Role of Textural Analysis of Pretreatment 18F Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Response Prediction in Esophageal Carcinoma Patients.

Introduction: Positron emission tomography/computed tomography (PET/CT) is routinely used for staging, response assessment, and surveillance in esophageal carcinoma patients. The aim of this study was to investigate whether textural features of pretreatment 18F-fluorodeoxyglucose (18F-FDG) PET/CT images can contribute to prognosis prediction in carcinoma oesophagus patients. Materials and Methods: This is a retrospective study of 30 diagnosed carcinoma esophagus patients. These patients underwent pretreatment 18F-FDG PET/CT for staging. The images were processed in a commercially available textural analysis software. Region of interest was drawn over primary tumor with a 40% threshold and was processed further to derive 92 textural and radiomic parameters. These parameters were then compared between progression group and nonprogression group. The original dataset was subject separately to receiver operating curve analysis. Receiver operating characteristic (ROC) curves were used to identify the cutoff values for textural features with a P < 0.05 for statistical significance. Feature selection was done with principal component analysis. The selected features of each evaluator were subject to 4 machine-learning algorithms. The highest area under the curve (AUC) values was selected for 10 features. Results: A retrospective study of 30 primary carcinoma esophagus patients was done. Patients were followed up after chemo-radiotherapy and they underwent follow-up PET/CT. On the basis of their response, patients were divided into progression group and nonprogression group. Among them, 15 patients showed disease progression and 15 patients were in the nonprogression group. Ten textural analysis parameters turned out to be significant in the prediction of disease progression. Cutoff values were calculated for these parameters according to the ROC curves, GLZLM_long zone emphasis (Gray Level Zone Length Matrix)_long zone emphasis (44.9), GLZLM_low gray level zone emphasis (0.006), GLZLM_short zone low gray level emphasis (0.0032), GLZLM_long zone low gray level emphasis (0.185), GLRLM_long run emphasis (Gray Level Run Length Matrix) (1.31), GLRLM_low gray level run emphasis (0.0058), GLRLM_short run low gray level emphasis (0.005496), GLRLM_long run low gray level emphasis (0.00727), NGLDM_Busyness (Neighborhood Gray Level Difference Matrix) (0.75), and gray level co-occurrence matrix_homogeneity (0.37). Feature selection by principal components analysis and feature classification by the K-nearest neighbor machine-learning model using independent training and test samples yielded the overall highest AUC. Conclusions: Textural analysis parameters could provide prognostic information in carcinoma esophagus patients. Larger multicenter studies are needed for better clinical prognostication of these parameters.

18F-Labeled Fluoro-2-Deoxyglucose Positron Emission Tomography and Computed Tomography Findings in a Case of Atypical Presentation of Adult Cutaneous T-cell Lymphoma.

Adult cutaneous T-cell lymphoma is an uncommon malignancy with poor prognosis and is usually seen in association with human T-cell lymphotropic virus type 1. We present the case of a 25-year-old female who gave a history of extensive whole-body polypoidal cutaneous and bilateral orbital and breast swellings. Biopsy was suggestive of cutaneous T-cell lymphoma and the patient was evaluated with 18F-labeled fluoro-2-deoxyglucose positron emission tomography and computed tomography for initial staging of the disease.

Primary Cutaneous Adenoid Cystic Carcinoma Of The Chest Wall With Axillary Lymph Node Metastases And Its Management: A Case Report.

Primary cutaneous adenoid cystic carcinoma (PCACC) is a rare form of adenoid cystic carcinoma (ACC) arising commonly from the salivary gland. Less often they originate outside the head and neck region, with the scalp being the commonest cutaneous site in 40% of the cases. The presentation on the chest wall is rare, with no reports to date on axillary lymph node metastases. Here we report a case of a 65-year-old female with previously operated PCACC of the chest wall at a different center, showing uptake on positron emission tomography imaging at the site of surgical scar that w as inconclusive on needle biopsy metastasized to the axillary lymph node confirmed by needle biopsy managed with wide local excision, axillary lymph node dissection, and chest wall reconstruction with keystone island flap. The postoperative outcome was uneventful with no recurrence or axillary complications at one year's follow-up. She was advised to receive adjuvant radiotherapy; however, she refused. To conclude, though PCACC is rare, they can have an aggressive presentation, and a multidisciplinary approach is necessary for a better outcome.

