Nephrotic syndrome as a possible indicator of colonic cancer: A case report.

The concept of paraneoplastic syndromes encompasses a spectrum of indirect clinical manifestations caused by secretion of bioactive products by malignant cells. Paraneoplastic glomerulopathy represent a distinct clinical entity where nephrotic syndrome can arise as a manifestation of underlying malignancies, particularly solid tumors. Membranous nephropathy is notably associated with such malignancies, highlighting the intricate relationship between nephrotic syndrome and cancer. The present study reports the case of a 44-year-old Caucasian male, smoker (22 pack-years) and chronic ethanol consumer who presented in the Emergency County Hospital of Craiova in March 2018 with abdominal distension, genital and leg edema and no prior medical history. Laboratory tests revealed inflammatory syndrome (erythrocyte sedimentation rate=110 mm/h, fibrinogen, 150 mg/dl, high levels of C reactive protein=6.87 mg/dl), as well as hypoproteinemia (total protein levels=3.90 g/l), hypertriglyceridemia=213 mg/dl, hypercholesterolemia=475 mg/dl, total urinary protein excretion of 12,500 mg/24 h and normal levels of urea (38 mg/dl) and creatinine (0.90 mg/dl). After meeting the diagnostic criteria for nephrotic syndrome (edema, proteinuria, hypoalbuminemia, and hyperlipidemia, it was investigated whether the syndrome was primary or secondary in origin. Notably, an unexplained inflammatory syndrome in conjunction with elevated tumor marker levels (carbohydrate antigen 19-9, 82.47 U/ml; Carcinoembryonic antigen-CEA=9.46 ng/ml) prompted a thorough imagistic investigation, using computer tomography. A polyp was discovered during colonoscopy, prompting a biopsy. The presence of adenocarcinoma was confirmed by histopathological analysis. The only clinical manifestation of the colonic malignancy was the symptomatic presentation of nephrotic syndrome, which led to early detection of the underlying cancer. Paraneoplastic nephropathy connects kidney disease with systemic cancer, showing that renal symptoms may aid in diagnosing hidden malignancies. Nephrotic syndrome, especially membranous nephropathy, is associated with various solid tumors. The present case demonstrated that paraneoplastic syndrome, though rare, may lead to early cancer detection. Ongoing research is essential for improving understanding, targeted therapy and patient management.

Nesfatin-1: A Novel Diagnostic and Prognostic Biomarker in Digestive Diseases.

Nesfatin-1, deriving from a precursor protein, NUCB2, is a newly discovered molecule with anti-apoptotic, anti-inflammatory, antioxidant, and anorexigenic effects. It was initially identified in the central nervous system (CNS) and received increasing interest due to its energy-regulating properties. However, research showed that nesfatin-1 is also expressed in peripheral tissues, including the digestive system. The aim of this review is to give a résumé of the present state of knowledge regarding its structure, immunolocalization, and potential implications in diseases with inflammatory components. The main objective was to focus on its clinical importance as a diagnostic biomarker and potential therapeutic molecule in a variety of disorders, among which digestive disorders were of particular interest. Previous studies have shown that nesfatin-1 regulates the balance between pro- and antioxidant agents, which makes nesfatin-1 a promising therapeutic agent. Further in-depth research regarding the underlying mechanisms of action is needed for a better understanding of its effects.

A Comparative Study on the Pain Threshold Experienced by Fibromyalgia Patients Following Acute SARS-CoV-2 Infection.

Significant gaps remain in the understanding of the etiology and pathogenesis of fibromyalgia (FM), and the COVID-19 pandemic has introduced even more unknowns. Social factors specific to that period, the viral infection itself, and/or vaccination are additional elements that can complicate the progression of the disease or the response to treatment. Aim: The primary hypothesis to be evaluated in this study is that an acute COVID-19 infection, even when considered recovered, may induce changes in the response to non-pharmacological treatment in FM patients, particularly concerning pain. Results: We included 128 patients diagnosed with FM before the pandemic began. The patients were divided based on their history of acute SARS-CoV-2 infection and COVID-19 vaccination status. All patients followed the same rehabilitation program (cognitive therapy, kinesitherapy). Perceived pain: The non-COVID-19 patient groups showed a statistically significant reduction in pain at the final evaluation compared to patients with a history of acute SARS-CoV-2 infection (p < 0.001). Algometric evaluation: Patients without COVID-19 infection and that were vaccinated exhibited the best improvement in pain threshold, both across evaluation times (p < 0.001) and compared to any of the other three groups studied (p < 0.001). Using the WHYMPI questionnaire, the same group of patients (those not having experienced acute COVID-19 and who were vaccinated) was the only group with a statistically significant improvement in pain severity (p = 0.009). In conclusion, to control and improve FM pain symptoms, in addition to appropriate medication, we propose paying additional attention to the history of acute SARS-CoV-2 infection and the COVID-19 vaccination status.

