Glycolytic Pfkp acts as a Lin41 protein kinase to promote endodermal differentiation of embryonic stem cells.

Unveiling the principles governing embryonic stem cell (ESC) differentiation into specific lineages is critical for understanding embryonic development and for stem cell applications in regenerative medicine. Here, we establish an intersection between LIF-Stat3 signaling that is essential for maintaining murine (m) ESCs pluripotency, and the glycolytic enzyme, the platelet isoform of phosphofructokinase (Pfkp). In the pluripotent state, Stat3 transcriptionally suppresses Pfkp in mESCs while manipulating the cells to lift this repression results in differentiation towards the ectodermal lineage. Pfkp exhibits substrate specificity changes to act as a protein kinase, catalyzing serine phosphorylation of the developmental regulator Lin41. Such phosphorylation stabilizes Lin41 by impeding its autoubiquitination and proteasomal degradation, permitting Lin41-mediated binding and destabilization of mRNAs encoding ectodermal specification markers to favor the expression of endodermal specification genes. This provides new insights into the wiring of pluripotency-differentiation circuitry where Pfkp plays a role in germ layer specification during mESC differentiation.

Molecular Pathogenic Mechanisms of IgA Nephropathy Secondary to COVID-19 mRNA Vaccination.

INTRODUCTION: Accumulating evidence has disclosed that IgA nephropathy (IgAN) could present shortly after the second dose of COVID-19 mRNA vaccine. However, the undying mechanism remains unclear and we aimed to investigate the potential molecular mechanisms. METHODS: We downloaded gene expression datasets of COVID-19 mRNA vaccination (GSE201535) and IgAN (GSE104948). Weighted Gene Co-Expression Network Analysis (WGCNA) was performed to identify co-expression modules related to the second dose of COVID-19 mRNA vaccination and IgAN. Differentially expressed genes (DEGs) were screened, and a transcription factor (TF)-miRNA regulatory network and protein-drug interaction were constructed for the shared genes. RESULTS: WGCNA identified one module associated with the second dose of COVID-19 mRNA vaccine and four modules associated with IgAN. Gene ontology (GO) analyses revealed enrichment of cell cycle-related processes for the COVID-19 mRNA vaccine hub genes and immune effector processes for the IgAN hub genes. We identified 74 DEGs for the second dose of COVID-19 mRNA vaccine and 574 DEGs for IgAN. Intersection analysis with COVID-19 vaccine-related genes led to the identification of two shared genes, TOP2A and CEP55. The TF-miRNA network analysis showed that hsa-miR-144 and ATF1 might regulate the shared hub genes. CONCLUSIONS: This study provides insights into the common pathogenesis of COVID-19 mRNA vaccination and IgAN. The identified pivotal genes may offer new directions for further mechanistic studies of IgAN secondary to COVID-19 mRNA vaccination.

A Novel PMVK Variant Associated with Familial Porokeratosis.

BACKGROUND: Porokeratosis is a rare chronic progressive hypokeratotic skin disease, possibly related to the mevalonate pathway. Variations in four enzymes, including phosphomevalonate kinase (PMVK) may alter this pathway, ultimately leading to porokeratosis. OBJECTIVES: The aim of the study was to identify the causative gene variant of porokeratosis in a Chinese family and investigate its population frequency and pathogenicity. METHOD: In this study, Sanger sequencing was used to identify the gene variant causative of porokeratosis; its population frequency was investigated by polymerase chain reaction-restriction fragment length polymorphism in 4 patients and three normal individuals as well as in 100 normal unrelated controls; finally, the pathogenicity of the mutation and the associated structural changes were predicted. RESULTS: We identified a novel heterozygous missense variant, c.207G>T (p. Lys69Asn) in the PMVK gene. This variant was found in all patients but not in the normal individuals in this family or in the 100 controls. In silico analysis indicated that the variant was pathogenic; p.Lys69Asn changed the length of the α-helix and the hydrogen bond pattern compared with the wild-type protein. CONCLUSIONS: The novel variant c.207G>T (p. Lys69Asn) in the PMVK gene was the causative variant in this porokeratosis family. This finding provides further evidence for the genetic basis of this disease.

