Search

Tubular epithelial cells (TECs) exposed to hypoxia incite tubulointerstitial inflammation (TII), while the exact mechanism is unclear. In this study, we identified that hypoxia evoked tubule injury as evidenced by tubular hypoxia-inducible factor-1α and kidney injury molecule-1 (KIM-1) expression and that renal small extracellular vesicle (sEV) production was increased with the development of TII after ischemia-reperfusion injury (IRI). Intriguingly, KIM-1-positive tubules were surrounded by macrophages and co-localized with sEVs. In vitro, KIM-1 expression and sEV release were increased in hypoxic TECs and the hypoxia-induced inflammatory response was ameliorated when KIM-1 or Rab27a, a master regulator of sEV secretion, was silenced. Furthermore, KIM-1 was identified to mediate hypoxic TEC-derived sEV (Hypo-sEV) uptake by TECs. Phosphatidylserine (PS), a ligand of KIM-1, was present in Hypo-sEVs as detected by nanoflow cytometry. Correspondingly, the inflammatory response induced by exogenous Hypo-sEVs was attenuated when KIM-1 was knocked down. In vivo, exogenous-applied Hypo-sEVs localized to KIM-1-positive tubules and exacerbated TII in IRI mice. Our study demonstrated that KIM-1 expressed by injured tubules mediated sEV uptake via recognizing PS, which participated in the amplification of tubule inflammation induced by hypoxia, leading to the development of TII in ischemic acute kidney injury.

The increasing prevalence of chronic kidney disease (CKD) is a major global public health concern. Despite the complicated pathogenesis of CKD, renal fibrosis represents the most common pathological condition, comprised of progressive accumulation of extracellular matrix in the diseased kidney. Over the last several decades, tremendous progress in understanding the mechanism of renal fibrosis has been achieved, and corresponding potential therapeutic strategies targeting fibrosis-related signaling pathways are emerging. Importantly, extracellular vesicles (EVs) contribute significantly to renal inflammation and fibrosis by mediating cellular communication. Increasing evidence suggests the potential of EV-based therapy in renal inflammation and fibrosis, which may represent a future direction for CKD therapy.

Hyperkalemia is a common complication of chronic kidney disease (CKD), diabetes mellitus (DM), and heart failure (HF) that can lead to severe arrhythmias and sudden death and is associated with a higher risk of mortality. Therefore, the prevention and treatment of hyperkalemia is important. Sodium zirconium cyclosilicate (SZC), a new oral potassium-lowering drug, has offered an additional treatment option for Chinese patients with hyperkalemia since its launch in China in late 2019, and some experience has been accumulated regarding its efficacy and safety.In this review, the authors summarize the epidemiological features of hyperkalemia in China and review the clinical data regarding the use of sodium zirconium cyclosilicate in Chinese patients.The prevalence of hyperkalemia is particularly high in Chinese patients with chronic kidney disease and heart failure. In China, recent clinical studies have shown that SZC rapidly reduces serum potassium, maintains normal potassium concentration, and is well tolerated and safe. Two Chinese expert consensus statements have recommended the use of SZC for the acute correction and chronic maintenance of potassium concentration.

Objectives This study was to explore the potential relationship between the fibrinogen-to-albumin ratio (FAR) and the presence and severity of coronary artery disease (CAD) in stage 3–5 predialysis chronic kidney disease (CKD) patients. Design This study included 978 patients undergoing coronary angiography (CAG). CAD was defined as the presence of obstructive stenosis > 50% of the lumen diameter in any of the four main coronary arteries. Gensini scores (GSs), left main coronary artery (LMCA) and three-vessel coronary artery disease (TVD) were used to elevate the severity of CAD. Results The adjusted odds ratios of CAD were 3.059 (95% CI: 1.859–5.032) and 2.670 (95% CI: 1.605–4.441) in the third and fourth quartiles of FAR compared with the first quartile, respectively. Among 759 patients diagnosed with CAD, multivariate logistic regression analysis showed that FAR (at the 0.01 level) was significantly positively associated with the presence of LMCA (adjusted OR = 1.177, 95% CI 1.067–1.299, P = 0.001) or TVD (adjusted OR = 1.154, 95% CI 1.076–1.238, P Conclusions FAR levels were independently associated with the presence and severity of CAD in stage 3–5 predialysis CKD patients.

