A Case of Budd-Chiari Syndrome Secondary to Tumor Thrombosis.

Budd-Chiari syndrome (BCS) is a rare constellation of conditions due to obstruction of venous flow from anatomical levels ranging from the hepatic veins to the confluence of the inferior vena cava (IVC) and right atrium. The resulting retrograde flow of blood leads to hepatomegaly, ascites, and liver failure among other features. Our case highlights the clinical features, diagnostic challenges, and management of a patient with a tumor thrombus from a metastatic prostate adenocarcinoma in a 67-year-old male leading to BCS. This patient, with a past history of prostate adenocarcinoma and aortic valve replacement on chronic warfarin anticoagulation, presented with acutely worsening abdominal pain and a distended abdomen, and imaging revealed an IVC filling defect. Subsequent imaging with a piflufolastat prostate-specific PET showing increased uptake in the IVC elucidated the diagnosis of tumor thrombosis. Management considerations include aggressive therapy and optimization of quality of life. The patient was offered both options, and options including surgical shunting, bypasses, and anticoagulation were discussed. After shared decision-making, the patient and family opted to choose the pathway of palliative radiation and anticoagulation.

Immunophenotypic characterization of leukemic stem cells in acute myeloid leukemia using single tube 10-colour panel by multiparametric flow cytometry: Deciphering the spectrum, complexity and immunophenotypic heterogeneity.

INTRODUCTION: Despite extensive research, comprehensive characterization of leukaemic stem cells (LSC) and information on their immunophenotypic differences from normal haematopoietic stem cells (HSC) is lacking. Herein, we attempted to unravel the immunophenotypic (IPT) characteristics and heterogeneity of LSC using multiparametric flow cytometry (MFC) and single-cell sequencing. MATERIALS AND METHODS: Bone marrow aspirate samples from patients with acute myeloid leukaemia (AML) were evaluated using MFC at diagnostic and post induction time points using a single tube-10-colour-panel containing LSC-associated antibodies CD123, CD45RA, CD44, CD33 and COMPOSITE (CLL-1, TIM-3, CD25, CD11b, CD22, CD7, CD56) with backbone markers that is, CD45, CD34, CD38, CD117, sCD3. Single-cell sequencing of the whole transcriptome was also done in a bone marrow sample. RESULTS: LSCs and HSCs were identified in 225/255 (88.2%) and 183/255 (71.6%) samples, respectively. Significantly higher expression was noted for COMPOSITE, CD45RA, CD123, CD33, and CD44 in LSCs than HSCs (p < 0.0001). On comparing the LSC specific antigen expressions between CD34+ (n = 184) and CD34- LSCs (n = 41), no difference was observed between the groups. More than one sub-population of LSC was demonstrated in 4.4% of cases, which further revealed high concordance between MFC and single cell transcriptomic analysis in one of the cases displaying three LSC subpopulations by both methods. CONCLUSION: A single tube-10-colour MFC panel is proposed as an easy and reproducible tool to identify and discriminate LSCs from HSCs. LSCs display both inter- and intra-sample heterogeneity in terms of antigen expressions, which opens the facets for single cell molecular analysis to elucidate the role of subpopulations of LSCs in AML progression.

Solitary Intestinal Lymphangiectasia Causing Transient Intussusception.

Lymphangiectasia is the benign malformation of lymphatic channels associated with either focal or diffuse dilation of vessels and impaired lymph drainage. This malformation has the potential to create a cystic mass due to the accumulation of lymphatic fluid. While rare in adults, intussusception, the telescoping of the proximal bowel into the distal bowel, can be caused by a mass within the bowel. In this case, a near-obstructing cystic colon mass developed in a 74-year-old man; this was later found to be a large lymphangiectasia. In addition, this near-obstructing colonic lymphangiectasia served as the lead point in a colo-colonic intussusception. Due to this complication, the mass was immediately removed by a laparoscopic oncologic right-extended hemicolectomy which proved to be both diagnostic and therapeutic.