The Efficiency of Kinesiotherapy versus Physical Modalities on Pain and Other Common Complaints in Fibromyalgia.

Due to its variety of signs and symptoms, there have been numerous attempts to treat fibromyalgia (FM), but a cure has yet to be established. The aim of this study was to evaluate the effects of a complex kinetic therapy program and a combined physical modality program on pain and other common symptoms of FM. Patients and methods: A total of 78 female patients were included in this study; 39 subjects underwent a kinesiotherapy (KT) intervention (combining aerobic and Pilates exercises), and 39 participated in a physical modality (PM) program (including electrotherapy (TENS and low-laser therapy) and thermotherapy). Results: Regarding the parameter of pain assessment, kinesiotherapy demonstrated its superiority both during the treatment period and in the evaluation 3 months after therapy cessation. Both in terms of patient-reported pain (inter-group comparisons: p = 0.000 at T3) and the examination of tender points (inter-group comparisons: p = 0.000 at T3), as well as the algometric assessment, pain was alleviated by the two forms of applied kinetic therapy. The observed functional impairment was statistically significantly influenced (p = 0.001) at the end of the kinetic program application, while for the perceived functional impairment, neither therapy proved superiority over the other at any point of evaluation (inter-group comparisons: p = 0.715 at T3). Regarding the influence of the emotional consequences implied by fibromyalgia, neither the forms of kinesiotherapy nor the chosen physical modalities proved superiority at any point of evaluation (HAQ anxiety inter-group comparisons: p = 0.000 at T3). In conclusion, even though kinesiotherapy had superior influences on fibromyalgia pain in the studied group, the current research lends credence to the significance of non-pharmacological therapy in managing fibromyalgia. Participants demonstrated positive advancements in subjective and objective pain assessments, as well as improvements in functional and emotional well-being.

Influence of Education, Cognition, and Physical Disability on Quality of Life of Romanian Patients with Multiple Sclerosis-A Cohort Study.

Background and Objectives: objective measures of disability and neurological impairmentare used to search for disease activity and monitor disease evolution in multiple sclerosis (MS). These are sometimes in disagreement with subjective quality-of-life measures. We aimed to establish the relations between the Multiple Sclerosis Quality of Life instrument (MSQOL-54) and objective measures of neurological impairment. Materials and Methods: 107 patients with MS were evaluated with the Single Digit Modalities Test (SDMT) for cognition, Nine Holes Peg Test (9HPT) for upper limb function, 25 Feet Walk Test (25FWT) for gait, and EDSS for global disability in a cohort study. Age and education level were recorded as sociodemographic factors. Results: the median EDSS was 3.5 (IQR 2.5); average SDMT score was 30.38 ± 13.54; and 9HPT speed was significantly higher for the dominant upper limb (0.3 ± 0.1 pegs/s versus 0.28 ± 0.11 pegs/s) (p = 0.016). The mental health composite score of the MSQOL-54 correlated with the SDMT, education level, and EDSS. Education level correlated with cognition and quality of life. The physical health composite score of the MSQOL-54 correlated with motor-function parameters and with SDMT. The motor-function parameters correlated well among themselves. A linear regression model found an important influence of SDMT and education level on the mental health composite score of the MSQOL-54. Although the linear regression model predicting the physical health composite score from physical disability parameters was statistically sound, none of the determinants had a significant individual influence. Conclusions: the subscores of the MSQOL-54 correlated well with the objective parameters. The strongest correlations were those with the cognitive function. Correlations with physical disability were less powerful, probably reflecting their indirect and more limited influence on quality of life compared to cognition and perception of disability.