18F Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Findings in a Case of Metastatic Eccrine Porocarcinoma - An Extremely Rare Malignant Adnexal Tumor.

Porocarcinoma is a rare malignant neoplasm of eccrine sweat glands representing 0.005 to 0.1% of all cutaneous tumors. As eccrine porocarcinoma carries a high risk of recurrence and metastases, early diagnosis and management are crucial to lower mortality rate. We present the case of porocarcinoma in a 69-years-old woman who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for staging the disease. PET/CT showed metabolically active multiple cutaneous lesions and also picked up lymph nodal and distant metastases to lungs and breast accurately. PET/CT is useful for accurate staging of the disease and for treatment planning.

Role of textural analysis parameters derived from FDG PET/CT in differentiating hepatocellular carcinoma and hepatic metastases.

INTRODUCTION: Texture and radiomic analysis characterize the tumor's phenotype and evaluate its microenvironment in quantitative terms. The aim of this study was to investigate the role of textural features of 18F-FDG PET/computed tomography (CT) images in differentiating hepatocellular carcinoma (HCC) and hepatic metastasis in patients with suspected liver tumors. METHODS: This is a retrospective, single-center study of 30 patients who underwent FDG PET/CT for the characterization of liver lesions or for staging a suspected liver tumor. The histological diagnosis of either primary or metastatic tumor was obtained from CT-guided biopsy, ultrasound-guided biopsy, or surgical removal of a liver lesion. The PET/CT images were then processed in commercially available textural analysis software. Region of interest was drawn over the primary tumor with a 40% threshold and was processed further to derive 42 textural and radiomic parameters. These parameters were then compared between HCC group and hepatic metastases group. Receiver-operating characteristic (ROC) curves were used to identify cutoff values for textural features with a P value <0.05 for statistical significance. RESULTS: A retrospective study of 30 patients with suspected liver tumors was done. After undergoing PET/CT, the histological diagnosis of these lesions was confirmed. Among these 30 patients, 15 patients had HCC, and 15 patients had hepatic metastases from various primary sites. Seven textural analysis parameters were significant in differentiating HCC from liver metastasis. Cutoff values were calculated for these parameters according to the ROC curves, standardized uptake value (SUV) Skewness (0.705), SUV Kurtosis (3.65), SUV Excess Kurtosis (0.653), gray-level zone length matrix_long zone emphasis (349.2), gray-level zone length matrix_long zone low gray-level emphasis (1.6), gray-level run length matrix_long run emphasis (1.38) and gray-level co-occurrence matrix_Homogeneity (0.406). CONCLUSION: Textural analysis parameters could successfully differentiate HCC and hepatic metastasis non-invasively. Larger multi-center studies are needed for better clinical prognostication of these parameters.

Cardiotoxicity as an adverse effect of immunomodulatory drugs and proteasome inhibitors in multiple myeloma: A network meta-analysis of randomized clinical trials.

