Significance and implications of FHIT gene expression and promoter hypermethylation in acute lymphoblastic leukemia (ALL).

BACKGROUND: Fragile histidine triad (FHIT) has been documented to play a vital role in various cancers including acute lymphoblastic leukemia (ALL). Keeping in view the plausible role of FHIT gene, we aimed to examine DNA promoter hypermethylation and mRNA expression in ALL cases in Kashmir (North India). METHODS: A total of 66 cases of ALL were analyzed for FHIT mRNA expression and promoter methylation by qRT-PCR and Methylation Specific-PCR (MS-PCR) respectively. RESULTS: FHIT mRNA expression showed significantly decreased expression in ALL cases with mean fold change of 9.24 ± 5.44 as compared to healthy controls (p = 0.01). The pattern of FHIT deregulation in ALL cases differed significantly between decreased and increased expression (p < 0.0001). A threefold decreased expression was observed in 75% of ALL cases than healthy controls (- 3.58 ± 2.32). ALL patients with FHIT gene promoter hypermethylation presented significantly higher in 80% (53/66) of cases (p = 0.0005). The association of FHIT gene hypermethylation and its subsequent expression showed FHIT mRNA expression as significantly lower in ALL cases with hypermethylation (p = 0.0008). B-ALL cases exhibited a highly significant association between the methylation pattern and its mRNA expression (p = 0.000). In low range WBC group, a significant association was found between increased expression (26%) of the cases and methylated (4%)/unmethylated group 86% (p = 0.0006). CONCLUSION: The present study conclude that FHIT gene hypermethylation and its altered expression may be linked in the pathogenesis of ALL and provide an evidence for the role of FHIT in the development of ALL.

Gastric Cancer: A Comprehensive Literature Review.

Gastric cancer stands as a significant global health concern, particularly prevalent in Eastern Asia, with high mortality rates urging urgent attention and research efforts. This article comprehensively explores the epidemiology, anatomy, risk factors, pathophysiology, clinical presentation, diagnosis, staging, treatment modalities, prevention strategies, and survival rates associated with gastric cancer. Notably, Helicobacter pylori infection, dietary choices, and intricate stomach anatomy play pivotal roles in disease development. Early detection, utilizing staging, grading, and genetic testing for personalized treatment approaches is emphasized. Treatment modalities encompass surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Prevention strategies involve lifestyle changes, screening, and genetic counseling. Survival rates vary by stage, highlighting the need for individualized care. In conclusion, a collaborative global effort is essential to address the impact of gastric cancer and improve outcomes.

Preoperative prescription opioid use as an independent predictor of 90-day mortality and adverse events in craniotomy and craniectomy patients.

OBJECTIVE: A growing body of literature suggests that preoperative opioid exposure is an independent predictor of poor outcomes in surgical patients. No outcomes data exist on preoperative opioid use and craniotomies/craniectomies. The objective of this study was to determine the impact of preoperative opioid use on 90-day adverse events after craniotomy or craniectomy. METHODS: A single-center retrospective cohort study of 2445 patients undergoing a craniotomy/craniectomy between January 1, 2013, and October 1, 2018, was conducted. Baseline demographics, pre- and postoperative opioid use (morphine milligram equivalents [MMEs]), and surgical metrics were recorded. Patients were categorized based on whether they took prescription opioids preoperatively, defined as within 1 month of surgery, or were opioid naive. The outcomes were mortality and adverse events 90 days after craniotomy/craniectomy. RESULTS: Overall, 26.6% of patients composed the preoperative opioid group. The median daily MME intake among this group was 34.6 (IQR 14.1-90) MMEs. Lower employment rates (p < 0.001), uninsured status (p = 0.016), and intravenous drug use (p = 0.006) were associated with preoperative opioid use. Preoperative opioid use was associated with increased venous thromboembolism (p = 0.001), acute kidney injury (p = 0.002), acute respiratory failure (p < 0.001), myocardial infarction (p = 0.002), delirium (p < 0.001), and infection (p < 0.001). Preoperative opioid use was an independent predictor of overall 90-day adverse events (OR 1.643, 95% CI 1.289-2.095; p < 0.001) and 90-day mortality (OR 1.690, 95% CI 1.254-2.277; p < 0.001). CONCLUSIONS: Preoperative opioid use was independently associated with 90-day postoperative adverse events and mortality. Opioid use increases vulnerability in craniotomy/craniectomy patients and necessitates close monitoring to improve outcomes.

