Managing common toxicities associated with checkpoint inhibitor and chemotherapy combinations for untreated classic Hodgkin lymphoma.

Combination checkpoint inhibitor (CPI) and chemotherapy is an effective and safe treatment strategy for patients with untreated classic Hodgkin lymphoma. Recent studies of programmed cell death protein 1 inhibitors combined with doxorubicin, vinblastine and dacarbazine have demonstrated high overall and complete response rates. This combination has a unique toxicity profile that should be managed appropriately so as not to compromise treatment efficacy. Common toxicities include rash, hepatoxicity, neutropenia and thyroid dysfunction. Here, we present four cases and the management strategies around such toxicities. In addition, we highlight key clinical decision-making around the administration of subsequent doses of CPI and chemotherapy.

Randomized singular value decomposition for integrative subtype analysis of 'omics data' using non-negative matrix factorization.

Integration of multiple 'omics datasets for differentiating cancer subtypes is a powerful technic that leverages the consistent and complementary information across multi-omics data. Matrix factorization is a common technique used in integrative clustering for identifying latent subtype structure across multi-omics data. High dimensionality of the omics data and long computation time have been common challenges of clustering methods. In order to address the challenges, we propose randomized singular value decomposition (RSVD) for integrative clustering using Non-negative Matrix Factorization: intNMF-rsvd. The method utilizes RSVD to reduce the dimensionality by projecting the data into eigen vector space with user specified lower rank. Then, clustering analysis is carried out by estimating common basis matrix across the projected multi-omics datasets. The performance of the proposed method was assessed using the simulated datasets and compared with six state-of-the-art integrative clustering methods using real-life datasets from The Cancer Genome Atlas Study. intNMF-rsvd was found working efficiently and competitively as compared to standard intNMF and other multi-omics clustering methods. Most importantly, intNMF-rsvd can handle large number of features and significantly reduce the computation time. The identified subtypes can be utilized for further clinical association studies to understand the etiology of the disease.

Discovery of sinomenine/8-Bis(benzylthio)octanoic acid hybrids as potential anti-leukemia drug candidate via mitochondrial pathway.

Traditional Chinese medicine Qingfengteng primarily acquired from the dried canes of Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils. and S. acutum (Thunb.) Rehd. et Wils. For the therapeutic treatment of rheumatism, acute arthritis, and rheumatoid arthritis based on Qingfengteng, sinomenine hydrochloride was recently made the principal active ingredient in various dosage forms. 8-Bis(benzylthio)octanoic acid (CPI-613) was an orphan medicine that the FDA and EMA approved orphan for the treatment of certain resistant malignancies. Its unique mode of action and minimal toxicity toward normal tissues made for an apt pharmacophore. In order to expand the field of sinomenine anticancer structures, sinomenine/8-Bis(benzylthio)octanoic acid derivatives were designed and synthesized. Among them, target hybrids e4 stood out for having notable cytotoxic effects against cancer cell lines, especially for K562 cells, with IC50 values of 2.45 µM and high safety. In-depth investigations demonstrated that e4 caused apoptosis by stopping the cell cycle at G1 phase, and doing so by altering the morphology of the nucleus and causing membrane potential of the in mitochondria to collapse. These results indicated e4 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

LY333531 attenuates contraction of tumor necrosis factor-α-sensitized human airway smooth muscle cells.

OBJECTIVE: Protein kinase C (PKC) has been implicated in the increased contraction of human airway smooth muscle cells (HASMCs) in asthma. Using the three-dimensional collagen gel contraction system, the study aimed to determine the effects of LY333531, a specific inhibitor of the PKC-ß isoform, on the contraction of tumor necrosis factor (TNF)-α-sensitized HASMCs. METHODS: Cultured HASMCs were divided into five groups: the control group received no treatment, and the cells in the TNF-α group were sensitized with 10 ng/mL TNF-α for 48 h, while TNF-α was administered to sensitize HASMCs in the presence of 0.1, 0.2, and 0.5 µM LY333531 for 48 h in the 0.1LY, 0.2LY, and 0.5LY groups, respectively. Following this, HASMCs contraction was stimulated with 1 mM acetylcholine (ACh) for up to 24 h in each group and assessed using a three-dimensional collagen gel contraction assay. Furthermore, western blot and immunofluorescence analysis were performed. RESULTS: The collagen gel contraction assay revealed that TNF-α increased the protein expression of phosphorylated PKC-ß2, CPI-17, and MLC while exacerbating ACh-induced HASMCs contraction. LY333531 significantly attenuated HASMCs contraction and downregulated the protein expression of both p-CPI-17 and p-MLC. CONCLUSIONS: At least in part by regulating CPI-17 and MLC phosphorylation, LY333531 attenuates augmented contraction of TNF-α-sensitized HASMCs in a collagen gel contraction system.