The efficacy and safety of traditional Chinese medicine (TCM) paired with western medicine in the treatment of patients with COVID-19 remains controversial. This meta-analysis was performed to identify the effects of TCM. Seven electronic databases were reviewed from the inception of these databases to 30 June 2022. A quality assessment of the included studies was performed with the Cochrane Collaboration’s tool to provide a score of high, unclear, or low risk of bias. The standard software program (Stata, version 12.0, statistical software) was used for endpoint analyses. A total of 13 RCTs involving 1398 patients conducted in China were included. The cross-sectional data from various studies were plotted, and the results illustrated that the statistically higher rates of total effectiveness (RR, 1.357; 95% CI, 1.259 to 1.464; P < 0.001 ), improvement of chest CT (RR, 1.249; 95% CI, 1.143 to 1.356; P < 0.001 ), and cough improvement (RR, 1.228; 95% CI, 1.057 to 1.570; P = 0.012 ) and a lower incidence of conversion to severe cases (RR, 0.408; 95% CI, 0.275 to 0.605; P < 0.001 ) were demonstrated in the TCM group than that of the control group. Of note, the subgroup on specific TCM of Lianhua Qingwen (LQ) revealed that the experiment group was associated with a higher rate of total effectiveness (RR, 1.248; 95% CI, 1.136 to 1.371; P < 0.001 ) and improvement of chest CT (RR, 1.226; 95% CI, 1.110 to 1.356; P < 0.001 ) and a lower rate of conversion to severe cases (RR, 0.469; 95% CI, 0.311 to 0.707; P < 0.001 ). However, there was no significant difference in fever improvement (RD, 0.110; 95% CI, -0.063 to 0.283; P = 0.213 ). The findings of this meta-analysis suggest that TCM combined with western medicine is more effective in treating COVID-19 via relieving symptoms, promoting patients’ recovery, and cutting the rate of patients developing into severe conditions. However, given the relevant possible biases in our study, adequately powered and better-designed studies with long-term follow-up are required to reach a firmer conclusion.

With the ever-increasing burden of kidney disease, the need for developing new therapeutics to manage this disease has never been greater. Extracellular vesicles (EVs) are natural membranous nanoparticles present in virtually all organisms. Given their excellent delivery capacity in the body, EVs have emerged as a frontier technology for drug delivery and have the potential to usher in a new era of nanomedicine for kidney disease. This review is focused on why EVs are such compelling drug carriers and how to release their fullest potentiality in renal therapeutics. We discuss the unique features of EVs compared to artificial nanoparticles and outline the engineering technologies and steps in developing EV-based therapeutics, with an emphasis on the emerging approaches to target renal cells and prolong kidney retention. We also explore the applications of EVs as natural therapeutics or as drug carriers in the treatment of renal disorders and present our views on the critical challenges in manufacturing EVs as next-generation renal therapeutics.

An-Ran Shen,1 Xiao-Xiao Jin,2 Tao-Tao Tang,1 Yan Ding,2 Xiao-Tao Liu,2 Xin Zhong,1 Yan-Dan Wu,2 Xue-Lian Han,3 Guang-Yu Zhao,3 Chuan-Lai Shen,2 Lin-Li Lv,1 Bi-Cheng Liu1 1Institute of Nephrology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, People’s Republic of China; 2Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, 210009, People’s Republic of China; 3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of ChinaCorrespondence: Lin-Li Lv; Bi-Cheng Liu, Institute of Nephrology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, People’s Republic of China, Tel +862583272512, Email lvlinli@seu.edu.cn; liubc64@163.comPurpose: Current vaccines for the SARS-CoV-2 virus mainly induce neutralizing antibodies but overlook the T cell responses. This study aims to generate an exosomal vaccine carrying T cell epitope peptides of SARS-CoV-2 for the induction of CD8+ T cell response.Methods: Thirty-one peptides presented by HLA-A0201 molecule were conjugated to the DMPE-PEG-NHS molecules, and mixed with DSPE-PEG to form the peptide-PEG-lipid micelles, then fused with exosomes to generate the exosomal vaccine, followed by purification using size-exclusion chromatography and validation by Western blotting, liquid nuclear magnetic resonance (NMR) test and transmission electron microscopy. Furthermore, the exosomal vaccine was mixed with Poly (I:C) adjuvant and subcutaneously administered for three times into the hybrid mice of HLA-A0201/DR1 transgenic mice with wild-type mice. Then, the epitope-specific T cell responses were detected by ex vivo ELISPOT assay and intracellular cytokine staining.Results: The exosomal vaccine was purified from the Peak 2 fraction of FPLC and injected into the hybrid mice for three times. The IFN-γ spot forming units and the frequencies of IFN-γ+/CD8+ T cells were 10– 82-fold and 13– 65-fold, respectively, higher in the exosomal vaccine group compared to the Poly (I:C) control group, without visible organ toxicity. In comparison with the peptides cocktail vaccine generated in our recent work, the exosomal vaccine induced significantly stronger T cell response.Conclusion: Exosomal vaccine loading T cell epitope peptides of SARS-CoV-2 virus was initially generated without pre-modification for both peptides and exosomes, and elicited robust CD8+ T cell response in HLA-A transgenic mice.Graphical Abstract: Keywords: the severe acute respiratory syndrome coronavirus-2, exosomal vaccine, T cell, epitope, human leukocyte antigen-A