E2F1 mediates competition, proliferation and response to cisplatin in cohabitating resistant and sensitive ovarian cancer cells.

Background: Tumor heterogeneity is one of the key factors leading to chemo-resistance relapse. It remains unknown how resistant cancer cells influence sensitive cells during cohabitation and growth within a heterogenous tumors. The goal of our study was to identify driving factors that mediate the interactions between resistant and sensitive cancer cells and to determine the effects of cohabitation on both phenotypes. Methods: We used isogenic ovarian cancer (OC) cell lines pairs, sensitive and resistant to platinum: OVCAR5 vs. OVCAR5 CisR and PE01 vs. PE04, respectively, to perform long term direct culture and to study the phenotypical changes of the interaction of these cells. Results: Long term direct co-culture of sensitive and resistant OC cells promoted proliferation (p < 0.001) of sensitive cells and increased the proportion of cells in the G1 and S cell cycle phase in both PE01 and OVCAR5 cells. Direct co-culture led to a decrease in the IC50 to platinum in the cisplatin-sensitive cells (5.92 µM to 2.79 µM for PE01, and from 2.05 µM to 1.51 µM for OVCAR5). RNAseq analysis of co-cultured cells showed enrichment of Cell Cycle Control, Cyclins and Cell Cycle Regulation pathways. The transcription factor E2F1 was predicted as the main effector responsible for the transcriptomic changes in sensitive cells. Western blot and qRT-PCR confirmed upregulation of E2F1 in co-cultured vs monoculture. Furthermore, an E2F1 inhibitor reverted the increase in proliferation rate induced by co-culture to baseline levels. Conclusion: Our data suggest that long term cohabitation of chemo-sensitive and -resistant cancer cells drive sensitive cells to a higher proliferative state, more responsive to platinum. Our results reveal an unexpected effect caused by direct interactions between cancer cells with different proliferative rates and levels of platinum resistance, modelling competition between cells in heterogeneous tumors.

Can Combining Hyaluronic Acid and Physiotherapy in Knee Osteoarthritis Improve the Physicochemical Properties of Synovial Fluid?

Known as the degenerative disease of the knee with the highest prevalence, knee osteoarthritis (KOA) is characterized by a gradual destructive mechanism that, in severe cases, can provoke the need for total knee substitution. As the disease progresses, various enzymatic, immunological, and inflammatory processes abnormally degrade hyaluronic acid (HA), SF's main component, and affect the concentrations of specific proteins, with the final results seriously endangering synovial fluid (SF)'s rheological and tribological features and characteristics. No effective treatments have been found to stop the progression of KOA, but the injection of HA-based viscoelastic gels has been considered (alone or combined with physiotherapy (PT)) as an alternative to symptomatic therapies. In order to evaluate the effect of viscosupplementation and PT on the characteristics of SF, SF aspirated from groups treated for KOA (HA Kombihylan® and groups that received Kombihylan® and complex PT) was analyzed and compared from analytical, spectrophotometrical, and rheological perspectives. In the patients treated with PT, the SF extracted 6 weeks after viscosupplementation had a superior elastic modulus (G') and viscous moduli (G″), as well as a homogeneous distribution of proteins and polysaccharides. The viscosupplementation fluid improved the bioadhesive properties of the SF, and the use of the viscosupplementation fluid in conjunction with PT was found to be favorable for the distribution of macromolecules and phospholipids, contributing to the lubrication process and the treatment of OA-affected joints.

Preclinical Evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer.

PURPOSE: DNA methylation causes silencing of tumor-suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) resensitize ovarian cancer to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development. EXPERIMENTAL DESIGN: The antitumor effects of NTX-301 were studied in ovarian cancer models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses, and stimulated Raman spectroscopy. RESULTS: Ovarian cancer cells (SKOV3, IC50 = 5.08 nmol/L; OVCAR5 IC50 = 3.66 nmol/L) were highly sensitive to NTX-301 compared with fallopian tube epithelial cells. NTX-301 downregulated expression of DNA methyltransferases 1-3 and induced transcriptomic reprogramming with 15,000 differentially expressed genes (DEG, P < 0.05). Among them, Gene Ontology enrichment analysis identified regulation of fatty acid biosynthesis and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase, known features of cancer stem cells. Low-dose NTX-301 reduced the ALDH(+) cell population and expression of stemness-associated transcription factors. Stearoyl-coenzyme A desaturase 1 (SCD), which regulates production of unsaturated fatty acids (UFA), was among the top DEG downregulated by NTX-301. NTX-301 treatment decreased levels of UFA and increased oxidized lipids, and this was blunted by deferoxamine, indicating cell death via ferroptosis. NTX-301-induced ferroptosis was rescued by oleic acid. In vivo, monotherapy with NTX-301 significantly inhibited ovarian cancer and patient-derived xenograft growth (P < 0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301-treated xenografts. CONCLUSIONS: NTX-301 is active in ovarian cancer models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death.

