Notes

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Three patients additionally received salvage radiation therapy (sRT) including the prostatic lodge and docetaxel chemotherapy was started in one case. At follow-up, a decrease of PSA-level was detected in all patients (median 2.05 ng/ml) after median 10 months. In six of eight patients we observed a decrease or complete regress of PSMA-uptake in MLN in the follow-up 68Ga-PSMA-PET/CT. Conclusion MLN metastases detected by 68Ga-PSMA-PET/CT seem to be a relevant localization of tumor manifestation and may serve as index lesion in the treatment of recurrent PCa. Besides the known oncological benefits of ADT and sRT, in case of sole MLN metastases individualized therapy like salvage lymphadenectomy or RT with a defined radiation field could be options for these patients.Objective To investigate temporal trends in prostate cancer (PCa) radical prostatectomy (RP) candidates. Materials and Methods Patients who underwent RP for PCa between January 2014 and December 2019 were identified form our institutional database. Trend analysis and logistic regression models assessed RP trends after stratification of PCa patients according to D'Amico classification and Gleason score. Patients with neoadjuvant androgen deprivation or radiotherapy prior to RP were excluded from the analysis. Results Overall, 528 PCa patients that underwent RP were identified. Temporal trend analysis revealed a significant decrease in low-risk PCa patients from 17 to 9% (EAPC -14.6%, p less then 0.05) and GS6 PCa patients from 30 to 14% (EAPC -17.6%, p less then 0.01). This remained significant even after multivariable adjustment [low-risk PCa (OR) 0.85, p less then 0.05 and GS6 PCa (OR) 0.79, p less then 0.001]. Furthermore, a trend toward a higher proportion of intermediate-risk PCa undergoing RP was recorded. Conclusion Our results confirm that inverse stage migration represents an ongoing phenomenon in a contemporary RP cohort in a European tertiary care PCa center. Our results demonstrate a significant decrease in the proportion of low-risk and GS6 PCa undergoing RP and a trend toward a higher proportion of intermediate-risk PCa patients undergoing RP. This indicates a more precise patient selection when it comes to selecting suitable candidates for definite surgical treatment with RP.Background The evidence regarding the association between added sugar (AS) intake and obesity remains inconsistent. The aim of this study was to investigate the association between changes in the percentage of energy intake from AS (EAS%) and changes in body weight in a cohort study of older Australians during 15 years of follow-up. In addition, associations were assessed according to whether EAS% intake was provided from beverage or non-beverage sources. Methods Data were analyzed from the participants of the Blue Mountains Eye Study Cohort. Dietary data were collected at baseline (1992-94) and three five-yearly intervals using a 145-item food frequency questionnaire. Participants' body weight was measured at each time point. Five-yearly changes in EAS% intake and body weight were calculated (n = 1,713 at baseline). A generalized estimating equation (GEE) model was used to examine the relationship between the overall five-yearly changes in EAS% intake and body weight, adjusted for dietary and lifestyle variables. Results In each time interval, the EAS% intake decreased by ~5% in the lowest quartile (Q1) and increased by ~5% in the highest quartile (Q4). The mean (SD) body weight change in Q1 and Q4 were 1.24 (8.10) kg and 1.57 (7.50) kg (first time interval), 0.08 (6.86) kg and -0.19 (5.63) kg (second time interval), and -1.22 (5.16) kg and -0.37 (5.47) kg (third time interval), respectively. In GEE analyses, the overall five-yearly change in EAS% intake was not significantly associated with body weight change (P trend = 0.837). Furthermore, no significant associations were observed between changes in EAS% intake from either beverage or non-beverage sources and changes in body weight (P trend for beverage sources = 0.621 and P trend for non-beverage sources = 0.626). Conclusion The findings of this older Australian cohort do not support the association between changes in EAS% intake and body weight, regardless of AS food sources (beverage or non-beverage).Background Drug interactions are the most common preventable cause of adverse drug reaction, which may result in drug toxicity or undesired therapeutic effect with harmful outcomes to patients. Given the rising use of combination therapies, the main objectives of this study were to estimate the degree to which physicians can identify potential drug-drug interactions (PDDIs) correctly and to describe the common source of information used by physicians when they need to check PDDIs. Methods A cross-sectional survey utilizing a self-administered online questionnaire was conducted among physicians in China. Participants were asked to classify 20 drug pairs as "no interaction," "may be used together with monitoring," "contraindication," and "not sure." We also collected data on the physician's source of information and altitude toward the PDDIs. An ordinary least square regression model was performed to investigate the potential predictors of PDDI knowledge. Results Eligible questionnaires were obtained from 618 phalf of the drug pairs were recognized, indicating unsatisfactory level of knowledge about the clinically significant drug interactions. Continuing education and accessible electronic database can help physicians detecting PDDIs and improve drug safety.Objectives To investigate the application of reflectance confocal microscopy (RCM) imaging in diagnosis of vulva syringoma. Methods Patients with lesions suspicious of syringoma on vulva were enrolled in the study. After informed consent was taken, the lesions were photographed and imaged with RCM. The features of the lesion in confocal images were then analyzed and compared with the biopsy findings for histology correlation. Results Eleven cases in total were included in the study. The typical RCM features observed in syringoma are the presence of round to oval high refractive, and relatively monomorphous mass of varying sizes in the superficial and middle dermis, usually surrounded with 1-2 layers of light-dark line structures, which were further confirmed by histological evaluation. Ten cases showed classic features of syringoma and 1 