1-30) CellSearch® ≥ 3 CTC (HR 2.77, 95% CI 0.77-9.95) and IsoFlux^TM ≥ 11 CTC (HR 4.14, 95% CI 1.05-16.19) were established as the best cutoff points for predicting survival. Using castPCR^TM we found KRAS mutations in CTC in 4 out of 8 patients from group 1 and in 2 out of 3 patients from group 2. None of these mutations were found in the primary tumor using standard methods, possibly reflecting intratumor heterogeneity or treatment selection pressure. We conclude that IsoFlux^TM is more efficient than CellSearch® in the isolation of CTC in patients with advCRC, achieving, in a majority of cases, the established minimum of CTC for castPCR^TM-based genetic analyses.

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

Gastric cancer is an intractable disease with a high incidence of peritoneal dissemination and obstructive symptoms (e.g. ileus, jaundice, and hydronephrosis) arising from accompanying marked fibrosis. Microenvironmental interactions between cancer cells and stromal cells are the suggested cause of the disease. Transforming growth factor (TGF-β) is an intriguing cytokine exhibiting dual roles in malignant disease, acting as an important mediator of cancer invasion, metastasis, and angiogenesis as well as exhibiting antitumor functions. Moreover, the TGF-β pathway contributes to the generation of a favorable microenvironment for tumor growth and metastasis throughout the steps of carcinogenesis. Among these effects, TGF-β induces the epithelial-to-mesenchymal transition with prometastatic functions, contributes to the conversion of stromal cells to carcinoma-associated fibroblasts, and suppresses the function of immune cells, which compromises the antitumor immune response, leading to cancer progression and stromal fibrosis. In this review, we address the role of the essential TGF-β signaling pathway in the regulation of the activities of components of the tumor microenvironment of gastric cancer and how this contributes to tumor progression and stromal fibrosis. We then explore the potential to optimize therapy that inhibits TGF-β signaling in the preclinical and clinical settings of gastric cancer.

Brain metastases are highly evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden with variable efficacy throughout the body. Historically, there has been a widely held view that brain metastases do not respond to circulating therapeutics because the blood-brain-barrier (BBB) restricts their uptake. However, emerging data are beginning to paint a far more complex picture where the brain acts as a sanctuary for dormant, subclinical proliferations that are initially protected by the BBB, but then exposed to dynamic selection pressures as tumours mature and vascular permeability increases. Here, we review key experimental approaches and landmark studies that have charted the genomic landscape of breast cancer brain metastases. These findings are contextualised with the factors impacting on clonal outgrowth in the brain: intrinsic breast tumour cell capabilities required for brain metastatic fitness, and the neural niche, which is initially hostile to invading cells but then engineered into a tumour-support vehicle by the successful minority. We also discuss how late detection, abnormal vascular perfusion and interstitial fluid dynamics underpin the recalcitrant clinical behaviour of brain metastases, and outline active clinical trials in the context of precision management.

Zucchini (Cucurbita pepo subsp. pepo) is a seasonal vegetable with high nutritional and medical value. Many useful properties of this fruit are attributed to its bioactive compounds. Zucchini fruits (“Yellow” and “Light Green” varieties) and four distinctive components (lutein, β-carotene, zeaxanthin and dehydroascorbic acid)were selected. Firstly it was determinated the lutein, β-carotene, zeaxanthin and dehydroascorbic acid content in these fruits and then, in order to measure the safety and suitability of their use different assays were carried out: (i) Genotoxicity and antigenotoxicity tests to determine the safety and DNA-protection against hydrogen peroxide; (ii) cytotoxicity and (iii) DNA fragmentation assay to evaluate the proapoptotic effect. Results showed that: (i) all the substances were non-genotoxic, (ii) all the substances were antigenotoxic except the highest concentration of lutein, (iii) “Yellow” Zucchini epicarp and mesocarp exhibited the highest cytotoxic activity (IC₅₀ > 0.1 mg/mL and 0.2 mg/mL, respectively) and iv) “Light Green” Zucchini skin and pulp induced internucleosomal DNA fragmentation . To sump up, Zucchini fruit could play a positive role in human health and nutrition due to this fruit and its components were safe, able to inhibit significantly the H₂O₂-induced damage and exhibit antiproliferative and pro-apoptotic properties toward HL60 tumour cells. The information generated from this research should take into account to select potential accessions for breeding programs purposes.

At nuclear scale, we present three heuristic relations pertaining to strong and electroweak coupling constants. With these relations, close to beta stability line, it is possible to study nuclear binding energy with a single energy coefficient of magnitude $\left(\frac{1}{{\alpha }_s}\right)\left[\frac{e^2}{4\pi {\epsilon }_0{R}_0}\right]\approx 10.0\text{MeV}\text{.}$ With reference to up and down quark masses, it is also possible to interpret that, nuclear binding energy is proportional to the mean mass of $\left[\left(2m_u+m_d\right)\text{and}\left(m_u+2m_d\right)\right]\approx 10.0\text{MeV}.$

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, DAPK, miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors hold considerable promise for the treatment of cholangiocarcinoma through re-activation of tumor suppressor genes and miRNAs as well as induction of an anti-viral immune response.

Using the techniques of computer-aided drug design, the docking of Survivin and known active small molecules was simulated and then the key amino acid residue fragment of the target protein was analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through the use of the natural product, Oleanolic Acid, as a lead compound, the introduction of the active groups onto the A-ring, and the modification of the carboxyl group at the C-28 position using esterification or amidation, twenty new Oleanolic acid derivatives had been designed and synthesized.A549 and SGC-7901 cells were used to screen the antitumor activity in vitro through the standard MTT method. The compounds, II₃, III₅ and Ⅳ_4, exhibited more potent cytotoxicity than positive drugs.

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1-2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2 and neuroendocrine carcinoma: NEC) on the basis of Ki-67 proliferation index and mitotic count according to the 2010 WHO classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic backround together with preclinical studies to develop new agents, including those already under investigation for SCLC, will be needed to improve the prognosis.

The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

Solid tumors display complex biology and most therapies including chemotherapy cannot prevent therapy resistance and relapse. Most therapeutics target cancer cells, but recent data suggest the presence of cancer stem cells as cells with self-renewal and tumorigenic abilities. Cancer stem cell markers have been suggested to have prognostic value and can be targeted during cancer treatment and in resistant disease. CSCs have been postulated to play significant contextual roles in tumor initiation, progression, therapy resistance and metastasis. CSCs have thus been targeted by new generation cancer drugs. The transcriptional expression of several CSC markers in different cancers was evaluated by searching publicly available The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. We report here new findings on expression and prognostic significance of CSC markers in several cancers by examining the expression of CSCs markers in tumor tissues versus the adjacent normal tissues. We found that CSC markers were mostly highly expressed various tumors such as colon, lung, pancreatic and esophageal cancers. No CSC marker is expressed in the same pattern in all cancers and individual CSC marker expression was not linked to patient survival. This analysis calls for continued research on CSCs and clinical evaluation of the CSC markers in relation to prognosis of cancers in large population samples. Novel cancer drugs ought to target CSCs, cancer cells and tumor microenvironment variations.

Human visual system (HVM) can quickly localize the most salient object in scenes, which has been widely applied on natural image segmentation [15]-[19]. In ultrasound (US) breast images, compared with background areas, tumor is more salient because of its higher contrast. In this paper, we develop a novel automatic localization method based on HVM for automatic segmentation of ultrasound (US) breast tumors. First, the input image is smoothed by convolution with a linearly separable Gaussian filter and then subsampled into a 9-layer Gaussian pyramid. Then intensity, blackness ratio, and superpixel contrast features are combined to compute saliency map, in which Winner Take All algorithm is used to localize the most salient region, presenting with a circle on the localized target. Finally the circle is taken as the initial contour of CV level set to finish the extraction of breast tumor. The localization method has been tested on 400 US beast images, among which 378 images have higher saliency than background areas and succeed in localization, with high accuracy 92.00%. The HVM localization method can be used to localize the tumors, combined with this method, CV level set can achieve the fully automatic segmentation of US breast tumors. By combing intensity, blackness ratio and superpixel contrast features, the proposed localization method can successfully avoid the interference caused by background areas with low echo and high intensity. Moreover, multi-object localization of US breast images can be considered in future employment.

Separation and interpretation of rebellious Circulating Tumor Cells (CTCs) originating from the primary tumor or cancer tissue plays a significant role in diagnostics, cancer progression analyses, suitable medicine exploration, and treatment proficiency examination. Cancer metastasis occurs when CTCs spread throughout the body and invade healthy tissues, leading to new tumors in that area. Although a dramatic rate of deaths begins from spreading CTCs around the body, valuable measures have been made to control their development. However, the first step is separating these harmful cells from the bloodstream and investigating their features. Having examined the characteristics of CTCs as cancer’s main strength, researchers can introduce complementary treatments that can affect cancerous cells without damaging the healthy cells. Therefore, according to their unique characteristics, numerous techniques have been established for continuous and fast separation and sorting of CTCs. Nevertheless, few separators enjoy the efficient performance and appropriate accuracy and can be produced in mass numbers due to the available fabrication equipment. Microfabrication advancements enable separators to combine the advantages of active and passive methods in a small-scale platform for probing individual cells and separation purposes. Reduction in reagents, sample volume, analysis time, and less harmfulness to patients are some of the motivations that encourage researchers to employ microfluidic instruments for CTCs separation from other blood cells over the last two decades. However, microfabrication limitations mean effective separators, and the diagnostic option they provide, are not readily available. Addressing these limitations requires optimizing the design and fabrication of separators such that they are reduced in their size and fabrication cost, while also maintaining high-throughput separating capability. The emergence of the Lab-On-a-Chip (LOC) and then Lab-On-a-CD (LOCD) technologies, having more inherent benefits than conventional microfluidic devices, has created new opportunities and become increasingly widespread in recent years. Evidence suggests that employing single methodologies or integrating approaches without sufficient understanding of potential outcomes is unlikely to result in successful diagnostic results. This paper contributes an extensive review of several separation systems, including fundamental theories and experimental details, and describes detailed operating principles and device performance.

