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Pulmonary hypertension (PH) significantly impairs exercise capacity and the quality of life in patients, which is influenced by dysfunctions in multiple organ systems, including the right ventricle, lungs, and skeletal muscles. Recent research has identified metabolic reprogramming and mitochondrial dysfunction as contributing factors to reduced exercise tolerance in PH patients. In this study, we investigated the therapeutic potential of enhancing mitochondrial function through the activation of the mitochondrial deacetylase SIRT3, using SIRT3 activator Honokiol combined with the SIRT3 co-factor nicotinamide adenine dinucleotide (NAD), in a Sugen/Hypoxia-induced PH rat model. Our results show that Sugen/Hypoxia-induced PH significantly impairs RV, lung, and skeletal muscle function, leading to reduced exercise capacity. Treatment with Honokiol and NAD notably improved exercise endurance, primarily by restoring SIRT3 levels in skeletal muscles, reducing proteolysis and atrophy in the gastrocnemius, and enhancing mitochondrial complex I levels in the soleus. These effects were independent of changes in cardiopulmonary hemodynamics. We concluded that targeting skeletal muscle dysfunction may be a promising approach to improving exercise capacity and overall quality of life in PH patients.

Purpose: Cervical cancer is a significant global health burden, with advancements in treatment modalities improving outcomes. However, vaginal toxicities following definitive chemoradiation remain a concern, impacting patients' quality of life. The aim of this systematic review and meta-analysis was to estimate the incidence of vaginal toxicities, explore associated factors, and assess the relationship with radiation dose in intact cervical cancer patients undergoing radical chemoradiation., Material and Methods: A systematic search of PubMed, Google Scholar, and Cochrane databases was conducted. Studies reporting on vaginal toxicities post-radical chemoradiation in intact cervical cancer patients were included. Data extraction and analysis were performed according to PRISMA guidelines., Results: Twenty-four studies with various designs were included. The meta-analysis revealed a pooled estimate of 39% (95% CI: 21-56%) for overall vaginal toxicities among cervical cancer patients following definitive chemoradiation. Vaginal stenosis was the most commonly reported toxicity, with a median incidence of 61.5% (range, 20-77.8%) across the studies. Severe toxicities (grade ≥ 3) were reported at rates of 12.74% (CTCAE v. 4.0), 0.98% (CTCAE v. 3.0), 10.41% (RTOG/EORTC), and 0% (LENT-SOMA). Factors, such as age, initial vaginal involvement, and radiation dose were associated with increased toxicity risk. Significant heterogeneity was observed in study populations and methodologies., Conclusions: Vaginal toxicities are common following definitive chemoradiation in intact cervical cancer patients, with vaginal stenosis being predominant. Standardization of toxicity scoring methods and radiotherapy dose reporting parameters is crucial for accurate comparison and interpretation of findings. Future research should focus on optimizing treatment strategies to minimize vaginal toxicities while maximizing efficacy and patient outcomes., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Termedia.)

Recent preclinical studies have shown that the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and naproxen could be an effective intervention strategy against TMPRSS2-ERG fusion-driven prostate tumorigenesis. Herein, as a follow-up mechanistic study, employing TMPRSS2-ERG (fusion) positive tumors and plasma from TMPRSS2-ERG. Pten flox/flox mice, we profiled the stage specific proteomic changes (focused on inflammatory circulating and prostate tissue/tumor-specific cytokines, chemokines, and growth factors/growth signaling-associated molecules) that contribute to prostate cancer (PCa) growth and progression in the TMPRSS2-ERG fusion-driven mouse model of tumorigenesis. In addition, the association of the protective effects of NSAIDs (aspirin 1400 ppm and naproxen 400 ppm) with the modulation of these specific molecular pathways was determined. A sandwich Elisa based membrane array-proteome profiler identifying 111 distinct signaling molecules was employed. Overall, the plasma and prostate tissue sample analyses identified 54 significant and differentially expressed cytokines, chemokines, and growth factors/growth signaling-associated molecules between PCa afflicted mice (TMPRSS2-ERG. Pten flox/flox , age-matched noncancerous controls, NSAIDs-supplemented and no-drug controls). Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M-CSF, IL-33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93), (b) growth factors- growth signaling-associated molecules (Chemerin, FGF acidic, Flt-3 ligand, IGFBP-5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2-ERG fusion-driven prostate tumorigenesis are associated with antiproliferative and anti-inflammatory effects and possible modulation of the immune cell enriched microenvironment., (© 2024 Wiley Periodicals LLC.)