case exhibited milia in RCM images. Conclusions Syringoma has distinct features in RCM imaging, which correlates well with histological findings, highlighting the potential role of RCM in the diagnosis and differential diagnosis of vulva syringoma.Background Anti-phospholipid syndrome (APS) and systemic lupus erythematous (SLE) are autoimmune disorders that often co-occur. Anti-phospholipid antibodies (aPL) are typical of both conditions and may be associated with vascular events and pregnancy-related morbidities. Whereas, aPL-screening is mandatory for individuals with suspected SLE, the clinical value of longitudinal aPL analyses in established SLE is unclear. Methods We investigated the occurrence and variation of IgG/IgA/IgM anti-cardiolipin (aCL) and anti-β2-glycoprotein-I (anti-β2GPI) antibodies, using both the manufacturer's cut-off and a cut-off based on the 99th percentile of 400 apparently healthy donors, in recent-onset SLE. Furthermore, we evaluated the relationships between aPL levels and SLE/APS manifestations, as well as the pharmacotherapy. Patients with SLE who met validated classification criteria were included in this prospective study (N = 54). Samples were obtained at 0, 6, 12, 24, 36, 48, 60, 72, 84, and 96 months after SLE diagnosis. Results Depending on the cut-off applied, 61.1 or 44.4% showed a positive result for at least one aPL isotype or the lupus anticoagulant test over time. Median values for all six aPL isotypes numerically decreased from inclusion to last follow-up, but none of the isotypes met statistical significance. Seroconversion (from positive to negative, or the opposite direction) was occasionally seen for both aCL and anti-β2GPI. IgA and IgM anti-β2GPI were the most common isotypes, followed by IgM aCL. Presence of IgG aCL associated significantly with myocardial infarction and miscarriage, and IgG/IgA anti-β2GPI with miscarriage. Conclusion aPL were common during the first years of SLE. Even though the levels fluctuated over time, the patients tended to remain aPL positive or negative. Repeated aPL testing in the absence of new symptoms seems to be of uncertain value in patients with recent-onset SLE.Objective This study aims to determine the acceptability of a COVID-19 vaccine among healthcare workers in Saudi Arabia and the factors affecting their intention to accept the vaccine. Methods The study used data from an online cross-sectional survey that was conducted in Saudi Arabia between 8 December 2020 and 14 December 2020. This study employed bivariate and multivariable regression analyses. The bivariate was used to describe and tabulate the frequency of all the variables, including the sociodemographic characteristics, the risk perception and the acceptance of the COVID-19 vaccination and a chi-squared test of independence was calculated. Multivariable logistic regression models were employed to examine and identify the factors associated with an intention to have the COVID-19 vaccination and the factors associated with its immediate acceptance. Results Of the total of 736 healthcare workers who began the online questionnaire, 673 completed it (a 91.44% completion rate). Among the study participants, 50.52% were willing to have the COVID-19 vaccine, of which 49.71% intended to have the vaccine as soon as it becomes available in the country, while 50.29% would delay until the vaccine's safety is confirmed. Being a male healthcare worker, perceiving a high risk of infection, and believing that the COVID-19 vaccine should be compulsory for all citizens and residents in the country increased the probability of intention to vaccinate against COVID-19 and the probability of accepting the COVID-19 vaccination as soon as possible. Conclusion This study calls for more health-related education among healthcare workers to alleviate any fears that might be associated with the COVID-19 vaccine.Neuropathic itch occurs due to damage of neurons of the peripheral or central nervous system. Several entities, including metabolic, neurodegenerative, orthopedic, infectious, autoimmune, malignant, and iatrogenic conditions, may affect the somatosensory system and induce neuropathic itch. Due to the complex nature of neuropathic itch, particularly concerning its clinical presentation and possible etiological factors, diagnostic work-up of this condition is challenging. A detailed medical history, especially in regard to the itch, and a comprehensive physical examination are relevant to detect characteristic signs and symptoms of neuropathic itch and to rule out other possible causes for chronic itch. Complementary diagnostic exams, especially laboratory tests, determination of the intraepidermal nerve fiber density via a skin biopsy and radiological examinations may be indicated to confirm the diagnosis of neuropathic itch and to identify underlying etiological factors. Functional assessments such as quantitative sensory testing, nerve conduction studies, evoked potentials, or microneurography may be considered in particular cases. This review article provides a comprehensive overview of the diagnostic work-up recommended for patients with neuropathic itch.A 43-year-old Armenian patient was diagnosed with salmonella infection and thrombotic microangiopathy (TMA). The clinical course was benign with resolution of all laboratory alterations after antibiotic treatment. Constantly deficient ADAMTS13 activity without ADAMTS13 inhibitors and evidence of homozygosity for a rare complex ADAMTS13 allele led to the diagnosis of congenital thrombotic thrombocytopenic purpura (cTTP). Half-life of ADAMTS13 after plasma infusion was calculated (27,6h) and double blinded plasma infusion as well as ergometric exercise with and without prior plasma infusion undertaken to investigate suspected smoldering TTP activity.Interleukin (IL)-18, a member of the IL-1 superfamily, is a pro-inflammatory cytokine that is structurally similar to IL-1β. IL-18 promotes the production of interferon gamma (IFN-γ) and strongly induces a Th1 response. IL-18 drives the same myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway as IL-1β. In physiological conditions, IL-18 is regulated by the endogenous inhibitor IL-18 binding protein (IL-18BP), and the activity of IL-18 is balanced. It is reported that in several inflammatory diseases, the IL-18 activity is unbalanced, and IL-18 neutralization by IL-18BP is insufficient. IL-18 acts synergistically with