Inhibition of Ephrin B2 Reverse Signaling Abolishes Multiple Myeloma Pathogenesis.

Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes. SIGNIFICANCE: Ephrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.

Recurrent Desmoid Fibromatosis of the Thyroid Gland: A Diagnostic Challenge.

A 31-year-old Indian female with a history of near-total thyroidectomy 2.5 years prior presented with recurrent neck swelling. Magnetic resonance imaging (MRI) of the neck revealed an infiltrating mass involving the thyroid bed. Biopsy from the mass and review of slides from the previous thyroidectomy revealed a spindle cell tumour with interspersed areas of fibrosis and infiltrative edges entrapping thyroid follicles. Beta-catenin immunopositivity and CTNNB1 mutation confirmed the diagnosis of fibromatosis. The case is being reported for its rarity and the discussion of its differential diagnoses.

Metabolic switching of estrogen-related receptor alpha in breast cancer aggression.

Orphan nuclear receptor estrogen-related receptor alpha (ERRα) is an important regulator of energy metabolism, whereas its hyperactivation in breast cancer has been shown to regulate cell migration, proliferation, and tumour development. These findings suggest a fine balance in the status of ERRα in regulating metabolic homeostasis or promoting cancer progression. In this issue, Brindisi et al. have shown that ERRα is endogenously activated by cholesterol and caused breast cancer aggressiveness. This study also supports the anti-tumour mechanisms of cholesterol-lowering drugs such as statins.

Gastric Outlet Obstruction Following Recurrent Pancreatitis Uncovers a Giant Parathyroid Adenoma: A Case Report.

A 35-year-old female presented with abdominal pain, fever, projectile vomiting, and a diffuse tender epigastric mass. She was diagnosed to have acute persistent pancreatitis with a pancreatic pseudocyst. Elevated serum calcium levels provided an etiologic link between hypercalcemia and pancreatitis. On examination, a nodule was found in the left side of her neck which was later diagnosed as a giant left inferior parathyroid adenoma. This report highlights the critical analysis of history, examination, and investigations to reach an ultimate diagnosis. Pseudocyst drainage and parathyroidectomy resolved her symptoms.

Laparoscopic management of type VI choledochal cyst with common bile duct stone: report of a case and review of literature.

A young adult male presented with biliary colic and intermittent jaundice for 1 year. Abdomen findings were unremarkable. Routine investigations revealed a raised total bilirubin. On abdominal ultrasonography, common bile duct (CBD) dilatation with multiple stones was noted. On further imaging with magnetic resonance cholangiopancreatography, type I choledochal cyst (CDC) was suspected. A laparoscopic approach was planned. Intraoperatively, dilatation of cystic duct was noted which constitute type VI CDC. Partial malrotation of the gut and accessory right hepatic artery were also noted as incidental finding. Laparoscopic cholecystectomy with CBD exploration and removal of stones, biliary stent placement, cystic duct cyst excision and primary repair of CBD was done. Postoperatively, the patient improved symptomatically with a fall in bilirubin to normal range. We are describing the laparoscopic management of a rare case of type IV CDC which was diagnosed intraoperatively.

A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's Disease and Type 2 Diabetes.

Alzheimer's Disease (AD) and Type 2 Diabetes (T2D) share a common hallmark of insulin resistance. Reportedly, two non-canonical Receptor Tyrosine Kinases (RTKs), ALK and RYK, both targets of the same micro RNA miR-1271, exhibit significant and consistent functional down-regulation in post-mortem AD and T2D tissues. Incidentally, both have Grb2 as a common downstream adapter and NOX4 as a common ROS producing factor. Here we show that Grb2 and NOX4 play critical roles in reducing the severity of both the diseases. The study demonstrates that the abundance of Grb2 in degenerative conditions, in conjunction with NOX4, reverse cytoskeletal degradation by counterbalancing the network of small GTPases. PAX4, a transcription factor for both Grb2 and NOX4, emerges as the key link between the common pathways of AD and T2D. Down-regulation of both ALK and RYK through miR-1271, elevates the PAX4 level by reducing its suppressor ARX via Wnt/ß-Catenin signaling. For the first time, this study brings together RTKs beyond Insulin Receptor (IR) family, transcription factor PAX4 and both AD and T2D pathologies on a common regulatory platform.

Pleomorphic liposarcoma of the male breast: lessons from a rare malignancy during COVID-19 pandemic.

