Increased alcohol dehydrogenase 1 activity promotes longevity.

Several molecules can extend healthspan and lifespan across organisms. However, most are upstream signaling hubs or transcription factors orchestrating complex anti-aging programs. Therefore, these molecules point to but do not reveal the fundamental mechanisms driving longevity. Instead, downstream effectors that are necessary and sufficient to promote longevity across conditions or organisms may reveal the fundamental anti-aging drivers. Toward this goal, we searched for effectors acting downstream of the transcription factor EB (TFEB), known as HLH-30 in C. elegans, because TFEB/HLH-30 is necessary across anti-aging interventions and its overexpression is sufficient to extend C. elegans lifespan and reduce biomarkers of aging in mammals including humans. As a result, we present an alcohol-dehydrogenase-mediated anti-aging response (AMAR) that is essential for C. elegans longevity driven by HLH-30 overexpression, caloric restriction, mTOR inhibition, and insulin-signaling deficiency. The sole overexpression of ADH-1 is sufficient to activate AMAR, which extends healthspan and lifespan by reducing the levels of glycerol-an age-associated and aging-promoting alcohol. Adh1 overexpression is also sufficient to promote longevity in yeast, and adh-1 orthologs are induced in calorically restricted mice and humans, hinting at ADH-1 acting as an anti-aging effector across phyla.

Significance of tumour budding and invasive characteristics in grading of oral squamous cell carcinoma.

Background: Tumour budding has been recognized as a morphologic marker of tumour invasion. Invasive characteristics such as depth of invasion, mode of invasion and worst pattern of invasion are potentially powerful parameters predicting the regional metastasis. Aim: This study was done to understand the significance of tumour budding and various characteristics of invasion and their impact on grading of oral squamous cell carcinoma. Materials and Methods: An immunohistochemical study was performed on tissue sections obtained from 34 paraffin-embedded blocks of clinically and histologically diagnosed cases of oral squamous cell carcinoma. The sections were stained with pan cytokeratin and observed under high power magnification. Results: Tumour budding and the invasive patterns were found to be significant in OSCC. A proposed grading system based on tumour budding and cell nest was found to have a significant correlation with the WHO grading system. Conclusion: This study demonstrated the importance of using tumour buds as an additional parameter in the grading system and also assessed the importance of invasive patterns, cellular atypia and stromal contents in OSCC.

Immunohistochemical evaluation of galectin-3 expression in oral squamous cell carcinoma, oral leukoplakia and normal mucosa.

Background: Galectin 3 (Gal-3) has diverse functions critical in cancer biology including cell proliferation, apoptosis, evasion of immune responses and angiogenesis. The expression of Gal-3 is heterogeneous in normal and neoplastic tissues. In oral squamous cell carcinoma (OSCC) and oral leukoplakia (OL), both increased and decreased expressions of Gal-3 were elicited in numerous studies. Aims: To evaluate, compare and correlate the immunohistochemical expression of Gal-3 in OSCC, OL and normal oral mucosa. Settings and Design: The study was conducted at the Department of Oral Pathology and Microbiology at PMS College of Dental Science and Research, Vattapara, Thiruvananthapuram. This is a retrospective analytical study. Methods and Material: Clinically diagnosed and histopathologically confirmed cases of OSCC (n = 21), OL (n = 21), and normal oral mucosa (n = 21) were included in the study. Paraffin-embedded tissues were subjected to immunohistochemical analysis for Gal-3 expression. Gal-3 staining expression, staining distribution and cellular localisation were evaluated. All sampled categories were compared using immunohistochemical scoring analysis such as the H-score, labelling index (LI), immunoreactive score (IRS) and staining intensity (SI). Statistical Analysis: The results were statistically analysed using multivariate analysis of variance (MANOVA) within and among the groups. Results and Conclusion: The statistical inferences obtained found that the H-score could be used as a guideline for better differentiation between the groups and among the groups. The P value obtained was < 0.0125 and was found to be significant. The observation in our study shows that the immunohistochemical expression of Gal-3 gradually decreased from normal oral mucosa to OL to OSCC.

Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions.

