High-dose opioids in advanced cancer: use factors-retrospective study.

OBJECTIVES: To evaluate factors associated with high-dose opioid use in patients with advanced cancer and examine the effect of high-dose opioid use on patients' survival. METHODS: This study retrospectively searched the medical records of 416 patients with advanced cancer in a home-based hospice in central China. Age, sex, type of cancer, type of pain, the maximum oral morphine equivalent daily dose, type of opioid, preadmission oral morphine equivalent daily dose, lung cancer or not, bone metastases, opioid switch and survival time were assessed. RESULTS: There were 416 subjects included from the 455 eligible participants (91.4%). 80 patients (19.2%) received high-dose opioids at home. Male (OR 2.471; 95% CI 1.054 to 5.792; p=0.037), preadmission morphine equivalent daily dose (OR 1.022; 95% CI 1.016 to 1.028; p=0.000) and the use of morphine at maximum morphine equivalent daily dose (OR 5.123; 95% CI 1.249 to 21.014; p=0.023) were positively predicted high-dose opioid use. No difference in survival was found when comparing the high-dose and very high-dose opioid use groups. CONCLUSIONS: Male home-based patients with advanced cancer who use morphine and have greater preadmission opioid doses should be aware of the necessity for high-dose opioid use. Regulated opioid use in adequate amounts does not shorten survival.

SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma.

The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclax and an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor and cooperates with the loss of KMT2D in lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several proapoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histone H3K4 demethylases restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. These results establish SETD1B as an epigenetic regulator of cell death and reveal a pharmacological strategy to augment Venetoclax sensitivity in lymphoma.

Highly sensitive CD40L protein discrimination via label-free fiber sensing technologies.

The recombinant Cluster of Differentiation 40 Ligand (CD40L) can be expressed in various cells and is closely related to various types of cancer. This association underscores the critical need for expedited and precise measurement of CD40L levels in clinical fluid specimens. A novel optical fiber biosensor has been devised, employing single-mode fibers that are sandwiched around a coreless fiber, with the diameter refined by etching with hydrogen fluoride. This innovative configuration allows for light transmission through the evanescent field, thereby enhancing the sensor's sensitivity to changes in the surrounding refractive index. Employing chemical binding techniques, CD40 was securely immobilized onto the fiber's surface, facilitating the detection of CD40L. The sensor exhibited a sensitivity of 1.126 nm (µg mL-1)-1 and a detection limit of 0.68 nM. Furthermore, the sensor's specificity for CD40L was validated using authentic clinical serum samples spiked with artificial analytes. In addition, the specificity of CD40L of the proposed sensor was proved using natural clinical serum samples with added artificial analyte, assisted by the ELISA method, and the results ideally conformed with the detection of standard samples. With the aid of the ELISA method, the outcomes were found to be in excellent agreement with those from standard sample detection. Consequently, the findings indicate that this sensor provides a specific, label-free, and highly sensitive method for CD40L detection, showcasing its significant potential for applications in molecular biology research.

Deep learning promoted target volumes delineation of total marrow and total lymphoid irradiation for accelerated radiotherapy: A multi-institutional study.

BACKGROUND AND PURPOSE: One of the current roadblocks to the widespread use of Total Marrow Irradiation (TMI) and Total Marrow and Lymphoid Irradiation (TMLI) is the challenging difficulties in tumor target contouring workflow. This study aims to develop a hybrid neural network model that promotes accurate, automatic, and rapid segmentation of multi-class clinical target volumes. MATERIALS AND METHODS: Patients who underwent TMI and TMLI from January 2018 to May 2022 were included. Two independent oncologists manually contoured eight target volumes for patients on CT images. A novel Dual-Encoder Alignment Network (DEA-Net) was developed and trained using 46 patients from one internal institution and independently evaluated on a total of 39 internal and external patients. Performance was evaluated on accuracy metrics and delineation time. RESULTS: The DEA-Net achieved a mean dice similarity coefficient of 90.1 % ± 1.8 % for internal testing dataset (23 patients) and 91.1 % ± 2.5 % for external testing dataset (16 patients). The 95 % Hausdorff distance and average symmetric surface distance were 2.04 ± 0.62 mm and 0.57 ± 0.11 mm for internal testing dataset, and 2.17 ± 0.68 mm, and 0.57 ± 0.20 mm for external testing dataset, respectively, outperforming most of existing state-of-the-art methods. In addition, the automatic segmentation workflow reduced delineation time by 98 % compared to the conventional manual contouring process (mean 173 ± 29 s vs. 12168 ± 1690 s; P < 0.001). Ablation study validate the effectiveness of hybrid structures. CONCLUSION: The proposed deep learning framework achieved comparable or superior target volume delineation accuracy, significantly accelerating the radiotherapy planning process.