Introduction: Hypoxia is a common pathological driver contributing to various forms of pulmonary vascular diseases leading to pulmonary hypertension (PH). Pulmonary interstitial macrophages (IMs) play pivotal roles in immune and vascular dysfunction, leading to inflammation, abnormal remodeling, and fibrosis in PH. However, IMs' response to hypoxia and their role in PH progression remain largely unknown. We utilized a murine model of hypoxia-induced PH to investigate the repertoire and functional profiles of IMs in response to acute and prolonged hypoxia, aiming to elucidate their contributions to PH development., Methods: We conducted single-cell transcriptomic analyses to characterize the repertoire and functional profiles of murine pulmonary IMs following exposure to hypobaric hypoxia for varying durations (0, 1, 3, 7, and 21 days). Hallmark pathways from the mouse Molecular Signatures Database were utilized to characterize the molecular function of the IM subpopulation in response to hypoxia., Results: Our analysis revealed an early acute inflammatory phase during acute hypoxia exposure (Days 1-3), which was resolved by Day 7, followed by a pro-remodeling phase during prolonged hypoxia (Days 7-21). These phases were marked by distinct subpopulations of IMs: MHCII hi CCR2 + EAR2 + cells characterized the acute inflammatory phase, while TLF + VCAM1 hi cells dominated the pro-remodeling phase. The acute inflammatory phase exhibited enrichment in interferon-gamma, IL-2, and IL-6 pathways, while the pro-remodeling phase showed dysregulated chemokine production, hemoglobin clearance, and tissue repair profiles, along with activation of distinct complement pathways., Discussion: Our findings demonstrate the existence of distinct populations of pulmonary interstitial macrophages corresponding to acute and prolonged hypoxia exposure, pivotal in regulating the inflammatory and remodeling phases of PH pathogenesis. This understanding offers potential avenues for targeted interventions, tailored to specific populations and distinct phases of the disease. Moreover, further identification of triggers for pro-remodeling IMs holds promise in unveiling novel therapeutic strategies for pulmonary hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kumar, Mickael, Kumar, Prasad, Campbell, Zhang, Li, McKeon, Allen, Graham, Yu and Stenmark.)

Objective: This study aimed to determine the factors associated with knowledge and practices related to menstrual hygiene management among adolescent girls in urban slums in Jaipur, India., Material and Methods: A cross-sectional study among 417 adolescent girls was conducted. Descriptive statistics, Chi-square, and bivariate and multivariate logistic regression methods were used to analyze the data and determine the associated factors., Findings: Only 48.7% of girls had a correct understanding of menstruation. In addition, 55.1% of the menstruating girls had faced health problems related to mensuration in the last 6 months; however, only 47.6% visited a health facility for treatment. Educational status of the girl (AOR = 1.89, 95% CI = 0.88-4.06), mother's education (AOR = 2.19, 95% CI = 1.30-3.67) and income (AOR = 1.89, 95% CI = 0.67-3.95), father's income (AOR = 1.42, 95% CI = 0.76-2.95), and counseling by field health workers (AOR = 2.08, 95% CI = 1.23-3.51) were found to be associated with knowledge about menstruation. Girl's education (AOR = 1.49, 95% CI = 0.74-2.95), mother's education (AOR = 1.46, 95% CI = 0.7-2.84) and income (AOR = 1.314, 95% CI = 0.44-2.02), father's education (AOR = 1.64, 95% CI = 0.55-3.08) and income (AOR = 2.0, 95% CI = 0.86-3.28), and counseling by field health workers (AOR = 1.48, 95% CI = 0.76-2.64) were found to be associated with the type of absorbents used., Conclusion: The findings from the study show that the awareness about mensuration and utilization of health services among adolescent girls is low. There is a need to create an enabling environment for girls to access knowledge and health services related to menstruation by creating awareness at the community level, strengthening outreach by field health workers, and ensuring privacy in healthcare facilities., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Background: To evaluate and compare the distribution of stress and displacement of teeth during mandibular arch distalization using buccal shelf screws., Materials and Methods: Three three-dimensional finite element models of mandibular arch were constructed with third molars extracted. Models 1, 2, and 3 were constructed on the basis of the lever arm heights of 0 mm, 3 mm, and 6 mm, respectively, between the lateral incisor and canine. A buccal shelf screw was placed at the area in the second molar region with the initial point of insertion being inter-dental between the first and second molars and 2 mm below the mucogingival junction. MBT pre-adjusted brackets (slot size 0.022 × 0.028") were placed over the clinical crown's center with a 0.019 × 0.025" stainless-steel archwire on three models. A retraction force of 300 g was applied with buccal shelf screws and a lever arm bilaterally using nickel-titanium closed coil springs. The displacement of each tooth was calculated on X, Y, and Z axes, and the von Mises stress distribution was visualized using color-coded scales using ANSYS 12.1 software., Result: The maximum von Mises stress in the cortical and cancellous bones was observed in model 1. The maximum von Mises stress in the buccal shelf screw and the cortical bone decreased as the height of the lever arm increased. Applying orthodontic forces at the level of 6 mm lever arm height resulted in greater biomechanical bodily movement in distalization of the mandibular molars compared to when the orthodontic forces were applied at the level of 0 mm lever arm height., Conclusion: Displacement of the entire arch may be dictated by a direct relationship between the center of resistance of the whole arch and the line of action generated between the buccal shelf screw and force application points at the archwire, which makes the total arch movement highly predictable., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Orthodontic Science.)