IL-12 to induce the production of IFN-γ as a Th1 cytokine, and IL-18 acts alone to induce the production of Th2 cytokines such as IL-4 and IL-13. In addition, IL-18 alone enhances natural killer (NK) cell activity and FAS ligand expression. The biological and pathological roles of IL-18 have been studied in many diseases. Here we review the knowledge regarding IL-18 signaling and the role of IL-18 in inflammatory kidney diseases. Findings on renal injury in coronavirus disease 2019 (COVID-19) and its association with IL-18 will also be presented.Background It has remained a concern whether any long-term pulmonary sequelae exist for COVID-19 survivors. Methods Forty-one patients (22 men and 19 women, 50 ± 14 years) confirmed with COVID-19 performed follow-up chest CT and cardiopulmonary exercise testing at 7 months after discharge. Patients were divided into fibrosis group and non-fibrosis group according to the evidence of fibrosis on follow-up CT. The clinical data and the CT findings were recorded and analyzed. Results The predominant CT patterns of abnormalities observed at 7 months after discharge were parenchymal band (41%), interlobular septal thickening (32%), and traction bronchiectasis (29%). Sixty-one percent of the patients achieved complete radiological resolution, and 29% of patients developed pulmonary fibrosis. Compared with the patients in the non-fibrosis group, the patients in the fibrosis group were older, with a longer hospital stay, a higher rate of steroid and mechanical ventilation therapy, lower levels of lymphocyte and T celllinical-radiological model may predict the formation of pulmonary fibrosis early.Chest X-ray imaging technology used for the early detection and screening of COVID-19 pneumonia is both accessible worldwide and affordable compared to other non-invasive technologies. Additionally, deep learning methods have recently shown remarkable results in detecting COVID-19 on chest X-rays, making it a promising screening technology for COVID-19. Deep learning relies on a large amount of data to avoid overfitting. While overfitting can result in perfect modeling on the original training dataset, on a new testing dataset it can fail to achieve high accuracy. In the image processing field, an image augmentation step (i.e., adding more training data) is often used to reduce overfitting on the training dataset, and improve prediction accuracy on the testing dataset. In this paper, we examined the impact of geometric augmentations as implemented in several recent publications for detecting COVID-19. We compared the performance of 17 deep learning algorithms with and without different geometric augmentations development of a robust COVID-19 X-ray-based detector.Background Complicated intra-abdominal infections (cIAIs) in the abdominal cavity or within an abdominal organ are numerous and frequent dangerous entities in the treatment of critically ill patients. Early clinical evaluation is necessary. Methods This retrospective multicenter study included patients from 10 intensive care units (ICUs). Risk factors for the overall survival (OS) of patients with cIAI were selected using least absolute shrinkage and selection operator regression, and a nomogram was constructed subsequently. Calibration curve and receiver operating characteristic (ROC) curve were used to evaluate the calibration and discriminative ability. Results In total, 544 patients diagnosed with cIAI were enrolled and divided into the study (n = 276) and validation (n = 268) sets. Sex, acute gastrointestinal injury, acute kidney injury, rare bacterium infection, Charlson score, and APACHE II score were identified as independent risk factors and were constructed for the nomogram. The nomogram showed marked calibration capability with a concordance index (C-index) of 0.909 and 0.831 in the study and validation set, respectively. Compared with the common clinical prognostic scoring system, the nomogram achieved the highest discrimination ability with an area under the curve (AUC) value of 0.91 and 0.83 in the study set and validation set, respectively. Conclusions Our newly constructed nomogram provides a useful tool for risk stratification and prognosis evaluation of cIAI.Objective The serum albumin-to-globulin ratio (AGR) may be a useful prognostic factor for various cancers. This study aimed to evaluate the prognostic value of the AGR in patients with metastatic non-small-cell lung cancer (NSCLC). Methods A retrospective study was conducted on patients with stage IV NSCLC diagnosed in Hubei Cancer Hospital from July 2012 to December 2013. The formula for calculating the AGR was serum albumin/total protein-serum albumin. The chi-square test or Fisher's exact test was used to analyze the classified variables. The Kaplan-Meier method was used to analyze the overall survival (OS) rate, which was plotted with the R language. The impact of the AGR on OS and progression-free survival (PFS) was analyzed by a multivariate Cox proportional hazard model. Results A total of 308 patients were included in the study population. The optimal cutoff values for the AGR in terms of OS and PFS were 1.12 and 1.09, respectively, as determined by X-Tile software. Kaplan-Meier curve analysis showed that the difference in survival rate between patients with different AGR levels was statistically significant (p = 0.04). The OS of patients with a high AGR (≥1.12) was longer than that of patients with a low AGR ( less then 1.12). PFS in the high AGR group were better than those in the low AGR group (16.90 vs. 32.07months, p = 0.008). The univariate and multivariate models proved that the AGR was an independent prognostic factor in metastatic NSCLC patients in terms of both OS (p = 0.009, hazard ratio [HR] = 0.55, 95% confidence interval [95% CI] = 0.35-0.86) and PFS (p = 0.004, HR = 0.55, 95% CI = 0.37-0.83). Conclusion The AGR, which is measured in routine clinical practice, is an independent prognostic factor in terms of OS and PFS in metastatic NSCLC and can serve as a prognostic tool for metastatic NSCLC.Objectives Osteoporosis and bone erosions are hallmarks of rheumatoid arthritis (RA) since disease onset is underpinned by the inflammatory burden. In this observational study, we aimed to dissect the putative RA-related parameters and bone-derived biomarkers associated with systemic and focal bone loss at disease onset and with their progression. Methods One-hundred twenty-eight