Exploring the connection between BRCA2 and thyroid cancer

Background:This study investigated the multifaceted role of BRCA2(breast cancer 2)in various cancer types,with a specific focus on thyroid carcinoma(THCA).Methods:Data sets were obtained from the University of California Santa Cruz database to analyze BRCA2 expression,genetic alterations,and clinical implications.Sample filtering criteria were applied,and immunohistochemistry from the Human Protein Atlas was used to validate protein expression.Correlation analyses were used to explore associations between immune-related genes,and immunological signatures were assessed using various tools.Genetic alterations in BRCA2 were analyzed using cBioPortal,and prognostic analysis involved evaluating gene expression differences at different clinical stages of THCA.Results:In patients with THCA,differences in BRCA2 expression were observed at both the mRNA and protein levels when comparing tumor and normal tissues.Correlation studies revealed associations between BRCA2 and immune-related genes,emphasizing its potential role in modulating the tumor microenvironment.Immunological signature analyses indicated distinct frequencies of tumor-infiltrating immune cell subsets in BRCA2 high versus low tumors.Moreover,genetic alterations in BRCA2,particularly the A2738S mutation in exon 18,have been identified in patients with THCA.The prognostic analysis demonstrated a significant correlation between altered BRCA2 levels and improved overall survival in patients with THCA.Additionally,BRCA2 expression was associated with prognostic factors such as stage and N.Conclusions:This study provides a holistic exploration of BRCA2 in cancer and highlights its diverse roles in expression,immune modulation,genetic alterations,and clinical prognosis.These findings underscore the potential significance of BRCA2 as a diagnostic and prognostic marker and offer valuable insights for future research and potential clinical applications in cancer management.

MicroRNAs in cancer biology and therapy:Current status and perspectives

The study of a class of small non-coding RNA molecules,named microRNAs(miRNAs),has advanced our understanding of many of the fundamental processes of cancer biology and the molecular mechanisms underlying tumor initiation and progression.MiRNA research has become more and more attractive as evidence is emerging that miRNAs likely play important regulatory roles virtually in all essential bioprocesses.Looking at this field over the past decade it becomes evident that our understanding of miRNAs remains rather incomplete.As research continues to reveal the mechanisms underlying cancer therapy efficacy,it is clear that miRNAs contribute to responses to drug therapy and are themselves modified by drug therapy.One important area for miRNA research is to understand the functions of miRNAs and the relevant signaling pathways in the initiation,progression and drug-resistance of tumors to be able to design novel,effective targeted therapeutics that directly target pathologically essential miRNAs and/or their target genes.Another area of increasing importance is the use of miRNA signatures in the diagnosis and prognosis of various types of cancers.As the study of noncoding RNAs is increasingly more popular and important,it is without doubt that the next several years of miRNA research will provide more fascinating results.

Transforming cancer cells for long-term living with cancer: An inspiring new approach

Cancer is the leading cause of human death and imposes a huge health burden. Currently, no matter what advanced therapeutic modalities or technologies are applied, it is still peculiarly rare for most cancers to be radically cured whereas therapy resistance and tumor recurrence are ever so common. The long-standing cytotoxic therapy is hard to achieve long-term tumor control, and produces side-effects or even promotes cancer progression. With growing understandings of tumor biology, we came to realize that it is possible to transform but not kill cancer cells to achieve long-term living with cancer, and directly altering cancer cells is a promising way. Remarkably, tissue microenvironment is involved in the fate determination of cancer cells. Of note, leveraging cell competition to combat malignant or therapy-resistant cells shows some therapeutic potentials. Furthermore, modulating tumor microenvironment to restore a normal state might help to transform cancer cells. Especially, reprogramming cancer-associated fibroblasts, and tumor-associated macrophages, or normalization of tumor vessel, tumor immune microenvironment, and tumor extracellular matrix or their combinations, et al., revealed some long-term therapeutic benefits. Despite the massive challenges ahead, it would be possible to transform cancer cells for long-term cancer control and living with cancer longevously. The related basic researches and corresponding therapeutic strategies are also ongoing.

Computational analyses for cancer biology based on exhaustive experimental backgrounds

Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from multiple points of view such as oncogenes,tumor suppressor genes,DNA mutations and repairs,autophagy,cancer stemness,and mitochondrial metabolism and alteration.Nowadays,not only medical data from hospitals but also public big data exist on internet websites.Consequently,the importance of computational science has vastly increased in biological and medical sciences.Using statistical or mathematical analyses of these medical data with conventional experiments,many researchers have recently shown that there is a strong relationship between the biological metabolism and chemoresistance for cancer therapy.For example,folate metabolism that mediates one-carbon metabolism and polyamine metabolism have garnered attention regarding their association with cancer.It has been suggested that these metabolisms may be involved in causing resistance to chemotherapy.

Effects of simulated zero gravity on adhesion,cell structure,proliferation,and growth behavior,in glioblastoma multiforme

All life on Earth has evolved under the influence of continuous gravity,and methods have been developed to balance this influence with the biological evolution of organisms at the cellular and system levels.However,when exposed to zero gravity in space,the balance between cell structure and external forces is destroyed,resulting in changes at the cellular level(e.g.,cell morphology,adhesion,viability,apoptosis,etc.),and understanding the molecular mechanism of cell response to zero gravity will help to cope with diseases that rely on mechanical response.Therefore,biological research in space and zero gravity is a unique step in developing the best anti-cancer treatments,which is a great challenge to humanity.In this study,multicellular glioma cancer cells from a brain tumor in a 72-year-old Iraqi patient were subjected to simulated zero gravity for 24 h,and the results showed that most of the cells lost their adhesion,which is considered to be the first step toward cell apoptosis.In addition to the formation of multicellular spheroids,the results also showed that the inhibition rate for cell death was 32%in comparison to the control cells.Moreover,the cells showed a clear change in their cellular morphology and growth behavior.These results give new hope for fighting cancer distinctively,and such a treatment method has no side effects in comparison to traditional chemical and radiological ones.