The transcription factor hypoxia-inducible factor-1α (HIF-1α), as a master regulator of adaptive responses to hypoxia, possesses two transcriptional activation domains [TAD, N-terminal (NTAD), and C-terminal (CTAD)]. Although the roles of HIF-1α NTAD in kidney diseases have been recognized, the exact effects of HIF-1α CTAD in kidney diseases are poorly understood. Here, two independent mouse models of hypoxia-induced kidney injury were established using HIF-1α CTAD knockout (HIF-1α CTAD−/−) mice. Furthermore, hexokinase 2 (HK2) and mitophagy pathway are modulated using genetic and pharmacological methods, respectively. We demonstrated that HIF-1α CTAD−/− aggravated kidney injury in two independent mouse models of hypoxia-induced kidney injury, including ischemia/reperfusion-induced kidney injury and unilateral ureteral obstruction-induced nephropathy. Mechanistically, we found that HIF-1α CTAD could transcriptionally regulate HK2 and subsequently ameliorate hypoxia-induced tubule injury. Furthermore, it was found that HK2 deficiency contributed to severe renal injury through mitophagy inhibition, while mitophagy activation using urolithin A could significantly protect against hypoxia-induced kidney injury in HIF-1α C-TAD−/− mice. Our findings suggested that the HIF-1α CTAD-HK2 pathway represents a novel mechanism of kidney response to hypoxia, which provides a promising therapeutic strategy for hypoxia-induced kidney injury.

Mixed-space cluster expansion (MSCE), a first-principles method to simultaneously model the configuration-dependent short-ranged chemical and long-ranged strain interactions in alloy thermodynamics, has been successfully applied to binary FCC and BCC alloys. However, the previously reported MSCE method is limited to binary alloys with cubic crystal symmetry on a single sublattice. In the current work, MSCE is generalized to systems with multiple sublattices by formulating compatible reciprocal space interactions and combined with a crystal-symmetry-agnostic algorithm for the calculation of constituent strain energy. This generalized approach is then demonstrated in a hypothetical HCP system and Mg-Zn alloys. The current MSCE can significantly improve the accuracy of the energy parameterization and account for all the fully relaxed structures regardless of lattice distortion. The generalized MSCE method makes it possible to simultaneously analyze the short- and long-ranged configuration-dependent interactions in crystalline materials with arbitrary lattices with the accuracy of typical first-principles methods.

Background: G-protein-coupled receptor 43 (GPR43) is a posttranscriptional regulator involved in cholesterol metabolism. This study aimed to investigate the possible roles of GPR43 activation in podocyte lipotoxicity in diabetic nephropathy (DN) and explore the potential mechanisms. Methods: The experiments were conducted by using diabetic GPR43-knockout mice and a podocyte cell culture model. Lipid deposition and free cholesterol levels in kidney tissues were measured by BODIPY staining and quantitative cholesterol assays, respectively. The protein expression of GPR43, LC3II, p62, beclin1, low-density lipoprotein receptor (LDLR) and early growth response protein 1 (EGR1) in kidney tissues and podocytes was measured by real-time PCR, immunofluorescent staining and Western blotting. Results: There were increased LDL cholesterol levels in plasma and cholesterol accumulation in the kidneys of diabetic mice. However, GPR43 gene knockout inhibited these changes. An in vitro study further demonstrated that acetate treatment induced cholesterol accumulation in high glucose-stimulated podocytes, which was correlated with increased cholesterol uptake mediated by LDLR and reduced cholesterol autophagic degradation, as characterized by the inhibition of LC3 maturation, p62 degradation and autophagosome formation. Gene knockdown or pharmacological inhibition of GPR43 prevented these effects on podocytes. Furthermore, GPR43 activation increased extracellular regulated protein kinases 1/2 (ERK1/2) activity and EGR1 expression in podocytes, which resulted in an increase in cholesterol influx and autophagy inhibition. In contrast, after GPR43 deletion, these changes in podocytes were improved, as shown by the in vivo and in vitro results. Conclusion: GPR43 activation-mediated lipotoxicity contributes to podocyte injury in DN by modulating the ERK/EGR1 pathway.