patients with early rheumatoid arthritis (ERA) were recruited at disease onset. At study entry, demographic, clinical, and immunological parameters were recorded. Each ERA patient underwent plain X-rays of the hands and feet at study entry and after 12 months to assess the presence of erosions. After enrollment, each patient was treated according to the recommendations for RA management and followed up based on a treat-to-target (T2T) strategy. At baseline, blood samples for soluble biomarkers were collected from each patient, and plasma levels of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), Dickkopfisease Activity Score measured on 44 joints (DAS44) [OR 2.46 (1.11-5.44)] and osteopenic/osteoporosis status [OR 7.13 (1.27-39.94)] arose as independent factors of erosiveness. Baseline osteopenic/osteoporotic status and ACPA positivity were associated with bone damage progression during the follow-up. Conclusions Bone erosions presence is associated with systemic bone loss since the earliest phases of RA, suggesting that the inflammatory burden and autoimmune biology, underpinning RA, represent crucial enhancers of bone remodeling either locally as at systemic level.Objectives The successful introduction of mycophenolate mofetil (MMF) as a treatment for renal allograft reduced the incidence of acute rejection. The inspiring effects obtained by the MMF have led to an evaluation of its therapeutic potency on ANCA-associated vasculitis (AAV). However, there is little evidence of the MMF's efficacy on the AAV. The meta-analysis is carried out to evaluate the efficacy of MMF as a remission induction therapy in AAV. Methods Up to June 30th, 2020, PubMed, Cochrane Library, and Embase have been searched comprehensively. According to heterogeneity, the pooled remission rates are synthesized by either fixed-effect or random-effect models. Results The eight included studies comprising 230 patients who were treated with MMF as induction therapy are included in our analysis. The pooled overall remission rate is 74% (95% CI 0.68-0.80). The remission rate, the infection rate and the rate of leukopenia of four randomized controlled trials aimed at comparing the effects of MMF with cyclophosphamide (CYC) during induction therapy for AAV have no statistical significance (P > 0.05). Conclusion MMF may be an alternative to CYC for remission induction therapy in AAV with MPO-ANCA, mild to moderate renal involvement and non-life-threatening state. Whether to observe the effect of MMF in AAV or to compare the difference between MMF and CYC in the future studies, risk stratification and subgrouping of AAV patients should be first carried out to correctly identify the AAV subgroup suitable for MMF.Objective To assess the variations of the blood levels of immunoglobulins (Ig) in septic shock patients treated with an Ig preparation enriched in IgM and IgA (eIg). Design The blood levels of Ig in survivors (S) and non-survivors (NS) of a group of septic shock patients were measured before the initial administration (D0) and 1 (D1), 4 (D4), and 7 (D7) days thereafter. The SAPS II score, the capillary permeability, the primary site of infection, the antibiotic appropriateness, and the outcome at 28 days were also assessed. Results In the interval D0-D7, the IgM increased significantly only in the S while remained stable in NS; the IgA significantly increased in both groups; the IgG did not vary significantly in both groups. At D4, the capillary permeability significantly decreased in S but not in NS. Conclusions The kinetics of the different classes of Ig after eIg were different between S and NS. This could be related either to (a) different capillary permeability in the two groups or to (b) higher Ig consumption in NS. Further studies to confirm the benefits of eIg in the treatment of sepsis syndrome and to define the specific target population and the correct eIg dose are warranted.Background Serum lactic acid is considered a prognostic indicator in critically ill patients. However, studies on linezolid-induced lactic acidosis (LILA) are still limited. Individuals older than 85 years old (very elderly) have limited capacity for organ compensation, and LILA data from these patients are lacking. In this study, we evaluated the risk factors for LILA in patients older than 85 years and established a risk prediction model for geriatric practice. Methods In this retrospective cohort study, blood gas analysis data and arterial lactate levels were monitored in patients older than 85 years during the use of teicoplanin or linezolid. After propensity score matching analyses, we compared the incidence of lactic acidosis between the teicoplanin and linezolid therapy groups and identified the risk factors of LILA. Results The incidence of lactic acidosis was found to be much lower in the group receiving teicoplanin than those receiving linezolid therapy (0 vs. 35.7%; p less then 0.0001). A duration of linezolid therapy ≥ 9 days [odds ratio (OR), 3.541; 95% confidence interval (CI), 1.161-10.793; p = 0.026], an arterial blood glucose level ≥ 8 mmol/L (OR, 4.548; 95% CI, 1.507-13.725; p = 0.007), and a high sequential organ failure assessment score (OR, 1.429; 95% CI, 1.213-1.685; p less then 0.0001) were risk factors for LILA. The constructed risk model could be used to predict LILA (area under the curve, 0.849; specificity, 65.1%; sensitivity, 91.4%, with a negative predictive value of 93.2% and a positive predictive value of 59.3%). Conclusions LILA can occur in patients older than 85 years after a relatively shorter duration of linezolid therapy. Therefore, close monitoring of blood gas and arterial lactate levels during linezolid therapy in the very elderly population is necessary.Objectives This study aims to develop an automatic deep-learning algorithm, which is based on Convolutional Neural Networks (CNNs), for ultrasound informative-image selection of hyaline cartilage at metacarpal head level. The algorithm performance and that of three beginner sonographers were compared with an expert assessment, which was considered the gold standard. Methods The study was divided into two steps. In the first one, an automatic deep-learning algorithm for image selection was developed using 1,600 ultrasound (US) images of the metacarpal head cartilage (MHC) acquired in 40 healthy subjects using a very high-frequency probe (up to 22 MHz). The algorithm task was to identify US images defined