Management of acute airway compromise secondary to cricoid chondroma.

The presentation of acute and rapidly deteriorating airway pathology can be a highly challenging situation for any hospital team. Cricoid chondromas are a challenging and potentially unfamiliar airway pathology requiring the combined expertise of anaesthetists, ear, nose and throat surgeons and a wider peri-operative team familiar with managing airway emergencies. Airway lesions which cause rigid and fixed stenosis require careful management and present additional challenges compared to soft tissue lesions. An important consideration in fixed airway stenosis is the external diameter of tracheal tubes compared to the diameter of the airway at its narrowest point. These are challenging cases to manage and a multi-disciplinary approach to the safe management of unfamiliar and critical airway pathology should be adopted.

Regulatory role of miR-125a expression with respect to its target genes LIFR, ERBB2 and STAT3 in the pathogenesis of recurrent pregnancy losses.

OBJECTIVES: Studies have investigated miR-125a for its predictable role in recurrent pregnancy loss (RPL) cases to regulate many biological events required for the maintenance of pregnancy by regulating its confirmed target genes LIFR, ERBB2 and STAT3. METHODS: The present study included 40 cases of women with at least two RPLs in ≤20 weeks of gestation against 40 healthy multiparous women without a previous history of abortion. Expression analysis of ERBB2, LIFR, STAT3 and miR-125a was conducted by quantitative real-time PCR (qPCR). RESULTS: The expression of miR-125a was significantly lower in the plasma of RPL cases (P = 0.0001) and showed a significantly increased mean expression level in product of conception (2.56-fold, P < 0.0001). Among the target gene of miR-125a, ERBB2 and STAT3 gene expression level was significantly increased (2.58-fold, P = 0.04; 1.87-fold, P = 0.025), respectively in RPL cases while the LIFR gene revealed comparable expression (P = 0.64). Furthermore, expression analysis of ERBB2 gene with respect to its regulatory miR-125a cases depicted a significant association (P = 0.0005). Kaplan-Meier survival analysis revealed cases with low miR-125a expression had significantly shorter time to miscarriages, (log-rank P = 0.02). Also, decreased expression of miR-125a significantly conferred >2-fold increased risk for RPL (HR = 2.34: P < 0.05). CONCLUSION: The overall conclusion of the study was that altered miR-125a expression may cause deregulation in target genes LIFR, ERBB2 and STAT3 resulting in adverse consequence in the outcome of pregnancy.

Direct Versus Indirect Revascularization for Moyamoya: a Large Multicenter Study.

BACKGROUND: Moyamoya is a chronic occlusive cerebrovascular disease of unknown etiology causing neovascularization of the lenticulostriate collaterals at the base of the brain. Although revascularization surgery is the most effective treatment for moyamoya, there is still no consensus on the best surgical treatment modality as different studies provide different outcomes. OBJECTIVE: In this large case series, we compare the outcomes of direct (DR) and indirect revascularisation (IR) and compare our results to the literature in order to reflect on the best revascularization modality for moyamoya. METHODS: We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational studies in Epidemiology guidelines of moyamoya affected hemispheres treated with DR and IR surgeries across 13 academic institutions predominantly in North America. All patients who underwent surgical revascularization of their moyamoya-affected hemispheres were included in the study. The primary outcome of the study was the rate of symptomatic strokes. RESULTS: The rates of symptomatic strokes across 515 disease-affected hemispheres were comparable between the two cohorts (11.6% in the DR cohort vs 9.6% in the IR cohort, OR 1.238 (95% CI 0.651 to 2.354), p=0.514). The rate of total perioperative strokes was slightly higher in the DR cohort (6.1% for DR vs 2.0% for IR, OR 3.129 (95% CI 0.991 to 9.875), p=0.052). The rate of total follow-up strokes was slightly higher in the IR cohort (8.1% vs 6.6%, OR 0.799 (95% CI 0.374 to 1.709) p=0.563). CONCLUSION: Since both modalities showed comparable rates of overall total strokes, both modalities of revascularization can be performed depending on the patient's risk assessment.