Purpose: This survey aimed to understand the practice pattern and attitude of Indian doctors towards prostate brachytherapy., Material and Methods: A 21-point questionnaire was designed in Google form and sent to radiation oncologists practicing in India, using texts, mails, and social media. Responses were collated, and descriptive statistical analysis was performed., Results: A total of 212 radiation oncologists from 136 centers responded to the survey questionnaire, with majority (66%) being post-specialty training > 6 years. We found that about 44.3% ( n = 94) of respondents do not practice interstitial brachytherapy for any site, and majority (83.3%, n = 175) do not practice high-dose-rate (HDR) prostate brachytherapy. Only 2.8% ( n = 6) of doctors preferred boost by brachytherapy compared with 38.1% ( n = 80) of respondents, who favored stereotactic body radiation therapy (SBRT) boost. When asked about the indication of HDR prostate brachytherapy in Indian setting, 32.5% ( n = 67) of respondents favored monotherapy, 46.1% ( n = 95) of oncologists thought boost as a good indication, and 21.4% ( n = 44) preferred re-irradiation/salvage setting. The most cited reason for prostate brachytherapy not being popularly practiced in India was lack of training (84.8%, n = 179). It was also noted that out of 80 respondents who practiced SBRT for prostate boost, 37 would prefer HDR brachytherapy boost if given adequate training and facilities., Conclusions: The present survey provided insight on practice of prostate brachytherapy in India. It is evident that majority of radiation oncologists do not practice HDR prostate brachytherapy due to lack of training and infrastructure. Indian physicians are willing to learn and start prostate brachytherapy procedures if dedicated training and workshops are organized., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Termedia.)

Objective: To evaluate the effectiveness of micro-osteoperforation (MOP) over a 56-day period and to determine the influence of number of perforations on the rate of canine retraction. In addition, the amount of pain and discomfort caused by the MOP was evaluated., Trial Design: A single-center, split-mouth, triple-blind, randomized, controlled trial., Methods: 22 patients (18-30 years) who need fixed orthodontic treatment were recruited and randomly assigned to MOP1 and MOP2 groups. The recruited patients were divided into two groups with 1:1 allocation ratio. Randomization for the determination of experimental side and number of perforations was done using sealed envelopes. On each patient, the other side of mouth worked as control side with no MOPs. 4 months after first premolar extraction, patients in MOP1 received 3MOPs on the buccal surface of alveolar bone, whereas patients in MOP2 received three buccal and three palatal MOPs in the experimental side. The amount of canine retraction was measured every 28 days at two intervals on both sides of mouth. Pain perception was measured after 1 hr, 24 hr, 72 hr, 7 days, and 28 days of procedure., Results: Result of the intra-examiner reliability using ICC is more than 0.97 ( P < 0.001), indicating excellent repeatability and reliability of the measurements. The baseline characteristics between groups were similar ( P > 0.05). A statistically significant difference in the rate of canine retraction on the MOP side was observed at the end of 56 days, amounting to two folds more than that of the control side. No significant difference was seen between MOP1 and MOP2 groups ( P > 0.05). Mild-to-moderate pain was experienced only in first 72 hours of procedure., Conclusion: The study recommends that MOP procedure has substantial potential to be used as an adjunct to the routine mechanotherapy for accelerating tooth movement, as it may reduce treatment time by half in the first four weeks after the MOP procedure., Trial Registration: Clinical trial registry of India (CTRI/2022/12/048181)., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Orthodontic Science.)

Pulmonary hypertension (PH) is a heterogeneous and life-threatening cardiopulmonary disorder in which mitochondrial dysfunction is believed to drive pathogenesis, although the underlying mechanisms remain unclear. To determine if abnormal SIRT3 (sirtuin 3) activity is related to mitochondrial dysfunction in adventitial fibroblasts from patients with idiopathic pulmonary arterial hypertension (IPAH) and hypoxic PH calves (PH-Fibs) and whether SIRT3 could be a potential therapeutic target to improve mitochondrial function, SIRT3 concentrations in control fibroblasts, PH-Fibs, and lung tissues were determined using quantitative real-time PCR and western blot. SIRT3 deacetylase activity in cells and lung tissues was determined using western blot, immunohistochemistry staining, and immunoprecipitation. Glycolysis and mitochondrial function in fibroblasts were measured using respiratory analysis and fluorescence-lifetime imaging microscopy. The effects of restoring SIRT3 activity (by overexpression of SIRT3 with plasmid, activation SIRT3 with honokiol, and supplementation with the SIRT3 cofactor nicotinamide adenine dinucleotide [NAD + ]) on mitochondrial protein acetylation, mitochondrial function, cell proliferation, and gene expression in PH-Fibs were also investigated. We found that SIRT3 concentrations were decreased in PH-Fibs and PH lung tissues, and its cofactor, NAD + , was also decreased in PH-Fibs. Increased acetylation in overall mitochondrial proteins and SIRT3-specific targets (MPC1 [mitochondrial pyruvate carrier 1] and MnSOD2 [mitochondrial superoxide dismutase]), as well as decreased MnSOD2 activity, was identified in PH-Fibs and PH lung tissues. Normalization of SIRT3 activity, by increasing its expression with plasmid or with honokiol and supplementation with its cofactor NAD + , reduced mitochondrial protein acetylation, improved mitochondrial function, inhibited proliferation, and induced apoptosis in PH-Fibs. Thus, our study demonstrated that restoration of SIRT3 activity in PH-Fibs can reduce mitochondrial protein acetylation and restore mitochondrial function and PH-Fib phenotype in PH.

