Machine learning algorithms predicting bladder cancer associated with diabetes and hypertension: NHANES 2009 to 2018.

Bladder cancer is 1 of the 10 most common cancers in the world. However, the relationship between diabetes, hypertension and bladder cancer are still controversial, limited study used machine learning models to predict the development of bladder cancer. This study aimed to explore the association between diabetes, hypertension and bladder cancer, and build predictive models of bladder cancer. A total of 1789 patients from the National Health and Nutrition Examination Survey were enrolled in this study. We examined the association between diabetes, hypertension and bladder cancer using multivariate logistic regression model, after adjusting for confounding factors. Four machine learning models, including extreme gradient boosting (XGBoost), Artificial Neural Networks, Random Forest and Support Vector Machine were compared to predict for bladder cancer. Model performance was assessed by examining the area under the subject operating characteristic curve, accuracy, recall, specificity, precision, and F1 score. The mean age of bladder cancer group was older than that of the non-bladder cancer (74.4 years vs 65.6 years, P < .001), and men were more likely to have bladder cancer. Diabetes was associated with increased risk of bladder cancer (odds ratio = 1.24, 95%confidence interval [95%CI]: 1.17-3.02). The XGBoost model was the best algorithm for predicting bladder cancer; an accuracy and kappa value was 0.978 with 95%CI:0.976 to 0.986 and 0.01 with 95%CI:0.01 to 0.52, respectively. The sensitivity was 0.90 (95%CI:0.74-0.97) and the area under the curve was 0.78. These results suggested that diabetes is associated with risk of bladder cancer, and XGBoost model was the best algorithm to predict bladder cancer.

Macrophage-Targeted Lipid Nanoparticle Delivery of microRNA-146a to Mitigate Hemorrhagic Shock-Induced Acute Respiratory Distress Syndrome.

The pro-inflammatory response of alveolar macrophages to injurious physical forces during mechanical ventilation is regulated by the anti-inflammatory microRNA, miR-146a. Increasing miR-146a expression to supraphysiologic levels using untargeted lipid nanoparticles reduces ventilator-induced lung injury but requires a high initial dose of miR-146a making it less clinically applicable. In this study, we developed mannosylated lipid nanoparticles that can effectively mitigate lung injury at the initiation of mechanical ventilation with lower doses of miR-146a. We used a physiologically relevant humanized in vitro coculture system to evaluate the cell-specific targeting efficiency of the mannosylated lipid nanoparticle. We discovered that mannosylated lipid nanoparticles preferentially deliver miR-146a to alveolar macrophages and reduce force-induced inflammation in vitro. Our in vivo study using a clinically relevant mouse model of hemorrhagic shock-induced acute respiratory distress syndrome demonstrated that delivery of a low dose of miR-146a (0.1 nmol) using mannosylated lipid nanoparticles dramatically increases miR-146a levels in mouse alveolar macrophages and decreases lung inflammation. These data suggest that mannosylated lipid nanoparticles may have the therapeutic potential to mitigate lung injury during mechanical ventilation.

Angiomatoid fibrous histiocytoma in the spinal canal of T3-T4: a case report and literature review.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumour that occurs in the superficial tissue of extremities of children and young adults. A painless mass in the deep dermis and subcutaneous tissue is the main clinical manifestation. AFH also occurs infrequently in the central nervous system and is relatively common in the cranium. However, spinal canal AFH has not been described yet. We report a rare case of AFH in the cervical canal of a 20-year-old male patient. Microsurgical gross total resection of the tumour was performed, and the diagnosis was confirmed by postoperative pathology. To our knowledge, this is the first case of AFH in the spinal canal.

Gentiopicroside alleviated epileptogenesis in immature rats through inactivation of NLRP3 inflammasome by inhibiting P2X7R expression.