Exploring the interaction of tepotinib with calf thymus DNA using molecular dynamics simulation and multispectroscopic techniques.

In recent times, there has been a surge in the discovery of drugs that directly interact with DNA, influencing gene expression. As a result, understanding how biomolecules interact with DNA has become a major area of research. One such drug is Tepotinib (TPT), an FDA-approved anti-cancer medication known as a MET tyrosine kinase inhibitor, used in chemotherapy for metastatic non-small cell lung cancer (NSCLC) with MET exon 14 skipping alterations. In our study, we adopted both biophysical and in-silico methods to investigate the binding relationship of TPT and ctDNA. The absorption spectra of ctDNA exhibited a hypochromic effect when titrated with TPT and the binding constant of TPT-ctDNA complex was calculated, Ka = 9.91 × 104 M-1. By computing bimolecular enhancement constant (KB) and thermodynamic enhancement constant (KD) in fluorometric investigations, it was found that the fluorescence enhancement is a result of a static process involving the ctDNA-TPT complex formation in the ground state, as opposed to a dynamic process. The displacement assay results further supported this finding, showing that TPT exhibits a binding preference for minor groove of ct-DNA and was also demonstrated by KI quenching and CD spectroscopy. The molecular docking and molecular dynamic simulations validated TPT's groove binding nature and binding pattern with ctDNA, respectively. Thus, the results of our present investigation offer valuable insights into the interaction between TPT and ctDNA. It is evident that TPT, as an anti-cancer medication, binds to the minor groove of ctDNA.

Computational and physicochemical insight into 4-hydroxy-2-nonenal induced structural and functional perturbations in human low-density lipoprotein.

Lipid peroxidation (LPO) is a biological process that frequently occurs under physiological conditions. Undue oxidative stress increases the level of LPO; which may further contribute to the development of cancer. 4-Hydroxy-2-nonenal (HNE), one of the principal by-products of LPO, is present in high concentrations in oxidatively stressed cells. HNE rapidly reacts with various biological components, including DNA and proteins; however, the extent of protein degradation by lipid electrophiles is not well understood. The influence of HNE on protein structures will likely have a considerable therapeutic value. This research elucidates the potential of HNE, one of the most researched phospholipid peroxidation products, in modifying low-density lipoprotein (LDL). In this study, we tracked the structural alterations in LDL by HNE using various physicochemical techniques. To comprehend the stability, binding mechanism and conformational dynamics of the HNE-LDL complex, computational investigations were carried out. LDL was altered in vitro by HNE, and the secondary and tertiary structural alterations were examined using spectroscopic methods, such as UV-visible, fluorescence, circular dichroism and fourier transform infrared spectroscopy. Carbonyl content, thiobarbituric acid-reactive-substance (TBARS) and nitroblue tetrazolium (NBT) reduction assays were used to examine changes in the oxidation status of LDL. Thioflavin T (ThT), 1-anilinonaphthalene-8-sulfonic (ANS) binding assay and electron microscopy were used to investigate aggregates formation. According to our research, LDL modified by HNE results in changes in structural dynamics, oxidative stress and the formation of LDL aggregates. The current investigation must characterize HNE's interactions with LDL and comprehend how it can change their physiological or pathological functions.Communicated by Ramaswamy H. Sarma.