In the last few decades, the dynamics of tumor cells and their growths are presented via clinical, experimental, and theoretical approaches, which leads to the development of the new idea of multiple cancer therapies to control and reduce the death rate for earlier detection. In this paper, we discussed the dynamics of tumor cell growth and its treatment process. We analyzed some simple mathematical models and generalized the study to understand the growth of tumor cells. The main proposed model is a system of ordinary differential equations which combines interactions among natural killer cells, dendritic cells and cytotoxic CD8+ T cells. The model is solved numerically to explain how the tumor cells spread and become more dangerous as well as the treatment process of cancer. It is also studied that how the cell behaves in the presence of different therapy and drugs. The optimal control of chemotherapy has been discussed. It has also been explained how much the model is effective in reducing tumor cells over time. Finally, a couple of spatially distributed models are discussed for tumor cell growth.

We introduce a new variation on the domination theme which we call vertex domination as reducing waste of time in transportation planning and optimization of transport routes. We determine the vertex domination number $\gamma_v$ for several classes of fuzzy graphs. The bounds is obtained for it. In fuzzy graphs, monotone decreasing property and monotone increasing property are introduced. We prove both of the vizing's conjecture and the Grarier-Khelladi's conjecture are monotone decreasing fuzzy graph property for vertex domination. We obtain Nordhaus-Gaddum (NG) type results for these parameters. The relationship between several classes of operations on fuzzy graphs with the vertex domination number of them is studied. Finally, we discuss about vertex dominating set of a fuzzy tree by using the bridges and $\alpha$-strong edges equivalence.

Metastasis is the leading cause of cancer-related death and drives patient morbidity as well as healthcare costs. For several cancers, breast and prostate in particular, bone is the primary site of metastasis. Efforts to treat bone metastases have been stymied by a lack of models to study the progression and cellular players and signaling pathways driving bone metastasis. In this review, we examine the newly described and classic models of bone metastasis. Through the use of current in vivo, microfluidic and in silico computational models bone metastasis models we may eventually understand how cells escape the primary tumor and how these circulating tumor cells then home to and colonize the bone marrow. Further, future models may uncover how cell enter and escape dormancy to develop into overt metastases. Recreating the metastatic process will lead to the discovery of therapeutic targets for disrupting and treating bone metastasis.

The search for improved therapeutic approaches to breast cancer are still on going. Breast tumor kinase (BRK, also known as PTK6) is one of the targets, it is highly expressed in breast carcinomas while displaying low or no expression in the normal mammary gland, which hints at the oncogenic role of this enzyme in breast cancer. In these twenty years, an increasing number of studies have focused on understanding the cellular roles of BRK in breast cancers. This review outlines the advances made towards understanding the cellular and physiological role of BRK, the molecular and chemical inhibitors and its therapeutic significance in breast cancer.

To systematically investigate the epidemiology of breast cancer risk factors in Iran, we performed a systematic search via PubMed, Scopus, Web of Science and Persian databases for identifying studies published on breast cancer risk factors up to March 2019. Meta-analyses were done for risk factors reported in more than one study. We calculated odds ratios (ORs) with corresponding 95% confidence intervals (CIs) using a fixed/random-effects models.Thirty-nine studies entered into the meta-analysis. Pooling of ORs showed a significant harmful effect for risk factors including family history (OR: 1.80, 95%CI 1.47-2.12), HRT (OR: 5.48, 95%CI 0.84-1.74), ER positive (OR: 1.87, 95%CI 1.41-2.33), PR positive (OR: 1.84, 95%CI 1.38-2.29), stress condition (OR: 2.67, 95%CI 1.84-3.50), passive smokers (OR: 1.68, 95%CI 1.34-2.03), full-term pregnancy at age 30 (OR: 3.41, 95%CI 1.19-5.63), abortion (OR: 1.84, 95%CI 1.35-2.33), sweets consumption (OR: 1.71, 95%CI 1.32-2.11) and genotype Arg/Arg (crude OR: 1.59, 95%CI 1.07-2.10), whereas a significant protective effect for late menarche (OR: 0.58, 95%CI 0.32-0.83), nulliparity (OR: 0.68, 95%CI 0.39-0.96), 13 to 24 months of breastfeeding (OR: 0.68, 95%CI 0.46-0.90), daily exercise (OR: 0.59, 95%CI 0.44-0.73) and vegetable consumption (crude OR: 0.28, 95%CI 0.10-0.46).This study suggest that factors such as family history, HRT, ER and PR positive status, stress condition, passive smokers, late full-term pregnancy, abortion, sweets consumption and genotype Arg/Arg might increase risk of breast cancer development, whereas late menarche, nulliparity, 13-24 months breastfeeding, daily exercise and vegetable consumption had an inverse association with breast cancer development.

The lymphocyte function–associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA’s role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.

There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors. The A2BAR, coupled to both Gαi and Gαq G proteins, is one of the several G-protein-coupled receptors that are expressed in a significantly higher level in some cancer tissues in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are potentially novel attractive anticancer agents. Several antagonists targeting at the A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various types cancers, and the rationale of using A2BAR antagonists in cancer therapy

The aim of this expository article is to present recent developments in the centuries-old discussion on the interrelations between several types of domination in graphs. However, the novelty even more prominent in the newly discovered simplified presentations of several older results. Domination can be seen as arising from real-world application and extracting classical results as first described by this article.The main part of this article, concerning a new domination and older one, is presented in a narrative that answers two classical questions: (i) To what extend must closing set be dominating? (ii) How strong is the assumption of domination of a closing set? In a addition, we give an overview of the results concerning domination. The problem asks how small can a subset of vertices be and contain no edges or, more generally how can small a subset of vertices be and contain other ones. Our work was as elegant as it was unexpected being a departure from the tried and true methods of this theory that had dominated the field for one fifth a century. This expository article covers all previous definitions. The inability of previous definitions in solving even one case of real-world problems due to the lack of simultaneous attentions to the worthy both of vertices and edges causing us to make the new one. The concept of domination in a variety of graphs models such as crisp, weighted and fuzzy, has been in a spotlight. We turn our attention to sets of vertices in a fuzzy graph that are so close to all vertices, in a variety of ways, and study minimum such sets and their cardinality. A natural way to introduce and motivate our subject is to view it as a real-world problem. In its most elementary form, we consider the problem of reducing waste of time in transport planning. Our goal here is to first describe the previous definitions and the results, and then to provide an overview of the flows ideas in their articles. The final outcome of this article is twofold: (i) Solving the problem of reducing waste of time in transport planning at static state; (ii) Solving and having a gentle discussions on problem of reducing waste of time in transport planning at dynamic state. Finally, we discuss the results concerning holding domination that are independent of fuzzy graphs. We close with a list of currently open problems related to this subject. Most of our exposition assumes only familiarity with basic linear algebra, polynomials, fuzzy graph theory and graph theory.

Worldwide, hundreds of thousands of people are diagnosed with kidney cancer and this disease is more common in developed and industrialized countries. Previously, kidney cancer was known as an elderly disease and was seen in people over a certain age; nowadays it is also seen in younger individuals and it is easier to diagnose thanks to new radiological diagnostic methods. A kidney tumor is a type of cancer that is extremely aggressive and needs surgical treatment rapidly. Today, approximately 30% of patients diagnosed with kidney cancer are unfortunately noticed at the stage of metastatic disease (spread to distant organs). The biggest factor that pushes us to this study is that kidney tumors progress unlike other cancer types with little or no symptoms. Therefore, conducting such studies is extremely important for early diagnosis. In this study, we compare the Unet3D models in order to help people who are dealing with difficulties in the diagnosis of kidney cancer. Unet, Unet+ResNet and Unet++ models were compared for image segmentation.

Macrophages and dendritic cells (DCs) acquire functionally distinct properties in response to various environmental stimuli; the interaction of these cells with myeloid-derived suppressor cells (MDSCs) in tumor microenvironments regulates cancer progression. Immunodeficient mice lacking T cells are less likely to reject human cancer cells because of major histocompatibility complex (MHC) mismatches. The xenograft tumor microenvironment, comprising human cancer and mouse host cells, exhibits more complex bidirectional signaling and function than a syngeneic tumor microenvironment. Here human and mouse colorectal cancer cells were transplanted into nude mice to elucidate differences in macrophage, DC, and MDSC functions in human xenograft and mouse allograft tumor models. Plasma interferon-γ and interleukin-18 concentrations in the former model after intraperitoneal lipopolysaccharide (LPS) administration were significantly higher than those in the latter model and non-transplanted control group. Splenic MHC class I, II, and CD80 expression increased in CD11b+ and MDSC populations after LPS administration in only the xenograft tumor model. The number of CD80- and MRC1-expressing cells decreased upon LPS administration in only the xenograft tumor. These results suggxest that macrophages and DCs function normally in xenograft tumor models, whereas their functions in response to LPS administration vary in allograft tumor models.

The Signal Transducer and Activator of Transcription (STAT)3 and 5 are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association to survival in cancer patients. The molecular mechanisms that underpins the oncogenic activity of STAT3/5 signaling includes the regulation of genes that control cell cycle, cell death, inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling including the p19ARF/p53 pathway, tyrosine phosphatases, suppressor of cytokine signaling 1 and 3, the sumo ligase PIAS3, the E3 ubiquitin ligase TMF/ARA160 and the miRNAs miR-124 and miR-1181. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated to STAT3/5 signaling explaining their context dependent association to tumor progression both in human cancers and animal models.