Helicase-like transcription factor (HLTF)-deleted CDX/TME model of colorectal cancer increased transcription of oxidative phosphorylation genes and diverted glycolysis to boost S-glutathionylation in lymphatic intravascular metastatic niches.

Helicase-like transcription factor (HLTF) also known as SMARCA3, protects genome integrity. A tumor suppressor, HLTF is expressed in tumor cells but not in the tumor microenvironment (TME) in early-stage colorectal cancer (CRC). With disease progression, there is high concordance between epigenetic silencing of HLTF in CRC cells and negligible HLTF expression in the TME. We developed a cell line-derived xenograft (CDX) model and show for the first time that HLTF-deletion in cancer cells and the TME results in metabolic reprogramming that mitigates oxidative stress in lymphatic intravascular metastatic niches. The two metabolic pathways that derive energy from glucose-glycolysis and oxidative phosphorylation (OXPHOS)-are variously utilized by cancer cells depending upon the TME. HIF-1α, a master regulator of glycolysis, was eliminated from a role in reprogramming metabolism to satisfy CDX energetic requirements by RNAseq and spatial transcriptomics. Variability in the gut microbiome, with a putative role in altered metabolism, was also eliminated. HLTF-deleted cancer cells recovered from DNA damage at a transcriptomic level induction of DNA repair and OXPHOS genes linked to an amoeboid-associated phenotype at the tumor border (confocal microscopy). HLTF-deleted cancer and endothelial cells of lymphatic (PDPN) intravascular niches in the TME shared a site-specific protein S-glutathionylation signature (2D DIGE, MALDI-TOF/TOF mass spectrometry) for three glycolytic enzymes (PGK1 Cys379/380, PGAM1 Cys55, ENOA1 Cys119) that diverted glycolysis in support of continued glutathione biosynthesis. The collective absence of HLTF/Hltf from tumor and TME achieved redox homeostasis throughout the CDX and promoted metastasis.

Helicase-like transcription factor (Hltf)-deletion activates Hmgb1-Rage axis and granzyme A-mediated killing of pancreatic ß cells resulting in neonatal lethality.

Epigenetic mechanisms are integral to pancreatic ß cell function. Promoter hypermethylation of the helicase like-transcription factor (HLTF) gene-a component of the cellular DNA damage response that contributes to genome stability-has been implicated in age-associated changes in ß cells. To study HLTF, we generated global and ß cell-specific (ß) Hltf knockout (KO) immune competent (IC) and immune deficient (ID) Rag2-/IL2- mice. IC global and ß Hltf KO mice were neonatal lethal whereas ID global and ß Hltf KO newborn mice had normal survival. This focused our investigation on the effects of Rag2 interruption with common gamma chain interruption on ß cell function/survival. Three-way transcriptomic (RNAseq) analyses of whole pancreata from IC and ID newborn ß Hltf KO and wild type (Hltf +/+) controls combined with spatially resolved transcriptomic analysis of formalin fixed paraffin embedded tissue, immunohistochemistry and laser scanning confocal microscopy showed DNA damage caused by ß Hltf KO in IC mice upregulated the Hmgb1-Rage axis and a gene signature for innate immune cells. Perforin-delivered granzyme A (GzmA) activation of DNase, Nme1, showed damaged nuclear single-stranded DNA (γH2AX immunostaining). This caspase-independent method of cell death was supported by transcriptional downregulation of Serpinc1 gene that encodes a serine protease inhibitor of GzmA. Increased transcriptional availability of complement receptors C3ar1 and C5ar1 likely invited crosstalk with Hmgb1 to amplify inflammation. This study explores the complex dialog between ß cells and immune cells during development. It has implications for the initiation of type I diabetes in utero when altered gene expression that compromises genome stability invokes a localized inflammatory response.

Bio-evaluation of poly(lactic-co-glycolic) acid nanoparticles loaded with radiolabelled rifampicin.

