Fc-null anti-CTLA-4 antibody: a novel strategy to facilitate cancer immunotherapy by ridding the colitis-inducing mishap.

Writing recently in Science, Lo and coworkers characterized a critical role of the gut microbiota in CTLA-4 blockade-induced colitis, revealing that an Fc domain deficient anti-CTLA-4 antibody can elicit antitumor responses effectively while avoiding the induction of colitis-like disease.1 This research opens up novel avenues for employing anti-CTLA-4 antibody therapy to circumvent the onset of colitis, which is often considered the Achilles' heel of what is arguably the most efficacious treatment for certain blood cancers and/or solid tumors.

Gastrodin ameliorates acute pancreatitis by modulating macrophage inflammation cascade via inhibition the p38/NF-κB pathway.

Acute pancreatitis (AP) is a prevalent, destructive, non-infectious pancreatic inflammatory disease, which is usually accompanied with systemic manifestations and poor prognosis. Gastrodin (4-hydroxybenzyl alcohol 4-O-ß-d-glucopyranoside) has ideal anti-inflammatory effects in various inflammatory diseases. However, its potential effects on AP had not been studied. In this study, serum biochemistry, H&E staining, immunohistochemistry, immunofluorescence, western blot, real-time quantitative PCR (RT-qPCR) were performed to investigate the effects of Gastrodin on caerulein-induced AP pancreatic acinar injury model in vivo and lipopolysaccharide (LPS) induced M1 phenotype macrophage model in vitro. Our results showed that Gastrodin treatment could significantly reduce the levels of serum amylase and serum lipase while improving pancreatic pathological morphology. Additionally, it decreased secretion of inflammatory cytokines and chemokines, and inhibited the levels of p-p38/p38, p-IκB/IκB as well as p-NF-κB p-p65/NF-κB p65. Overall our findings suggested that Gastrodin might be a promising therapeutic option for patients with AP by attenuating inflammation through inhibition of the p38/NF-κB pathway mediated macrophage cascade.

Integrated single-cell RNA-seq analysis revealed podocyte injury through activation of the BMP7/AMPK/mTOR mediated autophagy pathway.

BACKGROUND: Nephrotic syndrome (NS) is a chronic kidney disease mainly caused by impaired podocytes, ultimately resulting in massive proteinuria or even end-stage renal disease (ESRD). METHODS: The objective of this study was to explore the potential pathogenesis of NS caused by podocyte injury, and further explore the underlying mechanism through data mining, bioinformatics analysis, and experimental verification. The integrated analyses including Seurat, CellChat, gene ontology (GO), and molecular docking were performed based on the single-cell RNA-seq data (scRNA-seq). The adriamycin (ADR)-induced podocyte injury model in vitro was established to conduct the experimental verification for bioinformatics analysis results through western blot and real-time quantitative PCR (RT-qPCR). RESULTS: The results of bioinformatics analysis revealed that the bone morphogenetic protein (BMP) signaling pathway was involved in the podocyte-to-podocyte communication, which plays a crucial role in podocyte injury. The expression of BMP7 was significantly increased in ADR-induced podocytes through activating the Adenosine-monophosphate activated-protein kinase/Mammalian target of rapamycin (AMPK/mTOR) mediated autophagy pathway, and these findings were confirmed by in vitro experiments. CONCLUSION: This study first demonstrated that BMP7 participated in ADR-induced podocyte injury. The BMP7/AMPK/mTOR mediated autophagy pathway may play a crucial role in podocyte injury, which may be the potential therapeutic target for NS patients.

The protective roles of allicin on type 1 diabetes mellitus through AMPK/mTOR mediated autophagy pathway.