Breast cancer is the most common cause of death for women worldwide. Thus, the ability of artificial intelligence systems to predict and classify breast cancer is very important. In this paper, a hybrid ensemble method classification mechanism is proposed based on a majority voting mechanism. First, the performance of different state-of-the-art machine learning classification algorithms for the Wisconsin Breast Cancer Dataset (WBCD) were evaluated. The three best classifiers were then selected based on their F3 score. F3 score is used to emphasize the importance of false negatives (recall) in breast cancer classification. Then, these three classifiers, simple logistic Regression learning, stochastic gradient descent learning and multilayer perceptron network, are used for ensemble classification using a voting mechanism. We also evaluated the performance of hard and soft voting mechanism. For hard voting, majority-based voting mechanism was used and for soft voting we used average of probabilities, product of probabilities, maximum of probabilities and minimum of probabilities-based voting methods. The hard voting (majority-based voting) mechanism shows better performance with 99.42% as compared to the state-of-the-art algorithm for WBCD.

: Annona squamosa L. is an important medicinal plant used in traditional medicine for the treatment of various diseases. Different parts of A. squamosa L. have various therapeutic effects; however, the anticancer activity of the leaves has not yet been identified. In vitro, MTT, nuclear staining, and LDH assays were used to evaluate cell survival and proliferation in cells exposed to the extracts. The effect of the extracts on cell migration was investigated using a monolayer wound repair assay, and the apoptotic effects were evaluated using flow cytometry. A breast cancer model was used to study the effect of the extract on the tumor size, and the expression of different proliferative and apoptotic markers was evaluated by immunohistochemical analysis. At a concentration of 100 µg/mL, A. squamosa leaf extracts exerted strong antiproliferative and cytotoxic effects against various cell lines. The extracts reduced wound closure and strongly induced apoptosis. In vivo study, rats were sacrificed 24 h after the last injection, and tumor size, as well as the expression of proliferative and apoptotic markers, were observed to be greatly affected by treatment with the extracts. Therefore, A. squamosa leaf extract may be developed as a potential novel drug to treat breast cancer in the future

In this paper, some characterizations of fuzzifying strong compactness are given, including characterizations in terms of nets and pre -subbases. Several characterizations of locally strong compactness in the framework of fuzzifying topology are introduced and the mapping theorems are obtained.

Many cellular functions important for tumor initiation and progression are mediated by members of the integrin family, a diverse family of cell adhesion receptors. With recent studies emphasising on the role of the tumor microenvironment (TME) in tumor initiation and progression, it is not surprising that a lot of attention is being given to integrins. Several integrins are under trial with many demonstrating appealing activity in patients with different cancers. A deeper knowledge of the functions of integrins within the tumor microenvironment is still required, and might lead to better inhibitors being discovered. Integrin expression is commonly dysregulated in many tumors with integrins playing key roles in signaling as well as promotion of tumor cell invasion and migration. This review report new data on the differential expression of integrins within solid tumors using two publicly available resources: The Cancer Genomic Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA). In this analysis, I investigated the expression of integrin alpha 2 (ITGα2), ITGα3, ITGβ4 and ITGβ6 in tumor tissues versus adjacent normal tissues. This analysis showed that integrins were differentially expressed in cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), esophageal carcinoma (ESCA) and lung adenocarcinoma (LUAD). This analysis showed that ITGα2 and ITGβ6 expression are upregulated in CESC and ESCA, ITGα3 is upregulated in HNSC and ESCA whilst ITGβ4 is highly expressed in CESC, HNSC, ESCA and LUAD tumor tissues compared to adjacent normal tissues. Integrins also play a major role in adhesion of circulating tumor cells to new sites and the resulting formation of secondary tumors. Furthermore, integrins have demonstrated the ability to promoting stem cell-like properties in tumor cells as well as drug resistance. Anti-integrin therapies rely heavily on the doses or concentrations used as these determine whether the drugs act as antagonists or as integrin agonists. This review offers the latest synthesis in terms of current knowledge of integrins functions within the tumor microenvironment and potential targets for different cancers.

In this paper, we introduce a new iteration scheme, named as the S**-iteration scheme, for approximation of fixed point of the nonexpansive mappings. This scheme is faster than Picard, Mann, Ishikawa, Noor, Agarwal, Abbas, Thakur, and Ullah iteration schemes. We show the stability of our instigated scheme and give a numerical example to vindicate our claim. We also put forward some weak and strong convergence theorems for Suzuki's generalized nonexpansive mappings in the setting of uniformly convex Banach spaces. Our results comprehend, improve, and consolidate many results in the existing literature.

We propose a new theory beyond the standard model of elementary-particle physics. Employing the concept of a quantized spacetime, our theory demonstrates that the zero-point energy of the vacuum alone is sufficient to create all the fields, including gravity, the static electromagnetic field, and the weak and strong interactions. No serious undetermined parameters are assumed. Furthermore, the relations between the forces at the quantum-mechanics level is made clear. Using these relations, we quantize Einstein’s gravitational equation: Beginning with the zero-point energy of the vacuum, and after quantizing Newtonian gravity equation, we combine the energies of a static electromagnetic field and gravity in a quantum spacetime. Applying these results to the Einstein gravity equation, we substitute the energy density derived from the zero-point energy in addition to redefining differentials in a quantized spacetime. This is how we derive the quantized Einstein gravitational equation without assuming the existence of macroscopic masses. For the weak interaction, by considering plane-wave electron and the zero-point energy, we obtain a wavefunction that represents a β collapse. In this process, from a different point of view than Weinberg-Salam theory, we derive the masses of the W and Z bosons and the neutrino, and we calculate the radius and lifetime of the neutron. For the strong interaction, we previously reported an analytical theory for calculating the mass of a proton by providing a specific linear attractive potential obtained from the zero-point energy, which agrees well with the measurements. In the present study, we further calculate the strong interaction between two nucleons, i.e., the mass of the pi-meson. The resulting calculated quantities agree with the measurements, which verifies our proposed theory.

In this paper, we propose methods for brain tumor detection in MRI images based on ensemble learning. We build upon prior research on ensemble methods by testing the concatenation of pre-trained models: features extracted via transfer learning are merged and segmented by classification algorithms or a stacked ensemble of those algorithms. The proposed approach achieved accuracy scores of 0.98 , outperforming a benchmark VGG-16 model. Considerations to granular computing are given in the paper as well.

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Intriguingly, despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of stress response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

Photodynamic therapy (PDT) with a suitable photosensitizer molecule is a promising anticancer treatment. We evaluated two chlorin molecules as potential photosensitizers, methyl pyropheophorbide a (MPPa) and N-methoxyl purpurinimide (NMPi), against A549 human lung adenocarcinoma cells in vitro as well as in A549 tumor-bearing mice in vivo. Cell viability, microscopy, and FACS analyses were performed for the in vitro studies. MPPa and NMPi showed high phototoxicity in vitro, which was dependent on the concentration of the photosensitizers as well as the light irradiation time. In the animal study, tumor volume change, tumor surface alterations, and H&E and TUNEL staining analyses were performed and compared between small (tumor volume of <50 mm³) and large (tumor volume of >50 mm³) size of initial tumors. MPPa and NMPi showed high anticancer efficacy against small-size tumors, indicating that early treatment with PDT is effective. Especially, repeated two times PDT with NMPi allowed almost complete eradication against small-size tumors. However, MPPa and NMPi were not effective against large-size tumors. In conclusion, the two chlorin derivatives, MPPa and NMPi, show good anticancer efficacy as promising photosensitizers for PDT in vitro and in vivo. Moreover, their activity in vivo was significantly dependent on the initial tumor size in mice, which confirms the importance of early cancer treatment.

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance, culminating in relapse and metastatic disease continue to be associated with fatal disease. Cancer stem cells (CSCs) are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterised in many cancers with data illustrating that CSCs display great abilities to self-renew, withstand therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ABC membrane transporters, activation of several survival signaling pathways and increased immune evasion DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we re-visit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

Glioma tumors are one of the most devastating cancer types. Of the different glioma tumors, glioblastoma is the most advanced stage with the worst prognosis. Current therapies are still unable to provide an effective cure. Recent advantages in oncolytic immunotherapy have generated great expectations in the cancer therapy field. The use of oncolytic viruses (OV) in cancer treatment is one of those immune-therapeutic alternatives. OV have a double oncolytic action by both, directly destroying the cancer cells, sparing the patient’s life, and stimulating a tumor specific immune response to revert the ability of tumors to escape the control of the immune system. OV are one promising alternative to conventional therapies in glioma tumor treatment. Several clinical trials have proven the feasibility to use some viruses to specifically infect tumors eluding undesired toxic effects in the patient. Here we have revisited the literature in order to describe the main OV proposed so far as therapeutic alternatives to destroy glioma cells in vitro and trigger tumor destruction in vivo. Some clinical trials are exploring the use of this therapy as an alternative were other approaches provide limited hope.

During last decades multiple therapeutic approaches have been explored for improved management of peritoneally disseminated malignancies – a grim condition known as peritoneal carcinomatosis (PC). Intraperitoneal administration can be used to achieve elevated local concentration and extended half-life of the drugs in the peritoneal cavity to improve their anticancer efficacy. However, IP-administered chemotherapeutics have a short residence time in the IP space, and are not tumor selective. An increasing body of work suggests that functionalization of drugs and nanoparticles with targeting peptides increases their peritoneal retention and provides a robust and specific tumor binding and penetration that translates into improved therapeutic response. Here we review a progress in affinity targeting of intraperitoneal anticancer compounds, imaging agents and nanoparticles with tumor homing peptides. We review classes of tumor homing peptides relevant for PC targeting, payloads for peptide-guided precision delivery, applications for targeted compounds and the effects of nanoformulation of drugs and imaging agents on affinity-based tumor delivery.

