Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis.

Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes.

The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells.

CD8+ T cells play an important role in anti-tumor immunity. Better understanding of their regulation could advance cancer immunotherapies. Here we identify, via stepwise CRISPR-based screening, that CUL5 is a negative regulator of the core signaling pathways of CD8+ T cells. Knocking out CUL5 in mouse CD8+ T cells significantly improves their tumor growth inhibiting ability, with significant proteomic alterations that broadly enhance TCR and cytokine signaling and their effector functions. Chemical inhibition of neddylation required by CUL5 activation, also enhances CD8 effector activities with CUL5 validated as a major target. Mechanistically, CUL5, which is upregulated by TCR stimulation, interacts with the SOCS-box-containing protein PCMTD2 and inhibits TCR and IL2 signaling. Additionally, CTLA4 is markedly upregulated by CUL5 knockout, and its inactivation further enhances the anti-tumor effect of CUL5 KO. These results together reveal a negative regulatory mechanism for CD8+ T cells and have strong translational implications in cancer immunotherapy.

Biomarkers and biosensors for early cancer diagnosis, monitoring and prognosis.

Cancers continue to be of major concern due to their serious global socioeconomic impact, apart from the continued increase in the incidence of various cancer types. A major challenge that this disease poses is due to the low "early detection" rates which limit the therapeutic outcomes for the affected individuals. Current research has highlighted the discovering biomarkers that help in early cancer detection and the development of technologies for the detection and quantification of such biomarkers. Biomarkers range from proteins to nucleic acids, and can be specific to a particular cancer type. Detection and quantification of such biomarkers at low levels from biological samples is being made possible by the advent of developing biosensors and by using biomedical engineering technologies such as tumor-on-a-chip models. Here, we present biomarkers that can be helpful for the early detection of breast, colorectal, esophageal, lung, liver, ovarian, and prostate cancer. In addition, we discuss the potential of circulating tumor cell DNA (ctDNA) as an early diagnostic marker. Finally, biosensors available for the detection of cancer biomarkers, which is a recent advancement in this area of research, are discussed.

Role of homeobox d10 gene targeted signaling pathways in cancers.

Homeobox D10 (HOXD10) is a transcription factor from the homeobox gene family that controls cell differentiation and morphogenesis throughout development.Due to their functional interaction, changes in HOXD10 gene expression might induce tumors. This narrative review focuses on how and why the dysregulation in the signaling pathways linked with HOXD10 contributes to the metastatic development of cancer. Organ development and tissue homeostasis need highly conserved homeotic transcription factors from homeobox (HOX) genes. Their dysregulation disrupts regulatory molecule action, causing tumors. The HOXD10 gene is upregulated in breast, gastric, hepatocellular, colorectal, bladder, cholangiocellular carcinoma and prostate cancer. Tumor signaling pathways are affected by HOXD10 gene expression changes. This study examines HOXD10-associated signaling pathway dysregulation, which may alter metastatic cancer signaling. In addition, the theoretical foundations that alter HOXD10-mediated therapeutic resistance in malignancies has been presented. New cancer therapy methods will be simpler to develop with the newly discovered knowledge. This review showed that HOXD10 may be a tumor suppressor gene and a new cancer treatment target signaling pathway.

Recent and advanced therapy for oral cancer.

Oral cancer is a common and deadly kind of tissue invasion, has a high death rate, and may induce metastasis that mostly affects adults over the age of 40. Most in vitro traditional methods for studying cancer have included the use of monolayer cell cultures and several animal models. There is a worldwide effort underway to reduce the excessive use of laboratory animals since, although being physiologically adequate, animal models rarely succeed in exactly mimicking human models. 3D culture models have gained great attention in the area of biomedicine because of their capacity to replicate parent tissue. There are many benefits to using a drug delivery approach based on nanoparticles in cancer treatment. Because of this, in vitro test methodologies are crucial for evaluating the efficacy of prospective novel nanoparticle drug delivery systems. This review discusses current advances in the utility of 3D cell culture models including multicellular spheroids, patient-derived explant cultures, organoids, xenografts, 3D bioprinting, and organoid-on-a-chip models. Aspects of nanoparticle-based drug discovery that have utilized 2D and 3D cultures for a better understanding of genes implicated in oral cancers are also included in this review.

Insights of Endocytosis Signaling in Health and Disease.