Clinical value of soluble urokinase-type plasminogen activator receptor in predicting sepsis-associated acute kidney injury.

BACKGROUND: Sepsis-associated acute kidney injury (S-AKI) is a critical illness and is often associated with high morbidity and mortality rates. The soluble urokinase-type plasminogen activator receptor (suPAR) is an important immune mediator and is involved in kidney injury. However, its diagnostic value in S-AKI patients remains unclear. Therefore, we assessed the early predictive value of suPAR for S-AKI patients. METHODS: We prospectively enrolled adult patients, immediately after fulfilling the sepsis-3 criteria. Plasma suPAR levels at 0-, 12-, 24-, and 48-h post-sepsis diagnosis were measured. S-AKI development was the primary outcome. S-AKI risk factors were analyzed using logistic regression, and the value of plasma suPAR for early S-AKI diagnosis was assessed using receiver operating characteristic (ROC) curves. RESULTS: Of 179 sepsis patients, 63 (35.2%) developed AKI during hospitalization. At 12-, 24-, and 48-h post-sepsis diagnosis, plasma suPAR levels were significantly higher in patients with S-AKI than in patients without S-AKI (p < 0.05). The plasma suPAR had the highest area under the ROC curve of 0.700 (95% confidence interval (CI), 0.621-0.779) at 24-h post-sepsis diagnosis, at which the best discrimination ability for S-AKI was achieved with suPAR of ≥6.31 ng/mL (sensitivity 61.9% and specificity 71.6%). Logistic regression analysis showed that suPAR at 24-h post-sepsis diagnosis remained an independent S-AKI risk factor after adjusting for mechanical ventilation, blood urea nitrogen, and pH. CONCLUSIONS: The findings suggest that plasma suPAR may be a potential biomarker for early S-AKI diagnosis.

NIPSNAP1 directs dual mechanisms to restrain senescence in cancer cells.

BACKGROUND: Although the executive pathways of senescence are known, the underlying control mechanisms are diverse and not fully understood, particularly how cancer cells avoid triggering senescence despite experiencing exacerbated stress conditions within the tumor microenvironment. METHODS: Mass spectrometry (MS)-based proteomic screening was used to identify differentially regulated genes in serum-starved hepatocellular carcinoma cells and RNAi employed to determine knockdown phenotypes of prioritized genes. Thereafter, gene function was investigated using cell proliferation assays (colony-formation, CCK-8, Edu incorporation and cell cycle) together with cellular senescence assays (SA-ß-gal, SAHF and SASP). Gene overexpression and knockdown techniques were applied to examine mRNA and protein regulation in combination with luciferase reporter and proteasome degradation assays, respectively. Flow cytometry was applied to detect changes in cellular reactive oxygen species (ROS) and in vivo gene function examined using a xenograft model. RESULTS: Among the genes induced by serum deprivation, NIPSNAP1 was selected for investigation. Subsequent experiments revealed that NIPSNAP1 promotes cancer cell proliferation and inhibits P27-dependent induction of senescence via dual mechanisms. Firstly, NIPSNAP1 maintains the levels of c-Myc by sequestering the E3 ubiquitin ligase FBXL14 to prevent the proteasome-mediated turnover of c-Myc. Intriguingly, NIPSNAP1 levels are restrained by transcriptional repression mediated by c-Myc-Miz1, with repression lifted in response to serum withdrawal, thus identifying feedback regulation between NIPSNAP1 and c-Myc. Secondly, NIPSNAP1 was shown to modulate ROS levels by promoting interactions between the deacetylase SIRT3 and superoxide dismutase 2 (SOD2). Consequent activation of SOD2 serves to maintain cellular ROS levels below the critical levels required to induce cell cycle arrest and senescence. Importantly, the actions of NIPSNAP1 in promoting cancer cell proliferation and preventing senescence were recapitulated in vivo using xenograft models. CONCLUSIONS: Together, these findings reveal NIPSNAP1 as an important mediator of c-Myc function and a negative regulator of cellular senescence. These findings also provide a theoretical basis for cancer therapy where targeting NIPSNAP1 invokes cellular senescence.