informative as they show enough information to fulfill the Outcome Measure in Rheumatology US definition of healthy hyaline cartilage. The algorithm relied on VGG16 CNN, which was fine-tuned to classify US images in informative and non-informative ones. A repeated leave-four-subject out cross-validation was peasted only 2.0 ± 0.8 min. Conclusion This study paves the way for the automatic identification of informative US images for assessing MHC. This may redefine the US reliability in the evaluation of MHC integrity, especially in terms of intrareader reliability and may support beginner sonographers during US training.Background Chronic obstructive pulmonary disease (COPD) is associated with cardiovascular disease. We investigated whether sleeping at altitude increases nocturnal heart rate (HR) and other markers of cardiovascular risk or arrhythmias in lowlanders with COPD and whether this can be prevented by nocturnal oxygen therapy (NOT). Methods Twenty-four COPD patients, with median age of 66 years and forced expiratory volume in 1 s (FEV1) 55% predicted, living less then 800 m underwent sleep studies at Zurich (490 m) and during 2 sojourns of 2 days each at St. Moritz (2,048 m) separated by 2-week washout at less then 800 m. During nights at 2,048 m, patients received either NOT (2,048 m NOT) or ambient air (2,048 m placebo) 3 L/min via nasal cannula according to a randomized, placebo-controlled crossover trial. Sleep studies comprised ECG and pulse oximetry to measure HR, rhythm, HR-adjusted QT interval (QTc), and mean oxygen saturation (SpO2). Results In the first nights at 490 m, 2,048 m placebo, and 2,048 m NOT, medians (quartiles) of SpO2 were 92% (90; 94), 86% (83; 89), and 97% (95; 98) and of HR were 73 (66; 82), 82 (71; 85), and 78 bpm (67; 74) (P less then 0.05 all respective comparisons). QTc increased from 417 ms (404; 439) at 490 m to 426 ms (405; 440) at 2,048 m placebo (P less then 0.05) and was 420 ms (405; 440) at 2,048 m NOT (P = NS vs. 2,048 m placebo). The number of extrabeats and complex arrhythmias was similar over all conditions. Conclusions While staying at 2,048 m, lowlanders with COPD experienced nocturnal hypoxemia in association with an increased HR and prolongation of the QTc interval. NOT significantly improved SpO2 and lowered HR, without changing QTc. Whether oxygen therapy would reduce HR and arrhythmia during longer altitude sojourns remains to be elucidated.The adult liver has excellent regenerative potential following injury. In contrast to other organs of the body that have high cellular turnover during homeostasis (e.g., intestine, stomach, and skin), the adult liver is a slowly self-renewing organ and does not contain a defined stem-cell compartment that maintains homeostasis. However, tissue damage induces significant proliferation across the liver and can trigger cell-fate changes, such as trans-differentiation and de-differentiation into liver progenitors, which contribute to efficient tissue regeneration and restoration of liver functions. Epigenetic mechanisms have been shown to regulate cell-fate decisions in both embryonic and adult tissues in response to environmental cues. Underlying their relevance in liver biology, expression levels and epigenetic activity of chromatin modifiers are often altered in chronic liver disease and liver cancer. In this review, I examine the role of several chromatin modifiers in the regulation of cell-fate changes that determine efficient adult liver epithelial regeneration in response to tissue injury in mouse models. Specifically, I focus on epigenetic mechanisms such as chromatin remodelling, DNA methylation and hydroxymethylation, and histone methylation and deacetylation. Finally, I address how altered epigenetic mechanisms and the interplay between epigenetics and metabolism may contribute to the initiation and progression of liver disease and cancer.Noise-induced hearing loss (NIHL) is characterized by cellular damage to the inner ear, which is exacerbated by inflammation. High-mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP), acts as a mediator of inflammation or an intercellular messenger according to its cellular localization. Blocking or regulating HMGB1 offers an attractive approach in ameliorating NIHL. However, the precise therapeutic intervention must be based on a deeper understanding of its dynamic molecular distribution and function in cochlear pathogenesis after acoustic trauma. Here, we have presented the spatiotemporal dynamics of the expression of HMGB1, exhibiting distribution variability in specific cochlear regions and cells following noise exposure. After gene manipulation, we further investigated the characteristics of cellular HMGB1 in HEI-OC1 cells. The higher cell viability observed in the HMGB1 knocked-down group after stimulation with H2O2 indicated the possible negative effect of HMGB1 on cellular lifespan. In conclusion, this study demonstrated that HMGB1 is involved in NIHL pathogenesis and its molecular biology has essential and subtle influences, preserving a translational potential for pharmacological intervention.Acute myeloid leukemia (AML) is a malignant disease of hematopoietic stem/progenitor cells, and most AML patients are in a severe state. Internal tandem duplication mutations in FLT3 gene (FLT3-ITD) detected in AML stem cells account for 20-30 percent of AML patients. In this study, we attempted to study the impact of the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis in AML, and the possible mechanisms caused by the impact by bioinformatics. Gene set variation analysis (GSVA) revealed that the PI3K-Akt-mTOR pathway positively correlated with the status of FLT3-ITD mutation. Multiple survival analyses were performed on TCGA-AML to screen the prognostic-related genes, and RPS6KA1 and AP2M1 are powerful prognostic candidates for overall survival in AML. WGCNA, KEGG/GO analysis, and the functional roles of RPS6KA1 and AP2M1 in AML were clarified by correlation analysis. We found that the expression levels of RPS6KA1 and AP2M1 were significantly associated with chemoresistance of AML, and the CXCL12/CXCR4 axis would regulate RPS6KA1/AP2M1 expression. Besides, miR-138-5p, regulated by the CXCL12/CXCR4 axis, was the common miRNA target of RPS6KA1 and AP2M1. Taken together, the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis activated the PI3K-Akt-mTOR pathway, and the increased expression of RPS6KA1 