Endocytosis in mammalian cells is a fundamental cellular machinery that regulates vital physiological processes, such as the absorption of metabolites, release of neurotransmitters, uptake of hormone cellular defense, and delivery of biomolecules across the plasma membrane. A remarkable characteristic of the endocytic machinery is the sequential assembly of the complex proteins at the plasma membrane, followed by internalization and fusion of various biomolecules to different cellular compartments. In all eukaryotic cells, functional characterization of endocytic pathways is based on dynamics of the protein complex and signal transduction modules. To coordinate the assembly and functions of the numerous parts of the endocytic machinery, the endocytic proteins interact significantly within and between the modules. Clathrin-dependent and -independent endocytosis, caveolar pathway, and receptor mediated endocytosis have been attributed to a greater variety of physiological and pathophysiological roles such as, autophagy, metabolism, cell division, apoptosis, cellular defense, and intestinal permeabilization. Notably, any defect or alteration in the endocytic machinery results in the development of pathological consequences associated with human diseases such as cancer, cardiovascular diseases, neurological diseases, and inflammatory diseases. In this review, an in-depth endeavor has been made to illustrate the process of endocytosis, and associated mechanisms describing pathological manifestation associated with dysregulated endocytosis machinery.

Integrated transcriptome and trajectory analysis of cutaneous T-cell lymphoma identifies putative precancer populations.

The incidence of cutaneous T-cell lymphoma (CTCL) increases with age, and blood involvement portends a worse prognosis. To advance our understanding of the development of CTCL and identify potential therapeutic targets, we performed integrative analyses of paired single-cell RNA and T-cell receptor (TCR) sequencing of peripheral blood CD4+ T cells from patients with CTCL to reveal disease-unifying features. The malignant CD4+ T cells of CTCL showed highly diverse transcriptomic profiles across patients, with most displaying a mature Th2 differentiation and T-cell exhaustion phenotype. TCR-CDR3 peptide prediction analysis suggested limited diversity between CTCL samples, consistent with a role for a common antigenic stimulus. Potential of heat diffusion for affinity-based trajectory embedding transition analysis identified putative precancerous circulating populations characterized by an intermediate stage of gene expression and mutation level between the normal CD4+ T cells and malignant CTCL cells. We further revealed the therapeutic potential of targeting CD82 and JAK that endow the malignant CTCL cells with survival and proliferation advantages.

Prospect and retrospect of 3D bio-printing.

3D bioprinting has become a popular medical technique in recent years. The most compelling rationale for the development of 3D bioprinting is the paucity of biological structures required for the rehabilitation of missing organs and tissues. They're useful in a multitude of domains, including disease modelling, regenerative medicine, tissue engineering, drug discovery with testing, personalised medicine, organ development, toxicity studies, and implants. Bioprinting requires a range of bioprinting technologies and bioinks to finish their procedure, that Inkjet-based bioprinting, extrusion-based bioprinting, laser-assisted bioprinting, stereolithography-based bioprinting, and in situ bioprinting are some of the technologies listed here. Bioink is a 3D printing material that is used to construct engineered artificial living tissue. It can be constructed solely for cells, but it usually includes a carrier substance that envelops the cells, then there's Agarose-based bioinks, alginate-based bioinks, collagen-based bioinks, and hyaluronic acid-based bioinks, to name a few. Here we presented about the different bioprinting methods with the use of bioinks in it and then Prospected over various applications in different fields.

Gene expressions and their significance in organoid cultures obtained from breast cancer patient-derived biopsies.

Gene expression changes are one of the hallmarks of malignant cells and such changes in specific genes have been identified for a variety of human cancers. Such an association in gene expression changes becomes very significant for breast cancers due to the genetic heterogeneity seen in such cancers. It is due to such genetic implication that breast cancers are classified into several subtypes; based on the expression and the magnitude of expression of estrogen and progesterone receptor genes. Changes in the expression of ERBB2, ESR1, PLAU, MUC1, PGR, and TP53 are implicated in breast cancers. Of the various models available for cancer research, organoid cultures from patient-derived biopsies are being considered as the most relevant for invitro testing. Organoid cultures derived from patient biopsies mitigate several limitations of other commonly available models such as cancer cell lines. Such organoids retain the functional physiology of solid tumors which include gene expression. Also, utilizing patient derived organoids for in vitro testing paves way for personalized medicine which greatly enhances the effectiveness of cancer therapy for individuals. We present the genes implicated in breast cancers, the ways in which organoids can be derived from breast cancer biopsies and their applications for gene expression studies.

Development of patient derived organoids for cancer drug screening applications.

Cancer is a disease characterised by abnormal cell growth that can invade or spread to other regions of the body. Organoids are three-dimensional ex vivo tissue cultures made from embryonic stem cells, induced pluripotent stem cells, progenitor cells or tissue that serve as a physiological model for cancer research. These are designed to recapitulate the in vivo properties of tumours. Importantly, effective recapitulation of the structure of tissues and function is believed to predict patient response, allowing for the creation of personalised therapy in a timely manner that may be used in the clinic. This Review discusses the pre-clinical model and different types of human organoids as models for the development of high throughput drug screening and also aims to highlight how organoids are shaping the future of cancer research.