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

Targeting immune checkpoints such as programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for treating melanoma,gastric cancer(GC)and bladder cancer with clinical benefit.Nevertheless,many patients failed to respond to anti-PD-1/PD-L1 treatment,so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy.Here with the data from The Cancer Genome Atlas(TCGA)and our in-house tissue library,PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7(USP7)in GC.Furthermore,USP7 directly interacted with PD-L1 in order to stabilize it,Gastric cancer;Immunosuppression;Cancer biologywhile abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo.Besides,USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo.Collectively,our findings indicate that in addition to inhibiting cancer cells proliferation,USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously.Hence,these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.

Evolutionary dynamics of cancer:From epigenetic regulation to cell population dynamics——mathematical model framework, applications,and open problems

Predictive modeling of the evolutionary dynamics of cancer is a challenging issue in computational cancer biology. In this paper, we propose a general mathematical model framework for the evolutionary dynamics of cancer, including plasticity and heterogeneity in cancer cells. Cancer is a group of diseases involving abnormal cell growth, during which abnormal regulation of stem cell regeneration is essential for the dynamics of cancer development. In general, the dynamics of stem cell regeneration can be simplified as a G0 phase cell cycle model, which leads to a delay differentiation equation. When cell heterogeneity and plasticity are considered, we establish a differential-integral equation based on the random transition of epigenetic states of stem cells during cell division. The proposed model highlights cell heterogeneity and plasticity;connects the heterogeneity with cell-to-cell variance in cellular behaviors(for example, proliferation, apoptosis, and differentiation/senescence);and can be extended to include gene mutation-induced tumor development. Hybrid computational models are developed based on the mathematical model framework and are applied to the processes of inflammationinduced tumorigenesis and tumor relapse after chimeric antigen receptor(CAR)-T cell therapy. Finally, we propose several mathematical problems related to the proposed differential-integral equation. Solutions to these problems are crucial for understanding the evolutionary dynamics of cancer.

An update on the molecular biology of glioblastoma,with clinical implications and progress in its treatment

Glioblastoma multiforme(GBM)is the most aggressive and common malig-nant primary brain tumor.Patients with GBM often have poor prognoses,with a median survival of∼15 months.Enhanced understanding of the molecular biology of central nervous system tumors has led to modifications in their classifications,the most recent of which classified these tumors into new categories and made some changes in their nomenclature and grading system.This review aims to give a panoramic view of the last 3 years’findings in glioblastoma characterization,its heterogeneity,and current advances in its treatment.Several molecular parameters have been used to achieve an accurate and personalized characterization of glioblastoma in patients,including epigenetic,genetic,transcriptomic and metabolic features,as well as age-and sex-related patterns and the involvement of several noncoding RNAs in glioblastoma progression.Astrocyte-like neural stem cells and outer radial glial-like cells from the subven-tricular zone have been proposed as agents involved in GBM of IDH-wildtype origin,but this remains controversial.Glioblastoma metabolism is characterized by upregulation of the PI3K/Akt/mTOR signaling pathway,promotion of the gly-colytic flux,maintenance of lipid storage,and other features.This metabolism also contributes to glioblastoma’s resistance to conventional therapies.Tumor heterogeneity,a hallmark of GBM,has been shown to affect the genetic expresion,modulation of metabolic pathways,and immune system evasion.GBM’s aggressive invasion potential is modulated by cell-to-cell crosstalk within the tumor microenvironment and altered expressions of specific genes,such as ANXA2,GBP2,FN1,PHIP,and GLUT3.Nevertheless,the rising number of active clinical trials illustrates the efforts to identify new targets and drugs to treat this malignancy.Immunotherapy is still relevant for research purposes,given the amount of ongoing clinical trials based on this strategy to treat GBM,and neoantigen and nucleic acid-based vaccines are gaining importance due to their antitumoral activity by inducing the immune response.Furthermore,there are clinical trials focused on the PI3K/Akt/mTOR axis,angiogenesis,and tumor heterogeneity for developing molecular-targeted therapies against GBM.Other strategies,such as nanodelivery and computational models,may improve the drug pharmacokinetics and the prognosis of patients with GBM.

Interactome Analysis of Microtubule-targeting Agents Reveals Cytotoxicity Bases in Normal Cells

Cancer causes millions of deaths annually and microtubule-targeting agents （MTAs） are the most commonly-used anti-cancer drugs. However, the high toxicity of MTAs on normal cells raises great concern. Due to the non-selectivity of MTA targets, we analyzed the interaction net- work in a non-cancerous human cell. Subnetworks of fourteen MTAs were reconstructed and the merged network was compared against a randomized network to evaluate the functional rich- ness. We found that 71.4% of the MTA interactome nodes are shared, which affects cellular pro- cesses such as apoptosis, cell differentiation, cell cycle control, stress response, and regulation of energy metabolism. Additionally, possible secondary targets were identified as client proteins of interphase microtubules. MTAs affect apoptosis signaling pathways by interacting with client pro- teins of interphase microtubules, suggesting that their primary targets are non-tumor cells. The paclitaxel and doxorubicin networks share essential topological axes, suggesting synergistic effects. This may explain the exacerbated toxicity observed when paclitaxel and doxorubicin are used in combination for cancer treatment.