👤 Roopan Dhaliwal

Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital neurocutaneous disorder characterized by ocular, skin, and central nervous system manifestations. Despite its recognizable clinical features, such as nevus psiloliparus, histopathologic characterization of ECCL remains limited in the dermatopathology literature, and diagnosis is often clinical. This scarcity of published histopathological descriptions makes diagnostic confirmation challenging and underscores the value of synthesizing the available evidence. This comprehensive review synthesizes reported histopathological findings across cutaneous manifestations highlighting key tissue-level features that may aid diagnostic confirmation. Additionally, we review the emerging role of molecular diagnostics, particularly the identification of mosaic activating mutations in Show less

Gallbladder cancer (GBC) is a common gastrointestinal malignancy noted for its aggressive characteristics and poor prognosis, which is mostly caused by delayed detection. However, the scarcity of information regarding somatic mutations in Indian patients with GBC has hampered the development of efficient therapeutic options. In the present study, the authors attempted to bridge this gap by revealing the mutational profile of GBC. To evaluate the somatic mutation profile, whole exome sequencing (WES) was performed on 66 tumor and matched blood samples from individuals with GBC. Somatic variant calling was performed using GATK pipeline. Variants were annotated at pathogenic and oncogenic levels, using ANNOVAR, VEP tools and the OncoKB database. Mutational signature analysis, oncogenic pathway analysis and cancer driver genes identification were performed at the functional level by using the maftools package. Our findings focused on the eight most altered genes with pathogenic and oncogenic mutations: TP53, SMAD4, ERBB3, KRAS, ARID1A, PIK3CA, RB1, and AXIN1. Genes with pathogenic single nucleotide variations (SNVs) were enriched in oncogenic signaling pathways, particularly RTK-RAS, WNT, and TP53 pathways. Furthermore, our research related certain mutational signatures, such as cosmic 1, cosmic 6, and cosmic 18, 29, to known characteristics including patient age and tobacco smoking, providing important insights into disease etiology. Given the scarcity of exome-based sequencing studies focusing on the Indian population, this study represents a significant step forward in providing a framework for additional in-depth mutational analysis. Genes with substantial oncogenic and pathogenic mutations are promising candidates for developing targeted mutation panels, particularly for GBC detection. Show less

Our case report is of an elderly male with a history of IgM κ lymphoplasmacytic lymphoma (LPL) presenting with generalized neuropathy and weakness. Due to his LPL history and worsening renal function, he underwent a renal biopsy revealing the presence of μ heavy and λ light chains, revealing a diagnosis of amyloidosis with unbound heavy & light chains (AHL), a rare type of amyloidosis. His bone marrow biopsy demonstrated κ light chain restriction by flow cytometry and amyloid deposition. The patient's serum had elevated free κ and λ light chains with a free light chain (FLC) ratio of 3.17. Serum immunofixation was positive for IgM κ and λ light chain clones. He completed six cycles of cyclophosphamide, bortezomib, dexamethasone, and rituximab (CyBorD+R), normalizing the FLC ratio. Still, he continued to present with persistently elevated M protein, IgM κ, and λ light chains on immunofixation. Thereafter, daratumumab, a human monoclonal antibody directed against CD38 expressed on myeloma cells was initiated, which led to a negative immunofixation study after two cycles accompanied by a reduction in protein excretion in the urine. The patient achieved a complete hematological response with daratumumab. To date, our case is the only reported μ heavy and λ light chain amyloidosis patient with bi-clonal (IgM κ and λ) gammopathy to be successfully treated with daratumumab. Show less

Exercise reduces cognitive aging, neurodegeneration, and Alzheimer's disease (AD) risk. Acute exercise reduces the activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in the production of Aβ. However, mechanisms mediating these effects remain largely unknown. Work has implicated brain-derived neurotrophic factor (BDNF) in the processing of amyloid precursor protein (APP). BDNF is an exercise-induced neurotrophin known for its role in synaptic plasticity, neurite growth, and neuronal survival. Previously, our lab has shown using an ex vivo model that treatment of the prefrontal cortex with BDNF reduced BACE1 activity, highlighting a BDNF to BACE1 link. The purpose of this research was to examine whether BDNF treatments resulted in similar biochemical adaptations to APP processing as exercise training. Male C57BL6/J mice were assigned into one of four groups ( Show less