OBJECTIVES: This study aimed to elucidate the effects of Gentiopicroside (Gent) on epileptogenesis and underlying mechanisms. METHODS: The status epilepticus (SE) model was established by intraperitoneal (i.p.) injection of lithium chloride (127 mg/kg) and pilocarpine (50 mg/kg) in immature rats. HAPI microglial cellular inflammation model was induced by lipopolysaccharide (LPS, 1 µg/ml) and adenosine triphosphate (ATP, 5 mM). The differential concentrations of Gent were used to pretreat animal (200, 400, and 800 mg/kg) and model cells (50, 100, and 200 µM). Epileptic discharges were assessed by electroencephalography (EEG) and Racine scale. Changes in spatial memory function were measured using the Morris water maze task test. Nissl and FJB staining were employed to assess the damage to hippocampus tissues. ELISA was used to detect the production of IL-1ß, IL-18, and TNF-α. The expressions of P2X7R and NLRP3 were detected by q-PCR, immunofluorescence staining, and Western blot, and cell viability was determined by cell counting kit-8 (CCK-8). RESULTS: Lithium chloride and pilocarpine (LICL-PILO) induced abnormal EEG activities, behavioral alterations, brain damage, and inflammatory responses in immature rats. However, Gent pretreatment significantly reduced the neuronal damage and spatial memory dysfunction induced by LICL-PILO. Additionally, Gent suppressed the production of inflammatory cytokines and inhibited the expression of P2X7R, NLRP3, ASC, and Caspase-1 in LPS/ATP-induced HAPI microglial cells. DISCUSSION: Gent intervention could improve epileptogenesis in immature rats partially due to suppressing P2X7R and NLRP3 inflammasome.

Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors.

Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reported. Envafolimab was well tolerated and no new safety signals were identified compared with other marketed products of the same class. Three patients reported Grade ≥ 3 envafolimab-related treatment-emergent adverse events (TEAE), including adrenal insufficiency, cerebral infarction, and immune-mediated enterocolitis. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve (AUC) and maximum serum concentration (Cmax). The overall response rate (ORR) was 11.4% (n = 4) and disease control rate (DCR) was 34.3% (n = 12). Consistent with that observed in other envafolimab Phase 1 trials and approved PD-1/PD-L1 inhibitors, the safety profile of SC envafolimab in Japanese patients with advanced solid tumors was well tolerated with efficacy comparable to IV administered treatments. Pharmacokinetics data and preliminary anti-tumor response support dose regimens with longer dosing intervals (Q2W or Q4W). As such, envafolimab offers patients a more convenient treatment option than currently available intravenously administered PD-1/PD-L1 inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT03248843(August 14, 2017).

The Impact of the Corona Virus Disease 2019 Pandemic on Chinese Middle School Students' Self-Perceived Emotional States: A Wuhan Perspective.

This mixed-methods study examined the impact of the COVID-19 pandemic on 1493 Grades 7, 8, and 9 students' self-perceived emotional states in Wuhan, China when it was locked down for the pandemic on January 23, 2020 and when the lockdown was lifted on April 8, 2020, as well as the changes of their emotional states over the 1-year period after the lockdown was lifted. A five-point Likert scale survey was administered to the participants between March 1 and April 1, 2020 when Wuhan was blocked down; and three focus group interviews were conducted between May 1 and May 31, 2021, 1 year after the lockdown was lifted. The results showed that these students in Wuhan experienced feelings of loss of control and negative emotions when the city was locked down and they were home quarantined; furthermore, there were significant differences for their self-perceived feelings of loss of control and negative emotions across demographic variables of gender, grade level, physical activity, social economic status, and family cohesion; finally, their emotional states changed substantially at different time nodes during this pandemic. Implications for students, parents, and schools are discussed.

Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice.

Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V-VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.

First-in-Human Phase I Study of Envafolimab, a Novel Subcutaneous Single-Domain Anti-PD-L1 Antibody, in Patients with Advanced Solid Tumors.