When the economy falters, hearts suffer: Economic recessions as a social determinant of health in cardiovascular emergencies.

INTRODUCTION: While the relationships between cardiovascular disease (CVD), stress, and financial strain are well studied, the association between recessionary periods and macroeconomic conditions on incidence of disease-specific CVD emergency department (ED) visits is not well established. OBJECTIVES: This retrospective observational study aimed to assess the relationship between macroeconomic trends and CVD ED visits. METHODS: This study uses data from the National Hospital Ambulatory Care Survey (NHAMCS), Federal Reserve Economic Database (FRED), National Bureau of Economic Research (NBER), and CVD groupings from National Vital Statistics (NVS) and Center for Medicare and Medicaid Services (CMS) from 1999 to 2020 to analyze ED visits in relation to macroeconomic indicators and NBER defined recessions and expansions. RESULTS: CVD ED visits grew by 79.7% from 1999 to 2020, significantly more than total ED visits (27.8%, p < 0.001). A national estimate of 213.2 million CVD ED visits, with 22.9 million visits in economic recessions were analyzed. A secondary group including a 6-month period before and after each recession (defined as a "broadened recession") was also analyzed to account for potential leading and lagging effects of the recession, with a total of 50.0 million visits. A significantly higher proportion of CVD ED visits related to heart failure (HF) and other acute ischemic heart diseases (IHD) was observed during recessionary time periods both directly and with a 6-month lead and lag (p < 0.05). The proportion of aortic aneurysm and dissection (AAA) and atherosclerosis (ASVD) ED visits was significantly higher (p = 0.024) in the recession period with a 6-month lead and lag. When controlled for common demographic factors, economic approximations of recession such as the CPI, federal funds rate, and real disposable income were significantly associated with increased CVD ED visits. CONCLUSION: Macroeconomic trends have a significant relationship with the overall mix of CVD ED visits and represent an understudied social determinant of health.

Exploration into the Mechanism of Yiyi Baijiang Decoction Attenuating Chronic Pelvic Inflammation Based on Network Pharmacology and Experimental Verification.

Patients with chronic pelvic inflammation (CPI) experience irregular menstrual, ectopic pregnancy, and infertility. Yiyi Baijiang Decoction attenuates CPI in patients with uncovered mechanisms. CPI therapeutic targets intersected with those of Yiyi Baijiang Decoction, followed by importing into STRING to obtain protein-target interaction. "Drug-component-disease-target" interaction was constructed by Cytoscape. mRNA and protein levels were detected by real-time quantitative PCR (RT-qPCR) and western blot. Yiyi Baijiang Decoction contained 199 active ingredients. There were 1071 drug targets for Yiyi Baijiang Decoction and 1622 therapeutic targets for CPI. The GO functional enrichment analysis revealed 3445 biological processes, and the KEGG pathway enrichment analysis screened 67 signal pathways. Decreased ALB, increased protein kinase B (AKT1), interleukin (IL)-6, vascular endothelial growth factor A (VEGFA), and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K/AKT)-extracellular-regulated protein kinases (ERK)1/2 activation in CPI mice were abolished by Yiyi Baijiang Decoction. Yiyi Baijiang Decoction attenuates CPI by inactivating PI3K/AKT and ERK1/2 and regulating ALB, VEGFA, AKT1, and IL-6.

Phosphorylated CPI-17 and MLC2 as Biomarkers of Coronary Artery Spasm-Induced Sudden Cardiac Death.

Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.

Spatio-temporal variation in water quality due to the anthropogenic impact in Rudrasagar Lake, a Ramsar site in India.

Rudrasagar Lake, a vital habitat for diverse flora and fauna, supports over 2000 households to sustain their daily livelihoods. The current study attempts to examine the impact of human activities on spatio-temporal variation in the water quality of the study area. The study integrates extensive field surveys, sample processing, and statistical analysis to assess the recent status of wetland health. Latin Square Matrix (LSM) was employed to select the sampling sites while the Inverse Distance Weighting (IDW) interpolation technique was used for spatial variation mapping. Modified Weighted Arithmetic Water Quality Index (MWAWQI) and Comprehensive Pollution Index (CPI) were utilized for assessing seasonal variation water quality and pollution loads, respectively. The results showed that dissolved oxygen (DO) was strongly influenced by the tributaries, and recreational activities have substantially influenced the highest concentrations of biochemical oxygen demand (BOD), and total suspended solids (TSS). The central portion of the lake is particularly susceptible to pollution from extensive fishing and recreational activities while peripheral sites are strongly influenced by agricultural run-offs, seepages from brick industries, and municipal wastes characterized by high concentrations of pH, total hardness (TH), oxidation-reduction potential (ORP). The findings reveal remarkable spatio-temporal fluctuations and highlight the areas within the lake susceptible to anthropogenic activities. The study proposed a sustainable management model to ameliorate anthropogenic threats. Moreover, the study contributes to the scientific understanding of the challenges and ensures the long-term viability of wetland health as a vital ecological and socio-economic resource.

Gamma delta T-cell-based immune checkpoint therapy: attractive candidate for antitumor treatment.

As a nontraditional T-cell subgroup, γδT cells have gained popularity in the field of immunotherapy in recent years. They have extraordinary antitumor potential and prospects for clinical application. Immune checkpoint inhibitors (ICIs), which are efficacious in tumor patients, have become pioneer drugs in the field of tumor immunotherapy since they were incorporated into clinical practice. In addition, γδT cells that have infiltrated into tumor tissues are found to be in a state of exhaustion or anergy, and there is upregulation of many immune checkpoints (ICs) on their surface, suggesting that γδT cells have a similar ability to respond to ICIs as traditional effector T cells. Studies have shown that targeting ICs can reverse the dysfunctional state of γδT cells in the tumor microenvironment (TME) and exert antitumor effects by improving γδT-cell proliferation and activation and enhancing cytotoxicity. Clarification of the functional state of γδT cells in the TME and the mechanisms underlying their interaction with ICs will solidify ICIs combined with γδT cells as a good treatment option.

Comparison of survival for metastatic pancreatic cancer patients treated with CPI-613 versus resected borderline-resectable pancreatic cancer patients.

INTRODUCTION: Treatment of advanced pancreatic adenocarcinoma remains suboptimal. Therapeutic agents with a novel mechanism of action are desperately needed; one such novel agent is CPI-613 targets. We here analyze the outcomes of 20 metastatic pancreatic cancer patients treated with CPI-613 and FOLFIRINOX in our institution and evaluate their outcomes to borderline-resectable patients treated with curative surgery. METHODS: A post hoc analysis was performed of the phase I CPI-613 trial data (NCT03504423) comparing survival outcomes to borderline-resectable cases treated with curative resection at the same institution. Survival was measured by overall survival (OS) for all study cases and disease-free survival (DFS) for resected cases with progression-free survival for CPI-613 cases. RESULTS: There were 20 patients in the CPI-613 cohort and 60 patients in the surgical cohort. Median follow-up times were 441 and 517 days for CPI-613 and resected cases, respectively. There was no difference in survival times between CPI-613 and resected cases with a mean OS of 1.8 versus 1.9 year (p = 0.779) and mean PFS/DFS of 1.4 versus 1.7 years (p = 0.512). There was also no difference in 3-year survival rates for OS (hazard ratio [HR] = 1.063, 95% confidence interval [CI] 0.302-3.744, p = 0.925) or DFS/PFS (HR = 1.462, 95% CI 0.285-7.505, p = 0.648). CONCLUSION: The first study to evaluate the survival between metastatic patients treated with CPI-613 versus borderline-resectable cases undergoing curative resection. Analysis revealed no significant differences in survival outcomes between the cohorts. Study results are suggestive that there may be potential utility with the addition of CPI-613 to potentially resectable pancreatic adenocarcinoma, although additional research with more comparable study groups are required.

ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation.

The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs.

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas.

We review extensive progress from the cancer metabolism community in understanding the specific properties of lipid metabolism as it is redesigned in advanced carcinomas. This redesigned lipid metabolism allows affected carcinomas to make enhanced catabolic use of lipids in ways that are regulated by oxygen availability and is implicated as a primary source of resistance to diverse treatment approaches. This oxygen control permits lipid catabolism to be an effective energy/reducing potential source under the relatively hypoxic conditions of the carcinoma microenvironment and to do so without intolerable redox side effects. The resulting robust access to energy and reduced potential apparently allow carcinoma cells to better survive and recover from therapeutic trauma. We surveyed the essential features of this advanced carcinoma-specific lipid catabolism in the context of treatment resistance and explored a provisional unifying hypothesis. This hypothesis is robustly supported by substantial preclinical and clinical evidence. This approach identifies plausible routes to the clinical targeting of many or most sources of carcinoma treatment resistance, including the application of existing FDA-approved agents.

Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis.

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).

Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. In patients with MF, the bone marrow becomes overactive, leading to scarring and subsequently a lack of healthy blood cells being produced. The main symptoms of MF include anemia, fatigue, weakness and pain or discomfort in the abdomen. MF is associated with a shortened life expectancy. The current go-to treatment for MF is ruxolitinib. However, ruxolitinib has shown limited efficacy in improving clinical symptoms long term; so, new safe and effective treatments are needed. Pelabresib is a novel drug currently in clinical development for treating MF. The aim of this article is to describe the design of the ongoing, global phase III MANIFEST-2 study. MANIFEST-2 is evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with MF.

Weak and Maneuvering Target Detection with Long Observation Time Based on Segment Fusion for Narrowband Radar.

Detecting high-speed and maneuvering targets is challenging in early warning radar applications. Modern early warning radar has many functions such as detection, tracking, imaging, and recognition which need a high signal-to-noise ratio (SNR). Thus, long-time coherent integration is a necessary method to realize high SNR requirements. However, high-speed and maneuverable motion cause range and Doppler migration, which brings about serious coherent integration loss. Traditional integration methods usually have the drawbacks of model mismatching and high computational complexity. This paper establishes a novel long coherent processing interval (CPI) integration algorithm that detects maneuvering and weak targets which have a low reflection cross-section (RCS) and low echo SNR. The range and Doppler migration problems are solved via a layer integration by blending the association in a tracking-before-detection (TBD) technique. Compact SNR gain is achieved with a target information transmission mechanism and an updated constant false alarm ratio (CFAR) threshold. The algorithm is applicable in multiple target scenarios by considering different velocity ambiguities and maneuvers. A simulation and real-measured experiments confirm the effectiveness of the algorithm.

PD-1/PD-L1, MDSC Pathways, and Checkpoint Inhibitor Therapy in Ph(-) Myeloproliferative Neoplasm: A Review.

There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1 promoter, which are as follows: (a) the extrinsic mechanism, which is activated by interferon gamma (IFN γ) by tumor infiltration lymphocytes (TIL) and NK cells; (b) the intrinsic mechanism of EGFR or PTEN loss resulting in the activation of the MAPK and AKT pathways and then stat 1 and 3 activation; and (c) 9p24 amplicon amplification, resulting in PD-L1 and Jak2 activation. We also review the literature and postulate that many of the failures of CPI therapy in MPN are likely due to excessive MDSC activities. We list all of the anti-MDSC agents, especially those with ruxolitinib, IMID compounds, and BTK inhibitors, which may be combined with CPI therapy in the future as part of clinical trials applying CPI therapy to Ph(-) MPN.