Treatment plan complexity quantification for predicting gamma passing rates in patient-specific quality assurance for stereotactic volumetric modulated arc therapy.

PURPOSE: To investigate the beam complexity of stereotactic Volumetric Modulated Arc Therapy (VMAT) plans quantitively and predict gamma passing rates (GPRs) using machine learning. METHODS: The entire dataset is exclusively made of stereotactic VMAT plans (301 plans with 594 beams) from Varian Edge LINAC. The GPRs were analyzed using Varian's portal dosimetry with 2%/2 mm criteria. A total of 27 metrics were calculated to investigate the correlation between metrics and GPRs. Random forest and gradient boosting models were developed and trained to predict the GPRs based on the extracted complexity features. The threshold values of complexity metric were obtained to predict a given beam to pass or fail from ROC curve analysis. RESULTS: The three moderately significant values of Spearman's rank correlation to GPRs were 0.508 (p < 0.001), 0.445 (p < 0.001), and -0.416 (p < 0.001) for proposed metric LAAM, the ratio of the average aperture area over jaw area (AAJA) and index of modulation, respectively. The random forest method achieved 98.74% prediction accuracy with mean absolute error of 1.23% using five-fold cross-validation, and 98.71% with 1.25% for gradient boosting regressor method, respectively. LAAM, leaf travelling distance (LT), AAJA, LT modulation complexity score (LTMCS) and index of modulation, were the top five most important complexity features. The LAAM metric showed the best performance with AUC value of 0.801, and threshold value of 0.365. CONCLUSIONS: The calculated metrics were effective in quantifying the complexity of stereotactic VMAT plans. We have demonstrated that the GPRs could be accurately predicted using machine learning methods based on extracted complexity metrics. The quantification of complexity and machine learning methods have the potential to improve stereotactic treatment planning and identify the failure of QA results promptly.

LncRNA Gm15834 Aggravates Cardiac Hypertrophy by Interacting with Sam68 and Activating NF-κB Mediated Inflammation.

BACKGROUND: Cardiac hypertrophy is the common pathological process of multiple cardiovascular diseases. However, the molecular mechanisms of cardiac hypertrophy are unclear. Long non-coding RNA (lncRNA), a newly discovered type of transcript that has been demonstrated to function as crucial regulators in the development of cardiovascular diseases. This study revealed a novel regulatory pathway of lncRNA in cardiac hypertrophy. METHODS: The cardiac hypertrophy models were established by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) in HL-1 cardiomyocytes. Adeno-associated virus 9 (AAV9) in vivo and lncRNA Gm15834 and shRNA plasmids in vitro were used to overexpress and knock down lncRNA Gm15834. The myocardial tissue structure, cardiomyocyte area, cardiac function, protein expressions, and binding of lncRNA Gm15834 and Src-associated substrate during mitosis of 68 KDa (Sam68) were detected by hematoxylin and eosin (HE) staining, immunofluorescence staining, echocardiography, western blot and RNA immunoprecipitation (RIP), respectively. RESULTS: In cardiac hypertrophy models, inhibiting lncRNA Gm15834 could decrease Sam68 expression and nuclear factor kappa-B (NF-κB) mediated inflammatory activities in vivo and in vitro, but overexpressing lncRNA Gm15834 showed the opposite results. RIP experiments validated the binding activities between lncRNA Gm15834 and Sam68. Overexpression of Sam68 could counteract the anti-hypertrophy effects of lncRNA Gm15834 knockdown. Meanwhile, in vivo inhibition of lncRNA Gm15834 could inhibit Sam68 expression, reduce NF-κB mediated inflammatory activity and attenuate cardiac hypertrophy. CONCLUSION: Our study revealed a novel regulatory axis of cardiac hypertrophy, which comprised lncRNA Gm15834/Sam68/NF-κB/inflammation, shedding a new light for identifying therapy target of cardiac hypertrophy in clinic.