We aim to determine the cumulative and comparative risk of cardiovascular events associated with different Immunomodulatory Drugs (iMiDs) and Proteasome Inhibitor (PIs) in Multiple Myeloma (MM) patients through pairwise and network meta-analysis. Electronic searches were conducted using Ovid MEDLINE, EMBASE, CINAHL, Web of Science, and Clinical Trial Registry (Clinical Trials.gov) up to May 2021. Phase 3 randomized clinical trials (RCTs) reporting cardiotoxicity in MM patients (newly diagnoses and/or relapsed) treated with iMiD and/or PI. Studies, where iMiD or PI was used alongside the chemotherapy versus placebo or no additional drugs (control) in the other arm were included. The primary outcome was the presence of cardiotoxicity after follow-up. Pairwise meta-analysis and network meta-analysis were performed using the frequentist's approach to estimate the odds ratio (OR). Twenty RCTs with 10,373 MM patients were included in this analysis. Eleven studies compared iMiDs with control, seven studies compared PIs with control, and two studies compared bortezomib against carfilzomib. CTACE high-grade (≥grade 3) cardiotoxic events were increased with iMiDs compared to their control counterpart (OR 2.05; 95% CI 1.30-3.26). Similar high-grade cardiotoxicity was also noted more frequently with PI use when compared to the control group (OR 1.67; 95% CI 1.17-2.40). Among the PIs, carfilzomib was associated with a maximum risk of cardiotoxicity (OR 2.68; 95% CI 1.63-4.40). There was no evidence of publication bias among studies. iMiDs and PIs, particularly carfilzomib, appear to be associated with increased risk of high-grade cardiovascular events in MM patients.

Primary Biliary Tuberculosis Masquerading Cholangiocarcinoma in 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

Hepatobiliary involvement is a less common manifestation of abdominal tuberculosis. We present the case of a 42-year-old female who presented with fever, abdominal pain, and jaundice of 2 months duration. 18F-fluorodeoxyglucose positron emission tomography/computed tomography done for disease evaluation suggested the likely possibility of cholangiocarcinoma but excision biopsy from periportal lymph node later confirmed a granulomatous etiology and she was successfully treated with antitubercular therapy.

Molecular docking of SARS-COV-2 Spike epitope sequences identifies heterodimeric peptide-protein complex formation with human Zo-1, TLR8 and brain specific glial proteins.

SARS-COV-2 infection causes severe respiratory tract illness leading to asphyxia and death. The onset of infection is associated with loss of smell, blurred vision, headache with bronchopulmonary symptoms. The clinical observations of neurological abnormalities lead us to address the question, does the virus enter into brain and what is the underlying mechanism of brain infection? The working hypothesis is, SARS-COV-2 Spike epitopes modify blood brain barrier and infect glial cells to induce brain inflammation in genetically diverse human population. The hypothesis is tested by determining binding or interacting ability of virus Spike epitope peptides M1Lys60 and Ala240Glu300 with human toll-like receptor 8 (TLR 8), brain targeted Vascular Cell adhesion Molecules (VCAM1) proteins, Zonula Occludens (ZO), glial cell specific protein NDRG2 and Apo- S100B. The molecular dynamic experiments are performed, and root mean square deviation (RMSD) values are determined for interactions between the Spike peptides and selected proteins. The observations demonstrate formation of heterodimeric complex between the epitope peptides and selected protein structures. The viral epitopes have ability to bind with HLA-DRB1 15:01, 07:01 or 03.01 alleles thus found immunogenic in nature. The observations altogether suggest entry of these Spike protein epitopes into human brain causes inflammation.

Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes.

Breast Cancer Research in the Caribbean: Analysis of Reports From 1975 to 2017.

PURPOSE: Breast cancer is among the leading causes of death resulting from cancer in Caribbean women. Studies examining exogenous and genetically predetermined endogenous risk factors are critical to define breast cancer susceptibility in Caribbean women. The purpose of this systematic review is to assess the existing scientific literature in the last 42 years (1975 to 2017) to describe the body of research generated for the population of this region and determine future research directions. METHODS: We selected published research articles using a combination of definite keyword searches in PubMed. Only articles presenting the Caribbean population as the focus of their research objectives were included in this analysis. RESULTS: Studies on breast cancer in the Caribbean are limited. A majority of publications on Caribbean populations were descriptive, focusing on cancer trends and clinicopathologic factors. High incidence and mortality rates for breast cancer are reported for the region, and there seem to be some differences between countries in the frequency of cases according to age at presentation. A limited number of epidemiologic, behavioral, and genetic and molecular studies were conducted in more recent years. CONCLUSION: A regional strategy for cancer registration is needed for the Caribbean to address possible underestimates of breast cancer incidence. Furthermore, behavioral, molecular, genetic, and epidemiologic investigations of breast cancer are critical to address the concerns related to currently described high incidence and mortality rates in the Caribbean.