Biology-driven therapy advances in high-grade serous ovarian cancer.

Following a period of slow progress, the completion of genome sequencing and the paradigm shift relative to the cell of origin for high grade serous ovarian cancer (HGSOC) led to a new perspective on the biology and therapeutic solutions for this deadly cancer. Experimental models were revisited to address old questions, and improved tools were generated. Additional pathways emerging as drivers of ovarian tumorigenesis and key dependencies for therapeutic targeting, in particular, VEGF-driven angiogenesis and homologous recombination deficiency, were discovered. Molecular profiling of histological subtypes of ovarian cancer defined distinct genetic events for each entity, enabling the first attempts toward personalized treatment. Armed with this knowledge, HGSOC treatment was revised to include new agents. Among them, PARP inhibitors (PARPis) were shown to induce unprecedented improvement in clinical benefit for selected subsets of patients. Research on mechanisms of resistance to PARPis is beginning to discover vulnerabilities and point to new treatment possibilities. This Review highlights these advances, the remaining challenges, and unsolved problems in the field.

Nanoparticle Targeting in Chemo-Resistant Ovarian Cancer Reveals Dual Axis of Therapeutic Vulnerability Involving Cholesterol Uptake and Cell Redox Balance.

Platinum (Pt)-based chemotherapy is the main treatment for ovarian cancer (OC); however, most patients develop Pt resistance (Pt-R). This work shows that Pt-R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B-1 (SR-B1). SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and inhibition of tumor growth. Reduced cholesterol accumulation in cancer cells induces lipid oxidative stress through the reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion induces decreased cholesterol uptake through SR-B1 and re-sensitizes OC cells to Pt. Mechanistically, GPx4 knockdown causes lower expression of the histone acetyltransferase EP300, leading to reduced deposition of histone H3 lysine 27 acetylation (H3K27Ac) on the sterol regulatory element binding transcription factor 2 (SREBF2) promoter and suppressing expression of this key transcription factor involved in the regulation of cholesterol metabolism. SREBF2 downregulation leads to decreased SR-B1 expression and diminished cholesterol uptake. Thus, chemoresistance and cancer cell survival under high ROS burden obligates high GPx4 and SR-B1 expression through SREBF2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.

Defining the short-term and long-term skin manifestations of COVID-19: insights after more than three years of the pandemic.

AIM: This review aimed to assess the impact of coronavirus disease 2019 (COVID-19) on skin health to establish a classification of the skin lesions that occur most frequently during the disease and whether a particular category of skin damage is more likely to occur both in the short term and in the long term. METHODS: We conducted a literature search of the PubMed database. Ultimately, 109 articles were included in this review. The exact phrases∕syntax and connectors used for the database search∕query were as follows: "Coronavirus and skin", "COVID-19 and skin", "SARS-CoV-2 and skin", "Coronavirus cutaneous manifestations", "COVID-19 cutaneous manifestations", "SARS-CoV-2 cutaneous manifestations", "Coronavirus dermatology", "SARS-CoV-2 and dermatology", "COVID-19 and dermatology", "COVID-19 and skin eruption", "Coronavirus and skin rash", "COVID-19 and hair", "Coronavirus and hair", "Coronavirus and nails", "SARS-CoV-2 and hair", and "SARS-CoV-2 and nails". Only articles with abstracts referring strictly to cutaneous manifestations of COVID-19 were chosen. Articles without abstracts were not considered. RESULTS: We established six of the most frequently reported clinical patterns associated with COVID-19 and their probability of occurring during COVID-19 disease evolution based on the current literature reports. We did not identify the particular types of skin lesions that are most prone to long-term persistence; most such cases are rare, and no conclusion can be drawn based on them. CONCLUSIONS: Apart from classified COVID-19-related skin disorders, this pandemic has been a challenge for dermatologists and a wide range of cutaneous side effects related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) treatments have been reported. We are aware of other polymorphic clinical presentations, with novel data being reported periodically, but the pathophysiological mechanisms and evolution are largely unknown.

