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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.)