A 52-year-old man presented with a recurrent right side breast lump. He had undergone excision of a lump on the right breast followed by adjuvant chemoradiotherapy 1 year ago for a diagnosis of pleomorphic liposarcoma. Imaging revealed a 47×36 mm lesion on the right side of the chest wall involving the pectoralis muscle. The patient underwent right radical mastectomy. Histology of the specimen showed an undifferentiated pleomorphic sarcoma infiltrating into the underlying skeletal muscle. Therefore, he was planned for chemoradiotherapy. But due to lockdown during the COVID-19 pandemic, he was lost to follow-up and later presented with malignant pleural effusion. This case emphasises the impact of COVID-19 pandemic over such rare malignancies.

Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management.

Giant secretory multifocal adrenal myelolipoma: a diagnostic dilemma.

A 38-yearr-old man presented with erectile dysfunction and infertility. On examination, he was hypertensive and detected to have a left flank mass. Blood investigations were unremarkable except raised serum noradrenaline levels. Imaging revealed multiple well-defined fat-containing hypodense lesions in left suprarenal area with largest one measuring 14×16 cm, suggestive of left adrenal myelolipoma. Diagnostic dilemma was posed due to discordance between clinical, biochemical and imaging findings. Left adrenal mass resection was planned keeping the possibility of pheochromocytoma. However, histopathology revealed it to be adrenal myelolipoma. Hypertension was resolved in the postoperative period and serum noradrenaline levels were normalised. Final diagnosis of a secretary adrenal myelolipoma was made, which is an extremely rare entity.

Mucuna pruriens in Parkinson's and in some other diseases: recent advancement and future prospective.

Mucuna pruriens (Mp) is an annual and perennial legume which belongs to the family Fabaceae having different types of therapeutic activity. Anti-oxidative, anti-inflammatory, anti-epileptic, anti-microbial, etc. are the example of some most common activities of Mp. It is widely utilized as a potent aphrodisiac. The anti-Parkinsonian activity of Mp was explored since the nineteenth century. The neuroprotective activity of Mp was shown by several researchers. Levodopa (L-DOPA) is the important constituents responsible for the anti-Parkinsonian activity of Mp. Apart from L-DOPA, several other important bioactive components like Ursolic acid (UA) and Betulinic acid (BA) also exhibit a similar neuroprotective activity. Parkinson's disease (PD) is mainly sporadic. A very small proportion shows the genetic nature of PD. The anti-Parkinsonian activity of Mp was explored in different toxin-induced PD models as like MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), Rotenone, Paraquat, 6-hydroxydopamine (6-OHDA) as suggested by several pieces of literature. Various parts of Mp's like seed, leaf, and stem exhibit potent neuroprotective attributes. Among different parts, seeds are widely utilized as anti-PD agents because of the higher percentage of L-DOPA. Besides anti-PD activity, Mp's neuroprotective potential was also explored in the ischemic model of stroke that also shows positive results. Recently, several clinical trials have been performed on the anti-PD activity of Mp on PD patients that show convincing results. Although, a small population-based study needs to be further validated in the broader population. Apart from anti-PD activity, Mp also shows its therapeutic activity in some other diseases like cancer, diabetes, skin infection, anemia, antihypertensive, etc. that are summarized in Table 1. In this review, we have discussed the anti-PD potential of Mp in the sporadic and genetic model along with some clinical trials that have performed on PD patients. Some other activity of Mp is also summarized in this review. There is a strong need to test the efficacy of Mp in some other neurodegenerative diseases along with PD. Following this, this review emphasizes the role of Mp in PD systematically through literature analysis available to date. [Table: see text].

Protocol to Generate Senescent Cells from the Mouse Hepatic Cell Line AML12 to Study Hepatic Aging.

Previously developed senescent primary fibroblast models have limited relevance to study age-related changes in metabolically active tissues such as the liver. Here, we describe a protocol to generate senescent cells from the mouse hepatic cell line, AML12. These senescent cells exhibit molecular and metabolic signatures that are similar to those observed in livers from aged mice. These senescent AML12 cells should be a useful in vitro model to study the metabolic effects of aging in the liver. For complete details on the use and execution of this protocol, please refer to Singh et al. (2020).

Decreased autophagy and fuel switching occur in a senescent hepatic cell model system.