Antibacterial activity of Ricinus communis plant extract against antibiotic resistant Helicobacter pylori and Gluconobacter oxydans isolated from fresh apple juices samples

Abstract Bacteria were isolated from samples of Fresh Apple juices from shops of three different localities of Lahore. Analysis of samples from Liberty, Anarkali and Yateem khana Markets show different levels of contamination. There were pathogenic and non-pathogenic bacteria in all samples and were identified by the morphological and biochemical tests. Most of the plasmids of pathogenic bacteria were 4kb in their molecular size. Ribotyping of 16S ribosomal RNA gene sequencing was done to confirm Helicobacter pylori strain and Gluconobacter oxydans. The highest sensitivity of 210mm was shown by Enterobacter sp. against Aztheromysine disk (15µg) while Micrococcus sp. was highly resistant against all of the Antibiotics applied. The antibiotic resistance of pathogenic bacteria was also checked against Ricinus communis plant's extracts, all isolated bacterial pathogens were resistant but only, E.coli was inhibited at 300µl of the extracts. Presence of pathogenic bacteria in Apple juice samples was due to contamination of sewage water in drinking water while some of these pathogenic bacteria came from Apple's tree and other from store houses of fruits.

Resumo As bactérias foram isoladas de amostras de suco de maçã fresco de lojas de três diferentes localidades de Lahore. A análise de amostras dos mercados Liberty, Anarkali e Yateem khana mostram diferentes níveis de contaminação. Havia bactérias patogênicas e não patogênicas em todas as amostras e foram identificadas pelos testes morfológicos e bioquímicos. A maioria dos plasmídeos de bactérias patogênicas tinha 4 kb em seu tamanho molecular. A ribotipagem do sequenciamento do gene do RNA ribossômico 16S foi realizada para confirmar a cepa de Helicobacter pylori e Gluconobacter oxydans. A maior sensibilidade de 210 mm foi mostrada por Enterobacter sp. contra disco de azteromisina (15µg) enquanto Micrococcus sp. foi altamente resistente a todos os antibióticos aplicados. A resistência a antibióticos de bactérias patogênicas também foi verificada contra extratos de plantas de Ricinus communis, todos os patógenos bacterianos isolados foram resistentes, mas apenas E. coli foi inibida em 300µl dos extratos. A presença de bactérias patogênicas nas amostras de suco de maçã deveu-se à contaminação da água de esgoto na água potável, enquanto algumas dessas bactérias patogênicas vieram da árvore da maçã e outras de armazéns de frutas.

Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aß Aggregation for Alzheimer's Disease Therapy.

The development of multitargeted therapeutics has evolved as a promising strategy to identify efficient therapeutics for neurological disorders. We report herein new quinolinone hybrids as dual inhibitors of acetylcholinesterase (AChE) and Aß aggregation that function as multitargeted ligands for Alzheimer's disease. The quinoline hybrids (AM1-AM16) were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation. Among the tested compounds, AM5 and AM10 inhibited AChE activity by more than 80% at single-dose screening and possessed a remarkable ability to inhibit the fibrillation of Aß42 oligomers at 10 µM. In addition, dose-dependent screening of AM5 and AM10 was performed, giving half-maximal AChE inhibitory concentration (IC50) values of 1.29 ± 0.13 and 1.72 ± 0.18 µM, respectively. In addition, AM5 and AM10 demonstrated concentration-dependent inhibitory profiles for the aggregation of Aß42 oligomers with estimated IC50 values of 4.93 ± 0.8 and 1.42 ± 0.3 µM, respectively. Moreover, the neuroprotective properties of the lead compounds AM5 and AM10 were determined in SH-SY5Y cells incubated with Aß oligomers. This work would enable future research efforts aiming at the structural optimization of AM5 and AM10 to develop potent dual inhibitors of AChE and amyloid aggregation. Furthermore, the in vivo assay confirmed the antioxidant activity of compounds AM5 and AM10 through increasing GSH, CAT, and SOD activities that are responsible for scavenging the ROS and restoring its normal level. Blood investigation illustrated the protective activity of the two compounds against lead-induced neurotoxicity through retaining hematological and liver enzymes near normal levels. Finally, immunohistochemistry investigation revealed the inhibitory activity of ß-amyloid (Aß) aggregation.