Background: Type 1 diabetes mellitus (T1DM) is one of the most common endocrine and metabolic diseases in children. Pancreatic ß cells are thought to be critical cells involved in the progression of T1DM, and their injury would directly lead to impaired insulin secretion. Purpose: To investigate the protective effects of allicin on pancreatic ß cell injury and elucidate the underlying mechanism. Methods: The streptozotocin (STZ)-induced mouse T1DM model in vivo and STZ-induced pancreatic ß cell Min6 model in vitro were used to explore the effects of allicin on T1DM. The experiments include fasting blood glucose test, oral glucose tolerance detection, HE staining, immunohistochemistry, immunofluorescence, TUNEL staining, western blot, real-time quantitative PCR (RT-qPCR), and flow cytometry. Results: Allicin could significantly decrease blood glucose level, improve islet structure and insulin expression, and inhibit apoptosis to reduce STZ-induced pancreatic ß cell injury and loss through activating AMPK/mTOR mediated autophagy pathway. Conclusion: Allicin treatment significantly reduced STZ-induced T1DM progression, suggesting that allicin may be a potential therapy option for T1DM patients.

COVID-19 vaccine uptake and vaccine hesitancy in rural-to-urban migrant workers at the first round of COVID-19 vaccination in China.

BACKGROUND: Migration can be linked to the transmission of COVID-19. COVID-19 vaccine uptake and hesitancy among rural-to-urban migrant workers in China, the largest group of internal migrants in the world, has not been characterized. OBJECTIVE: To investigate COVID-19 vaccine uptake and identify vaccine hesitancy-associated factors among rural-to-urban migrant workers in the first round of COVID-19 vaccination in China. METHODS: A cross-sectional questionnaire-based survey was conducted, including 14,917 participants. Socio-demographics, COVID-19 vaccine uptake, vaccine hesitancy and its associated factors based on Vaccine Hesitancy Determinants Matrix (VHDM) were applied for the survey. Data were principally analyzed by logistic regression analysis. RESULTS: The COVID-19 vaccine uptake and vaccine hesitancy rates were 7.1% and 57.7%, respectively. Vaccine hesitancy was strongly associated with VHDM, including individual factors (female, higher annual income and fewer medical knowledge), group factors (less family support, friend support and public opinion support), COVID-19 epidemic factors (lower fatality, infection and emotional distress) and vaccine factors (less vaccine necessity, vaccine safety, vaccine efficacy, vaccine importance and vaccine reliability). CONCLUSION: The VHDM model has the potential utility in efforts to reduce COVID-19 vaccine hesitancy. Greater efforts should be put into addressing positive predictors associated with vaccine hesitancy.

Urine Screening and 9 Years' Medical Record System Follow-Up Among School Students in Wenzhou, China.

School urinary screening programming can be useful for the early detection of renal and urinary disorders. However, urine screening is not included in the school health check-up in our region. Therefore, from February 2012 to March 2021, 12,497 school students were screened for urinalysis, and a long-term follow-up took place via an electronic medical record system. Among these screened students, 719 (5.75%) positive individuals received a repeat urinalysis 2 weeks later. During the 9-year medical record system follow-up period, 5 children had renal biopsies and 2 children had a diagnosis of IgA nephropathy (IgAN), while the remaining 3 children were diagnosed with thin basement membrane disease (TBM), primary nephrotic syndrome (PNS), and were suspected of C3 glomerulopathy, respectively. By this, calling for the school urine screening program as a physical examination item for primary and secondary school-aged students will contribute to enabling early detection of urine abnormalities and allow for early treatment.

Evaluation of a new frequency-volume chart for children with primary monosymptomatic nocturnal enuresis: a prospective, comparative study.