AIMS: The poly(lactic-co-glycolic) acid (PLGA) nanoparticles of tubercular drugs have been demonstrated to have a sustained release profile over 7 days. There is no information on the location or mode of release of these nanoparticles in living systems. Therefore, we have planned the study to explore the pharmacokinetics and biodistribution of PLGA rifampicin nanoparticles in healthy human volunteers. We aim to study the distribution pattern of PLGA-loaded nano-formulation of radiolabelled rifampicin in humans. METHODS: Rifampicin was labelled with 99m Tc by indirect method and nanoparticles were prepared by a single emulsion evaporation method. To investigate the pharmacokinetics and biodistribution of nanoparticles, a single dose of 450 mg of rifampicin was administered orally to healthy human volunteers divided into two different groups. RESULTS: Following a single oral dosage of the rifampicin nanoformulation, the pharmacokinetic (PK) parameters were significantly different between the nanoparticle and conventional groups: area under the concentration-time curve (AUC = 113.8 vs. 58.6; P < .001), mean residence time (MRT = 16.2 vs. 5.8; P < .01) and elimination rate constant (Ke = 0.04 vs. 0.10; P < .05). Also, Single-photon emission computed tomography/computed tomography (SPECT/CT) images revealed biodistribution of nanoparticles in the distal portions of the intestine, which is consistent with our dosimetry analysis. CONCLUSIONS: Significant difference in PK parameters and biodistribution of nanoparticles in spleen and lymph nodes with maximum deposition were observed in the large intestine. The nanoparticle distribution pattern may be advantageous for the treatment of intestinal or lymph node tuberculosis (TB) and has the potential to result in a lower dose of rifampicin nanoformulation for the treatment of pulmonary TB.

BDL-SP: A Bio-inspired DL model for the identification of altered Signaling Pathways in Multiple Myeloma using WES data.

Identification of the genomic features responsible for the progression of Multiple Myeloma (MM) cancer from its precancerous stage MGUS can improve the understanding of the disease pathogenesis and, in devising suitable preventive and treatment measures. We have designed an innovative AI-based model, namely, the Bio-inspired Deep Learning architecture for the identification of altered Signaling Pathways (BDL-SP) to discover pivotal genomic biomarkers that can potentially distinguish MM from MGUS. The proposed BDL-SP model comprehends gene-gene interactions using the PPI network and analyzes genomic features using a deep learning (DL) architecture to identify significantly altered genes and signaling pathways in MM and MGUS. For this, whole exome sequencing data of 1174 MM and 61 MGUS patients were analyzed. In the quantitative benchmarking with the other popular machine learning models, BDL-SP performed almost similar to the two other best performing predictive ML models of Random Forest and CatBoost. However, an extensive post-hoc explainability analysis, capturing the application specific nuances, clearly established the significance of the BDL-SP model. This analysis revealed that BDL-SP identified a maximum number of previously reported oncogenes, tumor-suppressor genes, and actionable genes of high relevance in MM as the top significantly altered genes. Further, the post-hoc analysis revealed a significant contribution of the total number of single nucleotide variants (SNVs) and genomic features associated with synonymous SNVs in disease stage classification. Finally, the pathway enrichment analysis of the top significantly altered genes showed that many cancer pathways are selectively and significantly dysregulated in MM compared to its precursor stage of MGUS, while a few that lost their significance with disease progression from MGUS to MM were actually related to the other disease types. These observations may pave the way for appropriate therapeutic interventions to halt the progression to overt MM in the future.

Determining the Role of Employee Engagement in Nurse Retention along with the Mediation of Organizational Culture.

In today's unpredictable environment, the rapid emergence of the COVID-19 pandemic has shaken the world and its healthcare infrastructure immensely. As nurses are the building blocks of the healthcare personnel labor market, organizations should develop tactics that aid in their retention. With a solid theoretical foundation in self-determination theory, this study aims to understand the role of employee engagement in keeping nurses in 51 hospitals in the Northern Indian region, along with the mediation of organizational culture through smart PLS. In a complementary mediation relationship with organizational culture, nurse retention is positively correlated with employee engagement.

Killer cell immunoglobulin-like receptor three domains long cytoplasmic tail 1 gene *007 may modulate disease progression of human immunodeficiency virus-1 infection in the Japanese population.