HPLC Analysis and Risk Assessment of 15 Priority PAHs in Human Blood Serum of COPD Patient from Urban and Rural Areas, Iasi (Romania).

One of the leading risk factors for environmental health problems is air pollution. The World Health Organization (WHO) reports that this risk factor is associated with one of every nine deaths worldwide. Epidemiological studies conducted in this field have shown a solid connection between respiratory pathology and polycyclic aromatic hydrocarbon (PAH) exposure. COPD and asthma are respiratory diseases that were shown to have a strong association with exposure to PAHs. The purpose of the present study was to assess the serum levels of 15 PAHs in 102 COPD patients and to evaluate the results according to the residence environment of the investigated subjects. Analyses were carried out using a high-performance liquid chromatograph Nexera X2-Shimadzu Japan, which was equipped with an LC-30AD pump and an SIL-30AC autosampler. Spiked matrices, procedure blanks, spiked controls, and calibration standards in the acetonitrile were used as quality-assurance samples. Benzo(a)pyrene is the main representative of PAHs and was determined in higher concentrations in subjects with COPD versus the control group from the urban area (0.90/0.47 ng/mL) and rural area (0.73/0.44 ng/mL). The values obtained for the Benzo(a)pyrene-equivalent factor indicate a higher carcinogenic potential for patients diagnosed with COPD in urban areas compared to those in rural areas. These results could be due to traffic and vehicle emissions. This research identifies the need for legislative action to decrease semi-volatile organic compounds, especially PAHs, mainly in urban cities, in order to improve environmental management and health conditions.

Discovery and Characterization of PROTACs Targeting Tissue Transglutaminase (TG2).

Tissue transglutaminase (TG2) is a multifunctional enzyme involved in the cross-linking of extracellular matrix proteins, formation of complexes with fibronectin (FN) and integrins, and GTP hydrolysis. TG2 is activated in several pathological conditions, including cancer. We recently described a novel series of ligands that bind to TG2 and inhibit its interaction with FN. Because TG2 acts via multiple mechanisms, we set out to pursue a targeted protein degradation strategy to abolish TG2's myriad functions. Here, we report the synthesis and characterization of a series of VHL-based degraders that reduce TG2 in ovarian cancer cells in a proteasome-dependent manner. Degradation of TG2 resulted in significantly reduced cancer cell adhesion and migration in vitro in scratch-wound and migration assays. These results strongly indicate that further development of more potent and in vivo efficient TG2 degraders could be a new strategy for reducing the dissemination of ovarian and other cancers.

Integrated Multi-Omic Analysis Reveals Immunosuppressive Phenotype Associated with Poor Outcomes in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is characterized by a complex genomic landscape, with both genetic and epigenetic diversity contributing to its pathogenesis, disease course, and response to treatment. To better understand the association between genomic features and response to treatment among 370 patients with newly diagnosed HGSOC, we utilized multi-omic data and semi-biased clustering of HGSOC specimens profiled by TCGA. A Cox regression model was deployed to select model input features based on the influence on disease recurrence. Among the features most significantly correlated with recurrence were the promotor-associated probes for the NFRKB and DPT genes and the TREML1 gene. Using 1467 transcriptomic and methylomic features as input to consensus clustering, we identified four distinct tumor clusters-three of which had noteworthy differences in treatment response and time to disease recurrence. Each cluster had unique divergence in differential analyses and distinctly enriched pathways therein. Differences in predicted stromal and immune cell-type composition were also observed, with an immune-suppressive phenotype specific to one cluster, which associated with short time to disease recurrence. Our model features were additionally used as a neural network input layer to validate the previously defined clusters with high prediction accuracy (91.3%). Overall, our approach highlights an integrated data utilization workflow from tumor-derived samples, which can be used to uncover novel drivers of clinical outcomes.