Background and objectives: Primary brain tumors include any tumors arising in the brain whose prognosis is poor due to their histologic characteristics. The aim of this research was to evaluate the frequency of HER2 tumor marker in primary malignant brain tumors. Materials and Methods: This descriptive study was conducted on the samples admitted to the pathology laboratory with diagnosis of primary brain tumor during 2008–2015. Results: From among 107 patients (61.7% males and the rest females) with mean age of 40.4 years, the highest frequency of tumor location was in supratentorial region of the brain (including lobes and ventricles) (63.85% cases). High-grade astrocytoma had the highest prevalence at diagnosis (43.9%), followed by low-grade astrocytoma (37.4%). As for HER2 score, 42.1% of patients were HER2-positive (scores 2 & 3). On the other hand, 5.6% of patients were HER2-negative (-), 40.2% were positive (+), and 54.2% were positive (++). The patients with high-grade astrocytoma had older age (P < 0.001), higher HER2 positivity (P = 0.024) and percentage (P < 0.001) compared to the patients with low-grade astrocytoma. Conclusions: HER2 expression is dependent on the type of brain tumors. High expression of HER2 in high-grade astrocytoma may be useful for therapeutic purposes. The future research is needed to confirm these results with a large number of patients in different areas.

In this paper, a kind of single-walled carbon nanotube nonlinear model is developed, and the strongly nonlinear dynamic characteristics of such carbon nanotubes subjected to random magnetic field are studied. The nonlocal effect of microstructure is considered based on the theory of nonlocal elasticity. The natural frequency of the strongly nonlinear dynamic system is obtained by the energy function method, the drift coefficient and the diffusion coefficient are verified. The stationary probability density function of the system dynamic response is given and the fractal boundary of the safe basin is provided. Theoretical analysis and numerical simulation show that stochastic resonance occurs when varying the random magnetic field intensity. The boundary of safe basin has fractal characteristics and the area of safe basin decreases when the intensity of the magnetic field permeability increases.

Multiple myeloma (MM) is a genetically heterogenous disease that includes a subgroup of 10-15% of patients facing dismal survival despite most intensive treatment. The aim of this review article is to provide an integrated clinical and biological overview on the high-risk MM discussing the novel therapeutic perspectives aimed to target the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug resistance can foster a better tailored clinical management of high-risk profile and refractoriness to therapy. Among the current clinical difficulties in MM, patient’s management manipulating the tumor niche represents a major challenge given the limited knowledge about the MM-milieu interaction. The angiogenesis and bystander infiltrate constitute pivotal mechanisms of mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy but variable and unpredictable responses in high-risk MM. Therefore, it would be worth to better select the population and the MM stage that could profit to a dual immune/vasculogenesis targeting. The comprehensive knowledge of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Despite significant improvements in the biology knowledge, MM is still a chronic and incurable neoplasia and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. Here, we corroborate previous biological findings providing a synthetic outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better personalize the patient-oriented clinical management.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

We review the basics of nuclear binding energy scheme assumed to be associated with the existence of a new strong elementary charge associated with square root of reciprocal of the strong coupling constant.

In the present study, we have systematically examined the clinical significance of Nectin-4 (encoded by the PVRL-4 gene), a marker for breast cancer stem cells (CSCs), in cancer metastasis and angiogenesis using a variety of human specimens, including invasive duct carcinoma (IDC) with multiple grades, several types of primary tumors to local and distant relapses, lymph node metastases and circulating tumor cells (CTCs). Nectin-4 was overexpressed in more than 92% of samples with 65.2% Nectin-4 positive cells. The level of expression was increased with increasing tumor grade (GI-III) and size (T1-4) of IDC specimens. More induction of Nectin-4 was noted in relapsed samples from a variety of tumors (colon, tongue, liver, kidney, ovary, buccal mucosa) in comparison to primary tumors, while paired adjacent normal tissues do not express any Nectin-4. A high expression of Nectin-4 along with other representative markers in CTCs and lymph node metastasis was also observed in cancer specimens. An increased level of Nectin-4 along with representative metastatic (CD-44, Sca1, ALDH1, Nanog) and angiogenic (Ang-I, Ang-II, VEGF) markers was noted in metastatic tumors (local and distant) in comparison to primary tumors that were correlated with different grades of tumor progression. In addition, greater expression of Nectin-4 was observed in secondary tumors (distant metastasis, e.g., breast to liver or stomach to gallbladder) in comparison to primary tumors. Nectin-4 was overexpressed at all stages of metastasis and angiogenesis, thus appearing to play a major role in tumor relapse through the PI3K-Akt-NFκβ pathway.

Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking, chemo and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood brain barrier, immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to 1) optimize delivery of oncolytic viruses beyond the blood brain barrier; 2) trigger inflammatory immune responses in and around tumors; and 3) use of multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.

Tumor dormancy, a clinically undetectable state of cancer, makes a major contribution to the development of multidrug resistance (MDR), minimum residual disease (MRD), tumor outgrowth, cancer relapse, and metastasis. Despite its high incidence, the whole picture of dormancy-regulated molecular programs is far from clear. That is, it is unknown when and which dormant cells will resume proliferation causing late relapse, and which will remain asymptomatic and harmless to their hosts. Thus, identification of dormancy-related culprits and understanding their roles can help predict cancer prognosis and may increase the probability of a timely therapeutic intervention for the desired outcome. Here, we provide a comprehensive review of the dormancy-dictated molecular mechanisms, including an angiogenic switch, immune escape, cancer stem cells, extra cellular matrix (ECM) remodeling, metabolic reprogramming, miRNAs, epigenetic modifications, and stress-induced-p38 signaling pathways. Further, we analyze the possibility of leveraging these dormancy-related molecular cues to outmaneuver cancer, and discuss the implications of such approaches in cancer treatment.

Deep learning has shown remarkable results in every field, especially in the biomedical field, due to its ability to exploit large-scale datasets. A convolutional neural network (CNN) is a widely used deep learning approach to solve medical imaging problems. Over the past few years, many studies have focused on CNN-based techniques for brain tumor diagnosis. There are, however, still some critical challenges that CNNs face towards clinic application. This study presents a comprehensive review of current literature that involves CNN architectures for brain tumor classification. We compare the key achievements in the performance evaluation metrics of the applied classification algorithms. In addition, this review assesses the clinical effectiveness of the included studies to elaborate on the limitations and directions of this area for future work. No review focusing on the clinical effectiveness of previous works in this field has been published. We believe that this study has the potential to elevate the application of CNN-based deep learning methods in clinical practice and also can be a quick reference for biomedical researchers who are interested in this field.

Three-dimensional (3D) cell culture systems can be regarded as suitable platforms to bridge the huge gap between animal studies and two-dimensional (2D) monolayer cell culture to study chronic diseases such as cancer. In particular, the preclinical platforms for multicellular spheroid formation and culture can be regarded as ideal in vitro tumor models. The complex tumor microenvironment such as hypoxic region and necrotic core can be recapitulated in 3D spheroid configuration. Cells aggregated in spheroid structures can better illustrate the performance of anti-cancer drugs as well. Various methods have been proposed so far to create such 3D spheroid aggregations. Both conventional techniques and microfluidic methods can be used for generation of multicellular spheroids. In this review paper, we first discuss various spheroid formation phases. Then, the conventional spheroid formation techniques such as bioreactor flasks, liquid overlay and hanging droplet technique are explained. Next, a particular topic of the hydrogel in spheroid formation and culture is explored. This topic has received less attention in the literature. Hydrogels entail some advantages to the spheroid formation and culture such as size uniformity, the formation of porous spheroids or hetero-spheroids as well as chemosensitivity and invasion assays and protecting from shear stress. Finally, microfluidic methods for spheroid formation and culture are briefly reviewed.

This paper is a mini literature review about electromagnetic field’s effects on cells, tissues and new treatment modalities. We have reviewed a papers which have been published in high quality journals in the last 5 years as two authors. This review’s aim is to be a resource for experimental studies about electricity’s effects on cell biology and pathophysiology. As a result of this literature review, we found that especially extremely low electric frequency and intermediate frequency fields have very important pathophysiological effects. We have mentioned four important expressions on this subject; electroporation, electrofusion, electrochemotherapy, gene electrotransference. Two different new treatment approaches have been developed by use of these two important electrical waves. First is tumor treating fields and the other is pulsed electric fields. Most studies in literature have been done with extremely low frequency and pulsed electric fields. In terms of diseases, most studies are about glioblastoma multiforme and malign melanoma.Most studies in literature have been done with extremely low frequency and pulsed electric fields. In terms of diseases, most studies are about glioblastoma and melanoma.

Cyclin E2, a member of the cyclin family, is a key cell cycle-related protein. This protein plays essential roles in cancer progression, and as such, an inhibitor of cyclin E2 has been approved to treat several types of cancers. Even so, mechanisms underlying how to regulate cyclin E2 expression in cancer remain largely unknown. The current study found that miR-3687 is up-regulated in clinical bladder cancer (BC) tumor tissues, TCGA database and human BC cell lines. Inhibition of miR-3687 expression significantly reduces human BC cell proliferation in vitro and tumor growth in vivo, which are concurrently with the induction of G0/G1 cell cycle arrest and downregulation of cyclin E2 protein expression. Interestingly, overexpression of cyclin E2 reversed the inhibition of BC proliferation induced by miR-3687. Mechanistic studies suggest that miR-3687 could bind to the 3'-UTR of foxp1 mRNA, downregulates FOXP1 protein expression, and in turn promotes the transcription of cyclin E2, thereby promoting the growth of BC cells. Collectively, the current study not only establishes a novel regulatory axis of miR-3687/FOXP1 in regard to regulation of cyclin E2 expression in BC cells, but also provides strong suggestive evidence that miR-3687 and FOXP1 may be potentially promising targets in therapeutic strategies of human BC.