BackgroundThe predictive effects of liver metastases for immune-checkpoint inhibitors (ICIs) and the relationship between tumor mutational burden (TMB) and liver metastases (LM) remain unclear.MethodsA systematic review and meta-analysis were conducted to explore the heterogeneity of ICIs efficacy between patients with or without LM. A pan-cancer cohort of 1,661 patients who received ICIs was downloaded and analyzed to assess the association between TMB and LM.ResultsOf 21053 studies identified in our search, eight single-arm studies and 24 randomized controlled trials were included. Overall, 17957 patients with advanced or metastatic cancers (4805 patients (26.8%) with LM and 13151 patients (73.2%) without LM) were enrolled. The pooled objective response rate (ORR) was 8.5% (95% CI 4%–13%) in the LM group versus 21% (95% CI 16%–21%) in the non-LM group. The pooled hazard ratio (HR) for death was 0.85 (95% CI 0.80–0.90) in the LM group treated with ICIs compared with the standard of care. In patients without LM who were treated with ICIs, the pooled HR for death was 0.78 (95% CI 0.73–0.82) compared with the standard of care. The difference in efficacy between patients with or without LM treated with ICIs was significant (p=0.04). Pan-cancer analysis revealed that the TMB-high rate was 10.8% in liver metastatic lesions versus 21.4% in other metastatic lesions (p=0.004). In addition, TMB was also significantly associated with OS as a binary cutoff (p=0.05) and was an independent prognostic variable (HR=0.98, P=0.047) as a continuous variable in patients with LM.ConclusionsIn patients with LM, the efficacy of immunotherapy was attenuated, but TMB-high could predict better survival outcomes.

Previous studies revealed that MQEO (Maqian fruits essential oil), which is extracted from the fruit of Maqian (Zanthoxylum myriacanthum var. Pubescens), had a good anti-inflammatory effect, but the effect on endometriosis in vitro remains unknown. In the present study, the inhibitory effects of MQEO against the EESCs (ectopic endometrial stromal cells) were investigated. Cells were treated with a concentration gradient (from 0.025 % to 0.15 %) of MQEO for 24 h and cell viability was detected by CCK-8. In addition, apoptotic rates were investigated using flow cytometry. The effect of MQEO on cell migration was determined by wound-healing and transwell assay. The expression of apoptosis-associated and cell adhesion-related proteins was assessed by western blotting. The transcriptional levels of IL-1, IL-6 and TNF-α were determined by Real-time qPCR. RNA-seq was used to identify the DEGs (differentially expressed genes) in MQEO-pretreated EESCs. We found that the MQEO condition dosage-dependently reduced the cell viability of EESCs. Based on flow cytometry results, the number of apoptotic cells increased significantly with dosage. The wound-healing and transwell results showed that MQEO group exhibited a significantly decreased cell motility and migration ability in comparison with the normal group. Western blotting results showed that MQEO down-regulated the expression of Bcl-2, ICAM-1 (intercellular adhesion molecule 1) and CD44, but up-regulated the cleaved caspase-3 expression in EESCs. What's more, MQEO also inhibited the LPS-induced inflammation in human EECs (endometrial epithelial cells). RNA-seq revealed that 221 DEGs were up-regulated genes and 284 DEGs were down-regulated in MQEO-pretreated EESCs. Our data uncovered the beneficial effects of MQEO in endometriosis and provided new insights into the mechanism of the effect of MQEO on EESCs, suggesting MQEO could be a promising new therapeutic agent for endometriosis.