One of the KIR allele, KIR3DL1*007, was associated with the progression to acquired immunodeficiency syndrome and not with the susceptibility to HIV-1 infection in the Japanese and Indian populations, implying that KIR3DL1*007-positive NK cells might eliminate HIV-infected cells less effectively than NK cells bearing the other KIR3DL1 alleles or KIR3DS1 alleles.

Targets' Coping Responses to Workplace Bullying with Moderating Role of Perceived Organizational Tolerance: A Two-Phased Study of Faculty in Higher Education Institutions.

This study aims to examine the relationship between workplace bullying and Exit-Voice-Loyalty-Neglect (EVLN) coping responses with Perceived Organizational Tolerance (POT) of bullying as moderator using the integrated model of reactance and learned helplessness theory. The data has been collected from junior faculty in higher education institutes of Punjab. The study has been conducted in two phases, with phase 1 including identifying targets of workplace bullying using cut-off scores and phase 2 studying the perceived organizational tolerance. The results show that junior faculty chooses neglect as a coping response and that the level of perceived organizational tolerance moderates the relationship between workplace bullying and exit-voice-neglect. This study contributes to existing literature by employing integration of theories and using multi-level research design. It also is an addition to the literature on the coping response of targets to workplace bullying in higher education and is a rare attempt at operationalizing perceived organizational tolerance and its relation with workplace bullying.

Effect of Dietary Geranylgeraniol and Green Tea Polyphenols on Glucose Homeostasis, Bone Turnover Biomarkers, and Bone Microstructure in Obese Mice.

Previously, we demonstrated that the administration of either geranylgeraniol (GGOH) or green tea polyphenols (GTP) improved bone health. This study examined the combined effects of GGOH and GTP on glucose homeostasis in addition to bone remodeling in obese mice. We hypothesized that GGOH and GTP would have an additive or synergistic effect on improving glucose homeostasis and bone remodeling possibly in part via suppression of proinflammatory cytokines. Forty-eight male C57BL/6J mice were assigned to a high-fat diet (control), HFD + 400 mg GGOH/kg diet (GG), HFD + 0.5% GTP water (TP), or HFD + GGOH + GTP (GGTP) diet for 14 weeks. Results demonstrated that GTP supplementation improved glucose tolerance in obese mice. Neither GGOH nor GTP affected pancreas insulin or bone formation procollagen type I intact N-terminal, bone volume at the lumbar vertebrae, or bone parameters at the trabecular bone and cortical bone of the femur. There was an interactive effect for serum bone resorption collagen type 1 cross-linked C-telopeptide concentrations, resulting in no-GGOH and no-GTP groups having the highest values. GGOH increased trabecular number and decreased trabecular separation at the lumbar vertebrae. GTP increased trabecular thickness at lumbar vertebrae. The GG group produced the greatest connectivity density and the lowest structure model index. Only GTP, not GGOH, decreased adipokines concentrations (resistin, leptin, monocyte chemoattractant protein-1, and interleukin-6). In an obese male mouse model, individual GGOH and GTP supplementation improved glucose homeostasis, serum CTX, and trabecular microstructure of LV-4. However, the combined GGOH and GTP supplementation compromises such osteoprotective effects on serum CTX and trabecular bone of obese mice.

Integrated single-cell transcriptome analysis of CD34 + enriched leukemic stem cells revealed intra- and inter-patient transcriptional heterogeneity in pediatric acute myeloid leukemia.