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from serosal surface of abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within 3 years. The dismal survival makes DSRCT an orphan disease with urgent need of new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors have been evaluated in small studies. Recent works using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

The Internet of Things (IoT) has a growing presence in society's daily lives. These lightweight devices can be easily deployed and maintained, enabling extensive adoption in different environments. Furthermore, one of the most promising areas for using IoT devices is healthcare, comprising devices referred to as the Internet of Medical Things (IoMT). Several examples of healthcare services are supported by IoMT devices, e.g., continuous health monitoring. Conversely, there is an increasing concern with the cybersecurity aspects of these devices, and several attacks against IoT infrastructures have been launched in the past few years. These cybersecurity concerns also apply to healthcare applications, where the tradeoff between the benefits and security of IoMT devices must be observed. Given the complexity and amount of data IoMT network traffic generates, advanced methods become especially useful in these environments. Although Machine Learning (ML) brings various techniques and solutions to improve cyberattack detection, prevention, and mitigation, essential features are not addressed in the current state-of-the-art benchmark dataset contributions. Thereupon, the main goal of this research is to propose a realistic benchmark dataset to enable the development and evaluation of IoMT security solutions. In order to accomplish this, 18 attacks were executed against an IoMT testbed composed of 40 IoMT devices (25 real devices and 15 simulated devices), considering the plurality of protocols used in healthcare (e.g., Wi-Fi, MQTT, and Bluetooth). These attacks are categorized into five classes: DDoS, DoS, Recon, MQTT, and spoofing. This effort aims to establish a baseline complementary to the state-of-the-art contributions. The outcome supports researchers in investigating and developing new solutions to make healthcare systems more secure using different mechanisms (e.g., machine learning - ML). This research goes beyond merely conducting attacks on IoMT devices. We also attempt to capture the lifecycle of these devices in different vital phases, from the moment they join the network until they leave, which is called profiling. Profiling allows the different classifiers to identify anomalies of each device individually in the healthcare network. The CICIoMT2024 dataset has been published on CIC's dataset page, making it available for other researchers to use.

It is estimated that pancreatic cancer will be the 2^nd leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options in this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are incompletely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, poor antigenicity, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

Novel mechanism of ccRCC progression is essential, including PBRM1, BAP1, and SETD2 in histone-modifying and chromatin remodeling genes. The study aimed to investigate VHL, PD-1, PD-L1, PD-L2. BAP1, PBRM1, SETD2 expression in ccRCC primary cancers and metastatic tissues associated with the cancer dissemination. A total of 62 patients with RCC were enrolled in the study. Investigation of mRNA level of VHL, PD-1, PD-L1, PD-L2. PCR in real-time performed BAP1, PBRM1, SETD2 with the previous RNA isolation. Western Blotting analysis was used for detecting the p-VHL protein content in tissues. The VHL expression and p-VHL content determined the aggressive cancer behavior and elevated in disseminated tumors. The cancer dissemination was accompanied by an increase in both mRNA and VHL content. The PD-L2 prevalence in metastatic cancers is crucial in tumor progression. ccRCC progression in VHL overexpression is associated with the decrease in BAP1 gene expression. It is revealed the heterogeneity in molecular markers in primary tumors and metastases. The low mRNA level of BAP1, PBRM1, SETD2, PD-1, PD-L1, PD-L2 in metastases compared with primary tumors were found. We show a novel mechanism for VHL tumor progression and present a new instrument and factor targeting tumor-related pathologies with p-VHL/HIF altered function.

Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and T10 vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, IL-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL6, CSF3, and IL8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these up-regulated genes, IL8 expression in NSCLC tissues was associated with worse prognosis and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes.

Sporadic colorectal cancer (CRC) develops through distinct molecular events. Loss of 18q chromosome is a conspicuous event in the progression of adenoma to carcinoma. There is limited information regarding the molecular effectors of this event. Earlier, we had reported ATP8B1 as a novel gene associated with CRC. ATP8B1 belongs to the family of P-type ATPases (P4 ATPase) that primarily function to facilitate the translocation of phospholipids. In this study, we attempt to implicate ATP8B1 gene located on chromosome 18q as a tumor suppressor gene. We studied indigenous patient data and confirmed the reduced expression of ATP8B1 in tumor samples. CRC cell lines were engineered with reduced and enhanced levels of ATP8B1 which provided a tool to study its role on cancer progression. Forced reduction of ATP8B1 expression either by CRISPR/Cas9 or shRNA was associated with increased growth and proliferation of CRC cell line - HT29. In contrast, overexpression of ATP8B1 resulted in reduced growth and proliferation of SW480 cell line. We generated a network of genes that are downstream of ATP8B1. Further, we provide predicted effect of modulation of ATP8B1 levels on this network and possible effect on fatty acid metabolism related genes. These results provide evidence in support of ATP8B1 being a tumor suppressor that may affect fatty acid metabolism in CRC.

This article presents a study on brain tumor detection using the VGG-16 model, a convolutional neural network known for its performance in computer vision tasks. The aim of the study is to classify magnetic resonance imaging (MRI) images and accurately identify the presence of brain tumors. The dataset used consists of brain tumor MRI images, categorized into two classes: "NO" (no tumor) and "YES" (tumor). The methodology involves setting up the environment, importing and preprocessing the data, building the VGG-16 model, and evaluating its performance using metrics such as accuracy, precision, and recall. The results demonstrate an accuracy of approximately 88% on the validation set and 80% on the test set, indicating the potential of the VGG-16 model in supporting healthcare professionals in diagnosing brain tumors. The study contributes to the field of medical image analysis and offers insights into the application of deep learning for brain tumor detection.

(1) Background: The present study was carried out to provide new information about the relation between angiogenesis, tumor stage Oral squamous cell carcinoma (OSCC); (2) Materials and methods: Thirty formalin-fixed paraffin embedded blocks were used, 10 of them were previously diagnosed as well differentiated OSCC, 10 moderate differentiated OSCC and 10 poorly differentiated OSCC. To determine the expression of CD31 and D2-40 proteins, streptavidin-biotin immunoperoxidase staining technique was used. The areas with the most vascular density (hot spots) were determined. The stained vessels were counted independently in intratumoral and peritumoral stroma in five areas of hot spot at ×400 magnification; (3) Results: Immunohistochemical staining using CD 31 protein showed that CD31-positive vessels in the peritumoral and intratumoral stroma subjacent to the malignant invading nests which was recorded highest values in poor differentiated OSSC followed by moderate differentiated OSSC then well differentiated OSSC. D2-40 expression was positive in lymphatic vessel in the peritumoral and intratumoral stroma subjacent to the malignant invading nests. Poorly differentiated OSSC tissue sections recorded the highest vessels count followed by moderate differentiated OSSC then well differentiated OSSC. There was statistically significant difference found between the three studied groups regarding CD31 and D2-40 levels. Also there was statistically significant positive correlation found between CD31 level and D2-40 level and vice versa; (4) Conclusion: CD31 and D2-40 are related to stage of OSCC and are consistent with angiogenesis in tumor progression.

Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. The molecular mechanisms underlying such plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment. In this review, we discuss the recent developments in understanding CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity with implications in improving existing therapeutic approaches.

Over the last decades, cellular immunotherapy has revealed its curative potential. However, the inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes, in addition to the various strategies put in place to circumvent these effects. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer are discussed. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features is key to the development of improved cellular immunotherapies.

Exosomes are nano-sized extracellular vesicles excreted by mammalian cells that circulate freely in the bloodstream of living organisms. Exosomes have a lipid bilayer that encloses genetic material used in intracellular communication (e.g., double-stranded DNA, micro-RNAs, and messenger RNA). Recent evidence suggests that dysregulation of this genetic content within exosomes has a major role in tumor progression and in the surrounding microenvironment. Motivated by this discovery, we focused here on using exosomal biomarkers as a diagnostic and prognostic tool for cancer. In this review, we discuss recently discovered exosome-derived proteomic and genetic biomarkers used in cancer diagnosis and prognosis. Although several genetic biomarkers have been validated for their diagnostic values, proteomic biomarkers are still being actively pursued. We discuss both commercial technologies and emerging technologies for exosome isolation and analysis.

In this brief communication, we propose the concept that capillary regression may represent a primary pathogenic process underlying COVID-19 infection, particularly in the serious and life-threatening manifestations of the disease. We suggest that the marked elevations of pro-inflammatory mediators that are observed in these seriously ill patients may directly induce capillary regression and endothelial cell (EC) loss. Recent autopsy studies are demonstrating EC loss leading to widespread microthrombi and associated tissue damage. Recent work has indicated that interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNFα), and thrombin, individually and in combination, can potently cause capillary tube regression in experimental models in vitro and in vivo. Other pro-inflammatory mediators including interferon gamma (IFNγ), interleukin-4 (IL-4), and interleukin-13 (IL-13) were also shown to be pro-regressive and could be relevant mediators in COVID-19 patients. Interestingly, combinations of pharmacologic agents were identified that reduced capillary regression and protected capillary tube networks against these pro-inflammatory mediators. Such an approach might be an important therapeutic option going forward to treat key disease states where capillary regression plays a major underlying pathogenic role. Finally, if capillary regression is occurring in response to these pro-inflammatory mediators during COVID-19 infection, we suggest that combinations of blocking agents directed to these key pro-regressive mediators might be necessary to appropriately treat patients.

Colonization of distant organs by tumor cells is a critical step of cancer progression. The initial avascular stage of this process (micrometastasis) remains almost inaccessible to study due to the lack of relevant experimental approaches. Here, we introduce an in vitro/in vivo model of organ-specific micrometastases of triple-negative breast cancer (TNBC) that is fully implemented in a cost-efficient chick embryo (CE) experimental platform. The model is built as three-dimensional (3D) tissue engineering constructs (TECs) combining human MDA-MB-231 cells and decellular-ized CE organ-specific scaffolds. TNBC cells colonized CE organ-specific scaffolds in 2-3 weeks, forming tissue-like structures. The feasibility of this methodology for basic cancer research, drug development and nanomedicine was demonstrated on a model of hepatic micrometastasis of TNBC. We revealed that MDA-MB-231 differentially colonize parenchymal and stromal com-partments of the liver-specific extracellular matrix (LS-ECM) and become more resistant to the treatment with molecular Doxorubicin (Dox) and Dox-loaded mesoporous silica nanoparticles than in monolayer cultures. When grafted on CE chorioallantoic membrane, LS-ECM-based TECs induced angiogenic switch. These findings may have important implications for the diag-nosis and treatment of TNBC. The methodology established here is scalable and adaptable for pharmacological testing and cancer biology research of various metastatic and primary tumors.

