Marathi translation, linguistic validation, and cross-cultural adaptation of M.D. Anderson dysphagia inventory in patients of head and neck squamous cell cancer.

Background: Self-reported treatment outcome is a better way to measure patient's quality of life (QOL). This study was undertaken to translate dysphagia-specific QOL questionnaire M. D. Anderson Dysphagia Inventory (MDADI) in Marathi language, its linguistic validation, and cross-cultural adaptation in patients of head and neck squamous cell cancer (HNSCC). Methods: After Institutional ethics committee approval, MDADI was translated into Marathi with prior permission from the author of original English questionnaire (AOEQ). The translation procedure included - two forward translations (English to Marathi), formation of first intermediate Marathi translation (FIMT), two back translations (BT) (Marathi to English) of FIMT and interim Marathi translation (IMT) formation. Second intermediate Marathi translation (SIMT) was prepared after face validation of IMT by Marathi subject expert. Pretesting of SIMT was done in 10 patients of HNSCC for linguistic validation and cross-cultural adaptation. After incorporating the patients' suggestions, final Marathi translation was formulated and forwarded to primary author for approval. Results: The grammatically acceptable and conceptually equivalent face-validated SIMT was prepared and given to HNSCC patients. The questionnaire was well understood and unobjectionable reflecting its linguistic validity and cross-cultural adaptation. Some of the patients suggested changes in a few words which were then rectified, rechecked with BT, and the final Marathi translated questionnaire was prepared. The credit statement for AOEQ was used as a footnote in the translated questionnaire. Conclusion: Marathi translation of MDADI is well accepted and comprehensible. It can be used for future studies.

Subjective and perceptive assessment of speech/voice and swallowing function before and after radiation therapy in patients of head-and-neck squamous cell cancer.

Aim: To prospectively assess subjective and perceptive speech/voice and swallowing function before and after radiation therapy (RT) in patients of head-and-neck squamous cell cancer (HNSCC). Materials and Methods: The study cohort comprised eligible consecutive HNSCC patients planned for curative RT from April 2018 to July 2018 who consented for the study. Prospective evaluation of speech/voice and swallowing function was done before and after RT. For subjective and perceptive evaluation of speech/voice, speech handicap index (SHI) and Grade, Roughness, Asthenia, Breathiness, and Strain (GRABS) Scale was used, respectively. For subjective and perceptive evaluation of swallowing, M D Anderson Dysphagia Inventory (MDADI) and Performance Status Scale for head and neck (PSSHN) were used, respectively. All patients were taught speech/voice and swallowing exercises before RT. Statistical analysis was performed using SYSTAT version-12 (Cranes software, Bengaluru). Results: The study cohort comprised 30 patients of HNSCC with a median age of 57 years and male-to-female ratio of 4:1. The most common subsite was the oral cavity (43.33%) and a majority (76.66%) presented in the locally advanced stage. Post-RT there was significant improvement in speech/voice function (SHI P = 0.0006, GRABS score P = 0.003). Perceptive assessment of swallowing function by PSSHN showed significant improvement (P = 0.0032), but subjective assessment by MDADI showed no significant (P = 0.394) improvement until the first follow-up. Conclusion: Speech/voice function improved significantly after radiotherapy when combined with rehabilitation exercises. Swallowing function did not improve till the first follow-up. Future studies with the large number of patients and long-term follow-up are needed to document the changes in organ function.

Oncology treatment outcome in human immunodeficiency virus-positive cancer cervix patients: Where we are and what we achieved?

Objective: To find out the epidemiological factors and oncology treatment outcome in human immunodeficiency virus-positive cancer cervix patients (HPCCP). Materials and Methods: After institutional ethics committee approval, hospital case records of HPCCP registered at the radiation oncology department from January 2011 to December 2018 were retrospectively studied. Results: The case records of 22 eligible HPCCP were studied. Median age at presentation was 42.5 years. 90.90% of the patients were below 55 years of age. The duration of symptom was <3 months in 63.64% of patients. 68.18% of the patients were FIGO Stage III. Only 11 patients completed the planned treatment. Total target equivalent dose of 2 Gy per fraction delivered was 66 Gy. Seven patients had complete response. Four patients had local recurrence. Median disease-free and overall survival was 27 (14-38) and 18 months (2-48), respectively. Conclusion: HPCCP present at relatively early age and advanced stage despite short symptom duration. Poor patient compliance and treatment alteration have led to suboptimal outcome.

Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A.

Physiological aging is a complex process, influenced by a plethora of genetic and environmental factors. While being far from fully understood, a number of common aging hallmarks have been elucidated in recent years. Among these, transcriptomic alterations are hypothesized to represent a crucial early manifestation of aging. Accordingly, several transcription factors (TFs) have previously been identified as important modulators of lifespan in evolutionarily distant model organisms. Based on a set of TFs conserved between nematodes, zebrafish, mice, and humans, we here perform a RNA interference (RNAi) screen in C. elegans to discover evolutionarily conserved TFs impacting aging. We identify a basic helix-loop-helix TF, named HLH-2 in nematodes (Tcf3/E2A in mammals), to exert a pronounced lifespan-extending effect in C. elegans upon impairment. We further show that its impairment impacts cellular energy metabolism, increases parameters of healthy aging, and extends nematodal lifespan in a ROS-dependent manner. We then identify arginine kinases, orthologues of mammalian creatine kinases, as a target of HLH-2 transcriptional regulation, serving to mediate the healthspan-promoting effects observed upon impairment of hlh-2 expression. Consistently, HLH-2 is shown to epistatically interact with core components of known lifespan-regulating pathways, i.e. AAK-2/AMPK and LET-363/mTOR, as well as the aging-related TFs SKN-1/Nrf2 and HSF-1. Lastly, single-nucelotide polymorphisms (SNPs) in Tcf3/E2A are associated with exceptional longevity in humans. Together, these findings demonstrate that HLH-2 regulates energy metabolism via arginine kinases and thereby affects the aging phenotype dependent on ROS-signaling and established canonical effectors.

Impairing L-Threonine Catabolism Promotes Healthspan through Methylglyoxal-Mediated Proteohormesis.

Whether and how regulation of genes and pathways contributes to physiological aging is topic of intense scientific debate. By performing an RNA expression-based screen for genes downregulated during aging of three different species, we identified glycine-C-acetyltransferase (GCAT, EC 2.3.1.29). Impairing gcat expression promotes the lifespan of C. elegans by interfering with threonine catabolism to promote methylglyoxal (MGO; CAS 78-98-8) formation in an amine oxidase-dependent manner. MGO is a reactive dicarbonyl inducing diabetic complications in mammals by causing oxidative stress and damaging cellular components, including proteins. While high concentrations of MGO consistently exert toxicity in nematodes, we unexpectedly find that low-dose MGO promotes lifespan, resembling key mediators of gcat impairment. These were executed by the ubiquitin-proteasome system, namely PBS-3 and RPN-6.1 subunits, regulated by the stress-responsive transcriptional regulators SKN-1/NRF2 and HSF-1. Taken together, GCAT acts as an evolutionary conserved aging-related gene by orchestrating an unexpected nonlinear impact of proteotoxic MGO on longevity.

Dietary Carbohydrates Impair Healthspan and Promote Mortality.

The prospective cohort study, named PURE, found that in >135,000 participants from 18 countries, nutritive carbohydrates increase human mortality, whereas dietary fat reduces it, requesting a fundamental change of current nutritional guidelines. Experimental evidence from animal models provides synergizing mechanistic concepts as well as pharmacological options to mimic low-carb or ketogenic diets.

Branched-chain amino acid catabolism is a conserved regulator of physiological ageing.

Ageing has been defined as a global decline in physiological function depending on both environmental and genetic factors. Here we identify gene transcripts that are similarly regulated during physiological ageing in nematodes, zebrafish and mice. We observe the strongest extension of lifespan when impairing expression of the branched-chain amino acid transferase-1 (bcat-1) gene in C. elegans, which leads to excessive levels of branched-chain amino acids (BCAAs). We further show that BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFß, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner. The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing. Lastly and consistent with previous findings in rodents, nutritional supplementation of BCAAs extends nematodal lifespan. Taken together, BCAAs act as periphery-derived metabokines that induce a central neuro-endocrine response, culminating in extended healthspan.