Efficacy and Safety of Ferric Citrate on Hyperphosphatemia among Chinese Patients with Chronic Kidney Disease Undergoing Hemodialysis: A Phase III Multicenter Randomized Open-Label Active-Drug-Controlled Study.

INTRODUCTION: Hyperphosphatemia in chronic kidney disease (CKD) patients is positively associated with mortality. Ferric citrate is a potent phosphorus binder that lowers serum phosphorus level and improves iron metabolism. We compared its efficacy and safety with active drugs in Chinese CKD patients with hemodialysis. METHODS: Chinese patients undergoing hemodialysis were randomized into two treatment groups in a 1:1 ratio, receiving either ferric citrate or sevelamer carbonate, respectively, for 12 weeks. Serum phosphorus levels, calcium concentration, and iron metabolism parameters were evaluated every 2 weeks. Frequency and severity of adverse events were recorded. RESULTS: 217 (90.4%) patients completed the study with balanced demographic and baseline characteristics between two groups. Ferric citrate decreased the serum phosphorus level to 0.59 ± 0.54 mmol/L, comparable to 0.56 ± 0.62 mmol/L by sevelamer carbonate. There was no significant difference between two groups (p > 0.05) in the proportion of patients with serum phosphorus levels reaching the target range, the response rate to the study drug, and the changes of corrected serum calcium concentrations, and intact-PTH levels at the end of treatment. The change of iron metabolism indicators in the ferric citrate group was significantly higher than those in the sevelamer carbonate group. There are 47 (40.5%) patients in the ferric citrate group, and 26 (21.3%) patients in the sevelamer carbonate group experienced drug-related treatment emergent adverse events (TEAEs); most were mild and tolerable. Common drug-related TEAEs were gastrointestinal disorders, including diarrhea (12.9 vs. 2.5%), fecal discoloration (14.7 vs. 0%), and constipation (1.7 vs. 7.4%) in ferric citrate and sevelamer carbonate group. CONCLUSION: Ferric citrate capsules have good efficacy and safety in the control of hyperphosphatemia in adult patients with CKD undergoing hemodialysis. Efficacy is not inferior to sevelamer carbonate. The TEAEs were mostly mild and tolerated by the patients.

Erythropoietin Protects against Diffuse Alveolar Hemorrhage in Mice by Regulating Macrophage Polarization through the EPOR/JAK2/STAT3 Axis.

Macrophages play an important role in the pathogenesis of systemic lupus erythematosus-associated diffuse alveolar hemorrhage (DAH). The immunomodulation of macrophage responses might be a potential approach for the prevention and treatment of DAH. Erythropoietin (EPO) could regulate macrophage bioactivities by binding to the EPO receptor expressing on macrophages. This study assessed the effects of EPO on DAH protection using an immune-mediated DAH murine model with macrophages as the major contributor. A DAH murine model was established in female C57BL/6 mice by an i.p. injection of pristane. We found that EPO administration alleviates DAH by reducing pulmonary macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. EPO drove macrophages to the anti-inflammatory phenotype in the primary murine bone marrow-derived macrophages and macrophages cell line RAW 264.7 with LPS, IFN-γ, and IL-4 in vitro. Moreover, EPO treatment increases the expression of EPOR and decreases the expression of miR-494-3p, resulting in increased phosphorylation of JAK2 and STAT3. In conclusion, EPO can be a potential therapeutic agent in DAH by reducing cell apoptosis and regulating macrophage polarization through the EPOR/JAK2/STAT3 axis. Further studies are also needed to validate the direct target of miR-494-3p in regulating JAK2/STAT3 signaling transduction.

Advances in understanding the innate immune-associated diabetic kidney disease.

Millions of human deaths occur annually due to chronic kidney disease, caused by diabetic kidney disease (DKD). Despite having effective drugs controlling the hyperglycemia and high blood pressure, the incidence of DKD is increasing, which indicates the need for the development of novel therapies to control DKD. In this article, we discussed the recent advancements in the basic innate immune mechanisms in renal tissues triggered under the diabetes environment, leading to the pathogenesis and progression of DKD. We also summarized the currently available innate immune molecules-targeting therapies tested against DKD in clinical and preclinical settings, and highlighted additional drug targets that could potentially be employed for the treatment of DKD. The improved understanding of the disease pathogenesis may open avenues for the development of novel therapies to rein in DKD, which consequently, can reduce morbidity and mortality in humans in the future.