The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case-control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both TMPRSS2-ERG (fusion)-driven (with conditional deletion of Pten ) and non- TMPRSS2-ERG -driven (Hi-Myc +/- mice) PCa. Male mice ( n = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc +/- mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the TMPRSS2-ERG (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79-91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc +/- mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.

Endothelial dysfunction and inflammation contribute to the vascular pathology of coronavirus disease (COVID-19). However, emerging evidence does not support direct infection of endothelial or other vascular wall cells, and thus inflammation may be better explained as a secondary response to epithelial cell infection. In this study, we sought to determine whether lung endothelial or other resident vascular cells are susceptible to productive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and how local complement activation contributes to endothelial dysfunction and inflammation in response to hypoxia and SARS-CoV-2-infected lung alveolar epithelial cells. We found that ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) mRNA expression in lung vascular cells, including primary human lung microvascular endothelial cells (HLMVECs), pericytes, smooth muscle cells, and fibroblasts, was 20- to 90-fold lower compared with primary human alveolar epithelial type II cells. Consistently, we found that HLMVECs and other resident vascular cells were not susceptible to productive SARS-CoV-2 infection under either normoxic or hypoxic conditions. However, viral uptake without replication (abortive infection) was observed in HLMVECs when exposed to conditioned medium from SARS-CoV-2-infected human ACE2 stably transfected A549 epithelial cells. Furthermore, we demonstrated that exposure of HLMVECs to conditioned medium from SARS-CoV-2-infected human ACE2 stably transfected A549 epithelial cells and hypoxia resulted in upregulation of inflammatory factors such as ICAM-1 (intercellular adhesion molecule 1), VCAM-1 (vascular cell adhesion molecule 1), and IL-6 (interleukin 6) as well as complement components such as C3 (complement C3), C3AR1 (complement C3a receptor 1), C1QA (complement C1q A chain), and CFB (complement factor B). Taken together, our data support a model in which lung endothelial and vascular dysfunction during COVID-19 involves the activation of complement and inflammatory signaling and does not involve productive viral infection of endothelial cells.

In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Pten flox/flox ) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Pten flox/flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed. Conversely, in the Hi-Myc +/ - mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc +/ - mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Pten flox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis marker (CD-31). Importantly, there was a significant increase in immune cell infiltrations, which increased with the stage of tumorigenesis, in the TMPRSS2-ERG fusion-positive tumors relative to fusion negative tumors. Together, these findings are both novel and highly significant in establishing a working preclinical model for evaluating the efficacy of interventions during different stages of tumorigenesis in TMPRSS2-ERG fusion-driven PCa., (© 2022 Wiley Periodicals LLC.)

Prostate cancer (PCa) initiation and progression uniquely modify the prostate milieu to aid unrestrained cell proliferation. One salient modification is the loss of the ability of prostate epithelial cells to accumulate high concentrations of zinc; however, molecular alterations associated with loss of zinc accumulating capability in malignant prostate cells remain poorly understood. Herein, we assessed the stage-specific expression of zinc transporters (ZNTs) belonging to the ZNT (SLC30A) and Zrt- and Irt-like protein (ZIP) (SLC39A) solute-carrier family in the prostate tissues of different genetically engineered mouse models (GEMM) of PCa (TMPRSS2-ERG.Pten flox/flox , Hi-Myc +/ - , and transgenic adenocarcinoma of mouse prostate), their age-matched wild-type controls, and 104 prostate core biopsies from human patients with different pathological lesions. Employing immunohistochemistry, differences in the levels of protein expression and spatial distribution of ZNT were evaluated as a function of the tumor stage. Results indicated that the expression of zinc importers (ZIP1, ZIP2, and ZIP3), which function to sequester zinc from circulation and prostatic fluid, was low to negligible in the membranes of the malignant prostate cells in both GEMM and human prostate tissues. Regarding zinc exporters (ZNT1, ZNT2, ZNT9, and ZNT10) that export excess zinc into the extracellular spaces or intracellular organelles, their expression was low in normal prostate glands of mice and humans; however, it was significantly upregulated in prostate adenocarcinoma lesions in GEMM and PCa patients. Together, our findings provide new insights into altered expression of ZNTs during the progression of PCa and indicate that changes in zinc homeostasis could possibly be an early-initiation event during prostate tumorigenesis and a likely prevention/intervention target., (© 2022 Wiley Periodicals LLC.)