Although aging in the liver contributes to the development of chronic liver diseases such as NAFLD and insulin resistance, little is known about the molecular and metabolic details of aging in hepatic cells. To examine these issues, we used sequential oxidative stress with hydrogen peroxide to induce premature senescence in AML12 hepatic cells. The senescent cells exhibited molecular and metabolic signatures, increased SA-ßGal and γH2A.X staining, and elevated senescence and pro-inflammatory gene expression that resembled livers from aged mice. Metabolic phenotyping showed fuel switching towards glycolysis and mitochondrial glutamine oxidation as well as impaired energy production. The senescent AML12 cells also had increased mTOR signaling and decreased autophagy which likely contributed to the fuel switching from ß-oxidation that occurred in normal AML12 cells. Additionally, senescence-associated secretory phenotype (SASP) proteins from conditioned media of senescent cells sensitized normal AML12 cells to palmitate-induced toxicity, a known pathological effect of hepatic aging. In summary, we have generated senescent AML12 cells which displayed the molecular hallmarks of aging and also exhibited the aberrant metabolic phenotype, mitochondrial function, and cell signaling that occur in the aged liver.

Malignant Brenner tumour of the ovary manifesting as distal intestinal obstruction and perforation.

A rare case of malignant Brenner tumour of ovary manifesting with intestinal perforation due to colonic infiltration is elaborated in the present report. Brenner's tumour accounts for 1%-2% of all ovarian neoplasms and malignant Brenner tumour is even rarer and only about 5% of Brenner tumours are malignant. A 62-year-old woman came to surgical emergency with 1-month history of abdominal pain, vomiting and constipation with a palpable mass in right iliac fossa. Abdominal radiograph was suggestive of colonic obstruction. Contrast-enhanced CT of the abdomen revealed cystic right ovarian mass of 10.2×8.8 cm2 with pneumoperitoneum. Exploratory laparotomy was done, which revealed mass arising from right ovary involving terminal ileum, cecum and ascending colon. Possibility of ovarian malignancy was kept. Patient underwent debulking surgery along with ileostomy and descending colon mucous fistula was created. Histology was compatible with malignant Brenner tumour of the ovary.

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases.

The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism. ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including those involved in mitochondrial turnover and autophagy. Although ESRRA activity is well-characterized in several types of cancer, recent reports suggest that it also has an important role in metabolic diseases. This minireview focuses on the regulation of cellular metabolism and function by ESRRA and its potential as a target for the treatment of metabolic disorders.

Ileosigmoid knotting: an unusual cause of acute intestinal obstruction with bowel gangrene.

Ileosigmoid knotting (ISK) is a rare cause of intestinal obstruction rapidly progressing to bowel gangrene. It is characterised by the wrapping of loops of ileum and sigmoid colon around each other. The condition often remains undiagnosed preoperatively; however, it can be suspected by the triad of small bowel obstruction, radiographic features suggestive of predominately large bowel obstruction and inability to deflate the intestine by a sigmoidoscope. We are reporting a case of 56-year-old man who presented with features of acute intestinal obstruction and compensated shock within 24 hours of onset of symptoms. Exploratory laparotomy revealed ISK resulting in gangrene of ileum and sigmoid colon. In view of haemodynamic instability, end ileostomy was done after excising gangrenous segments. The patient improved and stoma closure and ileocolic anastomosis were done after 3 months in follow-up.

The Role of PI3K/Akt and ERK in Neurodegenerative Disorders.

Disruption of Akt and Erk-mediated signal transduction significantly contributes in the pathogenesis of various neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's diseases, Huntington's disease, and many others. These regulatory proteins serve as the regulator of cell survival, motility, transcription, metabolism, and progression of the cell cycle. Therefore, targeting Akt and Erk pathway has been proposed as a reasonable approach to suppress ND progression. This review has emphasized on involvement of Akt/Erk cascade in the neurodegeneration. Akt has been reported to regulate neuronal toxicity through its various substrates like FOXos, GSK3ß, and caspase-9 etc. Akt is also involved with PI3K in signaling pathway to mediate neuronal survival. ERK is another kinase which also regulates proliferation, differentiation, and survival of the neural cell. There has also been much progress in developing a therapeutic molecule targeting Akt and Erk signaling. Therefore, improved understanding of the molecular mechanism behind the regulatory aspect of Akt and Erk networks can make strong impact on exploration of the neurodegenerative disease pathogenesis.

Primary enterolithiasis with intestinal tuberculosis: rare presentation of a common disease.