Relationships among the Dosage of Erythropoiesis-Stimulating Agents, Erythropoietin Resistance Index, and Mortality in Maintenance Hemodialysis Patients.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) constitute an important treatment option for anemia in hemodialysis (HD) patients. We investigated the relationships among the dosage of ESA, erythropoietin resistance index (ERI) scores, and mortality in Chinese MHD patients. METHODS: This multicenter observational retrospective study included MHD patients from 16 blood purification centers (n = 824) who underwent HD in 2011-2015 and were followed up until December 31, 2016. We collected demographic variables, HD parameters, laboratory values, and ESA dosages. Patients were grouped into quartiles according to ESA dosage to study the effect of ESA dosage on all-cause mortality. The ERI was calculated as follows: ESA (IU/week)/weight (kg)/hemoglobin levels (g/dL). We also compared outcomes among the patients stratified into quartiles according to ERI scores. We used the Cox proportional hazards model to measure the relationships between the ESA dosage, ERI scores, and all-cause mortality. Using propensity score matching, we compared mortality between groups according to ERI scores, classified as either > or ≤12.80. RESULTS: In total, 824 patients were enrolled in the study; 200 (24.3%) all-cause deaths occurred within the observation period. Kaplan-Meier analyses showed that patients administered high dosages of ESAs had significantly worse survival than those administered low dosages of ESAs. A multivariate Cox regression identified that high dosages of ESAs could significantly predict mortality (ESA dosage >10,000.0 IU/week, HR = 1.59, 95% confidence intervals (CIs) (1.04, 2.42), and p = 0.031). Our analysis also indicated a significant increase in the risk of mortality in patients with high ERI scores. Propensity score matching-analyses confirmed that ERI > 12.80 could significantly predict mortality (HR = 1.56, 95% CI [1.11, 2.18], and p = 0.010). CONCLUSIONS: Our data suggested that ESA dosages >10,000.0 IU/week in the first 3 months constitute an independent predictor of all-cause mortality among Chinese MHD patients. A higher degree of resistance to ESA was related to a higher risk of all-cause mortality.

Analysis of CT signs, radiomic features and clinical characteristics for delta variant COVID-19 patients with different vaccination status.

OBJECTIVE: To explore the characteristics of peripheral blood, high resolution computed tomography (HRCT) imaging and the radiomics signature (RadScore) in patients infected with delta variant virus under different coronavirus disease (COVID-19) vaccination status. METHODS: 123 patients with delta variant virus infection collected from November 1, 2021 to March 1, 2022 were analyzed retrospectively. According to COVID-19 vaccination Status, they were divided into three groups: Unvaccinated group, partially vaccinated group and full vaccination group. The peripheral blood, chest HRCT manifestations and RadScore of each group were analyzed and compared. RESULTS: The mean lymphocyte count 1.22 ± 0.49 × 10^9/L, CT score 7.29 ± 3.48, RadScore 0.75 ± 0.63 in the unvaccinated group; The mean lymphocyte count 1.55 ± 0.70 × 10^9/L, CT score 5.27 ± 2.72, RadScore 1.03 ± 0.46 in the partially vaccinated group; The mean lymphocyte count 1.87 ± 0.70 × 10^9/L, CT score 3.59 ± 3.14, RadScore 1.23 ± 0.29 in the fully vaccinated group. There were significant differences in lymphocyte count, CT score and RadScore among the three groups (all p < 0.05); Compared with the other two groups, the lung lesions in the unvaccinated group were more involved in multiple lobes, of which 26 cases involved the whole lung. CONCLUSIONS: Through the analysis of clinical features, pulmonary imaging features and radiomics, we confirmed the positive effect of COVID-19 vaccine on pulmonary inflammatory symptoms and lymphocyte count (immune system) during delta mutant infection.