Research hot spots and trends in endocrine-related adverse events caused by immune checkpoint inhibitors: a bibliometric analysis and visualization research.

Background: In recent years, with the widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment, the toxicity associated with immunotherapy of ICIs has attracted more attention from scholars. Endocrine toxicity is the most likely immune-related adverse events (irAEs) and is often irreversible, posing a significant clinical treatment challenge. Methods: In this study, bibliometric methods were used to analyze relevant literature in screening endocrine-related adverse events caused by ICIs in the Web of Science core collection database (WoSCC) and to summarize the status, research hot spots, and future trends in this field. Results: 321 countries, 297 institutions, 365 authors, and 305 journals had published 671 English documents on endocrine adverse reactions of ICIs as of 1 December, 2022. The United States, Japan, and China were the top three countries with the most publications. The University of Texas MD Anderson Cancer Center, Harvard Medical School, and Memorial Sloan Kettering Cancer Center were the top three research institutions in terms of publication output. F Stephen Hodi, from the Dana-Farber Cancer Institute in the United States, contributed the largest number of publications. Frontiers in Oncology, which was the most widely distributed publication in the field. The main keywords or clusters identified that current research hotspots include the management of endocrine-related adverse events, hypophysitis, thyroid dysfunction, type I diabetes mellitus, and the impact of endocrine adverse events on survival of patients in this field. Conclusion: The basic knowledge structure of the field of endocrine-related adverse events of ICIs, including publication trends, authors, institutions, countries, keywords, journals and publications, and cited documents, was visually analyzed in this bibliometric analysis. The research results comprehensively demonstrated the hot spots and future trends in the research field, as well as its broad prospects, thus providing a reference for the researchers.

Clinical features and outcomes analysis of Gallbladder neuroendocrine carcinoma.

Purpose: Gallbladder neuroendocrine carcinoma (GB-NEC) is an uncommon and highly malignant tumor. This research aimed to investigate the clinical characteristics and prognostic factors of GB-NEC. Materials and Methods: Our survey of case reports from January 2000 to May 2022 screened a total of 84 patients with complete data who received surgical resection for gallbladder NEC. Log-rank generated survival curves using the Kaplan-Meier method for univariate survival analysis. To identify GB-NEC independent prognostic indicators for overall survival (OS), univariate and multivariate Cox proportional hazard analyses were conducted. Results: These patients consisted of 25 men and 59 women, with an average age of 60 (range 29-85). Patients under 60 years old made up 44% of the population, while patients over 60 made up 56%. Fifty-three tumors were advanced pathologic TNM stage III and IV. After surgery, 44 patients underwent chemotherapy or radiotherapy. The median OS of 84 patients with GB-NEC was 16.8 months. In univariate and multivariate analysis, tumor size (diameter ≥5 cm), TNM tumor stage, and the receipt of postoperative adjuvant chemotherapy are independent factors influencing the prognosis of patients with GB-NEC. Conclusion: Tumor size (diameter ≥5 cm) and TNM tumor stage were independently related to a shorter OS. An enhanced OS was independently linked to receiving postoperative adjuvant chemotherapy.

The role of cannabidiol in aging.

Aging is usually considered a key risk factor associated with multiple diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Furthermore, the burden of age-related diseases has become a global challenge. It is of great significance to search for drugs to extend lifespan and healthspan. Cannabidiol (CBD), a natural nontoxic phytocannabinoid, has been regarded as a potential candidate drug for antiaging. An increasing number of studies have suggested that CBD could benefit healthy longevity. Herein, we summarized the effect of CBD on aging and analyzed the possible mechanism. All these conclusions may provide a perspective for further study of CBD on aging.

Anthelmintic nitazoxanide protects against experimental pulmonary fibrosis.