The impact of immune system and inflammation on organ homeostasis and tissue stem cell niches in the absence of pathogen invasion has long remained a conundrum in the field of regenerative medicine. The paradoxical role of immune components in promoting tissue injury as well as resolving tissue damage has complicated therapeutic targeting of inflammation as a means to attain tissue homeostasis in degenerative disease contexts. This confound could be resolved by an integrated intricate assessment of cross-talk between inflammatory components and micro- and macro-environmental factors existing in tissues during health and disease. Prudent fate choice decisions of stem cells and their differentiated progeny are key to maintain tissue integrity and function. Stem cells have to exercise this fate choice in consultation with other tissue components. With this respect tissue immune components, danger/damage sensing molecules driving sterile inflammatory signaling cascades and barrier cells having immune-surveillance functions play pivotal roles in supervising stem cell decisions in their niches. Stem cells learn from their previous damage encounters, either endogenous or exogenous, or adapt to persistent micro-environmental changes to orchestrate their decisions. Thus understanding the communication networks between stem cells and immune system components is essential to comprehend stem cell decisions in endogenous tissue niches. Further the systemic interactions between tissue niches integrated through immune networks serve as patrolling systems to establish communication links and orchestrate micro-immune ecologies to better organismal response to injury and promote regeneration. Understanding these communication links is key to devise immune-centric regenerative therapies. Thus the present review is an integrated attempt to provide a unified purview of how inflammation and immune cells provide guidance to stem cells for tissue sculpting during development, organismal aging and tissue crisis based on the current knowledge in the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Garg, Chandanala, David-Luther, Govind, Prasad, Kumar and Prasanna.)

Human telomerase reverse transcriptase (hTERT), the essential catalytic subunit of telomerase, is associated with telomere homeostasis to prevent replicative senescence and cellular aging. However, hTERT reactivation also has been linked to the acquisition of several hallmarks of cancer, although the underlying mechanism beyond telomere extension remains elusive. This study demonstrated that hTERT overexpression promotes, whereas its inhibition by shRNA suppresses, epithelial-mesenchymal transition (EMT) in lung cancer cells (A549 and H1299). We found that hTERT modulates the expression of EMT markers E-cadherin, vimentin, and cytokeratin-18a through upregulation of the c-MET. Ectopic expression of hTERT induces expression of c-MET, while hTERT-shRNA treatment significantly decreases the c-MET level in A549 and H1299 through differential expression of p53 and c-Myc. Reporter assay suggests the regulation of c-MET expression by hTERT to be at the promoter level. An increase in c-MET level significantly promotes the expression of mesenchymal markers, including vimentin and N-cadherin, while a notable increase in epithelial markers E-cadherin and cytokeratin-18a is observed after the c-MET knockdown in A549., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Aims: We describe the absolute and per capita numbers of megavoltage radiotherapy machines (MVMs) in Western Africa from 1969 to 2019., Materials and Methods: Western Africa was defined in accordance with the United Nations' delineation and inclusive of 16 countries. A literature search for publications detailing the number of cobalt-60 machines (COs) and linear accelerators (LINACs) in radiotherapy centres was carried out. Population data from the World Bank Group and crude cancer rates from the International Agency for Research on Cancer were used to calculate ratios of million persons per MVM and MVMs per 1000 cancer cases., Results: The numbers of MVMs in Western Africa in 1969, 1979, 1989, 1999 and 2009 were zero, two, three, six and nine, respectively. In 2019 there were 22 MVMs distributed across Ghana (five), Côte d'Ivoire (two), Mali (one), Mauritania (two), Nigeria (nine) and Senegal (three). Nine countries (56.3%) had no history of external beam radiotherapy (EBRT). The largest increase in absolute EBRT capacity occurred from 2017 to 2019, during which 13 MVMs were commissioned. The largest decrease in EBRT capacity occurred from 2015 to 2017, during which four LINACs and three COs were rendered non-operational. The ratio of million persons per MVM improved from 67.0 in 1979 to 17.8 in 2019. As of 2019, there was 0.09 MVM per 1000 cancer cases., Conclusions: Western African nations have experienced an increase in the absolute number of MVMs and per capita radiotherapy capacity during the last 50 years, especially in the last decade. As non-functional LINACs contributed to a temporary decline in the EBRT infrastructure, dual use of CO/LINAC technologies may act to promote the availability of EBRT treatment in centres with capacity for multiple MVMs., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

This manuscript represents a collaboration from an international group of quality and safety expert radiation oncologists. It is a position/review paper with the specific aim of defining the role of the radiation oncologist in quality and safety management. This manuscript is unique in that we recommend specific quality assurance/control tasks and correlated quality and indicators and safety measures that are the responsibility of the radiation oncologist. The article addresses the role of the radiation oncologist in quality and safety from a strong perspective of multidisciplinarity and teamwork. Our manuscript is "cross-cutting" and applicable to radiation oncologist in any practice setting (i.e. low middle-income countries)., (Copyright © 2020. Published by Elsevier B.V.)