S-Nitrosylation in Regulation of Inflammation and Cell Damage.

BACKGROUND: Cell signaling through nitric oxide (NO) is a multifaceted mechanism, which regulates metabolic activities and fate in different tissues. The peroxynitrite (ONOO-) formed as reaction product of nitric oxide radical and superoxide interacts with cell membrane phospholipids and proteins causing damage. OBJECTIVE: The reaction kinetics to form nitrotyrosine (ONOO-tyrosine) and/or nitrosylated cysteine (ONOO-cysteine) in protein molecules during posttranslational modification and nitration of lipids are therefore critical in determining cells' signaling mechanism for survival or apoptosis. RESULTS: The nitrosylation was found to modulate GPCRs and activation of guanylate cyclase as well as regulate NF-κB activation. The recent findings have shown the neuroprotective effects of S- nitrosylation, though mechanism is unclear. CONCLUSION: While keeping the background in mind, we address here the biological function of NO derivatives in medicine. We target four known compounds: SNAP, SIN- 1 chloride, SNP and GSNO to understand the effect of NO in different tissues. Here we analyze the existing findings to assess therapeutic relevance of NO-signaling during inflammation, vasodilation and tolerance.

SIRT6 deacetylase transcriptionally regulates glucose metabolism in heart.

Sirtuins are a family of enzymes, which govern a number of cellular processes essential for maintaining physiological balance. SIRT6, a nuclear sirtuin, is implicated in the development of metabolic disorders. The role of SIRT6 in regulation of cardiac metabolism is unexplored. Although glucose is not the primary energy source of heart, defects in glucose oxidation have been linked to heart failure. SIRT6+/- mice hearts exhibit increased inhibitory phosphorylation of PDH subunit E1α. SIRT6 deficiency enhances FoxO1 nuclear localization that results in increased expression of PDK4. We show that SIRT6 transcriptionally regulates the expression of PDK4 by binding to its promoter. SIRT6+/- hearts show accumulation of lactate, indicating compromised mitochondrial oxidation. SIRT6 deficiency results in decreased oxygen consumption rate and concomitantly lesser ATP production. Mechanistically, SIRT6 deficiency leads to increased FoxO1-mediated transcription of PDK4. Our findings establish a novel link between SIRT6 and cardiac metabolism, suggesting a protective role of SIRT6 in maintaining cardiac homeostasis.

Therapeutic Interventions of Tissue Specific Autoimmune Onset in Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (lupus) is a female predominant autoimmune disease. The autoreactive B cells and T helper cells together are known to develop adverse immune responses in different tissues like kidney, bone, cardiovascular and central nervous system. Progression of disease is associated with deposition of immune complex which initiates tissue damage. The therapy for lupus still includes corticosteroids to reduce allergic manifestations and inflammatory immune responses. Recent observations suggested that, mycophenolate mofetil and cyclophosphamide treatment in combination with corticosteroids have benefit in lupus therapy. METHOD: The prospect of B cell depletion by CD20 targeted monoclonal antibody Rituximab has been demonstrated in lupus patients. The CD52 specific monoclonal antibody Alemtuzumab is another proposition for lupus therapy. The drug Belimumab inhibits B cell activation by altering BAFF/APRIL signal cascade. Recent discovery of the CD22 targeted Epratuzumab also shows therapeutic prospect. The researches on new generation drugs for autoimmune lupus include search for inhibitors of CD40- CD40Ligand interactions, CD86 activation, selective modulation of complement cascades. The choice of inhibitors of transcription factor NF-κBp65 and selective modulators for estrogen receptor alpha are proposed areas of lupus drug discovery research. RESULTS & CONCLUSION: Keeping a close eye on the mechanisms of disease onset, a comprehensive view is provided on recent therapy of systemic lupus erythematosus.