Autophagy promotes GSDME-mediated pyroptosis via intrinsic and extrinsic apoptotic pathways in cobalt chloride-induced hypoxia reoxygenation-acute kidney injury.

Cobalt is a transition element that abundantly exists in the environment. Besides direct hypoxia stress, cobalt ions indirectly induce hypoxia-reoxygenation injury (HRI), the main cause of acute kidney injury (AKI), a life-threatening clinical syndrome characterized by the necrosis of the proximal tubular epithelial cells (PTECs) and inflammation. Pyroptosis, a type of inflammatory programmed cell death, might play an essential role in HRI-AKI. However, whether pyroptosis is involved in cobalt chloride (CoCl2)-induced HRI-AKI remains unknown. Autophagy is a cellular biological process maintaining cell homeostasis that is involved in cell damage in AKI, yet the underlying regulatory mechanism of autophagy on pyroptosis has not been fully understood. In this study, the in vitro and in vivo models of CoCl2-induced HRI-AKI were established with HK-2 cell line and C57BL/6J mouse. Pyroptosis-related markers were detected with western blotting and immunofluorescence assays, and results showed that gasdermin E (GSDME)-mediated pyroptosis was involved in the cell damage in HRI-AKI. Specific chemical inhibitors of caspase 3, caspase 8, and caspase 9 significantly inhibited GSDME-mediated pyroptosis, verifying that GSDME-mediated pyroptosis was induced via the activation of caspase 3/8/9. The western blotting and immunofluorescence assays were adopted to detect the accumulation of the autophagosomes, and results suggested that HRI increased the autophagic level. The effects of autophagy on apoptosis and pyroptosis were evaluated using lentivirus transfection assays to knock down autophagy-specific genes atg5 and fip200, and results demonstrated that autophagy induced GSDME-mediated pyroptosis via apoptotic pathways in HRI-AKI. Our results revealed the involvement of GSDME-mediated pyroptosis in CoCl2-induced HRI-AKI and promoted the understanding of the regulatory mechanism of GSDME cleavage. Our study might provide a potential therapeutic target for HRI-AKI, and will be helpful for the risk evaluation of cobalt exposure.

Genotype-phenotype correlations of heterozygous HTRA1-related cerebral small vessel disease: case report and systematic review.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is caused by biallelic HTRA1 pathogenic variants. Recent studies have shown that heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease (CSVD). However, large studies evaluating heterozygous HTRA1 carriers are lacking and the genotype-phenotype correlation is unknown. This study aimed to describe these mutations to clarify factors playing a role in the clinical phenotype amongst these patients. We reported two unrelated families and performed a systematic review of all published cases of heterozygous HTRA1-related CSVD. The clinical phenotype severity was independently related to the pathogenicity score (CADD score; p < 0.05) and mutation in the loop 3/loop D domains (p = 0.05); the pathogenicity score was also associated with exon distribution. More importantly, patients with mutations in exon 4 (p = 0.0001) or vascular risk factors (p < 0.05) presented with more severe clinical symptoms. Thus, clinical phenotype severity is influenced by the mutation domain and vascular risk factors. Applying the pathogenicity score to predict clinical outcomes and adopting preventive measures against cerebral vascular risk factors is advantageous.