Metabolic dependencies and targets in ovarian cancer.

Reprogramming of cellular metabolism is a hallmark of cancer. Cancer cells undergo metabolic adaptations to maintain tumorigenicity and survive under the attack of immune cells and chemotherapy in the tumor microenvironment. Metabolic alterations in ovarian cancer in part overlap with findings from other solid tumors and in part reflect unique traits. Altered metabolic pathways not only facilitate ovarian cancer cells' survival and proliferation but also endow them to metastasize, acquire resistance to chemotherapy, maintain cancer stem cell phenotype and escape the effects of anti-tumor immune defense. In this review, we comprehensively review the metabolic signatures of ovarian cancer and their impact on cancer initiation, progression, and resistance to treatment. We highlight novel therapeutic strategies targeting metabolic pathways under development.

The Endocannabinoid System and Physical Exercise.

The endocannabinoid system (ECS) is involved in various processes, including brain plasticity, learning and memory, neuronal development, nociception, inflammation, appetite regulation, digestion, metabolism, energy balance, motility, and regulation of stress and emotions. Physical exercise (PE) is considered a valuable non-pharmacological therapy that is an immediately available and cost-effective method with a lot of health benefits, one of them being the activation of the endogenous cannabinoids. Endocannabinoids (eCBs) are generated as a response to high-intensity activities and can act as short-term circuit breakers, generating antinociceptive responses for a short and variable period of time. A runner's high is an ephemeral feeling some sport practitioners experience during endurance activities, such as running. The release of eCBs during sustained physical exercise appears to be involved in triggering this phenomenon. The last decades have been characterized by an increased interest in this emotional state induced by exercise, as it is believed to alleviate pain, induce mild sedation, increase euphoric levels, and have anxiolytic effects. This review provides information about the current state of knowledge about endocannabinoids and physical effort and also an overview of the studies published in the specialized literature about this subject.

N6-Methyladenosine RNA Modifications Regulate the Response to Platinum Through Nicotinamide N-methyltransferase.

Development of resistance to platinum (Pt) in ovarian cancer remains a major clinical challenge. Here we focused on identifying epitranscriptomic modifications linked to Pt resistance. Fat mass and obesity-associated protein (FTO) is a N6-methyladenosine (m6A) RNA demethylase that we recently described as a tumor suppressor in ovarian cancer. We hypothesized that FTO-induced removal of m6A marks regulates the cellular response of ovarian cancer cells to Pt and is linked to the development of resistance. To study the involvement of FTO in the cellular response to Pt, we used ovarian cancer cells in which FTO was knocked down via short hairpin RNA or overexpressed and Pt-resistant (Pt-R) models derived through repeated cycles of exposure to Pt. We found that FTO was significantly downregulated in Pt-R versus sensitive ovarian cancer cells. Forced expression of FTO, but not of mutant FTO, increased sensitivity to Pt in vitro and in vivo (P < 0.05). Increased numbers of γ-H2AX foci, measuring DNA double-strand breaks, and increased apoptosis were observed after exposure to Pt in FTO-overexpressing versus control cells. Through integrated RNA sequencing and MeRIP sequencing, we identified and validated the enzyme nicotinamide N-methyltransferase (NNMT), as a new FTO target linked to Pt response. NNMT was upregulated and demethylated in FTO-overexpressing cells. Treatment with an NNMT inhibitor or NNMT knockdown restored sensitivity to Pt in FTO-overexpressing cells. Our results support a new function for FTO-dependent m6A RNA modifications in regulating the response to Pt through NNMT, a newly identified RNA methylated gene target.

DOT1 L Regulates Ovarian Cancer Stem Cells by Activating ß-catenin Signaling.