BACKGROUND AND PURPOSE: Nitazoxanide is a therapeutic anthelmintic drug. Our previous studies found that nitazoxanide and its metabolite tizoxanide activated adenosine 5'-monophosphate-activated protein kinase (AMPK) and inhibited signal transducer and activator of transcription 3 (STAT3) signals. As AMPK activation and/or STAT3 inhibition are targets for treating pulmonary fibrosis, we hypothesized that nitazoxanide would be effective in experimental pulmonary fibrosis. EXPERIMENTAL APPROACH: The mitochondrial oxygen consumption rate of cells was measured by using the high-resolution respirometry system Oxygraph-2K. The mitochondrial membrane potential of cells was evaluated by tetramethyl rhodamine methyl ester (TMRM) staining. The target protein levels were measured by using western blotting. The mice pulmonary fibrosis model was established through intratracheal instillation of bleomycin. The examination of the lung tissues changes were carried out using haematoxylin and eosin (H&E), and Masson staining. KEY RESULTS: Nitazoxanide and tizoxanide activated AMPK and inhibited STAT3 signalling in human lung fibroblast cells (MRC-5 cells). Nitazoxanide and tizoxanide inhibited transforming growth factor-ß1 (TGF-ß1)-induced proliferation and migration of MRC-5 cells, collagen-I and α-smooth muscle cell actin (α-SMA) expression, and collagen-I secretion from MRC-5 cells. Nitazoxanide and tizoxanide inhibited epithelial-mesenchymal transition (EMT) and inhibited TGF-ß1-induced Smad2/3 activation in mouse lung epithelial cells (MLE-12 cells). Oral administration of nitazoxanide reduced the bleomycin-induced mice pulmonary fibrosis and, in the established bleomycin-induced mice, pulmonary fibrosis. Delayed nitazoxanide treatment attenuated the fibrosis progression. CONCLUSIONS AND IMPLICATIONS: Nitazoxanide improves the bleomycin-induced pulmonary fibrosis in mice, suggesting a potential application of nitazoxanide for pulmonary fibrosis treatment in the clinic.

Red mud-derived iron carbon catalyst for the removal of organic pollutants in wastewater.

In order to reduce the environmental hazards of red mud (RM) and realize its resource utilization, in this study, RM-based iron-carbon micro-electrolysis material (RM-MEM) were prepared by a carbothermal reduction process using RM as raw material. The influence of the preparation conditions on the phase transformation and structural characteristics of the RM-MEM were investigated during the reduction process. The ability of RM-MEM to remove organic pollutants from wastewater was evaluated. The results showed that RM-MEM prepared at a reduction temperature of 1100 °C, a reduction time of 50 min and a coal dosage of 50% had the best removal effect for the degradation of methylene blue (MB). When the initial MB concentration was 20 mg L-1, the amount of RM-MEM material was 4 g L-1, the initial pH was 7, and the degradation efficiency reached 99.75% after 60 min. When RM-MEM is split into carbon free and iron free parts for use, the degradation effect becomes worse. Compared to other materials, RM-MEM has lower cost and better degradation. X-ray diffraction (XRD) analysis showed that hematite was transformed to zero-valent iron with the increase in the roasting temperature. Scanning electron microscopy (SEM) and energy spectroscopy (EDS) analysis showed that micron-sized ZVI particles were formed in the RM-MEM, and increasing the carbon thermal reduction temperature was beneficial to the growth of zero-valent iron particles.

Effect of Prolonging the Duration of Stenting on Urethral Stricture in Proximal Hypospadias with Severe Curvature Repair: A Prospective Cohort Study.

INTRODUCTION: The aim of this study was to evaluate whether prolonged stenting reduces the risk of urethral stricture after proximal hypospadias (PH) with severe curvature (SC) repair. MATERIALS AND METHODS: We prospectively studied a cohort of patients with PH with SC repair who underwent urethral plate transection and urethroplasty between January 2010 and December 2020. According to the duration of stenting, the patients were divided into 2-, 4-, and 6-week groups. Postoperative complications and time of urethral stricture occurrence were analyzed. RESULTS: In total, 665 patients were included in the analysis. The overall incidence of complications was 26.6% (n = 177), including 42 cases of urethral strictures: 27 (64.3%) cases of urethral stricture occurred between 4 and 6 weeks after urethroplasty, 7 cases occurred between 7 weeks and 6 months after urethroplasty, 7 cases occurred more than 6 months after urethroplasty, and 1 case occurred at 3 weeks after urethroplasty. The incidence of urethral stricture in the 6-week group (1.8%) was significantly lower than that in the 4- (5.8%) and 2-week groups (10.9%) (p < 0.05). CONCLUSION: Prolonged stenting reduces the risk of urethral stricture in PH with SC repair. Four to six weeks after PH with SC repair may be the key period for the formation of early urethral strictures.