Accelerating precision anti-cancer therapy by time-lapse and label-free 3D tumor slice culture platform.

The feasibility of personalized medicine for cancer treatment is largely hampered by costly, labor-intensive and time-consuming models for drug discovery. Herein, establishing new pre-clinical models to tackle these issues for personalized medicine is urgently demanded. Methods: We established a three-dimensional tumor slice culture (3D-TSC) platform incorporating label-free techniques for time-course experiments to predict anti-cancer drug efficacy and validated the 3D-TSC model by multiphoton fluorescence microscopy, RNA sequence analysis, histochemical and histological analysis. Results: Using time-lapse imaging of the apoptotic reporter sensor C3 (C3), we performed cell-based high-throughput drug screening and shortlisted high-efficacy drugs to screen murine and human 3D-TSCs, which validate effective candidates within 7 days of surgery. Histological and RNA sequence analyses demonstrated that 3D-TSCs accurately preserved immune components of the original tumor, which enables the successful achievement of immune checkpoint blockade assays with antibodies against PD-1 and/or PD-L1. Label-free multiphoton fluorescence imaging revealed that 3D-TSCs exhibit lipofuscin autofluorescence features in the time-course monitoring of drug response and efficacy. Conclusion: This technology accelerates precision anti-cancer therapy by providing a cheap, fast, and easy platform for anti-cancer drug discovery.

Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics.

Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer type with high morbidity in Southeast Asia, however the pathogenic mechanism of this disease is poorly understood. Using integrative pharmacogenomics, we find that NPC subtypes maintain distinct molecular features, drug responsiveness, and graded radiation sensitivity. The epithelial carcinoma (EC) subtype is characterized by activations of microtubule polymerization and defective mitotic spindle checkpoint related genes, whereas sarcomatoid carcinoma (SC) and mixed sarcomatoid-epithelial carcinoma (MSEC) subtypes exhibit enriched epithelial-mesenchymal transition (EMT) and invasion promoting genes, which are well correlated with their morphological features. Furthermore, patient-derived organoid (PDO)-based drug test identifies potential subtype-specific treatment regimens, in that SC and MSEC subtypes are sensitive to microtubule inhibitors, whereas EC subtype is more responsive to EGFR inhibitors, which is synergistically enhanced by combining with radiotherapy. Through combinational chemoradiotherapy (CRT) screening, effective CRT regimens are also suggested for patients showing less sensitivity to radiation. Altogether, our study provides an example of applying integrative pharmacogenomics to establish a personalized precision oncology for NPC subtype-guided therapies.

Ethnic-specific BRCA1/2 variation within Asia population: evidence from over 78 000 cancer and 40 000 non-cancer cases of Indian, Chinese, Korean and Japanese populations.

BACKGROUND: Germline mutation in BRCA1 and BRCA2 (BRCA) is genetic predisposition for breast and ovarian cancer. Identification of mutation carriers is a critical step to prevent and treat the cancer in the mutation carriers. Human BRCA variation has been well determined as ethnic-specific by studies in Ashkenazi Jewish, Polish and Icelandic populations in the 1990s. However, sufficient evidence is lacking to determine if ethnic-specific BRCA variation is also present in Asia population, which is the largest and the most diversified in modern humans. Our current study aims to investigate ethnic-specific BRCA variation in Asian population. METHODS: We performed a comprehensive data mining to collect BRCA variation data in Indian, Chinese, Korean and Japanese populations derived from over 78 000 cancer and 40 000 non-cancer cases. We standardised all BRCA variation data following the international standard. We made a systematic comparison between the datasets including variant composition, variation spectrum, variant type, clinical class, founder mutation and high-frequent variants. RESULTS: Our analysis showed that over half of the Asian BRCA variants were Asian-specific, and significant differences were present between the four Asia populations in each category analysed. CONCLUSION: Data from our study reveal that ethnic-specific BRCA variation is commonly present in Asia population as existing in non-Asian populations. Our study indicates that ethnicity should be an important factor to consider in prevention and treatment of BRCA mutation-related cancer in the Asia population. We recommend that the current BRCA variation databases should include ethnic variation information in order to function as true global BRCA references.

NOTCH1 activation compensates BRCA1 deficiency and promotes triple-negative breast cancer formation.