The success of immune checkpoint therapy shows tumor-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumor micro-environment (TME). Cancer associated fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localize with T cells in non-small cell lung cancer. We demonstrate the bidirectional nature of CAF/T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bidirectional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells. Show less

Metabolic syndrome (MetS) comprises a cluster of risk factors including central obesity, hypertension, dyslipidemia, and impaired glucose homeostasis. Lifestyle interventions that promote improvements in diet quality and physical activity represent a first line of therapy for MetS. However, varying responses to lifestyle interventions are well documented and may be partially explained by underlying genetic differences. The aim of this study was to investigate if variants in genes previously associated with MetS influence the magnitude of change in MetS risk during a 1-year lifestyle intervention. The present study used data collected from the Canadian Health Advanced by Nutrition and Graded Exercise study cohort (n = 159 men and women) to investigate the effect of 17 candidate single nucleotide polymorphisms (SNPs) on response to a 1-year lifestyle intervention. Associations between SNPs and the continuous MetS (cMetS) score, as well as individual MetS components, were examined. Reductions in cMetS score at both 3 months and 1 year were significantly associated with 2 variants: rs662799 (A/G) in apolipoprotein A5 (APOA5) and rs1501299 (G/T) in adiponectin (ADIPOQ). Individuals carrying a minor T allele in rs1501299 experienced a greater reduction in cMetS score at both 3 months and 1 year, whereas major allele AA homozygotes in rs662799 experienced greater reductions in cMetS score during the intervention. No associations were identified between the aforementioned SNPs and individual components of MetS. Both un-weighted and weighted genetic risk scores (GRS) using these 2 SNPs revealed that individuals carrying none of the risk alleles experienced significantly greater reductions in cMetS score after 1 year. The findings from the current study suggest that individuals with certain genotypes may benefit more from a lifestyle intervention for MetS and that specific variants, either independently or as part of a GRS, could be used as a nutrigenomic tool to tailor the intervention to reduce the risk of MetS. Show less

To investigate the in vitro effects of atorvastatin on lipopolysaccharide (LPS)-induced gene expression in endometrial-endometriotic stromal cells. In vitro experimental study using flow cytometry, ELISA, semiquantitative reverse transcriptase polymerase chain reaction, and Western blot. Postgraduate Institute of Medical Education and Research. Twenty-five women undergoing laparoscopy (n = 10) and laparotomy (n = 15). Endometriotic cyst wall (group I) and endometrial biopsy (group II) collection. The endometrial-endometriotic stromal cells were isolated from ectopic (group I) and eutopic (group II) endometrium by established methods, cultured, and stimulated with LPS (1 μg/mL), followed by atorvastatin treatment in a time- and dose-dependent manner to investigate the effects of LPS on proliferation (Ki-67) and expression of cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), receptor for advanced glycation end products (RAGE), extracellular newly identified RAGE binding protein (EN-RAGE), peroxisome proliferator activated receptor-γ (PPAR-γ), and liver X receptor-α (LXR-α) genes in endometrial-endometriotic stromal cells and on levels of insulin-like growth factor binding protein-1 (IGFBP-1) and 17β-E(2) in endometrial-endometriotic stromal cell culture supernatant. Significant inhibition of Ki-67 and LPS-induced expression of inflammatory and angiogenic genes (COX-2, VEGF, RAGE, and EN-RAGE) was observed in atorvastatin-treated endometrial-endometriotic stromal cells. In contrast, a significant dose- and time-dependent increase in expression of anti-inflammatory genes (PPAR-γ and LXR-α) and levels of IGFBP-1 was observed after atorvastatin treatment in both the groups. However, atorvastatin treatment had no effect on 17β-E(2) levels in endometrial/endometriotic stromal cell culture supernatant. The data of the present study provide new insights for the implication of atorvastatin treatment for endometriosis in humans. Show less