Inflammatory response in lungs and extrapulmonary sites detected by [18F] fluorodeoxyglucose PET/CT in convalescing COVID-19 patients tested negative for coronavirus.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an ongoing global pandemic of coronavirus disease 2019 (COVID-19). The challenges associated with imaging infected patients have resulted, to date, in a paucity of metabolic imaging studies of patients with severe COVID-19 infection. Furthermore, it remains unclear if any abnormal metabolic events are taking place in patients who have recovered from COVID-19. PURPOSE: To use [18F] fluorodeoxyglucose ([18F] FDG) positron emission tomography/computed tomography (PET/CT) to measure metabolic activity in inflamed organs of patients convalescing post severe COVID-19 infection. MATERIALS AND METHODS: A prospective study was performed in seven convalescing patients who were recovering from severe COVID-19 infection in February 2020. Prior to [18F] FDG PET/CT, all patients had received two consecutive negative results of real-time reverse transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 nucleic acid. Clinical intake including symptoms, treatment, laboratory test results, and follow-up was performed. The PET/CT images of COVID-19 patients were compared to a control group of patients that were matched for age and sex. RESULTS: Residual pulmonary lesions were present in all patients and maximum standard uptake value (SUVmax), average standard uptake value (SUVavg), maximum CT intensity (CTmax), and average CT intensity (CTavg) were all significantly greater than in the control group (p < 0.01 for all). In addition, SUVmax and SUVavg were significantly greater in the mediastinal lymph node and liver, and SUVmax was significantly greater in the spleen, of COVID-19 patients compared with controls (p < 0.05 for all). For the spleen, SUVmax (r2 = 0.863, p = 0.003) and SUVavg (r2 = 0.797, p = 0.007) were significantly correlated with blood lymphocyte count, and which was below the normal range in five of the seven (71.4%) patients convalescing post severe COVID-19 infection. CONCLUSION: [18F] FDG PET/CT quantitative analysis has shown that significant inflammation remained in lungs, mediastinal lymph nodes, spleen, and liver after two consecutive negative RT-PCR tests in patients convalescing post severe COVID-19 infection.

Evaluation of amide proton transfer-weighted imaging for endometrial carcinoma histological features: a comparative study with diffusion kurtosis imaging.

OBJECTIVES: To investigate whether amide proton transfer-weighted imaging (APTWI) and diffusion kurtosis imaging (DKI) can be used to evaluate endometrial carcinoma (EC) in terms of clinical type, histological grade, subtype, and Ki-67 index. METHODS: Eighty-eight patients with EC underwent pelvic DKI and APTWI. The non-Gaussian diffusion coefficient (Dapp), apparent kurtosis coefficient (Kapp), and magnetization transfer ratio asymmetry (MTRasym (3.5 ppm)) were calculated and compared based on the clinical type (type I, II), histological grade (high- and low-grade), and subtype (endometrioid adenocarcinoma (EA) and non-EA). Correlation coefficients were calculated for each parameter with histological grades and the Ki-67 index. RESULTS: The MTRasym (3.5 ppm) and Kapp values were higher in the type II group and high-grade group than in the type I and low-grade groups, respectively, while the Dapp values were lower in the type I and low-grade groups, respectively (all p < 0.05). The Kapp value was higher in the EA group than in the non-EA group (p = 0.022). The Kapp value was the only independent predictor for the histological grade of EA and the clinical type of EC. The AUC (DKI) was higher than the AUC (APTWI) in the identification of type I and II EC and high- and low-grade EA (Z = 2.042, 2.013, p = 0.041, 0.044), while in the identification of EA and non-EA, only the difference in Kapp was statistically significant. Moreover, the Kapp and MTRasym (3.5 ppm) values and Dapp values correlated positively and negatively, respectively, with histological grade (r = 0.759, 0.555, 0.624, and 0.462, all p < 0.05) and Ki-67 index (r = -0.704, -0.507, all p < 0.05). CONCLUSION: Both DKI- and APTWI-related parameters have potential as imaging markers in estimating the histological features of EC, while DKI shows better performance than APTWI in this study. KEY POINTS: • DKI and APTWI can be used to preliminarily evaluate the histological characteristics of endometrial carcinoma (EC). • The Kapp was the only independent predictor for the histological grade of EA and the clinical type of EC. • The Kapp, MTRasym (3.5 ppm), and Dapp correlated positively and negatively, respectively, with histological grade and Ki-67 index.

Identification of fenoldopam as a novel LSD1 inhibitor to abrogate the proliferation of renal cell carcinoma using drug repurposing strategy.