and AP2M1 caused by hsa-miR-138-5p downregulation regulates the multi-resistance gene expression leading to drug indications.Cancer is a disease which frequently has a poor prognosis. Although multiple therapeutic strategies have been developed for various cancers, including chemotherapy, radiotherapy, and immunotherapy, resistance to these treatments frequently impedes the clinical outcomes. Besides the active resistance driven by genetic and epigenetic alterations in tumor cells, the tumor microenvironment (TME) has also been reported to be a crucial regulator in tumorigenesis, progression, and resistance. Here, we propose that the adaptive mechanisms of tumor resistance are closely connected with the TME rather than depending on non-cell-autonomous changes in response to clinical treatment. Although the comprehensive understanding of adaptive mechanisms driven by the TME need further investigation to fully elucidate the mechanisms of tumor therapeutic resistance, many clinical treatments targeting the TME have been successful. In this review, we report on recent advances concerning the molecular events and important factors involved in the TME, particularly focusing on the contributions of the TME to adaptive resistance, and provide insights into potential therapeutic methods or translational medicine targeting the TME to overcome resistance to therapy in clinical treatment.Glucose is a major energy source consumed by proliferating mammalian cells. Therefore, in general, proliferating cells have the preference of high glucose contents in extracellular environment. Here, we showed that high glucose concentrations impede the proliferation of satellite cells, which are muscle-specific stem cells, under adherent culture conditions. We found that the proliferation activity of satellite cells was higher in glucose-free DMEM growth medium (low-glucose medium with a glucose concentration of 2 mM) than in standard glucose DMEM (high-glucose medium with a glucose concentration of 19 mM). Satellite cells cultured in the high-glucose medium showed a decreased population of reserve cells, identified by staining for Pax7 expression, suggesting that glucose concentration affects cell fate determination. In conclusion, glucose is a factor that decides the cell fate of skeletal muscle-specific stem cells. Due to this unique feature of satellite cells, hyperglycemia may negatively affect the regenerative capability of skeletal muscle myofibers and thus facilitate sarcopenia.Kashin-Beck disease (KBD) is a degenerative osteoarticular disorder, and displays the significant differences with osteoarthritis (OA) regarding the etiology and molecular changes in articular cartilage. However, the underlying dysfunctions of molecular mechanisms in KBD and OA remain unclear. Here, we primarily performed the various genome-wide differential methylation analyses to reveal the distinct differentially methylated regions (DMRs) in conjunction with corresponding differentially methylated genes (DMGs), and enriched functional pathways in KBD and OA. We identified a total of 131 DMRs in KBD vs. Control, and 58 DMRs in OA vs. Controls, and the results demonstrate that many interesting DMRs are linked to DMGs, such as SMOC2 and HOXD3, which are all key genes to regulate cartilage/skeletal physiologic and pathologic process, and are further enriched in skeletal system and limb-associated pathways. Our DMR analysis indicates that KBD-associated DMRs has higher proportion than OA-associated DMRs in gene body regions. KBD-associated DMGs were enriched in wounding and coagulation-related functional pathways that may be stimulated by trace elements. The identified molecular features provide novel clues for understanding the pathogenetic and therapeutic studies of both KBD and OA.Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an essential role in the regulation of neural processes and control many functions of the central nervous system. Ion channels present a diverse group of membrane-spanning proteins that allow ions to penetrate the insulating cell membrane upon opening of their channel pores. This regulated ion permeation results in different electrical and chemical signals that are necessary to maintain physiological excitatory and inhibitory processes in the brain. Therefore, it is no surprise that disturbances in the functions of cerebral ion channels can result in a plethora of neurological disorders, which present a tremendous health care burden for our current society. The identification of ion channel-related brain disorders also fuel the research into the roles of ion channel proteins in various brain states. In the last decade, mounting evidence has been collected that indicates a pivotal role for transient receptor potential (TRP) ion channels in the development and various physiological functions of the central nervous system. For instance, TRP channels modulate neurite growth, synaptic plasticity and integration, and are required for neuronal survival. Moreover, TRP channels are involved in numerous neurological disorders. TRPM3 belongs to the melastatin subfamily of TRP channels and represents a non-selective cation channel that can be activated by several different stimuli, including the neurosteroid pregnenolone sulfate, osmotic pressures and heat. The channel is best known as a peripheral nociceptive ion channel that participates in heat sensation. However, recent research identifies TRPM3 as an emerging new player in the brain. In this review, we summarize the available data regarding the roles of TRPM3 in the brain, and correlate these data with the neuropathological processes in which this ion channel may be involved.
The purpose of the study is to describe the genetic and clinical features of 17 patients with ABCA4-related inherited retinal degenerations (IRDs) and define the phenotype-genotype correlations.

In this multicenter retrospective study, 17 patients from 16 families were enrolled, and ABCA4 gene variants were detected using targeted next-generation sequencing using a custom designed panel for IRDs. Sanger sequencing and co-segregation analysis of the suspected pathogenic variants were performed with the family members. The pathogenicities of variants were evaluated according to the American College of Medical Genetics and Genomics guidelines (ACMG). Protein structure modifications mediated by the variants were studied using bioinformatic analyses.