There are many theories of carcinogenesis arguing against the orthodox mutation theory, debating on such as “epigenetic alteration” that is inheritable and yet, theoretically, reversible. Our integrated theory describes that any extracellular, intracellular, or intranuclear stressors, mutagenic or not, can initiate a lengthy tumorigenesis to engender a benign or malignant tumor, but the aberrations directly establishing cellular immortality and autonomy may be epigenetic or genetic alterations in the genomic DNA. A neoplasm is considered a semi-new organism with autonomy; it therefore should have genetic mutations to be “new”. We may be able to direct cancer cells towards differentiation as a remedy, because the extracellular milieu may control the phenotype of a cell and the tissue or organ made of the cell’s progenies, and the cytoplasm of a cell may override the nucleus in the phenotypic control. However, the nucleus retains the capacity to manifest itself if allowed by the microenvironment, which then allows the already reversed cells to revert back to tumor cells again. Neoplasms are malignant if they bear epigenetic or genetic anomalies in mutator genes defined as those whose alterations allow or accelerate alterations to occur in other genes, whereas neoplasms are benign if they bear epigenetic or genetic aberrations only in non-mutator genes. It is imperative to identify the immediate tumor-causing cellular alterations defined as those directly responsible for immortality and autonomy, and for treatment purposes to identify the extracellular and intracellular factors that control the phenotype of cancer cells.

The interaction of electrons with strong laser fields is usually treated with semiclassical theory, where the laser is represented by an external field. There are analytic solutions for the free electron wave functions, which incorporate the interaction with the laser field exactly, but the joint effect of the atomic binding potential presents an obstacle for the analysis. Moreover, the radiation is a dynamical system, the number of photons changes during the interactions. Thus, it is legitimate to ask how can one treat the high order processes nonperturbatively, in such a way that the electron-atom interaction and the quantized nature of radiation be simultaneously taken into account? An analytic method is proposed to answer this question in the framework of nonrelativistic quantum electrodynamics. As an application, a quantum optical generalization of the strong-field Kramers-Heisenberg formula is derived for describing high-harmonic generation. Our formalism is suitable to analyse, among various quantal effects, the possible role of arbitrary photon statistics of the incoming field. The present paper is dedicated to the memory of Prof. Dr. Fritz Ehlotzky, who had significantly contributed to the theory of strong-field phenomena over many decades.

Extracellular vesicles (EVs), such as exosomes or oncosomes are released with molecules unfavorable for survival from cells. In addition, accumulating evidence has shown that tumor cells often eject anti-cancer drugs such as chemotherapeutics and targeted drugs within EVs, a novel mechanism of drug resistance. The EV-releasing, drug resistance phenotype is often coupled with cellular dedifferentiation and transformation, cells undergoing epithelial-mesenchymal transition (EMT) and taking on a cancer stem cell phenotype. Recent studies have shown that the release of EVs is also involved in immunosuppression. The concept of the resistance-associated secretory phenotype (RASP) is reviewed herein.

Conventional radiation therapy uses white X-rays that consist of a mixture of X-ray waves with various energy levels. In contrast, a monochromatic X-ray (monoenergetic X-ray) has a single energy level. Irradiation of high Z elements with a synchrotron generated monochromatic X-ray with the energy at or higher than the K-edge energy of the element results in the production of the Auger electrons that cause DNA damage leading to cell killing. Delivery of high Z elements into cancer cells and tumor mass can be facilitated by the use of nanoparticles. Mesoporous silica nanoparticles (MSNs) have been shown to be effective in delivering high Z elements to cancer cells. A proof of principle experiment was reported that demonstrated the feasibility of this approach. This opens up a possibility to pursue the Auger cancer therapy by the combined use of MSNs loaded with high Z elements and monochromatic X-rays. Similar cancer therapies using other types of quantum beams such as neutron, proton and carbon ion beams can be envisioned.

Alphaviruses, flaviviruses, measles viruses and rhabdoviruses are enveloped single-stranded RNA viruses, which have been engineered as expression vector systems for recombinant protein expression and vaccine development. Due to the presence of non-structural genes encoding the replicase complex, a 200,000-fold amplification of viral RNA occurs in the cytoplasm of infected cells providing extreme transgene expression levels, which is why they are named self-replicating RNA viruses. Expression of surface proteins of pathogens causing infectious disease and tumor antigens provide the basis for vaccine development against infectious diseases and cancer. The self-replicating RNA viral vectors can be administered as replicon RNA, recombinant viral particles, or layered DNA/RNA replicons. Self-replicating RNA viral vectors have been applied for vaccine development against influenza virus, HIV, hepatitis B virus, human papilloma virus, Ebola virus and recently coronaviruses, especially SARS-CoV-2 the causative agent of the COVID-19 pandemic. Measles virus and rhabdovirus vector-based SARS-CoV-2 vaccine candidates have been subjected to clinical trials. Moreover, RNA vaccine candidates based on self-amplifying alphaviruses have also been evaluated in clinical settings. Various cancers such as brain, breast, lung, ovarian, prostate cancer and melanoma have also been targeted for vaccine development. Robust immune responses and protection have been demonstrated in animal models. Clinical trials have shown good safety and target-specific immune responses. Ervebo, the VSV-based vaccine against Ebola virus disease has been approved for human use.

Pseudopterosin, produced by the sea whip of the genus Antillogorgia, possesses a variety of promising biological activities including potent anti-inflammatory effects. However, few studies examined pseudopterosin in the treatment of cancer cells and, to our knowledge, the ability to inhibit triple negative breast cancer (TNBC) proliferation or invasion has not been explored. Thus, we evaluated the as yet unknown mechanism of action of pseudopterosin: Pseudopterosin was able to inhibit proliferation of TNBC. Interestingly, analyzing breast cancer cell proliferation after knocking down glucocorticoid receptor α (GRα) revealed that anti-proliferative effects of pseudopterosin were significantly inhibited when GRα expression was reduced. Furthermore, pseudopterosin inhibited invasion of MDA-MB-231 3D tumor spheroids embedded in an extracellular-like matrix. Remarkably, the knockdown of GRα in 3D tumor spheroids revealed increased ability of cells to invade the surrounding matrix. In a co-culture, encompassing peripheral blood mononuclear cells (PBMC) and MDA-MB-231 cells, production of interleukin 6 (IL-6) and interleukin 8 (IL-8) significantly increased compared to monoculture. Notably, pseudopterosin proved to block cytokine elevation, representing key players in tumor progression, in the co-culture. Thus, our results reveal pseudopterosin treatment as a potential novel approach in TNBC therapy.

Background: PRAME, NY-ESO-1 and SSX2 are cancer testis antigens (CTAs), which in normal tissues are expressed in testicular germ cells with re-expression in numerous cancer types. Their ability to elicit humoral and cellular immune responses have rendered them promising targets for cancer immunotherapy, but they have never been studied in a large and well-characterized cohort soft tissue sarcomas (STS). Methods: On protein level, we examined PRAME, NY-ESO-1 and SSX2 expression in tumour tissues of 249 STS using immunohistochemistry. We correlated expression levels with clinicopathological parameters including Tumour-infiltrating lymphocyte (TIL) counts, grading and long- term survival. Results: Expression of PRAME, NY-ESO-1 and SSX2 was observed in 25 (10%), 19 (8%), and 11 (4%) of 249 specimens with distinct patterns for histo subtypes. Expression of PRAME was associated with shorter patient survival (p=0.005) and higher grade (G2 vs G3, p=0.001) while NY-ESO-1 expression was correlated with more favourable survival (p=0.037) and low grade (G2 vs G3, p=0.029). Both PRAME and NY-ESO-1 expression was more frequent in STS with low TILs counts. Conclusions: CTAs PRAME, NY-ESO-1 and SSX2 show distinct expression patterns in different STS subtypes. These results may guide future immunotherapeutic approaches in STS.

There exists an implicit potential limitation in every physical discoveries that has been implemented and understood. However, the limitations can be bounded within a safe limit to prevent any constructing theory to be free from errors. As, it’s the inert nature of the humans, to go far beyond the scope of experimental findings in order to pursue any studies with the sole help of logical reasoning and mathematics, the argument can be prevailed in the form of WEAK Clampdown Effect & STRONG Clampdown Effect. More, the theories are constructed out of physical nature, more the theory gets hypothetical without any finding evidence, but that does or doesn’t actually justify the phenomenon, that too with the more increment of KARDASHEV Scale, more moderate ways of experimentation got developed curbing down the limitations within the human limit of ‘ERRORS’, that does can be neglected by approximation. Relationship being cross-judgmental on the basis of the computational limits and calculation accuracy, leading to a soft singularity, as a warning, that if computer powers cannot be checked on the basis of error approximations, then this may lead to the hitting of a hard singularity, that in phase with the forbidden gap (or after the optimum limit that arises at the core constraints of nature) to prevent the computation being carried off with respect to super-intelligence machines that are cognitive capability oriented future computers responsible for self growth & reproduction with more improvement algorithm, restricting all forms of humanity & constraints the human growth by virtue of limiting capacities of the humans as compared to computers.

We present simple relations for nuclear stability and nuclear binding energy with respect to three gravitational constants associated with electroweak, strong and electromagnetic interactions.

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.