Although targeted therapy for renal cell carcinoma (RCC) has achieved good therapeutic effects in clinic, a considerable number of patients develop drug resistance over time. So, there is still an urgent need to develop new drugs for RCC treatment. As LSD1 is considered as a promising drug target in diverse cancers, including RCC, we tried to find new LSD1 inhibitor using drug repurposing strategy from a compound library, and fenoldopam, an FDA-approved drug, was identified as a potent LSD1 inhibitor with IC50 = 0.8974 µM in a reversible manner. Molecular docking predicted that fenoldopam occupied the FAD cavity of LSD1, forming hydrogen bonds with surrounding residues. Moreover, fenoldopam inactivated LSD1 and performed antiproliferative activity against ACHN cells and promoted cells apoptosis in vitro. Taken together, fenoldopam was identified as a novel LSD1 inhibitor firstly, and may serve as a new skeleton for RCC therapy.

The absorbing filter Oxiris in severe coronavirus disease 2019 patients: A case series.

Hypercytokines cause acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) patients, which is the main reason for intensive care unit treatment and the leading cause of death in COVID-19 patients. Cytokine storm is a critical factor in the development of ARDS. This study evaluated the efficacy and safety of Oxiris filter in the treatment of COVID-19 patients. Five patients with COVID-19 who received continuous renal replacement therapy (CRRT) in Henan provincial people's hospital between January 23, 2019 and March 28, 2020, were enrolled in this study. Heart rate (HR), mean arterial pressure (MAP), oxygenation index (PaO2 /FiO2 ), renal function, C-reactive protein (CRP), cytokines, procalcitonin (PCT), acute physiology and chronic health evaluation II (APACHE II), sequential organ failure score (SOFA), and prognosis were compared after CRRT. Five COVID-19 patients, three males and two females, aged 70.2 ± 19.6 years, were enrolled. After treatment, HR (101.4 ± 14.08 vs. 83.8 ± 6.22 bpm/min), CRP (183 ± 25.21 vs. 93.78 ± 70.81 mg/L), IL-6 (3234.49 (713.51, 16038.36) vs. 181.29 (82.24, 521.39) pg/mL), IL-8 (154.86 (63.97, 1476.1) vs. 67.19 (27.84, 85.57) pg/mL), and IL-10 (17.43 (9.14, 41.22) vs. 4.97 (2.39, 8.70) pg/mL), APACHE II (29 ± 4.92 vs. 18.4 ± 2.07), and SOFA (17.2 ± 1.92 vs. 11.2 ± 3.4) significantly decreased (P < .05), while MAP (75.8 ± 4.92 vs. 85.8 ± 6.18 mm Hg), and PaO2 /FiO2 (101.2 ± 7.49 vs. 132.6 ± 26.15 mm Hg) significantly increased (P < .05). Among the five patients, negative conversion of nucleic acid test was found in three cases, while two cases died. No adverse events occurred during the treatment. Our study observed a reduced level of overexpressed cytokines, stabilization of hemodynamic status, and staged improvement of organ function during the treatment with Oxiris filter.

Does ligation of the dorsal branch of the cephalic vein affect the patency of a distal forearm arteriovenous fistula? A randomised study.

BACKGROUND: Whether ligation of the dorsal branch of the cephalic vein during the surgical establishment of the radiocephalic arteriovenous fistula (RCAVF) favorably or adversely affects the patency rate of the RCAVF remains controversial. We performed a randomized controlled trial to evaluate the effect of dorsal branch ligation on the patency rate of RCAVF. METHODS: A total of 115 patients who underwent surgical establishment were randomized to two groups treated with or without ligation of the dorsal branch of the cephalic vein during the surgical process. The primary patency rates of the RCAVF at 90, 270, and 360 days after the surgery and the secondary patency rates during a follow-up up to 1 year were compared. RESULTS: The patency rate did not differ significantly between the two groups at 3, 9, or 12 months after the procedure (P > 0.05). The combined primary patency rates of the RCAVF in patients from both groups at 3, 9 and 12 months after the procedure were 87.6, 82, and 74.5% respectively, while the combined secondary patency rate was 92.2% at the 1-year follow-up. The Log-rank test indicated that the initial patency rate and secondary patency rate did not differ significantly between the two groups (P = 0.674 and 0.759, respectively). CONCLUSION: This clinical study indicated that ligation of the dorsal branch of the cephalic vein does not significantly affect the patency of the arteriovenous fistula with a 1-year follow-up. TRIAL REGISTRATION: ISRCTN ISRCTN12288675, Registered 25 September 2019 in the ISRCTN registry. retrospectively registered.