INTRODUCTION: To improve compliance with voiding diaries in children with primary monosymptomatic nocturnal enuresis (PMNE), a new modified 3-day weekend frequency-volume chart (FVC) was designed, and the compliance and validity of this modified FVC was evaluated by comparing with the International Children's Continence Society (ICCS) recommended voiding diary. METHODS: A total of 1200 patients with PMNE were enrolled in the study from 13 centers in China and were randomly assigned to record this modified FVC or the ICCS-recommended voiding diary. The primary outcome measure was the compliance, assessed by comparing the completing index and the quality score of diaries between two groups. The secondary outcome measure was the validity, evaluated by comparing the constituent of subtypes, micturition parameters and response rate to desmopressin. RESULTS: Among the 1200 participants enrolled in the study, 447 patients completed the ICCS-recommended voiding diary and 469 completed the modified diary. The diurnal completing index and the quality score of the modified FVC group were better than those of the ICCS group. In addition, there was no significant difference between these two groups in the subtype classification, or in the response rate to desmopressin. CONCLUSIONS: The modified FVC could be applied to obtain the voiding characteristics of children with PMNE as the ICCS-recommended voiding diary does and offers a reasonable and better choice for children with PMNE from the unselected population in the future.

Acyl-Coenzyme A: Cholesterol Acyltransferase-1 is Related to Hyperlipidemia in Children with Nephrotic Syndrome.

BACKGROUND: Hyperlipidemia is one of the characteristics of nephrotic syndrome, and cellular lipid accumulation in the kidney can accelerate kidney disease. ACAT1 plays important roles in cellular cholesterol homeostasis. The purpose of this study was to investigate the effect of ACAT1 on lipid metabolism in nephrotic syndrome, and its role in clinical diagnosis and efficacy evaluation. METHODS: In this case control study, 30 patients with nephrotic syndrome and 30 healthy controls were enrolled. ACAT1 mRNA was detected by qPCR, and methylation of ACAT1 promoter was assayed by sodium bisulfite sequencing. RESULTS: The expression of ACAT1 mRNA in NS group, remission group, and controls was 0.14 ± 0.06, 0.08 ± 0.03, and 0.08 ± 0.04, respectively. The methylation of ACAT1 promoter in NS group, remission group, and controls was 2.27 ± 2.71, 4.00 ± 3.15, and 4.93 ± 3.59, respectively. The AUC value of ACAT1 mRNA was 0.856 (95% CI: 0.760 - 0.951), while the AUC value of ACAT1 methylation was 0.653 (95% CI: 0.514 - 0.792). The results of Pearson's correlation suggested that the high expression of ACAT1 mRNA and the hypomethylation of ACAT1 were related to hyperlipidemia and hypoalbuminemia in nephrotic syndrome. CONCLUSIONS: This study shows that ACAT1 is related to hyperlipidemia and hypoproteinemia in nephrotic syndrome and can be a useful biomarker for the efficacy evaluation of nephrotic syndrome.

Establishment of a human induced pluripotent stem cell line (WMUi031-A) from a Lowe syndrome patient carrying a OCRL gene mutation (c.2626dupA).

Lowe Syndrome (LS) is a rare X-linked multisystemic disorder syndrome, which can be caused by the gene mutations of OCRL. In present study, the urine cells (UCs) derived from a 12-year-old male LS patient with the hemizygote OCRL gene mutation p.M876N (c.2626dupA) were reprogrammed into induced pluripotent stem cells (iPSCs) named WMUi031-A through the commercial Sendai virus reprogramming kit. The pluripotent markers OCT4 and SOX2 can be expressed positively in WMUi031-A, which can be differentiated into three germ layers in vitro as well as maintain a stable karyotype (46, XY).

[Clinical features of neurogenic bladder with vesicoureteral reflux in children].