BACKGROUND Dialysis unit blood pressure (BP) pattern showed superiority in prognostic evaluation and interdialytic BP burden assessment. However previous studies mainly focused on the recurrent BP pattern within a session (intradialytic BP change or intradialytic BP slope), the clinical value of the weekly pattern of dialysis unit BP is unknown. METHODS We performed a prospective cohort study in adult end stage renal disease (ESRD) patients on thrice weekly hemodialysis (HD). The slope and the change of the postdialysis systolic BP (SBP) in the course of a week (post-SBP slope and post-SBP change) were used to characterize the weekly pattern of dialysis unit BP. Outcomes included all-cause mortality, cardiovascular mortality, and first cardiovascular event. We also measured the home BP in our cohort. RESULTS One hundred and twenty-nine subjects were followed over a median of 31 months. Higher post-SBP slope (≥0.185) was independently associated with increased risk of all-cause mortality, cardiovascular mortality, and first cardiovascular event. Results were similar for increased post-SBP change. HD patients with a higher post-SBP slope or an increased post-SBP change also had significant increased interdialytic BP burden measured by home SBP on both dialysis days and non-dialysis days. CONCLUSIONS Post-SBP slope and post-SBP change might be promising dialysis unit BP markers for prognostic evaluation and interdialytic BP burden assessment.

Rubidium (Rb) generated from the β-decay of Kr-85 has been theorized to be corrosive toward steel, specifically in the storage of Kr-85 nuclear waste streams. In the present study, the phase equilibria of RbxCryOz with Rb in dry oxygen and water are investigated to understand a possible pathway to unusual deterioration of the corrosion resistance of canister steels in the presence of Rb. It was found that, in dry oxygen environments, the accumulation of Rb (more than 0.01 mol) can completely consume the Cr in 1 mol of AISI 4130 steel by forming α-Rb2CrO4 and Rb3CrO4 and prevent the formation of protective Cr2O3 scale. In aqueous environments, RbxCryOz are metastable species. In order to investigate their role, the probability of forming various oxides is invoked in order to avoid the all-or-nothing approach to oxide formation typical of E-pH diagram, which only predicts the most stable species dissolved, ionized, or solid ionized. Thus, the probability of forming RbxCryOz was considered and reported herein. It was found RbxCryOz can possess a larger than 7% probability of forming over Cr2O3 in the Rb-rich case and 15% in the Cr-rich case, indicating that it is expected to find a small amount of RbxCryOz in the thermodynamically formed reaction products. Even though Cr2O3 is more stable than RbxCryOz, the protective Cr2O3 scale is likely to have some vulnerability to Rb, leading to one possible route for the decline in the corrosion resistance of steel canisters in aqueous environments. Therefore, from a thermodynamic perspective, the current study supports the hypothesis that Rb can thermodynamically react with Cr in steels and can lead to the formation of RbxCryOz at certain potentials and pH levels, showing the Rb influence of steel corrosion cannot be discounted. The paper considers experimental mixed potential and pH levels observed and their relationship to thermodynamic probability. From this relative corrosion resistance can be assessed in a preliminary way in aqueous environments.

Phenotypic plasticity enables plants to buffer against environmental stresses and match their phenotypes to local conditions. However, consistent conclusive evidence for adaptive plasticity has only been obtained for a few traits. More studies on a wider variety of plant functional traits and environmental factors are still needed to further understand the adaptive significance of plasticity. We grew 21 genotypes of the stoloniferous clonal plant Duchesnea indica under different light and nutrient conditions, and used selection gradient analyses to test the adaptive value (benefits) of morphological and physiological plasticity responding to variation in light and nutrient availability. Plants grown in shade exhibited lower values for fitness measures (fruit number, ramet number and biomass), shortened thinner internode length and decreased adult leaf chlorophyll content, but higher petiole length, specific leaf area and old leaf chlorophyll content, than plants grown without shade. Plants grown in the low nutrient condition had shorter petiole length, thicker and smaller leaf area, lower chlorophyll content, but higher fruit number and root:shoot ratio than plants grown under the high nutrient condition. Selection gradient analyses revealed that plasticity of petiole length and old leaf chlorophyll content in response to light variation was adaptive, and plasticity of old and adult leaf chlorophyll content in response to nutrient variation was adaptive. Therefore, the adaptive value of plasticity in different traits depends on the specific ecological context. Our findings contribute to understanding the adaptive significance of phenotypic plasticity of clonal plants in response to environmental variation.

Background: Acute kidney injury (AKI) is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is currently available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this dilemma. Methods We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model following renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. Results REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney following I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to chronic kidney disease. Conclusions A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.