Hsa_circ_0035483 sponges hsa-miR-335 to promote the gemcitabine-resistance of human renal cancer cells by autophagy regulation.

Renal clear cell carcinoma (RCC) is the most common pathological type of renal carcinoma and drug resistance often occurs. We studied the effect of hsa_circ_0035483 on gemcitabine sensitivity in RCC, and explored its regulatory effect on downstream hsa-miR-335 and Cyclin B1 (CCNB1). High-throughput sequencing was used to analyze the differentially expressed circRNA in RCC. The expressions of hsa_circ_0035483, hsa-miR-335, CCNB1, and autophagy-related proteins were detected by RT-PCR or Western blot. The target relationships were revealed by RNA pulldown assay and dual luciferase report assay. Autophagy marker LC3 was detected by immunofluorescence. Cell viability was detected by MTT assay. Hsa_circ_0035483 can facilitate gemcitabine-induced autophagy, and enhance the resistance of RCC to gemcitabine. Hsa-miR-335 is the target regulatory point of hsa_circ_0035483. In addition, hsa_circ_0035483 promotes autophagy and tumor growth and enhances gemcitabine resistance in RCC by regulating hsa-miR-335/CCNB1, and silenced hsa_circ_0035483 can enhance gemcitabine sensitivity in vivo. Hsa_circ_0035483 may be the target of gemcitabine resistance in the treatment of RCC.

HLA-C*12:02 is strongly associated with Xuesaitong-induced cutaneous adverse drug reactions.

Xuesaitong (XST) is mainly used to treat cardiovascular and cerebrovascular diseases, sometimes causing cutaneous adverse drug reactions (cADRs) with unknown mechanisms of pathogenicity or risk factors. We aimed to verify whether human leukocyte antigen (HLA) alleles are associated with XST-related cADRs in Han Chinese population. We carried out an association study including 12 subjects with XST-induced cADRs, 283 controls, and 28 XST-tolerant subjects. Five out of 12 patients with XST-induced cADRs carried HLA-C*12:02, and all of them received XST via intravenous drip. The carrier frequency of HLA-C*12:02 was significantly high compare to that of the control population (Pc = 4.4 × 10-4, odds ratio (OR) = 21.75, 95% CI = 5.78-81.88). Compared with that of the XST-tolerant group, the patients who received XST through intravenous drip presented a higher OR of cADRs (Pc = 0.011, OR = 27.00, 95% CI = 2.58-282.98). The results suggest that HLA-C*12:02 is a potentially predictive marker of XST-induced cADRs in Han Chinese, especially when XST is administered via intravenous drip.

Risk Factor Analysis for AKI Including Laboratory Indicators: a Nationwide Multicenter Study of Hospitalized Patients.

BACKGROUND/AIMS: Risk factor studies for acute kidney injury (AKI) in China are lacking, especially those regarding non-traditional risk factors, such as laboratory indicators. METHODS: All adult patients admitted to 38 tertiary and 22 secondary hospitals in China in any one month between July and December 2014 were surveyed. AKI patients were screened according to the Kidney Disease: Improving Global Outcomes' definition of AKI. Logistic regression was used to analyze the risk factors for AKI, and Cox regression was used to analyze the risk of in-hospital mortality for AKI patients; additionally, a propensity score analysis was used to reconfirm the risk factors among laboratory indicators for mortality. RESULTS: The morbidity of AKI was 0.97%. Independent risk factors for AKI were advancing age, male gender, hypertension, and chronic kidney disease. All-cause mortality was 16.5%. The predictors of mortality in AKI patients were advancing age, tumor, higher uric acid level and increases in Acute Physiologic Assessment and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores. The hazard ratio (HR) for mortality with uric acid levels > 9.1 mg/dl compared with ≤ 5.2 mg/dl was 1.78 (95% CI: 1.23 to 2.58) for the AKI patients as a group, and was 1.73 (95% CI: 1.24 to 2.42) for a propensity score-matched set. CONCLUSION: In addition to traditional risk factors, uric acid level is an independent predictor of all-cause mortality after AKI.