Long-term, single-center study comparing open and laparoscopic procedures for congenital midureteral obstruction in children.

PURPOSE: To compare the safety and outcomes of open and laparoscopic procedures in the management of congenital midureteral obstruction in children (CMO). METHODS: Between February 2008 and February 2022, a total of 18 patients underwent open ureteroureterostomy (OU group), and 26 underwent laparoscopic ureteroureterostomy (LU group). The operative time, postoperative hospital stay, hospital costs, postoperative complications, and success rates of the two groups were compared. RESULTS: The median age of the patients was 59 months, with 29 patients presenting with asymptomatic hydronephrosis, 12 with intermittent abdominal pain, and 3 with flank mass. The median follow-up time was 42 months, and all patients were successfully treated surgically. The operative time and postoperative hospital stay in the LU group were shorter than those in the OU group (106.3 ± 21.4 vs. 85.8 ± 16.5 min, 11.6 ± 1.9 vs. 8.3 ± 1.7 days, respectively; p < 0.05). The OU group had two postoperative complications, both of which were classified as Clavien-Dindo grade II based on the Clavien-Dindo classification. One case of postoperative complication occurred in the LU group, which was classified as Clavien-Dindo Grade II. There was no significant statistical difference in complications between the two groups (P > 0.05). CONCLUSIONS: Our data showed that laparoscopic ureteroureterostomy is a safe and effective treatment for congenital midureteral obstruction in children, and provides several advantages, including fewer postoperative complications, shorter postoperative hospital stay, and a shorter operative time. Laparoscopic procedures should be the first choice for treating children with congenital midureteral obstructions.

Integrative network-based analysis on multiple Gene Expression Omnibus datasets identifies novel immune molecular markers implicated in non-alcoholic steatohepatitis.

Introduction: Non-alcoholic steatohepatitis (NASH), an advanced subtype of non-alcoholic fatty liver disease (NAFLD), has becoming the most important aetiology for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. This study were designed to explore novel genes associated with NASH. Methods: Here, five independent Gene Expression Omnibus (GEO) datasets were combined into a single cohort and analyzed using network biology approaches. Results: 11 modules identified by weighted gene co-expression network analysis (WGCNA) showed significant association with the status of NASH. Further characterization of four gene modules of interest demonstrated that molecular pathology of NASH involves the upregulation of hub genes related to immune response, cholesterol and lipid metabolic process, extracellular matrix organization, and the downregulation of hub genes related to cellular amino acid catabolic, respectively. After DEGs enrichment analysis and module preservation analysis, the Turquoise module associated with immune response displayed a remarkably correlation with NASH status. Hub genes with high degree of connectivity in the module, including CD53, LCP1, LAPTM5, NCKAP1L, C3AR1, PLEK, FCER1G, HLA-DRA and SRGN were further verified in clinical samples and mouse model of NASH. Moreover, single-cell RNA-seq analysis showed that those key genes were expressed by distinct immune cells such as microphages, natural killer, dendritic, T and B cells. Finally, the potential transcription factors of Turquoise module were characterized, including NFKB1, STAT3, RFX5, ILF3, ELF1, SPI1, ETS1 and CEBPA, the expression of which increased with NASH progression. Discussion: In conclusion, our integrative analysis will contribute to the understanding of NASH and may enable the development of potential biomarkers for NASH therapy.

Comprehensive characterization of ferroptosis in hepatocellular carcinoma revealing the association with prognosis and tumor immune microenvironment.