LESSONS LEARNED: Subcutaneous injection was an effective route of administration for envafolimab with a favorable pharmacokinetic profile in patients with previously treated advanced solid tumors. Subcutaneous envafolimab was well tolerated and had durable antitumor activity at a wide range of doses and schedules. Envafolimab has the potential to be a more convenient option than currently approved intravenous PD-1/PD-L1 inhibitors. BACKGROUND: Envafolimab is a novel fusion of a humanized single-domain PD-L1 antibody and human IgG1 Fc fragment formulated for subcutaneous injection. This study explored the safety and feasibility of subcutaneous administration of envafolimab as an alternative to intravenous administration of PD-1/PD-L1 inhibitors in the treatment of advanced, refractory solid tumors. METHODS: This was a first-in-human, open-label phase I trial. In a dose-escalation phase, patients received subcutaneous envafolimab 0.01-10 mg/kg once weekly following a modified 3+3 design. In a dose-exploration phase, patients received subcutaneous envafolimab 300 mg once every 4 weeks. RESULTS: Twenty-eight patients were enrolled (dose escalation n = 18, dose exploration n = 10, median age 66 years; 71% male; ECOG performance score = 0 [21%] or 1 [79%]). No dose-limiting toxicities or injection-site reactions were reported. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve and maximum plasma concentration. Median time to maximum plasma concentration was 4-7 days. In the dose-exploration phase, terminal half-life was 14 days after dose 1 in cycle 1 and 23 days at steady state. Three patients experienced a confirmed partial response. CONCLUSION: Subcutaneous envafolimab had a favorable safety and pharmacokinetic profile, with promising preliminary antitumor activity in patients with advanced solid tumors.

ALG13 participates in epileptogenesis via regulation of GABAA receptors in mouse models.

ALG13 (asparagine-linked glycosylation 13) plays crucial roles in the process of N-linked glycosylation. Mutations of the ALG13 gene underlie congenital disorders of glycosylation type I (CDG-I), a rare human genetic disorder with defective glycosylation. Epilepsy is commonly observed in congenital disorders of glycosylation type I (CDG-I). In our study, we found that about 20% of adult ALG13KO knockout mice display spontaneous seizures, which were identified in a simultaneous video and intracranial EEG recording. However, the mechanisms of ALG13 by which deficiency leads to epilepsy are unknown. Whole-cell patch-clamp recordings demonstrated that ALG13KO mice show a marked decrease in gamma-aminobutyric acid A receptor (GABAAR)-mediated inhibitory synaptic transmission. Furthermore, treatment with low-dose diazepam (a positive allosteric modulator of GABAA receptors), which enhances GABAAR function, also markedly ameliorates severity of epileptic seizures in ALG13KO mice. Moreover, ALG13 may influenced the expression of GABAARα2 membrane and total protein by changing transcription level of GABAARα2. Furthermore, protein interactions between ALG13 and GABAARα2 were observed in the cortex of wild-type mice. Overall, these results reveal that ALG13 may be involved in the occurrence of epilepsy through the regulation of GABAAR function, and may provide new insight into epilepsy prevention and treatment.

Pterygial body epithelium domination of pterygial proliferation with TCF4 as a potential key factor.

AIM: To characterize the proliferative capacity of pterygial epithelium in different regions (head, neck and body) of pterygium and explore the function of transcription factor 4 (TCF4) in pterygium proliferation. METHODS: Thirty pterygium tissues and 10 normal conjunctival tissues were obtained from Zhongshan Ophthalmic Center (ZOC) and Guangdong Eye Bank, respectively. Proliferative capacity of head, neck and body in pterygial epithelium was measured using clonal analysis, fold growth analysis and expression profile of proliferative markers revealed by immunofluorescent staining and real-time PCR. The expression of TCF4 was highlighted by double immunofluorescent staining with other proliferation related markers such as proliferating cell nuclear antigen (PCNA) and ATP-binding cassette sub-family G member 2 (ABCG2). RESULTS: The proliferative potential of pterygial epithelium was higher than that of normal conjunctival epithelium. High expression levels of proliferative markers (P63α, PCNA and ABCG2) in pterygial body epithelium were observed in immunofluorescent staining and real-time PCR (P<0.05). Also, epithelial cells isolated from pterygial body demonstrated higher proliferative capacity in clonal analysis and fold growth analysis, than those isolated from the head and neck regions. The TCF4 expression in pterygial epithelium was similar to other proliferative markers (P63α, PCNA and ABCG2), as higher in pterygial body than head and neck. Moreover, TCF4 showed coexpression with other proliferation-related markers (PCNA and ABCG2) in the double immunofluorescent staining experiment. CONCLUSION: The proliferative capacity in pterygial body epithelium is prominent than the head and neck regions, and upregulated TCF4 may be associated with enhanced proliferation in the pterygium.