To gain insights into the idiosyncrasies of CD34 + enriched leukemic stem cells, we investigated the nature and extent of transcriptional heterogeneity by single-cell sequencing in pediatric AML. Whole transcriptome analysis of 28,029 AML single cells was performed using the nanowell cartridge-based barcoding technology. Integrated transcriptional analysis identified unique leukemic stem cell clusters of each patient and intra-patient heterogeneity was revealed by multiple LSC-enriched clusters differing in their cell cycle processes and BCL2 expression. All LSC-enriched clusters exhibited gene expression profile of dormancy and self-renewal. Upregulation of genes involved in non-coding RNA processing and ribonucleoprotein assembly were observed in LSC-enriched clusters relative to HSC. The genes involved in regulation of apoptotic processes, response to cytokine stimulus, and negative regulation of transcription were upregulated in LSC-enriched clusters as compared to the blasts. Validation of top altered genes in LSC-enriched clusters confirmed upregulation of TCF7L2, JUP, ARHGAP25, LPAR6, and PRDX1 genes, and serine/threonine kinases (STK24, STK26). Upregulation of LPAR6 showed trend towards MRD positive status (Odds ratio = 0.126; 95% CI = 0.0144-1.10; p = 0.067) and increased expression of STK26 significantly correlated with higher RFS (HR = 0.231; 95% CI = 0.0506-1.052; p = 0.04). Our findings addressed the inter- and intra-patient diversity within AML LSC and potential signaling and chemoresistance-associated targets that warrant investigation in larger cohort that may guide precision medicine in the near future.

Potential Role of 68Ga-NOTA-Duramycin PET/CT Imaging for Early Response Evaluation in a Lymphoma Patient: A Case Report.

ABSTRACT: Duramycin, a 19 amino acids peptide, is known for its potential to target phosphatidylethanolamine. During cell death (apoptosis), rearrangement of membrane phospholipids results in the externalization of phosphatidylethanolamine to the outer leaflet of the cell membrane, which can be imaged using 68Ga-NOTA-duramycin. We report 68Ga-NOTA-duramycin imaging in a 50-year-old man with biopsy-proven diffuse large B-cell lymphoma planned for anthracycline-based chemotherapy. 68Ga-NOTA-duramycin PET/CT imaging along with 18F-FDG PET/CT was performed before and after 2 cycles of chemotherapy. The tracer avidity in interim 68Ga-NOTA-duramycin PET/CT showed its diagnostic potential to assess early response to chemotherapy.

Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection.

An effective treatment and possible cure for type 1 diabetes is transplantation of pancreatic islets. Unfortunately, transplanted islets are rejected by the immune system with humoral-mediated responses being an important part of rejection. Sertoli cells (SC), an immune regulatory cell shown to survive as allografts long-term without immunosuppressants, have the potential to be used as a cell-based gene therapy vehicle to deliver endogenous insulin-a possible alternative to islets. Previously, we transduced a mouse SC line to produce human insulin. After transplantation into diabetic mice, these cells consistently produced low levels of insulin with graft survival of 75% at 50 days post-transplantation. The object of this study was to assess humoral immune regulation by these engineered SC. Both nontransduced and transduced SC survived exposure to human serum with complement in vitro. Analysis of allografts in vivo at 20 and 50 days post-transplantation revealed that despite IgG antibody detection, complement factor deposition was low and grafts survived through 50 days post-transplantation. Furthermore, the transduced SC secreted elevated levels of the complement inhibitor C1q binding protein. Overall, this suggests SC genetically engineered to express insulin maintain their ability to prevent complement-mediated killing. Since inhibiting complement-mediated rejection is important for graft survival, further studies of how SC modifies the immune response could be utilized to advance the use of genetically engineered SC or to prolong islet allograft survival to improve the treatment of diabetes.

Mouse Sertoli Cells Inhibit Humoral-Based Immunity.

Transplantation is used to treat many different diseases; however, without the use of immunosuppressants, which can be toxic to the patient, grafted tissue is rejected by the immune system. Humoral immune responses, particularly antibodies and complement, are significant components in rejection. Remarkably, Sertoli cells (SCs), immunoregulatory testicular cells, survive long-term after transplantation without immunosuppression. The objective of this study was to assess SC regulation of these humoral-based immune factors. Mouse SCs survived in vitro human complement (model of robust complement-mediated rejection) and survived in vivo as allografts with little-to-no antibody or complement fragment deposition. Microarray data and ELISA analyses identified at least 14 complement inhibitory proteins expressed by mouse SCs, which inhibit complement at multiple points. Interestingly, a mouse SC line (MSC-1), which was rejected by day 20 post transplantation, also survived in vitro human complement, showed limited deposition of antibodies and complement, and expressed complement inhibitors. Together this suggests that SC inhibition of complement-mediated killing is an important component of SC immune regulation. However, other mechanisms of SC immune modulation are also likely involved in SC graft survival. Identifying the mechanisms that SCs use to achieve extended survival as allografts could be utilized to improve graft survival.