Background Urinary sediment messenger RNAs (mRNAs) have been shown as novel biomarkers of kidney disease. We aimed to identify targeted urinary mRNAs in diabetic nephropathy (DN) based on bioinformatics analysis and clinical validation. Methods Microarray studies of DN were searched in the GEO database and Nephroseq platform. Gene modules negatively correlated with estimated glomerular filtration rate (eGFR) were identified by informatics methods. Hub genes were screened within the selected modules. In validation cohorts, a quantitative polymerase chain reaction assay was used to compare the expression levels of candidate mRNAs. Patients with renal biopsy–confirmed DN were then followed up for a median time of 21 months. End-stage renal disease (ESRD) was defined as the primary endpoint. Multivariate Cox proportional hazards regression was developed to evaluate the prognostic values of candidate mRNAs. Results Bioinformatics analysis revealed four chemokines (CCL5, CXCL1, CXLC6 and CXCL12) as candidate mRNAs negatively correlated with eGFR, of which CCL5 and CXCL1 mRNA levels were upregulated in the urinary sediment of patients with DN. In addition, urinary sediment mRNA of CXCL1 was negatively correlated with eGFR (r = −0.2275, P = 0.0301) and CCL5 level was negatively correlated with eGFR (r = −0.4388, P Conclusions Urinary sediment CCL5 and CXCL1 mRNAs were upregulated in DN patients and associated with a decline in renal function and degree of renal interstitial fibrosis. Urinary sediment CCL5 mRNA could be used as a potential prognostic biomarker of DN.

Non-small-cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) exon 20 mutant occurs in 3% of NSCLCs. Targeted agents for this population remain an unmet need. In this analysis, we pooled-analyzed the efficacy and safety of poziotinib, a novel tyrosine kinase inhibitor, in HER2 exon 20 mutant NSCLC.PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were systematically searched on March 9, 2022. The primary endpoints were objective response rate (ORR) and disease control rate. The secondary endpoint was treatment-related adverse events.Three prospective clinical trials, involving 126 patients, were identified. The pooled ORR and disease control rate of poziotinib in HER2 exon 20 mutant NSCLC were 27% (95% CI, 19-35) and 72% (95% CI, 64-80), respectively. Patients with G778_P780dupGSP had the highest ORR (88%; 95% CI, 33-100; n = 12), followed by Y772_A775dupYVMA (20%; 95% CI, 12-30; n = 88) and G776delinsVC (19%; 95% CI, 0-50; n = 13). The most common grade 3 to 4 treatment-related adverse events were skin rash (36%), diarrhea (23%), and oral mucositis (13%).Poziotinib demonstrates moderate antitumor activity in previously treated HER2 exon 20 mutant NSCLC patients with a manageable safety profile. In addition, different subgroup mutations show various benefits of poziotinib treatment. Large-scale and multiarm clinical trials are warranted to confirm a suitable population and therapeutic strategies.

To explore changes of C-terminal cleavage epitope of type Ⅱ collagen 3/4 fragment in cartilage metabolism (Col2-3/4Clong mono or C2C), carboxyl-terminal telopeptide of type Ⅱ collagen (CTX-Ⅱ) and knee joint function before and after osteotomy of fibula in patients with knee osteoarthritis.From January 2019 to March 2020, 65 patients with knee osteoarthritis who underwent fibular osteotomy treatment accompanied with medial pain were selected, including 25 males and 40 females, aged from 44 to 70 years old with an average of (56.20±10.05) years old;25 patients were gradeⅠ, 19 patients with gradeⅡ, 17 patients with grade Ⅲ, and 4 patients with grade Ⅳ according to Kellgren-Lawrence grading. The content of CTX-Ⅱ and C2C in knee joint fluid, serum interleukin 1β ( IL-1β), tumor necrosis factor-α (TNF-α) before osteotomy and 6 months after osteotomy were detected. Visual analogue scale(VAS) was used to evaluate degree of pain relief, American Knee Society Score (KSS) and Hospital for Special Surgery (HSS) were applied to evaluate recovery of knee joint function.Sixty-five patients were followed up from 6 to 18 months with an average of(12.4±3.6) months. VAS, KSS and HSS score at 6 months after osteotomy were better than that of before osteotomy(Fibula osteotomy could relieve pain of knee osteoarthritis, maintain balance of joint stress, reduce organism inflammatory response, improve cartilage metabolism, reduce decomposition of articular cartilage, and reduce level of CTX-Ⅱand C2C, which is benefit for regeneration of articular cartilage and promote recovery of knee joint function.