Skin is the largest human organ that shields the inner body from contact with xenobiotic and genotoxic agents, and in this process, the skin's cellular genome faces continuous stress due to direct exposure to these noxious factors. Accumulation of genetic stress results in genomic alterations leading to undesirable gene or protein alteration/expression in skin cells, which eventually causes the formation of non-melanoma skin cancers (NMSCs). Ultraviolet B (UVB) radiation from sun is the most prominent factor contributing to ∼5 million skin cancer cases (which are mostly NMSCs) in the United States (US) and western countries. UVB exposure causes aberrations in a range of biochemical and molecular pathways such as: thymine dimer formation, DNA damage, oxidative stress, inflammatory responses, altered cellular signaling, which ultimately contribute to the development of NMSCs. The focus of this review is to summarize the protective and preventive potential of silymarin and/or silibinin against UVB-induced NMSC in pre-clinical skin cancer studies. Over two decades of research has shown the strong potential of silibinin, a biologically active flavonolignan (crude form Silymarin) derived from milk thistle plant, against a wide range of cancers, including NMSCs. Silibinin protects against UVB-induced thymine dimer formation and in turn promotes DNA repair and/or initiates apoptosis in damaged cells via an increase in p53 levels. Additionally, silibinin has shown strong efficacy against NMSCs via its potential to target aberrant signaling pathways, and induction of anti-inflammatory responses. Overall, completed comprehensive studies suggest the potential use of silibinin to prevent and/or manage NMSCs in humans., Competing Interests: The authors declare that there are no conflicts to disclose., (© 2020 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

The neutron spectrum at KAMINI reactor south beam tube end has been determined using multifoil activation method. This beam tube is being used for characterizing neutron attenuation of novel shield materials. Starting from a computed guess spectrum, the spectrum adjustment/unfolding procedure makes use of minimization of a modified constraint function representing (a) least squared deviations between the measured and calculated reaction rates, (b) a measure of sharp fluctuations in the adjusted spectrum and (c) the square of the deviation of adjusted spectrum from the guess spectrum. The adjusted/unfolded spectrum predicts the reaction rates accurately. The results of this new procedure are compared with those of widely used SAND-II code., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Monitoring/supervision is an essential component for improving the quality of health services including rational use of medicines. A new bottom-up approach of monitoring/supervision consisting of self-assessment/ peer-group discussion was found to be effective in improving prescribing practices. The new strategy significantly improved the prescribing practices based on standard treatment guidelines. The government has implemented it as a Program in primary health care services of Nepal. This article aims to share the implementation status of the self-assessment/peer-group discussion Program for improving the prescribing practices of common health problems and availability of drugs in the district health system., Methods: Concurrent mixed research design was applied for data collection. The data were collected at different levels of health care system using in-depth interviews, participatory observations and documentary analysis., Results: The Management Division, Department of Health Services implemented the Program in 2009-10 and the PHC Revitalization Division, DoHs is the implementation division since 2010-11. The Program comprised revision of participant's and trainer's manuals, training of trainers and prescribers, finalisation of health conditions and indicators, distribution of carbon copy prescription pads, and conduction of peer-group discussions.The Program was implemented in number of districts., Conclusions: The government made the policy decision to implement the Program for monitoring prescribing practices and the availability of free drugs in districts. However, it has covered only few districts and needs escalation to cover all 75 districts of the country.

Indira Gandhi Institute of Medical Sciences, Regional Cancer Center was established in 1993. It's one of the main Health-Care Institution in the state of Bihar. The data of 205 patients was presented in the ICON meeting and 98% of patients were diagnosed in chronic phase. Complete hematological response was seen in 91% of patients in 3 months. A total of 197 (96%) patients were alive at the time of analysis of which 179 (87%) were still in chronic phase with hematological remission.

Background: In most Asian countries, 50 - 90% of pharmaceutical sales are made in private drug outlets, by personnel with some training in drugs but not for the treatment of common health problems. The objective of the study was to determine effects of focused training for private drug sellers to improve practices in treating acute respiratory infections and diarrhoea in children, and anaemia in pregnancy in Nepal., Methods: Randomized controlled, four way nested design study incorporating four interventions for drug retailers in both hill and terai districts. One group received mailed printed educational materials followed by mailed feedback; a second received small group training followed by feedback; a third received small group training only; and a fourth, the control group, received no intervention. Surrogate customer method was used to assess practices. Outcomes were measured using multivariate linear regression., Results: A significant increase in the asking of key history questions, recommendation ( prescribing by drug retailers) of cotrimoxazole, and advice-giving for pneumonia; a significant increase in ORS recommendation, and advice giving for diarrhoea including the avoidance of antidiarrhoeals; and a significant increase in asking key history questions and recommending appropriate products in pregnancy cases., Conclusions: Training intervention as well as training followed by practice feedback was effective in improving the management of common illnesses and pregnancy by private drug sellers.