Enterolithiasis is the formation of intestinal calculi due to stasis. Tubercular strictures resulting in intestinal stasis provide a favourable environment for enterolith formation. Intestinal tuberculosis occurs commonly in India, but coexistent enterolithiasis has been reported rarely. We are describing three cases of enterolithiasis secondary to tubercular intestinal strictures among female patients in the fourth to fifth decades of life, all of them having pulmonary tuberculosis in the past. All the cases presented with features of subacute intestinal obstruction. X-ray abdomen done for all of them revealed single to multiple round, oval and rectangular, radio-opaque shadows suggestive of stones. Coexistence of enterolithiasis with intestinal tuberculosis may worsen the symptoms of intestinal obstruction and surgery remains the mainstay of treatment. All the patients underwent exploratory laparotomy, resection and anastomosis of the diseased bowel and antitubercular therapy was started. Two patients responded well to the treatment and the third one expired due to cardiac comorbidity.

Novel Transcriptional Mechanisms for Regulating Metabolism by Thyroid Hormone.

The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actions by TH, the post-translational modification of THR, the THR co-regulation of transcription with other nuclear receptors and transcription factors, and the microRNA (miR) control of RNA transcript expression to encode proteins involved in the cellular metabolism. Together, these novel mechanisms enlarge and diversify the panoply of metabolic genes that can be regulated by TH.

Azadiradione Restores Protein Quality Control and Ameliorates the Disease Pathogenesis in a Mouse Model of Huntington's Disease.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expansion of CAG repeats in the coding area of huntingtin gene. In the HD brain, mutant huntingtin protein goes through proteolysis, and its amino-terminal portion consisting of polyglutamine repeats accumulate as inclusions that result in progressive impairment of cellular protein quality control system. Here, we demonstrate that partial rescue of the defective protein quality control in HD model mouse by azadiradione (a bioactive limonoids found in the seed of Azadirachta indica) could potentially improve the disease pathology. Prolonged treatment of azadiradione to HD mice significantly improved the progressive deterioration in body weight, motor functioning along with extension of lifespan. Azadiradione-treated HD mice brain also exhibited considerable decrease in mutant huntingtin aggregates load and improvement of striatal pathology in comparison with age-matched saline-treated HD controls. Biochemical analysis further revealed upregulation and activation of not only HSF1 (master regulator of protein folding) but also Ube3a (an ubiquitin ligase involved in the clearance of mutant huntingtin) in azadiradione-treated mice. Our results indicate that azadiradione-mediated enhanced folding and clearance of mutant huntingtin might underlie improved disease pathology in HD mice and suggests that it could be a potential therapeutic molecule to delay the progression of HD.

BH3-only protein BIM: An emerging target in chemotherapy.

BH3-only proteins constitute major proportion of pro-apoptotic members of B-cell lymphoma 2 (Bcl-2) family of apoptotic regulatory proteins and participate in embryonic development, tissue homeostasis and immunity. Absence of BH3-only proteins contributes to autoimmune disorders and tumorigenesis. Bim (Bcl-2 Interacting Mediator of cell death), most important member of BH3-only proteins, shares a BH3-only domain (9-16 aa) among 4 domains (BH1-BH4) of Bcl-2 family proteins and highly pro-apoptotic in nature. Bim initiates the intrinsic apoptotic pathway under both physiological and patho-physiological conditions. Reduction in Bim expression was found to be associated with tumor promotion and autoimmunity, while overexpression inhibited tumor growth and drug resistance as cancer cells suppress Bim expression and stability. Apart from its role in normal homeostasis, Bim has emerged as a central player in regulation of tumorigenesis, therefore gaining attention as a plausible target for chemotherapy. Regulation of Bim expression and stability is complicated and regulated at multiple levels viz. transcriptional, post-transcriptional, post-translational (preferably by phosphorylation and ubiquitination), epigenetic (by promoter acetylation or methylation) including miRNAs. Furthermore, control over Bim expression and stability may be exploited to enhance chemotherapeutic efficacy, overcome drug resistance and select anticancer drug regimen as various chemotherapeutic agents exploit Bim as an executioner of cell death. Owing to its potent anti-tumorigenic activity many BH3 mimetics e.g. ABT-737, ABT-263, obatoclax, AT-101and A-1210477 have been developed and entered in clinical trials. It is more likely that in near future strategies commanding Bim expression and stability ultimately lead to Bim based therapeutic regimen for cancer treatment.