Antigen presentation for priming T cells in central system.

Generation of myelin antigen-specific T cells is a major event in neuroimmune responses that causes demyelination. The antigen-priming of T cells and its location is important in chronic and acute inflammation. In autoimmune multiple sclerosis, the effector T cells are considered to generate in periphery. However, the reasons for chronic relapsing-remitting events are obscure. Considering mechanisms, a feasible aim of research is to investigate the role of antigen-primed T cells in lupus cerebritis. Last thirty years of investigations emphasize the relevance of microglia and infiltrated dendritic cells/macrophages as antigen presenting cells in the central nervous system. The recent approach towards circulating B-lymphocytes is an important area in the context. Here, we analyze the existing findings on antigen presentation in the central nervous system. The aim is to visualize signaling events of myelin antigen presentation to T cells and lead to the strategy of future goals on immunotherapy research.

Non-genomic oestrogen receptor signal in B lymphocytes: An approach towards therapeutic interventions for infection, autoimmunity and cancer.

The non-genomic membrane bound oestrogen receptor (mER) regulates intracellular signals through receptor-ligand interactions. The mER, along with G-protein coupled oestrogen receptor GPR 30 (GPER), induces diverse cell signalling pathways in murine lymphocytes. The mER isoform ER-alpha46 has recently been demonstrated in human B and T lymphocytes as an analogue receptor for chemokine CCL18, the signalling events of which are not clearly understood. Ligand-induced mER and GPER signalling events are shared with BCR, CD19 mediated intracellular signalling through phospholipase C, PIP2/IP3/PI3 mediated activation of Akt, MAP kinase, and mTOR. Oestrogen has the ability to induce CD40-mediated activation of B cells. The complete signalling pathways of mER, GPR30 and their interaction with other signals are targeted areas for novel drug development in B cells during infection, autoimmunity and cancer. Therefore, an in depth investigation is critical for determining shared signal outputs during B cell activation. Here, we focus on the mode of action of membrane bound ER in B cells as therapeutic checkpoints.

Humanized Monoclonal Antibody Alemtuzumab Treatment in Transplant.

Successful attenuation of allograft rejection rate is a major clinical aspect in transplant. The CD52 binding monoclonal antibody CAMPATH1 or alemtuzumab, in this aspect, shows a promise as an effective immunomodifier. This humanized monoclonal antibody efficiently depletes CD52-bearing mature B- and T lymphocytes from circulation and thereby causes transient lymphopenia, a condition for generalized immunosuppression. Alemtuzumab is an approved drug for the treatment of B cell chronic lymphocytic leukemia. However, its implication in transplant as nonsteroidal drug is a growing area of investigation. Here, we provided a brief account on alemtuzumab as an immunomodifier in allotransplant.

Estrogen receptor signal in regulation of B cell activation during diverse immune responses.

The role of signalling through oestrogen receptors (ERs) in the regulation of B cell activation is an area of growing importance not only in terms protective immunity but also in the determination of the mechanisms of the onset of autoimmune disorders and cancers. The mode of signalling action of this single chain nuclear receptor protein molecule depends on its ability to bind to the promoters of Pax5, HOXC4 and apolipoprotein B RNA-editing enzyme activation-induced cytidine deaminase (AID) genes. ER-mediated transcriptional regulation induces class switch recombination of the immunoglobulin heavy chain variable (VH) to DH-JH genes and somatic hypermutation in developing B cells. The mode of action of ER is associated with BCR-signal pathways that involve the regulator proteins BAFF and APRIL. Additionally, the plasma membrane-bound G protein-coupled oestrogen receptor-1 (GEPR1) directs diverse cell signalling events in B cells that involve the MAPK pathways. These signals are immensely important during progenitor and precursor B cell activation. We have focused our goals on the medicinal aspects of ER-signalling mechanisms and their effects on polyclonal B cell activation.