Accurately assessing and optimizing the implosion performance of inertial confinement fusion capsules is a crucial step to achieving ignition on the NIF. We have applied differential filtering (matched Ross filter pairs) to provide broadband time-integrated absolute x-ray self-emission images of the imploded core of cryogenic layered implosions. This diagnostic measures the temperature- and density-sensitive bremsstrahlung emission and provides estimates of hot spot mass, mix mass, and pressure.

We have fielded a hard x-ray (>100 keV) imager with high aspect ratio pinholes to measure the spatially resolved bremsstrahlung emission from energetic electrons slowing in a plastic ablator shell during indirectly driven implosions at the National Ignition Facility. These electrons are generated in laser plasma interactions and are a source of preheat to the deuterium-tritium fuel. First measurements show that hot electron preheat does not limit obtaining the fuel areal densities required for ignition and burn.

The compact Wedge Range Filter (WRF) proton spectrometer was developed for OMEGA and transferred to the National Ignition Facility (NIF) as a National Ignition Campaign diagnostic. The WRF measures the spectrum of protons from D-(3)He reactions in tuning-campaign implosions containing D and (3)He gas; in this work we report on the first proton spectroscopy measurement on the NIF using WRFs. The energy downshift of the 14.7-MeV proton is directly related to the total ρR through the plasma stopping power. Additionally, the shock proton yield is measured, which is a metric of the final merged shock strength.

Vitiligo is in most cases diagnosed clinically, so obvious are the features of a well developed lesion of this disease. Other investigations are rarely required. However, occasionally vitiligo especially in its early evolving stage or in some of its localised expressions may pose diagnostic difficulties as the lesions are hypopigmented rather than depigmented and other differential diagnoses may be considered. The histopathological changes in vitiligo in sections stained with haematoxylin and eosin (H&E) are often very subtle and may be inconclusive. Special staining procedures like the Fontana-Masson staining may help in reaching a definite diagnosis. The DOPA reaction which demonstrates viable and functional melanocytes may also be used but is technically difficult to perform.

We demonstrate the hohlraum radiation temperature and symmetry required for ignition-scale inertial confinement fusion capsule implosions. Cryogenic gas-filled hohlraums with 2.2 mm-diameter capsules are heated with unprecedented laser energies of 1.2 MJ delivered by 192 ultraviolet laser beams on the National Ignition Facility. Laser backscatter measurements show that these hohlraums absorb 87% to 91% of the incident laser power resulting in peak radiation temperatures of T(RAD)=300 eV and a symmetric implosion to a 100 μm diameter hot core., (© 2011 American Physical Society)

Understanding hot electron distributions generated inside Hohlraums is important to the national ignition campaign for controlling implosion symmetry and sources of preheat. While direct imaging of hot electrons is difficult, their spatial distribution and spectrum can be deduced by detecting high energy x-rays generated as they interact with target materials. We used an array of 18 pinholes with four independent filter combinations to image entire Hohlraums with a magnification of 0.87× during the Hohlraum energetics campaign on NIF. Comparing our results with Hohlraum simulations indicates that the characteristic 10-40 keV hot electrons are mainly generated from backscattered laser-plasma interactions rather than from Hohlraum hydrodynamics.

Background: World Health Organisation (WHO) estimates that about half of all medicines are inappropriately prescribed, dispensed and sold and about half of all patients fail to take their medicines properly., Objective: The overall objective of the study was improving use of medicines in the community by creating awareness among different target groups., Materials and Methods: It was a pre-post comparison of intervention implemented at the community level in purposively selected Bhaktapur District of Kathmandu Valley, Nepal. The study was conducted in the private schools of the study district. Twelve schools were randomly selected. Thereafter, students from 6-9 grades were listed from the selected schools. Then 15% of the total students in each grade were randomly selected to get six students from each grade of the each school, totaling 288 students. The households of the selected students served as the sample households for the study. Thus, there were 288 households sampled for the study. The intervention and the targeted intermediary groups consisted of a. training of schools teachers b. training of journalists c. interactive discussions of trained school teachers with school children using key messages and c. communication of key messages through the local F.M. radio, newspaper/magazine., Results: There was a significant increase in correct knowledge on action of antibiotics and excellent knowledge on the methods of administration of antibiotics of households after the intervention. Similarly, there was a significant increase in knowledge on cough as a disease and a significant decrease in the use of cough medicines after intervention. There was also a significant increase in excellent knowledge on the sources of vitamins and a significant decrease in the use of vitamin/tonics after the intervention., Conclusion: The participation of intermediary groups eg. school teachers, journalists and school children in the implementation of intervention were successful. The groups have fulfilled the commitments in implementing the plan of action. The key messages have effectively reached the households, and the knowledge and practices of the community members in drug use have improved.