A Rare Case of Co-existing Non-small Cell Lung Carcinoma and Non-tuberculous Mycobacteria.

A solitary pulmonary mass is commonly associated with malignancy; however, the possibility of co-existence with a pulmonary infection is rarely considered. Here, we present an extraordinary case, underscoring the importance of considering the possibility of concurrent lung cancer even when a bronchoscopy examination and bronchial lavage yield a positive mycobacterium culture result.

Advancements and Challenges in the Application of Artificial Intelligence in Surgical Arena: A Literature Review.

This literature review delves into the transformative potential of artificial intelligence (AI) in the field of surgery, exploring its evolution, applications, and technological advancements. AI, with its ability to mimic human intelligence, presents a paradigm shift in surgical practices. The review critically analyzes a broad range of research, encompassing machine learning, deep learning, natural language processing, and their diverse applications in preoperative planning, surgical simulation, intraoperative guidance, and postoperative analysis. Ethical, legal, and regulatory considerations, as well as challenges and future directions, are also explored. The study underscores AI's ability to revolutionize surgical visualization and its role in shaping the future of healthcare.

Journey Through Words: Exploring Esophageal Cancer in Literature.

Esophageal cancer is a significant global health challenge, characterized by its aggressive nature and high mortality rates. The disease disproportionately affects males and ranks among the leading causes of cancer-related deaths worldwide. Alarming projections indicate that the prevalence of esophageal cancer is expected to surge by approximately 140% by the year 2025. This trend starkly contrasts with the anticipated decline in incidence observed for many other types of cancers. The cancer manifests primarily in two major subtypes: esophageal squamous cell carcinoma and adenocarcinoma, each with distinct epidemiological and biological characteristics. This review provides an in-depth exploration of the risk factors, anatomy, clinical presentation, diagnosis, staging, prognosis, treatment modalities, recurrence, advancements, and emerging therapies in esophageal cancer. Additionally, preventive and early detection strategies are discussed, focusing on primary, secondary, and tertiary prevention approaches. A comprehensive understanding of esophageal cancer is vital for formulating effective management strategies and improving patient outcomes.

Beyond the Horizon: Unveiling the Frontiers of Rectal Cancer Research and Treatment.

Colorectal cancer, ranking among the most prevalent causes of cancer-related mortality, is an escalating global health concern. The incidence and mortality of colorectal cancer are expected to surge substantially by 2030, posing a significant public health challenge. This article provides a comprehensive overview of rectal cancer, encompassing its epidemiology, anatomical intricacies, pathophysiology, clinical presentation, and diagnosis. The tumor-node-metastasis (TNM) classification system for rectal cancer is detailed, offering crucial insights for staging and treatment decisions. Various treatment modalities are discussed, including surgical approaches, systemic therapies, radiation therapy, and local therapies for metastases. Recent advances in robotic surgery and innovative radiation technologies are explored. Furthermore, prevention strategies are elucidated, focusing on lifestyle modifications and pharmacological interventions that may mitigate the risk of colorectal cancer. The article underscores the importance of understanding rectal cancer for healthcare professionals and patients, enabling informed decision-making and enhanced management of this disease. Prognostic factors are outlined, with survival rates and the prognosis of rectal cancer contingent on several influential elements, highlighting the multifaceted nature of this condition. In conclusion, accurate diagnosis, diverse treatment options, and prevention strategies, including advances like robotic surgery, influence rectal cancer outcomes. A comprehensive overview empowers healthcare professionals and patients to make informed decisions for improved disease management and prognosis.

Revolutionizing Surgical Care: The Power of Enhanced Recovery After Surgery (ERAS).

The development of Enhanced Recovery After Surgery (ERAS) has brought about substantial transformations in perioperative care, substituting conventional methods with a patient-centric, evidence-based strategy. ERAS protocol adopts a holistic approach to patient care, which includes all stages preceding, during, and following the operation. These programs prioritize patient-specific therapies that are tailored to their specific requirements. Nutritional assessment and enhancement, patient education, minimally invasive procedures, and multimodal pain management are all fundamental components of ERAS. ERAS provides a multitude of advantages, including diminished postoperative complications, abbreviated hospital stays, heightened patient satisfaction, and healthcare cost reductions. This article examines the foundational tenets of ERAS, their incorporation into the field of general surgery, their suitability for diverse surgical specialties, the obstacles faced during implementation, and possible directions for further investigation, such as the integration of digital health technologies, personalized patient care, and the long-term viability of ERAS protocols.