OBJECTIVE: To study the clinical features of vesicoureteral reflux (VUR) in children with neurogenic bladder (NB), and to provide a reference for its early diagnosis and treatment. METHODS: Clinical data were collected from 26 children with NB and urinary tract infection who were admitted to the Department of Pediatric Nephrology from January 2014 to December 2019. According to the presence or absence of VUR, the children were divided into a VUR group with 11 children and a non-VUR group with 15 children. Clinical features were compared between the two groups. RESULTS: Compared with the non-VUR group, the VUR group had a significantly higher proportion of children with non-Escherichia coli urinary tract infection, hydronephrosis (the severity of hydronephrosis increased with the grade of VUR), abnormal 99mTc-DMSA renal scanning findings, elevated ratios of urinary albumin, urinary IgG and urinary transferrin to creatinine, increased residual urine volume, and increased detrusor leak point pressure (P < 0.05). CONCLUSIONS: When NB children have the clinical manifestations of non-Escherichia coli urinary tract infection, hydronephrosis, abnormal 99mTc-DMSA renal scanning findings, glomerular proteinuria, increased bladder residual urine volume, and high detrusor leak point pressure, such children may already have VUR, and so diagnosis and intervention should be performed as early as possible.

Generation of a human induced pluripotent stem cell line (WMUi021-A) from a Gitelman syndrome patient carrying a SLC12A3 gene mutation (c.179C > T).

Gitelman Syndrome (GS) is an inherited autosome recessive disorder syndrome, which can be caused by the gene mutations of solute carrier family 12 member 3 gene (SLC12A3). In present study, the urine cells (UCs) of a 7-year-old male GS patient with the homozygote SLC12A3 gene mutation p.T60M (c.179C > T) were reprogrammed into induced pluripotent stem cells (iPSCs) named WMUi021-A through the commercial Sendai virus reprogramming kit. The pluripotent markers OCT4 and SOX2 can be expressed positively in WMUi021-A, which can be differentiated into three germ layers in vitro as well as maintain a stable karyotype (46, XY).

Establishment of an induced pluripotent stem cell line (WMUi016-A) from a patient with X-linked Dent disease (X-Dent) carrying the hemizygote mutation p.R718* (c.2152C > T) in the CLCN5 gene.

The gene mutations of the chloride channel gene (CLCN5) can lead to the inherited X-linked Dent disease (X-Dent). The urine cells of a 4-year-old male X-Dent patient with the hemizygous CLCN5 gene mutation p.R718* (c.2152C > T) were reprogrammed into induced pluripotent stem cells (iPSCs) using integration free Sendai virus reprogramming system. The generated iPSCs stably expressed pluripotent stem cell markers and can be induced to differentiate into three germ layers in vitro. The karyotype of the generated iPSCs was normal (46, XY).

Generation of an induced pluripotent stem cell line from a Bartter syndrome patient with the homozygote mutation p.A244D (c.731C>A) in SLC12A1 gene.

Bartter Syndrome (BS) is a group of rare inherited autosome-recessive disease, which can be caused by the gene mutations of sodium-potassium-chloride cotransporter gene (SLC12A1). Here, the urine cells (UCs) derived from a 4-year-old female BS patient with the homozygote SLC12A1 gene mutation p.A244D (c.731C>A) were reprogramming into induced pluripotent stem cells (iPSCs) named WMUi019-A using a commercial Sendai virus reprogramming kit. The pluripotent stem cell markers like OCT4 and SSEA4 can be positively expressed in this iPSC line, which can also be induced to differentiate into three germ layers in vitro and maintain a stable karyotype (46, XY).

Establishment of an induced pluripotent stem cell line from a Antley-Bixler Syndrome (ABS) patient with the homozygote mutation p.R457H (c.1370G>A) in POR gene.

Antley-Bixler syndrome (ABS) is a rare inherited autosome recessive malformation syndrome, which can be caused by the gene mutations of cytochrome P450 oxidoreductase (POR). In this study, the urine cells (UCs) derived from a 5-year-old female ABS patient with the homozygote POR gene mutation p.R457H (c.1825C>G) were reprogramming into induced pluripotent stem cells (iPSCs) named WMUi018-A using a commercial Sendai virus reprogramming kit. The pluripotent markers of stem cells like OCT4 and SOX2 can be positively expressed in this iPSC line, which can be induced to differentiate into three germ layers in vitro and maintain a stable karyotype (46, XX).