Plasticity in multicellular organisms involves signaling pathways converting contexts-either natural environmental challenges or laboratory perturbations-into context-specific changes in gene expression. Congruently, the interactions between the signaling molecules and transcription factors (TF) regulating these responses are also context specific. However, when a target gene responds across contexts, the upstream TF identified in one context is often inferred to regulate it across contexts. Reconciling these stable TF-target gene pair inferences with the context-specific nature of homeostatic responses is therefore needed. The induction of the Caenorhabditis elegans genes lipl-3 and lipl-4 is observed in many genetic contexts and is essential to survival during fasting. We find DAF-16/FOXO mediating lipl-4 induction in all contexts tested; hence, lipl-4 regulation seems context independent and compatible with across-context inferences. In contrast, DAF-16-mediated regulation of lipl-3 is context specific. DAF-16 reduces the induction of lipl-3 during fasting, yet it promotes it during oxidative stress. Through discrete dynamic modeling and genetic epistasis, we define that DAF-16 represses HLH-30/TFEB-the main TF activating lipl-3 during fasting. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, which promotes C. elegans survival through induction of lipl-3 Furthermore, the TF MXL-3 contributes to the dominance of HSF-1 at the expense of HLH-30 during oxidative stress but not during fasting. This study shows how context-specific diverting of functional interactions within a molecular network allows cells to specifically respond to a large number of contexts with a limited number of molecular players, a mode of transcriptional regulation we name "contextualized transcription."

Evaluation of aryl hydrocarbon receptor expression in oral squamous cell carcinoma and normal oral mucosa using western blot.

BACKGROUND: Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that acts as a binding site for toxic chemicals, particularly the dioxin group of chemicals. Elevated levels of AHR have been observed in various human cancers, including lung carcinomas, hepatic carcinomas and in mammary tumors. However, the expression of AHR in oral squamous cell carcinoma (OSCC) patients who are tobacco users are less explored. AIMS AND OBJECTIVES: The aim of the present study is to evaluate and compare AHR levels in OSSC patients and in normals using Western blot technique in an attempt to explore the possible role of AHR in oral carcinogenesis. MATERIALS AND METHODS: The study sample consisted of ten oral squamous cell carcinoma cases which were diagnosed clinically and confirmed histopathologically as OSCC and four samples of the normal oral mucosa. AHR protein expression was evaluated using Western blot technique and chemiluminescence detection kit. The densitometry was performed on a Microtek scan maker MSP flatbed scanner and quantified using Image J software. Mean AHR protein levels were calculated and compared between OSCC and normal oral mucosa using Student's t-test. RESULTS: The mean AHR protein level in OSCC samples (n = 10) was 2878.90 ± 1231.27 and 975.75 ± 227.27 in the normal oral mucosa (n = 4). The OSCC samples showed significantly higher levels of AHR protein compared to the normal oral mucosa (P = 0.008). CONCLUSION: The study showed a significantly higher expression of AHR in oral squamous cell carcinoma samples when compared to the normal oral mucosa, suggesting a possible role of AHR in the initiation, promotion and progression of oral squamous cell carcinoma.

Expression of transmembrane protein aquaporin-3 in oral epithelial dysplasia and oral squamous cell carcinoma.

OBJECTIVES: The objective of this study was to evaluate aquaporin-3 (AQP3) expression in patient samples of oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), thereby assessing the potential of AQP3 as a molecular marker for tumor progression. STUDY DESIGN: An in vitro comparative study was done to determine the AQP3 expression on 20 surgical biopsy specimens each of OED and OSCC using immunohistochemistry. Twenty specimens of normal oral mucosa were kept as controls. The results were statistically analyzed using one-way analysis of variance and post hoc analysis. RESULTS: The expression of AQP3 was analyzed and further semiquantified using H-scores. The mean H-score showed a statistically significant difference between OSCC, OED, and normal oral mucosa (P < .05). There was a significant increase in the expression of AQP3 in OSCC and OED compared to normal oral mucosa. The highest expression was observed in OSCC (P < .01). CONCLUSION: The observations of the study indicate that staining intensity of AQP3 increased from dysplastic noninvasive lesion to invasive OSCC, suggesting a possible role of AQP3 as a biomarker for tumor progression.

Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion.