Tamoxifen Attenuates Lipopolysaccharide/Galactosamine-induced Acute Liver Failure by Antagonizing Hepatic Inflammation and Apoptosis.

Bacterial lipopolysaccharide (LPS)-induced acute liver failure (ALF) is a common severe clinical syndrome in intensive care unit. No other methods are available for its prevention apart from supportive treatment and liver transplantation. Tamoxifen (TAM) was reported to attenuate ALF induced by excessive acetaminophen, while its effect on LPS-induced ALF remained unknown. For this, in the present study, we comprehensively assessed whether TAM can attenuate ALF induced by LPS/galactosamine (GaIN). Mice were given TAM once a day for three times. Twelve hours after the last treatment, mice were given LPS/GaIN (intraperitoneally [i.p.]). Survival, plasma transaminases, and histopathology were examined. Serum TNF-α and IL-1ß were analyzed by ELISA. Hepatic apoptosis was analyzed by TUNEL and caspase-3 Western blotting, respectively. Compared to the model group, ALF induced by LPS/GaIN was alleviated remarkably following TAM administration, as evidenced by the improvement of survival (87.5% vs. 37.5%), hepatic swell, moderate transaminases, slightly increased serum TNF-α, IL-1ß (P < 0.05), and moderate histopathology. In respect of apoptosis, severe hepatocellular apoptosis was reduced notably by TAM treatment confirmed by less TUNEL-positive hepatocytes and decreased caspase-3 cleavage. The results demonstrated that TAM could attenuate LPS/GaIN-induced ALF effectively, probably due to hepatic inflammation and apoptosis antagonism. Furthermore, it was the first report about the effect of TAM on LPS/GaIN-induced ALF.

Protective effect of Bu-zhong-yi-qi decoction, the water extract of Chinese traditional herbal medicine, on 5-fluorouracil-induced renal injury in mice.

BACKGROUND: Drug-induced renal injury is a serious toxic side effect of 5-fluorouracil (5-FU) treatment. Bu-zhong-yi-qi decoction (BZYQD), a water extract of Chinese traditional herbal medicine, is widely used in Asia as an alternative treatment to reduce the side effects of chemotherapy and also improve cancer survival. However, the mechanism is unknown. This study is designed to investigate the protective effect of BZYQD on 5-FU-induced renal injury in mice. METHODS: Mice were divided into four groups: the control, 5-FU, 5-FU + low, and high BZYQD group. Mice in the three latter groups were administered 5-FU (100 mg/kg/day, intraperitoneally) for six days, and in the 5-FU + low and high BZYQD groups were given BZYQD (1 or 2 g raw herb/kg/day, intragastrically) beginning four days before 5-FU and continuing until the termination of the experiment. The right kidney fixed in formalin for histological examination and the left was homogenized to measure the levels of apoptosis-related proteins and activities of oxidative stress-related biomarkers. Blood samples were collected for measuring renal function-related biochemical indices. RESULTS: Renal morphology injury, increased urea nitrogen and creatinine concentration, and decreased SOD, CAT, and GSH-Px were all observed in 5-FU-administrated mice. However, BZYQD almost reversed the morphological injury as well as renal function-related indices and antioxidant enzyme activity. CONCLUSION: These results suggest that BZYQD inhibits 5-FU-induced renal injury, possibly through the reduction of apoptosis and necrosis in renal tubular epithelial cells via the antioxidant mechanism. Henceforth, BZYQD may be a potential antioxidant against drug-induced oxidative stress.

Tcf7l2 localization of putative stem/progenitor cells in mouse conjunctiva.