Cancer stem cells (CSC) represent a population of cancer cells responsible for tumor initiation, chemoresistance, and metastasis. Here, we identified the H3K79 methyltransferase disruptor of telomeric silencing-1-like (DOT1L) as a critical regulator of self-renewal and tumor initiation in ovarian CSCs. DOT1 L was upregulated in ovarian CSCs versus non-CSCs. shRNA-mediated DOT1 L knockdown decreased the aldehyde dehydrogenase (ALDH)+ cell population, impaired the tumor initiation capacity (TIC) of ovarian CSCs, and blocked the expression of stemness-associated genes. Inhibition of DOT1L's methyltransferase activity by the small-molecule inhibitor (DOT1Li) EPZ-5676 also effectively targeted ovarian CSCs. Integrated RNA-sequencing analyses of ovarian cancer cells in which DOT1 L was knocked down versus control cells and of ovarian CSCs versus non-CSCs, identified Wnt signaling as a shared pathway deregulated in both CSCs and in DOT1L-deficient ovarian cancer cells. ß-catenin, a key transcription factor regulated by Wnt, was downregulated in ovarian cancer cells in which DOT1 L was knocked down and upregulated in DOT1 L overexpressing ovarian cancer cells. Chromatin immunoprecipitation (ChIP) revealed enrichment of the H3K79Me3 mark at the ß-catenin promoter, suggesting that its transcription is regulated by DOT1L. Our results suggest that DOT1 L is critical for the self-renewal and TIC of ovarian CSCs by regulating ß-catenin signaling. Targeting DOT1 L in ovarian cancer could be a new strategy to eliminate CSCs. IMPLICATIONS: This study found that the histone methyltransferase DOT1 L regulates the self-renewal and tumor initiation capacity of ovarian CSCs and suggests DOT1 L as a new cancer target.

The Lipid Profile and Biochemical Parameters of COPD Patients in Relation to Smoking Status.

Tobacco consumption is the most incriminated and studied risk factor for Chronic obstructive pulmonary disease (COPD), but other factors such as air pollution, are also linked to this disease. One of the known aspects of this chronic lung disease is that its occurrence is mainly due to the chronic inflammation of the airways. Lipid metabolism seems to be affected by smoking, with studies showing a correlation between this habit and high levels of triglycerides and low levels of high-density lipoprotein cholesterol (HDL-CHOL). Uric acid concentration is thought to reflect the antioxidative capacity of the body because it is the most abundant aqueous antioxidant. The aim of this study was to investigate the lipid profile and biochemical parameters of COPD patients in relation to smoking status. The present study was conducted between 2020 and 2021 in the Clinical Hospital of Pneumology in Iasi, Romania. Patients diagnosed with COPD (n = 52) were included and divided in three groups depending on their smoking status: non-smokers, smokers and ex-smokers. The obtained results show low correlations between COPD stages and serum uric acid concentrations (r = 0.4; p ˂ 0.05), smoking status (smoker/non-smoker/ex-smoker) and total serum cholesterol values (r = 0.45; p ˂ 0.05), but also between serum urea concentrations and the number of packs-years for the smoker/ex-smoker groups (r = 0.45, p ˂ 0.05). Smoking was associated with changes in the lipid profile of smokers and ex-smokers, along with increased low-density lipoprotein cholesterol (LDL-CHOL) and low serum uric acid values.

Polycyclic Aromatic Hydrocarbons Induced by Smoking and Air Pollution: Correlation with Oxidative Stress in Chronic Obstructive Pulmonary Disease Patients.

Oxidative stress is induced by tobacco smoking and is also associated with exposure to air pollution, which are two of the most important risk factors for chronic obstructive pulmonary disease (COPD). The aim of this study was to correlate tobacco use and exposure to air pollution with oxidative stress markers useful in clinical practice in patients with COPD. A total of 102 patients were included and the levels of polycyclic aromatic hydrocarbons (PAHs), malondialdehyde, uric acid and number of packs-years (PY) were determined. Also, six different ratios were used to assess the source of exposure. The results obtained in this study show an admission of pollutants according to smoking status (former smokers/smoker/non-smokers) quantified in average total concentrations for the group of patients with COPD of 4.12 ng/mL, 6.76 ng/mL, 6.04 ng/mL. The six ratios used show that in COPD, the content of PAHs in the blood could be a result of diesel emissions and fuel combustion. Uric acid levels were lower in the smoker group of COPD patients (mean = 5.21 mg/dL), which indicates that oxidative stress is intensified with each cigarette smoked. Additionally, high concentrations of malondialdehyde were quantified for smoking patients diagnosed with COPD (mean = 2.72 µmol/L) compared to former smokers (mean = 2.43 µmol/L) and non-smoking (mean = 2.32 µmol/L) patients, which is another indicator of the implication of smoking in oxidative stress in COPD patients.