Ginger Root Extract Improves GI Health in Diabetic Rats by Improving Intestinal Integrity and Mitochondrial Function.

Background Emerging research suggests hyperglycemia can increase intestinal permeability. Ginger and its bioactive compounds have been reported to benefit diabetic animals due to their anti-inflammatory and antioxidant properties. In this study, we revealed the beneficial effect of gingerol-enriched ginger (GEG) on intestinal health (i.e., barrier function, mitochondrial function, and anti-inflammation) in diabetic rats. Methods Thirty-three male Sprague Dawley rats were assigned to three groups: low-fat diet (control group), high-fat-diet (HFD) + streptozotocin (single low dose 35 mg/kg body weight (BW) after 2 weeks of HFD feeding) (DM group), and HFD + streptozotocin + 0.75% GEG in diet (GEG group) for 42 days. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were conducted at baseline and prior to sample collection. Total pancreatic insulin content was determined by ELISA. Total RNA of intestinal tissues was extracted for mRNA expression using qRT-PCR. Results Compared to the DM group, the GEG group had improved glucose tolerance and increased pancreatic insulin content. Compared to those without GEG (DM group), GEG supplementation (GEG group) increased the gene expression of tight junction (Claudin-3) and antioxidant capacity (SOD1), while it decreased the gene expression for mitochondrial fusion (MFN1), fission (FIS1), biogenesis (PGC-1α, TFAM), mitophagy (LC3B, P62, PINK1), and inflammation (NF-κB). Conclusions Ginger root extract improved glucose homeostasis in diabetic rats, in part, via improving intestinal integrity and mitochondrial dysfunction of GI health.

A Unified Computational Framework for a Robust, Reliable, and Reproducible Identification of Novel miRNAs From the RNA Sequencing Data.

In eukaryotic cells, miRNAs regulate a plethora of cellular functionalities ranging from cellular metabolisms, and development to the regulation of biological networks and pathways, both under homeostatic and pathological states like cancer.Despite their immense importance as key regulators of cellular processes, accurate and reliable estimation of miRNAs using Next Generation Sequencing is challenging, largely due to the limited availability of robust computational tools/methods/pipelines. Here, we introduce miRPipe, an end-to-end computational framework for the identification, characterization, and expression estimation of small RNAs, including the known and novel miRNAs and previously annotated pi-RNAs from small-RNA sequencing profiles. Our workflow detects unique novel miRNAs by incorporating the sequence information of seed and non-seed regions, concomitant with clustering analysis. This approach allows reliable and reproducible detection of unique novel miRNAs and functionally same miRNAs (paralogues). We validated the performance of miRPipe with the available state-of-the-art pipelines using both synthetic datasets generated using the newly developed miRSim tool and three cancer datasets (Chronic Lymphocytic Leukemia, Lung cancer, and breast cancer). In the experiment over the synthetic dataset, miRPipe is observed to outperform the existing state-of-the-art pipelines (accuracy: 95.23% and F 1-score: 94.17%). Analysis on all the three cancer datasets shows that miRPipe is able to extract more number of known dysregulated miRNAs or piRNAs from the datasets as compared to the existing pipelines.

Correlation of changes in subclonal architecture with progression in the MMRF CoMMpass study.