Although pancreatic neuroendocrine neoplasms (PNENs) are relatively rare tumors, their number is increasing with advances in diagnostic imaging modalities. Even small lesions that are difficult to detect using computed tomography or magnetic resonance imaging can be detected with endoscopic ultrasound (EUS). Contrast-enhanced EUS is useful, and not only diagnosis but also malignancy detection have become possible by evaluating the vascularity of tumors. Pathological diagnosis using EUS with fine-needle aspiration (EUS-FNA) is useful when diagnostic imaging is difficult. EUS-FNA can also evaluate the grade of malignancy. Pooling the data of the studies which compared the PNENs grading between EUS-FNA samples and surgical specimen, the concordance rate was 77.5% (κ-statistic: 0.65, 95% confidence interval = 0.59 - 0.71, P< 0.01). EUS is a particularly important modality for the treatment of PNENs.

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed-Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They are invisible to antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation, and “educate” (i.e., reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies, targeting not only tumor cells but also the tumor microenvironment, are being developed. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become protective or immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

During the progression from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), cells have to overcome the physically restraining basement membrane (BM) which compartmentalizes the epithelium from the stroma. Since the extracellular matrix (ECM) of the epithelial and stromal compartment is biochemically and physically distinct from one another, the progression demands a certain degree of cellular plasticity being essentially required for a primary tumor to become invasive. The Epithelial-to-Mesenchymal Transition depicts such a cell program equipping cancer cells with features allowing for dissemination from the epithelial entity and stromal invasion on the single-cell level. Here, we investigated the reciprocal interference between an altering tumor microenvironment and the EMT-phenotype in vitro. BM-typical collagen IV and stroma-typical collagen I coatings were applied as provisional 2-D matrices. Pro-inflammatory growth factors were introduced to improve tissue mimicry. Whereas the growth on coated surfaces did only slightly affect the EMT-phenotype, the combinatorial action of collagen with growth factor TGF-β1 induced prominent phenotypic changes. However, the EMT-induction was independent of the collagen type and cellular accessibility for EMT-like changes was strongly cell line dependent. Summarizing the entire body of data, we computed an EMT-phenotyping model that was used to decide on cellular EMT-status and estimate EMT-like changes. We confirmed that miR200c-mediated reversion of mesenchymal MDA-MB-231 cells is reflected by our EMT-phenotype model emphasizing its potential to predict the therapeutic efficacy of EMT-targeting drugs in the future.

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.

Cancer immunotherapy reaches a remarkable achievement in various cancer types and brings new possibilities to improve cancer patients’ long-term survival. However, outcomes vary from case to case, and the present protocol benefits a small fraction of patients. One notable factor is the tumor microenvironment, especially the immune cell components, that may reflect the immune response's status quo on site. Thus, understanding the content of infiltrating immune cells in tumors is not only for research interesting but also a crucial subject toward precision medicine. We implement an algorithm for resolving relative proportions of twenty-one immune cell subclasses from a human tissue profiled transcriptome by microarray technology to reach the goal above. By selecting gene features and then adopting ?-Support Vector Regression, we can construct a deconvolution model and resolve the immune cell context. The excellent consistency between the estimated values and the correct immune-cell composition further demonstrates this approach provides a more natural alternative to revealing samples' immune cell content and reliable results like recent single-cell technologies. Based on this algorithm, the web-based deconvolution tool implemented named mySORT provides a user-friendly interface for estimating the immune cell content by uploading gene expression profiling. We also present comprehensive visualization 2D/3D plots in mySORT so that users can easily make a comparison between different samples. Finally, we synthesized pseudo-bulk expression data from single-cell transcriptomic datasets of 17 melanoma and 16 head and neck cancer patients. The deconvolution results of microarray-based data in the previous study and synthetic pseudo-bulk data all proved the excellent performance of mySORT. We believe that mySORT can help researchers in all fields easily understand complex immune microenvironment. The website of mySORT is freely accessible on https://symbiosis.iis.sinica.edu.tw/mySORT/.

Brain Tumor is one of the severe diseases and occurrence of this disease threats human life. Detection of brain tumor in advance can secure patient’s life from unwanted loss. Well-timed and swift disease detection and treatment strategy can lead to improved quality of life in these patients. This paper attempts to use Machine Learning based ensemble approaches for recognising patients with brain tumor. Ensemble technique based AdaBoost classifier and 10-fold stratified cross-validation method are assembled in single platform is proposed in this paper for prediction of brain tumor. This prediction is compared against three baseline classifiers such as Gradient Boost, Random Forest and Extra Trees classifier. Experimental result implies the superiority of this model with an accuracy of 98.97%, f1-score of 0.99, kappa statistics score of 0.95 and MSE of 0.0103.

With reference to our earlier published views on large nuclear gravitational constant , nuclear elementary charge and strong coupling constant , in this paper, we present simple relations for nuclear stability range, binding energy of isotopes and magic proton numbers.

Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage. Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy. Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in-depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.

Tumorigenesis is a complex biological phenomenon that includes extensive genetic and phenotypic heterogeneities and complicated regulatory mechanisms. In the recent few years, our studies demonstrate that tumor-initiating cells are similar to neural stem/progenitor cells in regulatory networks, tumorigenicity and pluripotent differentiation potential. In the review, I will make further discussion on these observations and propose a rule of cell biology by integrating these findings with evidence from developmental biology, tumor biology and evolution, which suggests that neural stemness underlies two coupled cell properties, tumorigenicity and pluripotent differentiation potential. Tumorigenicity and phenotypic heterogeneity in tumor is a result of acquirement of neural stemness in cells. The neural stemness property of tumor-initiating cells can hopefully integrate different concepts/hypotheses underlying tumorigenesis. Neural stem cells/neural progenitors and tumor-initiating cells share regulatory networks; both exhibit neural stemness, tumorigenicity and differentiation potential; both are dependent on expression or activation of ancestral genes (the atavistic effect); both rely primarily on aerobic glycolytic metabolism; both can differentiate into various cells or tissues that are derived from three germ layers, resembling severely disorganized or more severely degenerated process of embryonic development; both are enriched in long genes with more splice variants that provide more plastic scaffolds for cell differentiation, etc. The property of neural stemness might be a key point to understand tumorigenesis and pluripotent differentiation potential, and possibly explain certain pathological observations in tumors that have been inexplicable. Therefore, behind the complexity of tumorigenesis might be a general rule of cell biology, i.e., neural stemness represents the ground state of cell tumorigenicity and pluripotent differentiation potential.

Immunotherapy has gained great momentum with chimeric antigen receptor T cell (CAR-T) therapy, in which patient’s T lymphocytes are genetically manipulated to recognize tumor-specific antigens increasing tumor elimination efficiency. In the last years, CAR-T cell immunotherapy for hematological malignancies achieved a great response rate on patients and is a very promising therapy for several other malignancies. Each new CAR design requires a preclinical proof-of-concept experiment using immunodeficient mouse models. The absence of a functional immune system in these mice makes them simple and suitable to be mathematically modeled. In this work, we developed a three population mathematical model to describe tumor response to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for several phenomena, such as tumor-induced immunosuppression, memory pool formation, and conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual donor and tumor specificities were considered as uncertainties in the model parameters. Our model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly depends on some specific parameters such as the differentiation of effector to memory CAR-T cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In summary, our model can contribute to reduce and optimize the number of in vivo experiments with in silico tests to select specific scenarios that could be tested in experimental research. Such in silico laboratory was made available in a Shiny R-based platform called CARTmath. It is an open-source, easy to run simulator, available at github.com/tmglncc/CARTmath or directly on the webpage cartmath.lncc.br, containing this manuscript results as examples and documentation. The developed model, together with the CARTmath platform, provides potential use for assessing different CAR-T cell immunotherapy protocols and associated efficacy, becoming an accessory towards in silico trials.

Background: Tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). The dysfunctional TME promotes drug resistance, disease recurrence and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins and microRNAs. Results: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Co-culture of GAMs (and GAM derived exosomes) and GBM cell lines resulted in the increased GBM cells’ resistance against temozolomide (TMZ) by upregulating pro-survival gene, PDCD4 and stemness markers Sox2, STAT3, Nestin and miR-21-5p and increased M2 cytokines, IL-6 and TGF-β1 secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed markedly reduced ability to secret M2 cytokines and reduced miR-21 enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which tumor suppressor PDCD4 was targeted. We subsequently established a patient-derived xenograft models where mice bore patient GBM and GAMs. The treatment of pacritinib, and the combination of pacritinib/TMZ appeared to significantly reduce tumorigenesis of GBM/GAM PDX mice, overcome TMZ-resistance, and M2 polarization of GAMs. Conclusion: In summation, we showed that potential of pacritinib alone or in combination with TMZ for suppressing GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in the clinical settings.

Mechanical properties of tumor cytoskeleton are extremely vital for any phases of cancer, especially in tumor invasion and metastasis. However, in current category of anticancer drugs, the cytoskeleton-targeting drugs are limited and its role in tumor progression is unclear. Here, we present the mechanical characteristics of tumor stiffness are tightly regulated by cancer cytoskeleton including actin filaments and microtubule during tumor initiation, growth and metastasis, and review the natural drugs that target cancer cytoskeleton. We define cytoskeleton dynamics as target mechanisms for anticancer drug, and summary the plant, microbial and marine sources of natural products. Furthermore, the material approaches to active cancer mechanics are supplied in this review. We aim to promote the development of anticancer drugs that target tumor mechanics by using those material approaches in future and find its pharmacological application.

Recently, Mulroney,et.al., demonstrated that Pfizer’s ModRNA Covid vaccine, but not AstraZeneca Covid vaccine, produce aberrant foreign proteins in vivo due to reading frame shift in ribosomes. This phenomenon could elucidate the notable surge in autoimmune diseases following the administration of ModRNA vaccines compared to Influenza vaccines between 2020 and 2023, as found in the VAERS database. These findings bear significant implications for the future application of mRNA technology, emphasizing the necessity of modifying the design of the mRNA sequence to mitigate these defects. Remarkably, Mulroney and collaborators achieved a reduction in frame shift proteins by introducing additional edits to the mRNA sequences. This adjustment is pivotal for rectifying the flawed design of the ModRNA employed by Pfizer. In light of these findings, many advocate for the immediate recall and further investigation of these products. The notion of a "future mRNA-based therapy" should be postponed indefinitely.