A novel scoring system to predict survival in cirrhotic patients undergoing isolated lung transplantation: The PENS-CEPT score.

Cirrhosis is usually regarded as a contraindication to isolated lung transplantation (ILT). We sought to determine which patients with cirrhosis could safely undergo ILT. Based on a retrospective analysis of patients with cirrhosis who underwent ILT at our center between 2007 and 2020, we developed an exclusionary algorithm (PENS-CEPT: Pittsburgh ExclusioN Score in Cirrhotics Evaluated for Pulmonary Transplant) to help determine which patients can undergo ILT with minimal incurred risk from their underlying liver disease. The score utilizes a combination of readily available clinical data and the presence (or absence) of spontaneous portosystemic shunts on preoperative cross-sectional imaging. Sixteen patients underwent ILT with a diagnosis of cirrhosis: nine with cystic fibrosis. On univariate analysis, only our model was able to predict 1 year survival. Of the nine patients that would have been approved using our model, there was only one short term death. Of the seven patients that would have been rejected by the model, all but one died within the first year with six dying of complications from liver failure. We are proposing a simple score utilizing routine clinical parameters and pre-operative imaging to determine the safety of ILT in cirrhotic patients. Further studies are required to validate this scoring system with the goal of safely increasing the opportunity for cirrhotic patients who would otherwise be rejected for ILT.

Evaluation of chromosome 1p/19q deletion by Fluorescence in Situ Hybridization (FISH) as prognostic factors in malignant glioma patients on treatment with alkylating chemotherapy.

BACKGROUND: Either deletion or co-deletion of chromosomal arms 1p or 19q is a characteristic and early genetic event in oligodendroglial tumors that is associated with a better prognosis and enhanced response to therapy. Information of 1p/19q status is now regarded as the standard of care when managing oligodendroglial tumors for therapeutic options in anticipation of the increased survival and progression-free survival times associated with it. Keeping this in view, we first time attempted to establish the FISH based detection of 1p/19q deletion in glioma tissue samples to evaluate its role and involvement in the disease. METHOD: Overall 39 glioma cases of different histologies were evaluated by fluorescence in situ hybridization (FISH) technique using specific FISH probes with Olympus BX43 fluorescent microscope to detect chromosomes 1p and 19q or co-deletions therein. RESULTS: Of the 39 glioma samples, overall 27 (69.2%) were found to have deletion either in 1p, 19q or both. Deletions were observed in 23.0%, 7.6% and 38.4% in 1p, 19q and 1p/19q co-deletions respectively. Overall oligidendrioglioma presented with 53.8% (21 of 39) deletions, astrocytoma group showed 12.8% and GBM accounted for 2.5% deletions. Overall survival and disease free survival was seen significantly better in oligidendrioglioma and astrocytoma with deleted tumors as compared to non-deleted ones (p<0.05). CONCLUSION: Allelic losses on 1p and 19q, either discretely or shared, were more frequent in classic oligodendrogliomas than in either astrocytoma or Glioblastoma with better survival and response to therapy.

Incidence of hepatocellular carcinoma in nonalcoholic fatty liver disease without cirrhosis or advanced liver fibrosis.