The probands were diagnosed with Stargardt disease 1 (7), cone-rod dystrophy type 3 (8), cone dystrophy (1), and retinitis pigmentosa 19 (1). Onset of symptoms occurred between 5 and 27 years of age (median age = 12.4 years). A total of 30 unique ABCA4 suspicioul expand the spectrum of disease-causing variants in ABCA4, which will further facilitate genetic counseling.Brown adipose tissue (BAT) plays critical thermogenic, metabolic and endocrine roles in mammals, and aberrant BAT function is associated with metabolic disorders including obesity and diabetes. The major BAT depots are clustered at the neck and forelimb levels, and arise largely within the dermomyotome of somites, from a common progenitor with skeletal muscle. However, many aspects of BAT embryonic development are not well understood. Hoxa5 patterns other tissues at the cervical and brachial levels, including skeletal, neural and respiratory structures. Here, we show that Hoxa5 also positively regulates BAT development, while negatively regulating formation of epaxial skeletal muscle. HOXA5 protein is expressed in embryonic preadipocytes and adipocytes as early as embryonic day 12.5. Hoxa5 null mutant embryos and rare, surviving adults show subtly reduced iBAT and sBAT formation, as well as aberrant marker expression, lower adipocyte density and altered lipid droplet morphology. Conversely, the epaxial muscles that arise from a common dermomyotome progenitor are expanded in Hoxa5 mutants. Conditional deletion of Hoxa5 with Myf5/Cre can reproduce both BAT and epaxial muscle phenotypes, indicating that HOXA5 is necessary within Myf5-positive cells for proper BAT and epaxial muscle development. However, recombinase-based lineage tracing shows that Hoxa5 does not act cell-autonomously to repress skeletal muscle fate. Interestingly, Hoxa5-dependent regulation of adipose-associated transcripts is conserved in lung and diaphragm, suggesting a shared molecular role for Hoxa5 in multiple tissues. Together, these findings establish a role for Hoxa5 in embryonic BAT development.Objective To identify new microRNA (miRNA)-mRNA networks in non-syndromic cleft lip with or without cleft palate (NSCL/P). Materials and Methods Overlapping differentially expressed miRNAs (DEMs) were selected from cleft palate patients (GSE47939) and murine embryonic orofacial tissues (GSE20880). Next, the target genes of DEMs were predicted by Targetscan, miRDB, and FUNRICH, and further filtered through differentially expressed genes (DEGs) from NSCL/P patients and controls (GSE42589), MGI, MalaCards, and DECIPHER databases. The results were then confirmed by in vitro experiments. NSCL/P lip tissues were obtained to explore the expression of miRNAs and their target genes. Results Let-7c-5p and miR-193a-3p were identified as DEMs, and their overexpression inhibited cell proliferation and promoted cell apoptosis. PIGA and TGFB2 were confirmed as targets of let-7c-5p and miR-193a-3p, respectively, and were involved in craniofacial development in mice. Negative correlation between miRNA and mRNA expression was detected in the NSCL/P lip tissues. They were also associated with the occurrence of NSCL/P based on the MGI, MalaCards, and DECIPHER databases. Conclusions Let-7c-5p-PIGA and miR-193a-3p-TGFB2 networks may be involved in the development of NSCL/P.Autophagy is involved in many physiological processes. Transcription factor EB (TFEB) is a master regulator of autophagy and coordinates the expression of autophagic proteins, lysosomal hydrolases, and lysosomal membrane proteins. Though autophagy has been implicated in several human diseases, little is known regarding TFEB gene expression and regulation in the process. Since dysfunctional autophagy plays critical roles in acute myocardial infarction (AMI), dysregulated TFEB gene expression may be associated with AMI by regulating autophagy. In this study, the TFEB gene promoter was genetically and functionally analyzed in AMI patients (n = 352) and ethnic-matched controls (n = 337). A total of fifteen regulatory variants of the TFEB gene, including eight single-nucleotide polymorphisms (SNPs), were identified in this population. Among these, six regulatory variants [g.41737274T>C (rs533895008), g.41737144A>G, g.41736987C > T (rs760293138), g.41736806C > T (rs748537297), g.41736635T > C (rs975050638), and g.41736544C > T] were only identified in AMI patients. These regulatory variants significantly altered the transcriptional activity of the TFEB gene promoter. Further electrophoretic mobility shift assay revealed that three of the variants evidently affected the binding of transcription factors. Therefore, this study identified novel TFEB gene regulatory variants which affect the gene expression. These TFEB gene regulatory variants may contribute to AMI development as a rare risk factor.The relevance of microRNA-15a (miR-15a) to autoimmunity has been reported. Herein, we intended to probe the potential roles of miR-15a shuttled by adipose-derived mesenchymal stem cells (adMSCs)-derived extracellular vesicles (Evs) in colorectal cancer (CRC). Initially, CRC cells were treated with interferon gamma (IFN-γ) to screen out differentially expressed genes by transcriptome sequencing. Following a 24-h co-culture with 20 μM adMSCs-derived Evs, CRC cell viability, migration, invasion, and apoptosis were assessed. After the determination of histone lysine demethylase 4B (KDM4B) as our target, its regulatory miRNA was predicted by the bioinformatics websites and verified by dual-luciferase and RNA pull-down assays. Intriguingly, KDM4B downregulated homeobox C4 (HOXC4) expression, while HOXC4 bound to the promoter sequence of programmed death-ligand 1 (PD-L1). Thus, we conducted rescue experiments to study the role of KDM4B and HOXC4. Finally, we evaluated the effects of adMSCs on CRC cell growth and immune evasion through in vivo tumorigenesis experiments. AdMSCs-derived Evs overexpressing miR-15a repressed proliferation, migration, and invasion, while it promoted the apoptosis of CRC cells via downregulation of KDM4B. These in vivo findings were reproduced in vitro on CRC immune evasion. Collectively, adMSCs-derived Evs overexpressing miR-15a restricted the immune evasion of CRC via the KDM4B/HOXC4/PD-L1 axis.Purpose Congenital nystagmus (CN) is a genetically and clinically heterogeneous