Conjunctival integrity and preservation is indispensable for vision. The self-renewing capacity of conjunctival cells controls conjunctival homeostasis and regeneration; however, the source of conjunctival self-renewal and the underlying mechanism is currently unclear. Here, we characterize the biochemical phenotype and proliferative potential of conjunctival epithelial cells in adult mouse by detecting proliferation-related signatures and conducting clonal analysis. Further, we show that transcription factor 7-like 2 (T-cell-specific transcription factor 4), a DNA binding protein expressed in multiple types of adult stem cells, is highly correlated with proliferative signatures in basal conjunctival epithelia. Clonal studies demonstrated that Transcription factor 7-like 2 (Tcf7l2) was coexpressed with p63α and proliferating cell nuclear antigen (PCNA) in propagative colonies. Furthermore, Tcf7l2 was actively transcribed concurrently with conjunctival epithelial proliferation in vitro. Collectively, we suggest that Tcf7l2 may be involved in maintenance of stem/progenitor cells properties of conjunctival epithelial stem/progenitor cells, and with the fornix as the optimal site to isolate highly proliferative conjunctival epithelial cells in adult mice.

Physiological analyses indicate superoxide dismutase, catalase, and phytochelatins play important roles in Pb tolerance in Eremochloa ophiuroides.

Phytoremediation is considered to be a promising approach to restore or stabilize soil contaminated by lead (Pb). Turfgrasses, due to their high biomass yields, are considered to be suitable for use in phytoextraction of soil contaminated with heavy metal. It has been demonstrated that centipedegrass (Eremochloa ophiuroides (Munro) Hack., Poaceae) is a good turfgrass for restore of soil contaminated by Pb. However, the enhanced tolerant mechanisms in metallicolous (M) centipedegrass accessions remain unknown. In this study, we made a comparative study of growth performance, Pb accumulation, antioxidant levels, and phytochelatin concentrations in roots and shoots from M and nonmetallicolous (NM) centipedegrass accessions. Results showed that turf quality and growth rate were less repressed in M accessions than in NM accession. Pb stress caused generation of reactive oxygen species in centipedegrass with relatively lower levels in M accessions. Antioxidant activity analysis indicated that superoxide dismutase and catalase played important roles in Pb tolerance in M accessions. M accessions accumulated more Pb in roots and shoots. Greatly increased phytochelatins and less repressed sulfur contents in roots and shoots of M accessions indicated that they correlated with Pb accumulation and tolerance in centipedegrass.

Normative anthropometric analysis and aesthetic indication of the ocular region for young Chinese adults.

PURPOSE: The ocular region is of prime importance for the facial aesthetic outlook. Various anthropometric analyses for the periocular region have developed to ensure a pleasing postoperative appearance. However, little information exists for Chinese young adults. In this study, authors not only analyzed the periocular anthropometric characteristics, but, more importantly, searched out the most meaningful aesthetic indicators of the population. METHODS: The cross-sectional study was executed using two-dimensional photogrammetry acquired from 162 Chinese young adults (79 males, 83 females) between 20-30 years old. Anthropometric parameters including palpebral fissure length and height, intercanthal and outercanthal width, crease height, angle of endocanthion and exocanthion, axis of palpebral fissure, palpebral fissure index, canthal index, and angular index were acquired from standardized photographs. Then, 134 volunteers (20-30 years old) gave each photograph a score within 1-5 points to evaluate their ocular aesthetic attractiveness. The correlation between anthropometric parameters and aesthetic assessment was analyzed. RESULTS: A statistical difference between genders was found for palpebral fissure length and height, outercanthal width, angle of exocanthion, palpebral fissure index and canthal index (p < 0.05), with no statistical difference found for crease height between genders. Moreover, the palpebral fissure index, canthal index, crease height, and angle of exocanthion were significantly associated with aesthetic assessment. CONCLUSIONS: The normative anthropometric parameters are fundamental to interpret the morphology of eyes and to design plastic surgery for young Chinese adults. The parameters of palpebral fissure index, canthal index, crease height, and angle of exocanthion are strong indicators of aesthetic assessment.