Background: Ferroptosis is a type of regulatory cell death (RCD) mode that depends on iron-mediated oxidative damage. It has the potential to improve the efficacy of tumor immunotherapy by modulating the tumor microenvironment (TME). Currently, immunotherapy has significantly improved the overall treatment strategy for advanced hepatocellular carcinoma (HCC), but the distinct immune microenvironment and high tolerance to the immune make massive differences in the immunotherapy effect of HCC patients. As a result, it is imperative to classify HCC patients who may benefit from immune checkpoint therapy. Simultaneously, the predictive value of ferroptosis in HCC and its potential role in TME immune cell infiltration also need to be further clarified. Methods: Three ferroptosis molecular models were built on the basis of mRNA expression profiles of ferroptosis-related genes (FRGs), with notable variations in immunocyte infiltration, biological function, and survival prediction. In order to further investigate the predictive impact of immunotherapy response in HCC patients, the ferroptosis score was constructed using the principal component analysis (PCA) algorithm to quantify the ferroptosis molecular models of individual tumors. Results: In HCC, there were three totally different ferroptosis molecular models. The ferroptosis score can be used to assess genetic variation, immunotherapy response, TME characteristics, and prognosis. Notably, tumors with low ferroptosis scores have extensive tumor mutations and immune exhaustion, which are associated with a poor prognosis and enhanced immunotherapy response. Conclusions: Our study indicates that ferroptosis plays an indispensable role in the regulation of the tumor immune microenvironment. For HCC, the ferroptosis score is an independent prognostic indicator. Assessing the molecular model of ferroptosis in individual tumors will assist us in better understanding the characteristics of TME, predicting the effect of immunotherapy in HCC patients, and thus guiding a more reasonable immunotherapy program.

Synthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma.

Spontaneous whole genome duplication and the adaptive mutations that disrupt genome integrity checkpoints are infrequent events in B cell lymphomas. This suggests that lymphomas might be vulnerable to therapeutics that acutely trigger genomic instability and polyploidy. Here, we report a therapeutic combination of inhibitors of the Polo-like kinase 4 and BCL-2 that trigger genomic instability and cell death in aggressive lymphomas. The synthetic lethality is selective for tumor cells and spares vital organs. Mechanistically, inhibitors of Polo-like kinase 4 impair centrosome duplication and cause genomic instability. The elimination of polyploid cells largely depends on the pro-apoptotic BAX protein. Consequently, the combination of drugs that induce polyploidy with the BCL-2 inhibitor Venetoclax is highly synergistic and safe against xenograft and PDX models. We show that B cell lymphomas are ill-equipped for acute, therapy-induced polyploidy and that BCL-2 inhibition further enhances the removal of polyploid lymphoma cells.

Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells.

BACKGROUND AND PURPOSE: Piezo1 channels are mechanosensitive cationic channels that are activated by mechanical stretch or shear stress. Endothelial Piezo1 activation by shear stress caused by blood flow induces ATP release from endothelial cells; however, the link between shear stress and endothelial ATP production is unclear. EXPERIMENTAL APPROACH: The mitochondrial respiratory function of cells was measured by using high-resolution respirometry system Oxygraph-2k. The intracellular Ca2+ concentration was evaluated by using Fluo-4/AM and mitochondrial Ca2+ concentration by Rhod-2/AM. KEY RESULTS: The specific Piezo1 channel activator Yoda1 or its analogue Dooku1 increased [Ca2+ ]i in human umbilical vein endothelial cells (HUVECs), and both Yoda1 and Dooku1 increased mitochondrial oxygen consumption rates (OCRs) and mitochondrial ATP production in HUVECs and primary cultured rat aortic endothelial cells (RAECs). Knockdown of Piezo1 inhibited Yoda1- and Dooku1-induced increases of mitochondrial OCRs and mitochondrial ATP production in HUVECs. The shear stress mimetics, Yoda1 and Dooku1, and the Piezo1 knock-down technique also demonstrated that Piezo1 activation increased glycolysis in HUVECs. Chelating extracellular Ca2+ with EGTA or chelating cytosolic Ca2+ with BAPTA-AM did not affect Yoda1- and Dooku1-induced increases of mitochondrial OCRs and ATP production, but chelating cytosolic Ca2+ inhibited Yoda1- and Dooku1-induced increase of glycolysis. Confocal microscopy showed that Piezo1 channels are present in mitochondria of endothelial cells, and Yoda1 and Dooku1 increased mitochondrial Ca2+ in endothelial cells. CONCLUSION AND IMPLICATIONS: Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells, suggesting a novel role of Piezo1 channel in endothelial ATP production.