Multiple myeloma (MM) is a heterogeneous plasma cell proliferative disorder that arises from its premalignant precursor stages through a complex cascade of interactions between clonal mutations and co-evolving microenvironment. The temporo-spatial evolutionary trajectories of MM are established early during myelomatogenesis in precursor stages and retained in MM. Such molecular events impact subsequent disease progression and clinical outcomes. Identification of clonal sweeps of actionable gene targets in MM could reveal potential vulnerabilities that may exist in early stages and thus potentiate prognostication and customization of early therapeutic interventions. We have evaluated clonal evolution at multiple time points in 76 MM patients enrolled in the MMRF CoMMpass study. The major findings of this study are (a) MM progresses predominantly through branching evolution, (b) there is a heterogeneous spectrum of mutational landscapes that include unique actionable gene targets at diagnosis compared to progression, (c) unique clonal gains/ losses of mutant driver genes can be identified in patients with different cytogenetic aberrations, (d) there is a significant correlation between co-occurring oncogenic mutations/ co-occurring subclones e.g., with mutated TP53+SYNE1, NRAS+MAGI3, and anticorrelative dependencies between FAT3+FCGBP gene pairs. Such co-trajectories may synchronize molecular events of drug response, myelomatogenesis and warrant future studies to explore their potential for early prognostication and development of risk stratified personalized therapies in MM.

Sertoli Cell Immune Regulation: A Double-Edged Sword.

The testis must create and maintain an immune privileged environment to protect maturing germ cells from autoimmune destruction. The establishment of this protective environment is due, at least in part, to Sertoli cells. Sertoli cells line the seminiferous tubules and form the blood-testis barrier (BTB), a barrier between advanced germ cells and the immune system. The BTB compartmentalizes the germ cells and facilitates the appropriate microenvironment necessary for spermatogenesis. Further, Sertoli cells modulate innate and adaptive immune processes through production of immunoregulatory compounds. Sertoli cells, when transplanted ectopically (outside the testis), can also protect transplanted tissue from the recipient's immune system and reduce immune complications in autoimmune diseases primarily by immune regulation. These properties make Sertoli cells an attractive candidate for inflammatory disease treatments and cell-based therapies. Conversely, the same properties that protect the germ cells also allow the testis to act as a reservoir site for infections. Interestingly, Sertoli cells also have the ability to mount an antimicrobial response, if necessary, as in the case of infections. This review aims to explore how Sertoli cells act as a double-edged sword to both protect germ cells from an autoimmune response and activate innate and adaptive immune responses to fight off infections.

Characterizing the mutational landscape of MM and its precursor MGUS.

Mutational Signatures and Tumor mutational burden (TMB) have emerged as prognostic biomarkers in cancer genomics. However, the association of TMB with overall survival (OS) is still unknown in newly diagnosed multiple myeloma (NDMM) patients. Further, the change in the mutational spectrum involving both synonymous and non-synonymous mutations as MGUS progresses to MM is unexplored. This study addresses both these aspects via extensive evaluation of the mutations in MGUS and NDMM. WES data of 1018 NDMM patients and 61 MGUS patients collected from three different global regions were analyzed in this study. Single base substitutions, mutational signatures and TMB were inferred from the variants identified in MGUS and MM patients. The cutoff value for TMB was estimated to divide patients into low TMB and high TMB (hypermutators) groups. This study finds a change in the mutational spectrum with a statistically significant increase from MGUS to MM. There was a statistically significant increase in the frequency of all the three categories of variants, non-synonymous (NS), synonymous (SYN), and others (OTH), from MGUS to MM (P<0.05). However, there was a statistically significant rise in the TMB values for TMB_NS and TMB_SYN only. We also observed that 3' and 5'UTR mutations were more frequent in MM and might be responsible for driving MGUS to MM via regulatory binding sites. NDMM patients were also examined separately along with their survival outcomes. The frequency of hypermutators was low in MM with poor OS and PFS outcome. We observed a statistically significant rise in the frequency of C>A and C>T substitutions and a statistically significant decline in T>G substitutions in the MM patients with poor outcomes. Additionally, there was a statistically significant increase in the TMB of the patients with poor outcome compared to patients with a superior outcome. A statistically significant association between the APOBEC activity and poor overall survival in MM was discovered. These findings have potential clinical relevance and can assist in designing risk-adapted therapies to inhibit the progression of MGUS to MM and prolong the overall survival in high-risk MM patients.