The Particulate Matter (PM), particles of variable but small diameter could penetrate the respiratory system via inhalation, causing respiratory and/or cardiovascular diseases. This study aims to evaluate the association of environmental particulate matter (PM2.5) and black carbon (BC) with respiratory health and physical activity in users traveling by transportation modes over four roads in Bogotá. This was a mixed-method study, in 300 healthy participants, based on a convergent parallel design. Including a descriptive qualitative component focused on asserting the individual perception of air pollution by semi-structured interviews and a cross-sectional study measuring the individual exposure to PM2.5 and BC to evaluate the pulmonary function by spirometry. The analysis included concurrent triangulation and a Poisson regression. This study provides integration of air pollution exposure variables and respiratory health effects in different transport microenvironments. To our knowledge, this is the first mixed-methods study focused on PM2.5, BC, and respiratory health effects in a city above 2.000 meters above sea level.

β₂-m, β₂-microglobulin; CAF, cancer associated fibroblast; CSC, cancer stem cell; CTL, cytotoxic T lymphocyte; DC, dendritic cell; ECM, extracellular matrix; EGF-R, epidermal growth factor receptor; ER, endoplasmic reticulum; FDA, Food and Drug Administration; HLA, human leukocyte antigen; HNSCC, head and neck squamous cell carcinoma; HPV, human papilloma virus; ICP immune checkpoint; ICPi, immune checkpoint inhibitor; IFN, interferon; LMP, low molecular weight protein; mAb, monoclonal antibody; MDSC, myeloid-derived suppressor cell; mTOR, mammalian target of rapamycin; MSI, multispectral imaging; NK, natural killer; OS, overall survival; PBL, peripheral blood lymphocytes; PBMNC, peripheral blood mononuclear cells; PD1, programmed death receptor 1; PD-L1, programmed death ligand 1; PFS, progression-free survival; PI3K, phosphatidyl-linositol-3-kinase; R/M, recurrence and or metastatic; STAT, signal transducer and activator of transcription; TAA, tumor-associated antigen; TAM, tumor associated macrophages; TAP, transporter associated with antigen processing; TCR, T cell receptor; TIL, tumor-infiltrating lymphocyte; TLS, tertiary lymphoid structure; TME, tumor microenvironment; Treg, regulatory T cell; TSA, tumor-specific antigen; VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor.

At present more than 9 million people die of cancer every year. Simple and broad-spectrum drugs are still an urgent need for cancer patients. Recently, we proposed a new hypothesis that intracellular osmotic pressure (IOP) is the driving force of cell division, and abnormal tumor proliferation is the result of uncontrolled IOP in cells. On the one hand, aneuploidy and abnormal function of Na⁺/K⁺ pump lead to a faster rise of IOP in tumor cell than normal cells, on the other hand, abnormality of cytoskeleton assembly leads to the decrease of tolerance limit of cell membrane (TLCM) of tumor cells for resisting IOP. This hypothesis predicts: 1)Tumor cells were more intolerant to hypotonic stress than normal cells. 2) Maligancies may be sellectively killed by a suddenn increase of IOP and combined with decrease of the TLCM of tumors. Na⁺/K⁺ pump inhibitors can promotely increase the IOP of tumor cells and cytoskeleton inhibitors can dramatically lower the TLCM of tumor cells. Therefore, Na⁺/K⁺ pump and cytoskeleton inhibitors may have a synergetic effect to kill tumor cells. 3) Molecules regulating cell osmolality may be new targets for cancer treatment.

Circulating tumor DNA (ctDNA), the tumor-derived cell-free DNA fragments in the bloodstream carrying tumor-specific genetic and epigenetic alterations, represents an emerging novel tool for minimal residual disease (MRD) assessment in patients with resected colorectal cancer (CRC). For many decades, precise risk-stratification following curative-intent colorectal surgery has remained an enduring challenge. The current risk stratification strategy relies on clinicopathologic characteristics of the tumors that lacks precision and results in over-and undertreatment in a significant proportion of patients. Consequently, a biomarker that can reliably identify patients harboring MRD would be of critical importance in refining patient selection for adjuvant therapy. Several prospective cohort studies have provided compelling data suggesting that ctDNA could be a robust biomarker for MRD that outperforms all existing clinicopathologic criteria. Numerous clinical trials are currently underway to validate the ctDNA-guided MRD assessment and adjuvant treatment strategies. Once validated, the ctDNA technology will likely transform the adjuvant therapy paradigm of colorectal cancer, supporting ctDNA-guided treatment escalation and de-escalation. The current article presents a comprehensive overview of the published studies supporting the utility of ctDNA for MRD assessment in patients with CRC. We also discuss ongoing ctDNA-guided adjuvant clinical trials that will likely shape future adjuvant therapy strategies for patients with CRC.

Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.

Per- and polyfluoroalkyl substances (PFAS), a large group of developing contaminants, have recently become the subject of increased concern due to their potentially hazardous effects. They are classified as poisonous substances that can be found in a variety of aquatic situations. The widespread usage of PFAS across numerous industries has resulted in a high environmental and biological accumulation of the substance. Identification and elimination of PFAS from the environment is crucial since they are tenacious and have the potential to cause cancer. Traditional methods of PFAS content assessment, while useful in some cases, are often inadequate for continuing environmental control and monitoring. Within academia, there is a noticeable desire for rapid, cost-effective, durable, and readily transportable techniques targeted at detecting PFAS compounds in field settings. As a result, environmental labs and other governmental and non-governmental bodies may start testing more often as mandated by legislation. PFAS-detecting sensors, which offer an innovative solution that can be applied in situ and is affordable and simple to use, have emerged as a promising method for assessment based on the existing research. In addition, it may give administrators and users of water worldwide useful information they can use. This article provides a thorough summary of recent developments, limitations, and performance considerations in PFAS detection sensors. The Surface-enhanced Raman scattering (SERS) method has also been covered because of its excellent sensitivity and specificity for detecting pollutants, making it a potential solution for sensing PFAS. Intelligent sensing systems for PFAS detection should benefit from this research.

Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders, including coeliac disease (CD) and Crohn’s disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in tumour cell phenotype, frequency of microsatellite instability and nuclear β-catenin expression, as well as in prognosis. For these patients, high tumor-infiltrating lymphocyte density and glandular/medullary histotype represent independent positive prognostic factors. Dysplasia adjacent to SBC is rare and characterized by intestinal phenotype and nuclear β-catenin in CD, while it is frequent and typified by gastro-pancreatobiliary marker expression and preserved membranous β-catenin in CrD. Recent evidence suggests that Epstein-Barr virus-positive dysplasia and SBC, albeit exceptional, do exist and are associated with CrD. In this review we summarize the novel pathological and molecular insights of clinical and therapeutic interest to guide the care of CD-SBC and CrD-SBC.

About 50% of colorectal cancer patients develop liver metastases. Patients with metastatic colorectal cancer have 5-year survival rates below 20% despite new therapeutic regimens. Tumor heterogeneity has been linked with poor treatment response and clinical outcome, but was so far mainly studied via bulk genomic analyses. In this study we performed spatial proteomics via MALDI mass spectrometry imaging on six patient-matched CRC primary tumor and liver metastases to characterize interpatient, intertumor and intratumor hetereogeneity. We found several peptide features that were enriched in vital tumor areas of primary tumors and liver metastasis and tentatively derived from tumor cell specific proteins such as annexin A4 and prelamin A/C. Liver metastases of colorectal cancer showed higher heterogeneity between patients than primary tumors while within patients both entities show similar intratumor heterogeneity sometimes organized in zonal pattern. Together our findings give new insights into the spatial proteomic heterogeneity of primary CRC and patient-matched liver metastases.

Caribbean sponges of the genus Smenospongia are a prolific source of chlorinated secondary metabolites. The use of molecular networking as a powerful dereplication tool revealed the presence in the metabolome of S. aurea of two new members of the smenamide family, namely smenamide F (1) and G (2). The structure of smenamide F (1) and G (2) was determined by spectroscopic analysis (NMR, MS, ECD). The relative and the absolute configuration at C-13, C-15, and C-16 was determined on the basis of the conformational rigidity of a 1,3-disubstituted alkyl chain system (i.e. the C-12/C-18 segment of compound 1). Smenamide F (1) and G (2) were shown to exert a selective moderate antiproliferative activity against cancer cell lines MCF-7 and MDA-MB-231, while being inactive against MG-63.

In this paper, we study a three step iterative scheme to approximate fixed points of Suzuki's generalized non-expansive mappings. We establish some weak and strong convergence results for such mappings in uniformly convex Banach spaces. Further, we show numerically that iterative scheme (1.8) converges faster than some other known iterations for Suzuki's generalized non-expansive mappings. To support our claim, we give an illustrative example and approximate fixed points of such mappings using Matlab program. Our results are new and generalize several relevant results in the literature.

For the first time, We do fuzzification the concept of domination in crisp graph on a generalization of fuzzy graph by using membership values of vertices, α-strong edges and edges. In this paper, we introduce the first variation on the domination theme which we call vertex domination. We determine the vertex domination number γ_v for several classes of t-norm fuzzy graphs which include complete t-norm fuzzy graph, complete bipartite t-norm fuzzy graph, star t-norm fuzzy graph and empty t-norm fuzzy graph. The relationship between effective edges and α-strong edges is obtained. Finally, we discuss about vertex dominating set of a fuzzy tree with respect to a t-norm ⨂ by using the bridges and α-strong edges equivalence.