Identification of Dihydrolipoamide Dehydrogenase as Potential Target of Vemurafenib-Resistant Melanoma Cells.

BACKGROUND: Despite recent improvements in therapy, the five-year survival rate for patients with advanced melanoma is poor, mainly due to the development of drug resistance. The aim of the present study was to investigate the mechanisms underlying this phenomenon, applying proteomics and structural approaches to models of melanoma cells. METHODS: Sublines from two human (A375 and SK-MEL-28) cells with acquired vemurafenib resistance were established, and their proteomic profiles when exposed to denaturation were identified through LC-MS/MS analysis. The pathways derived from bioinformatics analyses were validated by in silico and functional studies. RESULTS: The proteomic profiles of resistant melanoma cells were compared to parental counterparts by taking into account protein folding/unfolding behaviors. Several proteins were found to be involved, with dihydrolipoamide dehydrogenase (DLD) being the only one similarly affected by denaturation in all resistant cell sublines compared to parental ones. DLD expression was observed to be increased in resistant cells by Western blot analysis. Protein modeling analyses of DLD's catalytic site coupled to in vitro assays with CPI-613, a specific DLD inhibitor, highlighted the role of DLD enzymatic functions in the molecular mechanisms of BRAFi resistance. CONCLUSIONS: Our proteomic and structural investigations on resistant sublines indicate that DLD may represent a novel and potent target for overcoming vemurafenib resistance in melanoma cells.

Periodontal status of students living with disability in Amhara region, Ethiopia: a cross-sectional study.

BACKGROUND: Periodontal disease is the most common oral health problem among individuals living with disabilities. Any physical impairment and/or mental handicap can compromise the capability to perform oral health care. Individuals with poor oral hygiene practice were prone to dental caries, periodontal disease, and upper respiratory tract infections. Despite the high prevalence of disabled people in Ethiopia, data are scarce about their periodontal status. The aim of this study was to determine the prevalence and determinant factors of periodontal disease among students living with disability in the Amhara region. METHODS: A school-based cross-sectional study was done on eight special needs schools in Amhara regional state from November 30, 2020, to April 10, 2021. A simple random sampling technique using a computer random generator was employed to recruit the study participants. The participants were interviewed for sociodemographic characteristics, oral hygiene practice, type of disability, and medical condition through a pre-tested semi-structured questionnaire. The periodontal status of the participants was evaluated using the community periodontal index (CPI). Data entry was done using the Epi-data and analyzed using SPSS 26. Binary logistic regression analysis was used to identify the predictors of periodontal disease at a 5% level of significance. RESULTS: A total of 443 study participants were involved with a mean age of 15.84 ± 3.882. Among these, 27.5% (95%CI 23.4-32.0) had a periodontal pocket depth of ≥ 4 mm, and 56.7% had bleeding on probing. The prevalence of periodontal disease was higher in participants with poor oral health status (52.2%), dental caries (34.8%), class-2 malocclusion (46.1%), and low monthly income (30.4%), visually impaired (30%), and mentally disorder (29.9%). Age of above 18 years (AOR = 3.41, 95%CI 1.40, 8.28), low family monthly income (AOR = 2.21; 95%CI 1.22, 4.03), malocclusion (AOR = 1.59, 95%CI 1.01, 2.54), poor oral health status (AOR = 9.41; 95%CI 4.92, 17.98), and dental caries (AOR = 1.85, 95%CI 1.21, 2.82) were independent predictors of periodontal disease. CONCLUSIONS: A substantial amount of disabled school students in the study area had periodontal disease. The study found that there was a statistically significant association between age, family monthly income, malocclusion, oral health status, and dental caries with periodontal disease. The implementation of school oral health programs has a great benefit for the oral health status of disabled school students.

[Implementation of the prevention program in the school dentistry system in the context of healthcare modernization]. / Realizatsiya programmy profilaktiki v sisteme shkol'noi stomatologii v usloviyakh modernizatsii zdravookhraneniya.