BACKGROUND: HCC can develop in the absence of cirrhosis in patients with NAFLD. We aimed to estimate the incidence of HCC in patients with NAFLD with and without cirrhosis or advanced liver fibrosis. METHODS: We performed a cohort study to determine the incidence of HCC in patients with NAFLD identified by the International Classification of Diseases 9/10 codes in the electronic health records of a US health care system between 2004 and 2018. The incidence of HCC was stratified by the presence or absence of cirrhosis and by the Fibrosis-4 index (FIB-4) at the time of HCC diagnosis. RESULTS: Of 47,165 patients with NAFLD aged 40-89 years, 981 (2.1%) developed HCC (mean follow-up 3.4 y). Among patients with HCC, 842 (85.8%) had cirrhosis, while 139 (14.2%) did not. Of the 139 patients with HCC without cirrhosis-related diagnostic codes, 26 (2.7%) had FIB-4 >2.67 (advanced fibrosis likely), whereas 43 (4.4%) had FIB-4 < 1.30 (excluding advanced fibrosis). The annual incidence of HCC in patients with NAFLD with and without cirrhosis was 23.6 and 1.1 per 1000 person-years, respectively. Among patients without cirrhosis, the annual incidence of HCC was 2.8 per 1000 person-years with FIB-4 >2.67 and 0.7 per 1000 person-years with FIB-4 <1.30. Patients with NAFLD and cirrhosis were 31.8 times (95% CI, 23.3-43.4) more likely to develop HCC than those without cirrhosis and FIB-4 <1.30, after adjustment for age and sex. CONCLUSIONS: Patients with NAFLD without cirrhosis nor advanced fibrosis have a low incidence of HCC.

Mechanism underlying follicular hyperproliferation and oncogenesis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a skin disorder that causes chronic painful inflammation and hyperproliferation, often with the comorbidity of invasive keratoacanthoma (KA). Our research, employing high-resolution immunofluorescence and data science approaches together with confirmatory molecular analysis, has identified that the 5'-cap-dependent protein translation regulatory complex eIF4F is a key factor in the development of HS and is responsible for regulating follicular hyperproliferation. Specifically, eIF4F translational targets, Cyclin D1 and c-MYC, orchestrate the development of HS-associated KA. Although eIF4F and p-eIF4E are contiguous throughout HS lesions, Cyclin D1 and c-MYC have unique spatial localization and functions. The keratin-filled crater of KA is formed by nuclear c-MYC-induced differentiation of epithelial cells, whereas the co-localization of c-MYC and Cyclin D1 provides oncogenic transformation by activating RAS, PI3K, and ERK pathways. In sum, we have revealed a novel mechanism underlying HS pathogenesis of follicular hyperproliferation and the development of HS-associated invasive KA.

Differential expression of SLITRK6 gene as a potential therapeutic target for urothelial carcinoma in particular upper tract cancer.

BACKGROUND: Urinary bladder urothelial carcinoma (UBUC) and upper tract urothelial carcinoma (UTUC) harbor analogous morphology with comparable cytogenetic changes as well as prognostic factors but their similar biological activities still remain controversial. SLITRK6 gene has been demonstrated to have distinct role in urothelial cancers with a distinction between UTUC and UBUC. METHOD: The study included a total of 80 patients of urothelial carcinoma including 60 UBUC and 20 UTUC cases. The tumor tissues from both the groups were evaluated for gene expression at mRNA level by qRT-PCR, and protein expression by immunohistochemistry (IHC) and western blot. RESULTS: Significantly more than 4-fold high mRNA expression of SLITRK6 was observed in UTUC against 1.2-fold in UBUC (p < 0.0001). The overall SLITRK6 expression by IHC was observed in 80% of the UBUC cases in comparison to 100% strong expression in UTUC patients and among two groups expression exhibited a significant difference for moderate to strong expression (p = 0.0005). The protein expression by western blot analysis in UTUC samples was considerably higher as compared to UBUC samples (1.64 vs. 0.76 respectively: p = 0.01). A strong concordance exhibited for the higher mRNA and protein expression in both UTUC and UBUC cases (∼75%) wherein 80%, 75% and 70% higher expression of SLITRK6 was detected by qRT-PCR, Western blot and IHC respectively. CONCLUSION: To conclude, although SLITRK6 exhibits a strong expression in both UTUC and UBUC but was considerably observed higher in majority of UTUC cases. Therefore, SLITRK6 appears as a promising novel possible gene target for urothelial carcinoma in particular UTUC.