To improve the quality of health care in Nepal, supervision/ monitoring involving periodic visits by the district supervisor to health facilities (top-down approach) is in practice. It is not objectively implemented because of time and financial constraints and terrain of the country. To assess the effectiveness of a pre-tested strategy i.e. peer-group discussion with self-assessment piloted through the district health system in improving quality of care. A pre-post pilot study was conducted in 41 PHC facilities of Chitwan district of Central Nepal. The intervention included small-group training to prescribers followed by peer-group discussion with self-assessment data. It involved visit of in-charges from health facilities to district level regular meeting with self-assessment data on the treatment of four targeted health problems and also the availability of drugs of their health facilities as well as from health facilities which were under their supervision (bottom-up approach). In under-five children, there was a significant improvement in use of antimicrobials in diarrhoea, paracetamol alone and antibiotics in no pneumonia, and co-trimoxazole or amoxycillin alone or with paracetamol in pneumonia. The use of benzyl benzoate or gamma benzene hexachloride alone and antibiotics in scabies were also significantly improved. The peer-group discussion, a bottom-up approach of supervision/monitoring implemented through district health system improves the prescribing practices and availability of drugs in the district.

Introduction: Promoting appropriate use of drugs is an essential element in achieving quality of health and medical cares for patients and the community, and also to minimize financial burden., Objective: The objective of this paper is to assess the successful intervention for sustainability and effects in post research phase. To address these problems, a variety of educational, managerial and regulatory strategies to improve prescribing have been tried in Nepal. When training is combined with a managerial intervention i.e. peer-group discussion, it results into improved changes in prescribing practices of paramedics in several practices., Methodology: A prospective, three-way design study consisting of small group training, small group training followed by peer-group discussion and control was conducted in three regions of Nepal including one hill and two terai (plains) districts from each region. The study included all health post from the sampled districts, making 80 health posts the study population., Results: The study revealed the effectiveness of the peer-group discussion approach in improving the prescribing practices. An assessment to identify the sustainability of the strategy and its effect within the district healthcare system after the completion of the research phase was undertaken. The study found that peer-group discussion was discontinued in all targeted districts and the improved practices were not sustained after the completion of the research. Various reasons have been found for not continuing the effective intervention.

In this article the epidemiology of cancer according to the data source, burden and pattern of common cancer and its future have been described in brief in Indian scenario.

In developing countries, inappropriate, inefficient and ineffective use of pharmaceuticals have resulted into the poor health and medical cares for the community people. For improving the situation, various interventions have been tested and proved effective in different settings. In Nepal also, various strategies have been tested and found effective to improve the prescribing and dispensing practices. This paper has examined the process and results of different studies. The educational intervention, the training has not been effective in improving the prescribing practices but has limited effect on dispensing practices in the public sector. However, it becomes effective in improving prescribing practices if combined with a managerial intervention e.g. peer-group discussion. In private sector, training alone is effective in changing the drug recommendation practices of retailers. But none of interventions have been found to be effective in improving dispensing practices. After examining the effectiveness of different interventions, training combined with peer-group discussion is recommended for piloting in all Primary Health Care (PHC) outlets of a district to improve the prescribing practices. For improving the dispensing practices in both public and private sector, additional studies have to be carried out using different strategies.

Adenoid cystic carcinoma (ACC) is a relatively common malignant neoplasm which occurs in the head and neck region, particularly in the salivary glands. It is a slow growing, locally aggressive neoplasm with a unique feature of perineural spread. Intracranial extension can occur by direct extension, hematogenous metastases or by perineural spread. However, the occurrence of primary intracranial ACC with no evidence of a primary, is rare, with only ten cases reported in reviewed English literature until now. One such case is presented here with brief review of literature. This patient showed a good response to treatment with surgery followed by post-operative radiotherapy and has remained disease free, 32 months after the completion of treatment.

Distant metastases from carcinoma of the palatine tonsil are very uncommon. We encountered a case of a carcinoma involving the tonsillar region that resulted in subarachnoid mestastases following local radical radiotherapy. Metastases were diagnosed following magnetic resonance imaging and spinal fluid cytology. The patient succumbed to the disease after a rapid downhill course, 1 month following diagnosis of the secondary deposit. The present paper describes the rare site of distant metastasis and reviews the relevant literature.

During a period of 5 yr, 2,418 fine-needle aspirations (FNA) were performed on 2,216 patients with superficial lymphadenopathy. Chronic nonspecific lymphadenitis was the commonest inflammatory lesion followed by tuberculosis. Among malignant lesions, metastatic tumors were most common followed by non-Hodgkin's lymphoma. The FNAC findings were correlated with subsequent histopathological diagnosis in 1,041 cases. The sensitivity rates of FNAC in tuberculosis, metastatic tumors, Hodgkin's disease, and non-Hodgkin's lymphoma were found to be 83.3, 97, 30, and 80.3%, respectively, the specificity being 94.3, 98.9, 98.6, and 95.4% in the same order. Immunocytochemical tests performed on the aspirated material helped in classifying the metastatic poorly differentiated tumors and confirming the diagnosis of non-Hodgkin's lymphomas. Effects of FNA on subsequent biopsy in 81 lymph nodes with benign hyperplasia were studied and showed that aspiration does not interfere with subsequent histologic assessment. Thus FNAC is a simple, inexpensive procedure, and when complemented by appropriate immunocytochemical studies is accurate and reliable for routine diagnosis of lymphadenopathy.