THE AIM OF THE STUDY: The aim of the study was to develop and implement a program for the prevention of dental diseases for school-age children based on an individual approach to treatment and preventive measures. MATERIAL AND METHODS: 1848 children aged from 6 to 17 were examined. The main observation group consisted of children from school No. 1694 in the South-Western Administrative District of Moscow (935 children), the comparison group with no prevention program consisted of children from school No 1206 (913 children) of the same Moscow district. The effectiveness of the prevention program was assessed in key age groups of children 6, 12 and 15 years old. The prevention program included the study of dental morbidity, assessment of the level of oral hygiene of children, parents and teachers, conducting sanitary and educational work, teaching children hygiene and monitoring its implementation, developing and implementing the individual plan of therapeutic and preventive measures for children of all age groups. RESULTS: As a result of the prevention program, the number of healthy children without caries increased. The introduction of a prevention program showed its effectiveness, the reduction of caries growth among 12-years-old children who participated in the prevention program over 5 years was 37%, and the number of healthy children increased by 15%. CONCLUSION: Carrying out a prevention program at school has shown that coordinated actions of parents, teachers and dentists lead to an improvement in the condition of hard tissues of the permanent teeth of schoolchildren, a decrease in the risk of inflammatory periodontal diseases in adolescence, and an improvement in the quality of individual oral hygiene. Of particular importance is the presence of a dental office and a dental hygienist in the school, for the possibility of carrying out preventive measures for children of all age groups.

Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma.

The metabolism in tumors is reprogrammed to meet its energetic and substrate demands. However, this metabolic reprogramming creates metabolic vulnerabilities, providing new opportunities for cancer therapy. Metabolic vulnerability as a therapeutic target in esophageal squamous cell carcinoma (ESCC) has not been adequately clarified. Here, we identified pyruvate dehydrogenase (PDH) component X (PDHX) as a metabolically essential gene for the cell growth of ESCC. PDHX expression was required for the maintenance of PDH activity and the production of ATP, and its knockdown inhibited the proliferation of cancer stem cells (CSCs) and in vivo tumor growth. PDHX was concurrently upregulated with the CD44 gene, a marker of CSCs, by co-amplification at 11p13 in ESCC tumors and these genes coordinately functioned in cancer stemness. Furthermore, CPI-613, a PDH inhibitor, inhibited the proliferation of CSCs in vitro and the growth of ESCC xenograft tumors in vivo. Thus, our study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex-associated metabolic vulnerability.

Targeted Delivery of IL-12 Adjuvants Immunotherapy by Oncolytic Viruses.

The great hopes raised by the discovery of the immunoregulatory cytokine interleukin 12 (IL-12) as an anticancer agent were marred during early clinical experimentation because of severe adverse effects, which prompted a search for alternative formulations and routes of administration. Onco-immunotherapeutic viruses (OIVs) are wild-type or genetically engineered viruses that exert antitumor activity by causing death of the tumor cells they infect and by overcoming a variety of immunosuppressive mechanisms put in place by the tumors. OIVs have renewed the interest in IL-12, as they offer the opportunity to encode the cytokine transgenically from the viral genome and to produce it at high concentrations in the tumor bed. A large body of evidence indicates that IL-12 serves as a potent adjuvant for the immunotherapeutic response elicited by OIVs in murine tumor models. The list of OIVs includes onco-immunotherapeutic herpes simplex, adeno, measles, Newcastle disease, and Maraba viruses, among others. The large increase in IL-12-mediated adjuvanticity was invariably observed for all the OIVs analyzed. Indirect evidence suggests that locally delivered IL-12 may also increase tumor antigenicity. Importantly, the OIV/IL-12 treatment was not accompanied by adverse effects and elicited a long-lasting immune response capable of halting the growth of distant tumors. Thus, OIVs provide an avenue for reducing the clinical toxicity associated with systemic IL-12 therapy, by concentrating the cytokine at the site of disease. The changes to the tumor microenvironment induced by the IL-12-armed OIVs primed the tumors to an improved response to the checkpoint blockade therapy, suggesting that the triple combination is worth pursuing in the future. The highly encouraging results in preclinical models have prompted translation to the clinic. How well the IL-12-OIV-checkpoint inhibitors' combination will perform in humans remains to be fully investigated.