BRCA1 mutation carriers have a higher risk of developing triple-negative breast cancer (TNBC), which is a refractory disease due to its non-responsiveness to current clinical targeted therapies. Using the Sleeping Beauty transposon system in Brca1-deficient mice, we identified 169 putative cancer drivers, among which Notch1 is a top candidate for accelerating TNBC by promoting the epithelial-mesenchymal transition (EMT) and regulating the cell cycle. Activation of NOTCH1 suppresses mitotic catastrophe caused by BRCA1 deficiency by restoring S/G2 and G2/M cell cycle checkpoints, which may through activation of ATR-CHK1 signalling pathway. Consistently, analysis of human breast cancer tissue demonstrates NOTCH1 is highly expressed in TNBCs, and the activated form of NOTCH1 correlates positively with increased phosphorylation of ATR. Additionally, we demonstrate that inhibition of the NOTCH1-ATR-CHK1 cascade together with cisplatin synergistically kills TNBC by targeting the cell cycle checkpoint, DNA damage and EMT, providing a potent clinical option for this fatal disease.

Pharmacoinformatic Approach to Explore the Antidote Potential of Phytochemicals on Bungarotoxin from Indian Krait, Bungarus caeruleus.

Venomous reptiles especially serpents are well known for their adverse effects after accidental conflicts with humans. Upon biting humans these serpents transmit arrays of detrimental toxins with diverse physiological activities that may either lead to minor symptoms such as dermatitis and allergic response or highly severe symptoms such as blood coagulation, disseminated intravascular coagulation, tissue injury, and hemorrhage. Other complications like respiratory arrest and necrosis may also occur. Bungarotoxins are a group of closely related neurotoxic proteins derived from the venom of kraits (Bungarus caeruleus) one of the six most poisonous snakes in India whose bite causes respiratory paralysis and mortality without showing any local symptoms. In the current study, by employing various pharmacoinformatic approaches, we have explored the antidote properties of 849 bioactive phytochemicals from 82 medicinal plants which have already shown antidote properties against various venomous toxins. These herbal compounds were taken and pharmacoinformatic approaches such as ADMET, docking and molecular dynamics were employed. The three-dimensional modelling approach provides structural insights on the interaction between bungarotoxin and phytochemicals. In silico simulations proved to be an effective analytical tools to investigate the toxin-ligand interaction, correlating with the affinity of binding. By analyzing the results from the present study, we proposed nine bioactive phytochemical compounds which are, 2-dodecanol, 7-hydroxycadalene, indole-3-(4'-oxo)butyric acid, nerolidol-2, trans-nerolidol, eugenol, benzene propanoic acid, 2-methyl-1-undecanol, germacren-4-ol can be used as antidotes for bungarotoxin.

A comprehensive genomic meta-analysis identifies confirmatory role of OBSCN gene in breast tumorigenesis.

The giant multifunctional protein "OBSCURIN" is encoded by OBSCN gene and is mostly expressed in cardiac and other skeletal muscles responsible for myofibrils organization. Loss of OBSCURIN affects the entire downstream pathway proteins vital for various cellular functions including cell integration and cell adhesion. The OBSCN gene mutations are more frequently observed in various muscular diseases, and cancers. Nevertheless, the direct role of OBSCN in tumorigenesis remains elusive. Interestingly, in clinical breast cancer samples a significant number of function changing mutations have been identified in OBSCN gene. In this study, we identified a significant role of OBSCN by conducting an integrative analysis of copy number alterations, functional mutations, gene methylation and expression data from various BRCA cancer projects data available on cBioPortal and TCGA firebrowse portal. Finally, we carried out genetic network analysis, which revealed that OBSCN gene plays a significant role in GPCR, RAS, p75 or Wnt signaling pathways. Similarly, OBSCN gene interacts with many cancer-associated genes involved in breast tumorigenesis. The OBSCN gene probably regulates breast cancer progression and metastasis and the prognostic molecular signatures such as copy number alterations and gene expression of OBSCN may serve as a tool to identify breast tumorigenesis and metastasis.

Characterization of potential driver mutations involved in human breast cancer by computational approaches.

Breast cancer is the second most frequently occurring form of cancer and is also the second most lethal cancer in women worldwide. A genetic mutation is one of the key factors that alter multiple cellular regulatory pathways and drive breast cancer initiation and progression yet nature of these cancer drivers remains elusive. In this article, we have reviewed various computational perspectives and algorithms for exploring breast cancer driver mutation genes. Using both frequency based and mutational exclusivity based approaches, we identified 195 driver genes and shortlisted 63 of them as candidate drivers for breast cancer using various computational approaches. Finally, we conducted network and pathway analysis to explore their functions in breast tumorigenesis including tumor initiation, progression, and metastasis.