Immunotherapeutic Impact of Toll-like Receptor Agonists in Breast Cancer.

Onset of tumors in breast cancer is a multi-factorial event at different ages and ethnic populations. The conventional treatment strategy suggests use of anti-estrogen drugs and selective estrogen receptor modulators (SERMs). Although, this strategy has achieved significant success to prevent tumor growth and metastasis and is still developing under an active field of research, the emergence of immunotherapy is a potential modern approach for breast cancer. In addition to SERMs, the screening of selective agonists for toll-like receptor (TLR) signals confers a new area of breast cancer therapy. Recent investigations also indicate significance of TLR signals in the regulation of tumor suppressor p53 gene expression. The TLR agonists have an ability to facilitate activation of natural killer cells, CD8 T cells, B cells, and alpha and beta interferons and induce cellular cytotoxicity. The ongoing developments in cancer research also suggested an approach for intra-tumoral generation of cellular cytotoxicity to induce apoptosis. Both of these events promote destruction of tumor cells in a localized manner and thus, having impact on immunotherapy. Keeping a cautious eye on the context, we propose the prospect of TLR signals in the development of therapy for breast cancer.

Estrogen receptor alpha modulates mesangial cell responses to toll-like receptor ligands.

The female predominance in lupus is incompletely understood. The mechanisms for this difference are multifactorial involving the sex chromosomes, the hormones, and their receptors. We, and others, demonstrated that estrogen receptor alpha (ERα)-deficient female mice developed significantly less lupus-like renal disease. This protective effect of ERα deficiency occurred despite no impact on glomerular immune complex deposition. We hypothesized that decreased renal disease in ERα-deficient mice was due to a dampened renal response to inflammatory stimuli. Given the role of Toll-like receptors (TLRs) in lupus, we assessed whether there was an interaction between TLR responses and ERα. Herein, we show that TLR3, 4, and 7 ligands all enhanced mesangial cell (MC) ERα expression, whereas neither estrogen, nor ERα, impacted TLR3, 4, or 7 expression in MCs. The lack of ERα markedly decreased MC production of interleukin 6 and monocyte chemoattractant protein 1 (MCP-1) following addition of TLR3, 4, and 7 ligands. In MCs, TLR ligands induced ERα phosphorylation and nuclear localization. TLR3-induced nuclear factor κB nuclear translocation in MCs was not significantly affected by estrogen or ERα. Finally, we demonstrate that female MCs express more TLR3 and respond to TLR ligands with a significantly increased production of interleukin-6 compared with male MCs. These results identify a significant impact/interaction of ERα in TLR-mediated inflammatory responses in MCs.

Estrogen receptor-alpha mediates Toll-like receptor-2 agonist-induced monocyte chemoattractant protein-1 production in mesangial cells.

TLR2 agonists are well known for inducing NF-kB activation and inflammation, while estrogen receptor-alpha (ER-α) is a regulator of estrogen-mediated anti-inflammatory responses. In the present work, we determined the role of ER-α and phosphorylated ER-α in TLR2 agonist-induced MCP1 production in mesangial cells. We found that TLR2 agonists induced nuclear localization of phospho-ER-α (serine 118), and estrogen and TLR2 agonists both induced phosphorylation of ER-α at the serine 118 and 104/106 positions. Incubation of MRL/lpr mesangial cells with estrogen was found to attenuate TLR2 agonist-mediated MCP1 production. To determine the mode of action of ER-α/pER-α (serine-118), we used the ER-α inhibitor MPP and transfected mesangial cells with ER-α siRNA. ER-α inhibition was found to decrease MCP1 production in mesangial cells. Thus, ER-α/pER-α is an intermediate regulator for both TLR2-mediated MCP1 production during inflammation and estrogen-mediated anti-inflammatory signals in mesangial cells.