Association of Renal Function (Estimate Glomerular Filtration Rate) with the Number of Febrile Urinary Tract Infections in Children with Neurogenic Bladder.

INTRODUCTION: Our objective was to evaluate whether renal function, assessed as the estimated glomerular filtration rate (eGFR), is associated with the number of febrile urinary tract infections (FUTIs) in children diagnosed with neurogenic bladder (NB). MATERIALS AND METHODS: Clinical information of patients diagnosed with NB was prospectively collected between January 2013 and January 2022. Episodes of FUTI were recorded during the follow-up period, and the eGFR was calculated based on the serum cystatin C level. Grading (G1-G5) of chronic kidney disease (CKD) was conducted as described by the eGFR. RESULTS: In total, 463 children were included in the final analysis (265 males and 198 females; mean age: 23 months). The median follow-up time was 51 months. A total of 302 children had four or more FUTIs and 161 children had none to three FUTIs. The incidence of developing CKD G3 to G5 gradually increased from the first to third (1.3-2.4%) episodes of FUTI and drastically increased after four episodes (≥ 22.5%), with the incidence recorded to be 100% after eight FUTIs. The odds of CKD G3 to G5 in children with four FUTIs were 17.3 and 43.7 times greater after four and six FUTIs, respectively, than in children with one FUTI. CONCLUSION: This study showed that recurrent FUTIs are common in children with NB and that the risk of rapid progression to CKD G3 to G5 increases substantially after four or more FUTIs episodes.

Aberrant circulating tumor DNA methylation and exosomal microRNA biomarkers for early detection of colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) became the third most commonly diagnosed malignancy and the second leading cause of cancer death in 2020. However, the rates of early screening and early diagnosis for CRC remain unsatisfactory. Thus, it is essential to explore the initiating factors of CRC and strategies for its early diagnosis. Research progress in liquid biopsy has led to the finding that circulating tumor-derived DNA (ctDNA) and exosomes play vital roles in early detection of CRC. THE APPLICATIONS OF LIQUID BIOPSY FOR EARLY DETECTION OF COLORECTAL CANCER: Moreover, the increased understanding of epigenetics has highlighted the role of ctDNA methylation in CRC carcinogenesis, and the detection of aberrant ctDNA methylation markers is a feasible strategy for diagnosis of early-stage CRC. Among exosomal markers, microRNAs (miRNAs) are abundant and are the most researched. Upregulated or downregulated expression of exosome-derived miRNAs can indicate the occurrence of early-stage CRC. FUTURE PERSPECTIVE: The current research progress on aberrant ctDNA methylation and tumor exosomal miRNA biomarkers in early detection of CRC is summarized in this review, and the advantages and shortcomings of the methods are discussed.

Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy in stage II-III non-small cell lung cancer: a single-center, single-arm, phase I study in China.

BACKGROUND: Neoadjuvant and adjuvant immune checkpoint inhibitor treatments for non-small cell lung cancer (NSCLC) patients with resectable disease have presented promising results. This is a phase I study to evaluate the safety and efficacy of neoadjuvant toripalimab in combination with chemotherapy for NSCLC. METHODS: Treatment-naive patients with resectable NSCLC (stage II-IIIB) received two to four cycles of toripalimab (240 mg, intravenously, q3w) combined with platinum-paclitaxel chemotherapy. Surgical operation was performed approximately 4 weeks after the last cycle. The primary end point was safety. The efficacy endpoints included radiographic and pathological response rates, expression of programmed death ligand 1 (PD-L1) and molecular targets. RESULTS: A total of 11 patients were enrolled, consisting of 2 patients (18%) with adenocarcinoma and 9 patients (82%) with squamous cell carcinoma. All patients received two to four cycles of toripalimab plus chemotherapy and underwent radical resection. Regarding safety, 5 of 11 patients (45%) had neoadjuvant treatment-related adverse events, and 1 patient (9%) experienced grade 3 or worse treatment-related adverse events. Radiographic partial response was achieved in 10 patients, with an objective response rate of 91%. Among 11 patients, 6 (55%) achieved pathological complete response, including 1 PD-L1-negative patient. CONCLUSION: Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy was tolerable and induced a pathological complete response in 55% of resectable NSCLC patients.