ocular disorder that manifests as involuntary, periodic oscillations of the eyes. To date, only FRMD7 and GPR143 have been reported to be responsible for causing CN. Here, we aimed to identify the disease-causing mutations and describe the clinical features in the affected members in our study. Methods All the subjects underwent a detailed ophthalmic examination. Direct sequencing of all coding exons and splice site regions in FRMD7 and GPR143 and a mutation assessment were performed in each patient. Results We found 14 mutations in 14/37 (37.8%) probands, including nine mutations in the FRMD7 gene and five mutations in the GPR143 gene, seven of which are novel, including c.284G>A(R95K), c.964C>T(P322S), c.284+10T>G, c.901T>C (Y301H), and c.2014_2023delTCACCCATGG(S672Pfs*12) in FRMD7, and c.250+1G>C, and c.485G>A (W162*) in GPR143. The mutation detection rate was 87.5% (7/8) of familial vs. 24.1% (7/29) of sporadic cases. Ten mutations in 24 (41.7%) non-syndromic subjects and 4 mutations in 13(30.8%) syndromic subjects were detected. A total of 77.8% (7/9) of mutations in FRMD7 were concentrated within the FERM and FA domains, while all mutations in GPR143 were located in exons 1, 2, 4 and 6. We observed that visual acuity tended to be worse in the GPR143 group than in the FRMD7 group, and no obvious difference in other clinical manifestations was found through comparisons in different groups of patients. Conclusions This study identified 14 mutations (seven novel and seven known) in eight familial and 29 sporadic patients with congenital nystagmus, expanding the mutational spectrum and validating FRMD7 and GPR143 as mutation hotspots. These findings also revealed a significant difference in the screening rate between different groups of participants, providing new insights for the strategy of genetic screening and early clinical diagnosis of CN.Fifty percent of male subfertility diagnosis is idiopathic and is usually associated with genetic abnormalities or protein dysfunction, which are not detectable through the conventional spermiogram. Glutathione S-transferases (GSTs) are antioxidant enzymes essential for preserving sperm function and maintaining fertilizing ability. However, while the role of GSTP1 in cell signaling regulation via the inhibition of c-Jun N-terminal kinases (JNK) has been enlightened in somatic cells, it has never been investigated in mammalian spermatozoa. In this regard, a comprehensive approach through immunoblotting, immunofluorescence, computer-assisted sperm assessment (CASA), and flow cytometry analysis was used to characterize the molecular role of the GSTP1-JNK heterocomplex in sperm physiology, using the pig as a model. Immunological assessments confirmed the presence and localization of GSTP1 in sperm cells. The pharmacological dissociation of the GSTP1-JNK heterocomplex resulted in the activation of JNK, which led to a significant decrease in sperm viability, motility, mitochondrial activity, and plasma membrane stability, as well as to an increase of intracellular superoxides. No effects in intracellular calcium levels and acrosome membrane integrity were observed. In conclusion, the present work has demonstrated, for the first time, the essential role of GSTP1 in deactivating JNK, which is crucial to maintain sperm function and has also set the grounds to understand the relevance of the GSTP1-JNK heterocomplex for the regulation of mammalian sperm physiology.The poor predictability of human liver toxicity is still causing high attrition rates of drug candidates in the pharmaceutical industry at the non-clinical, clinical, and post-marketing authorization stages. This is in part caused by animal models that fail to predict various human adverse drug reactions (ADRs), resulting in undetected hepatotoxicity at the non-clinical phase of drug development. In an effort to increase the prediction of human hepatotoxicity, different approaches to enhance the physiological relevance of hepatic in vitro systems are being pursued. Three-dimensional (3D) or microfluidic technologies allow to better recapitulate hepatocyte organization and cell-matrix contacts, to include additional cell types, to incorporate fluid flow and to create gradients of oxygen and nutrients, which have led to improved differentiated cell phenotype and functionality. This comprehensive review addresses the drug-induced hepatotoxicity mechanisms and the currently available 3D liver in vitro models, their characteristics, as well as their advantages and limitations for human hepatotoxicity assessment. In addition, since toxic responses are greatly dependent on the culture model, a comparative analysis of the toxicity studies performed using two-dimensional (2D) and 3D in vitro strategies with recognized hepatotoxic compounds, such as paracetamol, diclofenac, and troglitazone is performed, further highlighting the need for harmonization of the respective characterization methods. Finally, taking a step forward, we propose a roadmap for the assessment of drugs hepatotoxicity based on fully characterized fit-for-purpose in vitro models, taking advantage of the best of each model, which will ultimately contribute to more informed decision-making in the drug development and risk assessment fields.
Some colorectal adenocarcinoma (CRC) patients are susceptible to recurrence, and they rapidly progress to advanced cancer stages and have a poor prognosis. There is an urgent need for efficient screening criteria to identify patients who tend to relapse in order to treat them earlier and more systematically.

We identified two groups of patients with significantly different outcomes by unsupervised cluster analysis of GSE39582 based on 101 significantly differentially expressed immune genes. To develop an accurate and specific signature based on immune-related genes to predict the recurrence of CRC, a multivariate Cox risk regression model was constructed with a training cohort composed of 519 CRC samples. The model was then validated using 129, 292, and 446 samples in the real-time quantitative reverse transcription PCR (qRT-PCR), test, and validation cohorts, respectively.

This classification system can also be used to predict the prognosis in clinical subgroups and patients with different mutation states.
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