Generation of an urine-derived induced pluripotent stem cell line WMUi017-A from a X-linked Renpenning syndrome (X-RSY) patient with the hemizygous PQBP1 gene mutation p.P609A (c.1825C>G).

The mutations of polyglutamine binding protein 1 gene (PQBP1) can lead to the rare inherited X-linked Renpenning syndrome (X-RSY). Here, an induced pluripotent stem cell (iPSC) line WMUi017-A was generated through reprogramming the urine cells of a 5-year-old male X-RSY patient with the hemizygous PQBP1 gene mutation p.P609A (c.1825C>G) using the commercial Sendai virus reprogramming system. The established iPSCs can stably express pluripotent stem cell markers OCT4 and NANOG, and can be induced into three germ layers and maintain a normal karyotype (46, XY) in vitro.

Effect of core-based exercise in people with scoliosis: A systematic review and meta-analysis.

OBJECTIVE: To systematically assess the effectiveness of core-based exercise for correcting a spinal deformity and improving quality of life in people with scoliosis. DATA SOURCES: The PubMed, Embase, Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Web of Science databases were searched from inception up to September 30, 2020. METHODS: Clinical controlled trials were eligible if they compared the effectiveness of core-based exercise to other nonsurgical interventions in people with scoliosis. The revised Cochrane risk of bias assessment tool for randomized trials and the methodological index for non-randomized studies scale were used to assess the risk of bias. The outcomes included the Cobb angle, the angle of trunk rotation and quality of life. RevMan 5.3 was used, and intergroup differences were determined by calculating mean differences (MD) and 95% confidence intervals (CIs). RESULTS: After screening 1348 studies, nine studies with 325 participants met the inclusion criteria. The exercise group had significantly lower Cobb angles (MD = -2.08, 95% CI: -3.89 to -0.28, P = 0.02) and significantly better quality of life as measured by the Scoliosis Research Society-22 questionnaire (MD = 0.25, 95% CI: 0.02 to 0.49, P = 0.03) than the control groups. However, no significant difference was observed regarding the angle of trunk rotation between groups (MD = -0.69, 95% CI: -2.61 to 1.22, P = 0.48). Furthermore, no serious adverse events were reported. The overall quality of evidence ranged from low to very low. CONCLUSION: Core-based exercise may have a beneficial role in reducing the Cobb angle and improving quality of life in people with scoliosis in the short term. PROSPERO REGISTRATION NUMBER: CRD42020160509 (Available at http://www.crd.york.ac.uk/prospero/).

Generation of a human induced pluripotent stem cell line with Cas9 driven by Tet-on operator via AAVS1 safe harbor gene-editing.

Human induced pluripotent stem (iPS) cells expressing Cas9 protein are valuable for the pathogenic mechanism study and drug discovery. These cells can be efficiently induced to differentiate into disease cell models with specific mutations through adding designed sgRNAs. Here, we generated a human gene-editable iPS cell line by gene editing method that Cas9 gene driven by Tet-on operator was perfectly integrated into the human AAVS1 safe harbor locus. The established Cas9 expression iPS cell line named as WMUi013-A can express endogenous pluripotent markers, has the ability to differentiate into the three germ layers, and possesses a normal karyotype.

Direct effect of protein kinase A on four putative phosphorylation sites of aquaporin 2 in vitro.