The gut microbiota metabolizes drugs and alters their efficacy and toxicity. Diet alters drugs, the metabolism of the microbiota, and the host. However, whether diet-triggered metabolic changes in the microbiota can alter drug responses in the host has been largely unexplored. Here we show that dietary thymidine and serine enhance 5-fluoro 2'deoxyuridine (FUdR) toxicity in C. elegans through different microbial mechanisms. Thymidine promotes microbial conversion of the prodrug FUdR into toxic 5-fluorouridine-5'-monophosphate (FUMP), leading to enhanced host death associated with mitochondrial RNA and DNA depletion, and lethal activation of autophagy. By contrast, serine does not alter FUdR metabolism. Instead, serine alters E. coli's 1C-metabolism, reduces the provision of nucleotides to the host, and exacerbates DNA toxicity and host death without mitochondrial RNA or DNA depletion; moreover, autophagy promotes survival in this condition. This work implies that diet-microbe interactions can alter the host response to drugs without altering the drug or the host.

Intramuscular hemangioma of the masseter muscle- a case report and review of literature.

INTRODUCTION: Intramuscular hemangioma, is a distinctive type of vascular tumor occurring within the skeletal muscle. Most IMH are located in the lower extremity, particularly in the muscles of the thigh and rarely in head and neck region. PRESENTATION OF CASE: 35 years old male reported with a swelling in the left cheek region since 3 years. Clinical and radiological evaluation leads to the diagnosis of Intramuscular hemangioma. Surgical excision was performed and histopathology confirmed the diagnosis. DISCUSSION: Hemangiomas of skeletal muscle represent 0.8% of all benign vascular neoplasm Welsch and Hengerer, 1980 [4]. Of these 13.8% occur in the head and neck region, with the masseter muscle being the most common site, followed by the trapezius and sternocleidomastoid muscles respectively. The lesions previously described as deep infiltrating angiolipomas have now been recognized by the WHO as intramuscular hemangiomas. numerous theories proposed for ethiopathogenisis of vascular lesions have been discussed. CONCLUSION: In conclusion, angiolipomas are rare in the head and neck region, and it should be considered in the differential diagnosis of masses in these regions. Proper radiological and clinical examination will reveal the type of vascular lesion. Excellent results can be obtained with timely management and good surgical skills.

A lysosome-centered view of nutrient homeostasis.

Lysosomes are highly acidic cellular organelles traditionally viewed as sacs of enzymes involved in digesting extracellular or intracellular macromolecules for the regeneration of basic building blocks, cellular housekeeping, or pathogen degradation. Bound by a single lipid bilayer, lysosomes receive their substrates by fusing with endosomes or autophagosomes, or through specialized translocation mechanisms such as chaperone-mediated autophagy or microautophagy. Lysosomes degrade their substrates using up to 60 different soluble hydrolases and release their products either to the cytosol through poorly defined exporting and efflux mechanisms or to the extracellular space by fusing with the plasma membrane. However, it is becoming evident that the role of the lysosome in nutrient homeostasis goes beyond the disposal of waste or the recycling of building blocks. The lysosome is emerging as a signaling hub that can integrate and relay external and internal nutritional information to promote cellular and organismal homeostasis, as well as a major contributor to the processing of energy-dense molecules like glycogen and triglycerides. Here we describe the current knowledge of the nutrient signaling pathways governing lysosomal function, the role of the lysosome in nutrient mobilization, and how lysosomes signal other organelles, distant tissues, and even themselves to ensure energy homeostasis in spite of fluctuations in energy intake. At the same time, we highlight the value of genomics approaches to the past and future discoveries of how the lysosome simultaneously executes and controls cellular homeostasis.

Clear cell myoepithelioma of palate with emphasis on clinical and histological differential diagnosis.

Myoepitheliomas account for less than 1% of all salivary gland tumors and mostly occur in the parotid gland and palate. A 58-year old male patient reported to the Outpatient Department of PMS College of Dental Science and Research (Kerala, India) with a slow growing painless swelling on the palate for 4 years. Pleomorphic adenoma, basal cell adenoma, myoepithelioma, cyst adenoma, lipoma, neurofibroma, neurilemmoma and leiomyoma were considered. Histopathology revealed a thinly encapsulated tumor composed mainly of sheets of clear cells mixed with cells having eosinophilic cytoplasm. Histopathological differential diagnosis included pleomorphic adenoma, oncocytoma, oncocytic hyperplasia, sebaceous adenoma, malignant salivary gland neoplasms and metastatic lesions from kidney and thyroid. Myoepitheliomas mostly occur in the parotid gland and palatal region and various histological types of myoepithelioma are described. Myoepitheliomas of the palate are rare with clear cell variant even rarer.