The water channel aquaporin 2 (AQP2) has four phosphorylation sites at Ser256, Ser261, Ser264, and Ser269 in the C-terminus and these sites are important for AQP2 bioactivity. However, the exact role of each phosphorylation site still remains unclear. In this study, we generated unique AQP2 mutants in which we eliminated three phosphorylation sites but maintained only one site at the C-terminal end. The AQP2 phosphorylation of each single site by protein kinase A (PKA) was examined by in vitro translation and 32P incorporation. The ability of AQP2 trafficking to the cell membrane was evaluated by cell surface biotinylation. Among the four phosphorylation sites, AQP2 mutant with only S256 preserved the most ability of AQP2 to cell membrane expression. The AQP2 water permeability was measured in oocyte. Ser256 is the most important site for AQP2 function. Interestingly, Ser261 and Ser264 significantly inhibit AQP2 activity. Ser269 slightly but not statistically reduced AQP2 activity. Our data suggest that the four phosphorylation sites execute differential roles in concert in AQP2 functional regulation. AQP2 activity regulated by phosphorylation at Ser256 can be counterbalanced by phosphorylation at Ser261 and Ser264.

Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia: A case report and literature review.

RATIONALE: Methylmalonic acidemia (MMA) is a common organic acidemia, mainly due to methylmalonyl-CoA mutase (MCM) or its coenzyme cobalamin (VitB12) metabolic disorders. Cobalamin C (CblC) type is the most frequent inborn error of cobalamin metabolism; it can develop symptoms in childhood and often combine multisystem damage, which leads to methylmalonic acid, propionic acid, methyl citrate, and other metabolites abnormal accumulation, causing nerve, liver, kidney, bone marrow, and other organ damage. PATIENT CONCERNS: A 4-year-old girl presented with paleness, fatigue, severe normochromic anemia, and acute kidney injury. DIAGNOSIS: Based on severe normochromic anemia and acute kidney injury, renal biopsy showed membranous proliferative glomerular lesions and thrombotic microvascular disease, supporting the diagnosis of aHUS. Although the serum vitamin B12 was normal, further investigation found the concentration of urinary methylmalonic acid and serum homocysteine increased obviously, genetic analysis revealed a heterozygous MMACHC mutation (exonl: c. 80A >G, c. 609G >A). The final diagnosis was aHUS induced by inherited methylmalonic acidemia (MMACHC heterozygous mutation exonl: c. 80A >G, c. 609G >A). INTERVENTIONS: The patient was treated with a 1mg vitamin B12 intramuscular injection daily for 4 days after which the dose was then adjusted to a 1mg intramuscular injection twice a week. At the same time, the girl was given levocarnitine, betaine, folic acid, along with supportive treatment. OUTCOMES: After treated by vitamin B12 for 10 days, the patient condition significantly improved, Follow-up results showed complete recovery of hemoglobin and renal function. LESSONS: Although the majority of MMA onset from neurological damage, our case illustrates that partial CblC-type MMA can onset with severe metabolic aHUS. On the basis of chronic thrombotic microangiopathy (TMA)-induced renal damage, it can be complicated by acute hemolytic lesions. MMA should be considered in those patients with unclear microangiopathic hemolytic anemia accompany significant megaloblastic degeneration in bone marrow. We should pay attention to the causes and adopt a reasonable treatment strategy.

Perillyl alcohol protects human renal tubular epithelial cells from hypoxia/reoxygenation injury via inhibition of ROS, endoplasmic reticulum stress and activation of PI3K/Akt/eNOS pathway.

Ischemia/reperfusion (I/R) injury plays an essential role in renal transplantation, and represents a crucial risk factor for allograft dysfunction and acute renal failure. Modulation of oxidative stress is an effective therapeutic strategy for I/R injury. Perillyl alcohol (POH), a dietary monoterpene with antioxidant activity is found in a variety of plants. The study was carried out to investigate whether treatment of POH could reduce hypoxia/reoxygenation (H/R)-induced injury. H/R induced significant injury in HK-2 cells. H/R caused an increase in ROS level, apoptosis and ER stress. Meanwhile H/R also inhibited the cell viability and PI3K/Akt/eNOS signaling pathway. Pretreatment with POH prior to H/R improved cell viability, reduce ROS level, ER stress and apoptosis. Moreover, POH could also activate the PI3K/Akt/eNOS pathway. Therefore, POH may possess protective effects in H/R-induced cellular damage.