Parental environmental effects can be a rapid and effective means for clonal plants in response to temporally or spatially varying environments. However, few studies have quantitatively measured the ecological significance of parental effects in aquatic clonal plants. In this study, we developed a two-generation (parent-offspring) growth model to examine the parental effects of nitrogen (N) conditions on summed and mean performance of clonal offspring of one wetland species Alternanthera philoxeroides. We also examined the role of survival status and developmental stage of clonal offspring in the consequence of parental effects in aquatic clonal plants. Our results indicated direct evidence that (1) there were significant non-linear correlations between the performance of parental plants and initial status of clonal offspring (i.e., the mass and number of clonal propagules); (2) parental N effects on the summed performance of clonal offspring were content-dependent (i.e., there were significant interactions between parental and offspring N effects), while parental effects on the mean performance of offspring were independent of offspring conditions; (3) parental effects mainly occurred at the early development stage of clonal offspring, and then gradually declined at the late stage; (4) the context-dependent parental effects on the summed performance of clonal offspring gradually strengthened when offspring survival was high. The mathematical models derived from the experimental data may help researchers to not only deeply explore the ecological significance of parental environmental effects in aquatic clonal plants, but also to reveal the importance of potential factors that have been often neglected in empirical studies.

BackgroundHeart failure (HF) is a life-threatening complication of cardiovascular disease. HF patients are more likely to progress to acute kidney injury (AKI) with a poor prognosis. However, it is difficult for doctors to distinguish which patients will develop AKI accurately. This study aimed to construct a machine learning (ML) model to predict AKI occurrence in HF patients.Materials and methodsThe data of HF patients from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database was retrospectively analyzed. A ML model was established to predict AKI development using decision tree, random forest (RF), support vector machine (SVM), K-nearest neighbor (KNN), and logistic regression (LR) algorithms. Thirty-nine demographic, clinical, and treatment features were used for model establishment. Accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve (AUROC) were used to evaluate the performance of the ML algorithms.ResultsA total of 2,678 HF patients were engaged in this study, of whom 919 developed AKI. Among 5 ML algorithms, the RF algorithm exhibited the highest performance with the AUROC of 0.96. In addition, the Gini index showed that the sequential organ function assessment (SOFA) score, partial pressure of oxygen (PaO2), and estimated glomerular filtration rate (eGFR) were highly relevant to AKI development. Finally, to facilitate clinical application, a simple model was constructed using the 10 features screened by the Gini index. The RF algorithm also exhibited the highest performance with the AUROC of 0.95.ConclusionUsing the ML model could accurately predict the development of AKI in HF patients.

Invasive plants are a major threat to biodiversity and may adversely affect food security. Clonal integration enables the sharing of resources between connected ramets and can enhance plant performance in many invasive species. However, few studies have examined the role of clonal integration when weeds are exposed to plant growth regulators (PGRs). PGRs are used extensively in agriculture and may affect nearby weeds through soil leaching, erosion and runoff. Our aim was to investigate the effects of clonal integration on growth in a noxious weed, Alternanthera philoxeroides (alligator weed), in response to two PGRs frequently used in agriculture, gibberellins (GAs) and paclobutrazol (PAC). Ramets of A. philoxeroides were propagated in the greenhouse, and treated with PGRs. PGRs were applied to the older ramets (i.e. ‘basal’ part), with half of the plants having the stems between the apical (younger) and basal parts left connected, while the remaining plants had the stems between the two parts severed. Following the growing period, plants were measured for growth traits. We found that GA and PAC had contrasting effects on plant growth. GA significantly promoted above-ground growth of the apical ramets via clonal integration. Alternatively, PAC inhibited above-ground growth in the basal and apical parts, and enhanced below-ground growth of the basal and apical ramets through clonal integration. Our results highlight how clonal integration can promote growth in A. philoxeroides following the application of PGRs, which is likely an important mechanism for this species to invade new environments.

Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.

Objectives An increase in the incidence of congenital hypothyroidism (CH) with eutopic gland has been reported worldwide due to neonatal screening programs. In this study, we aimed to determine the prevalence of transient CH (TCH) and to investigate predictive factors that could distinguish between permanent and transient CH in patients with eutopic thyroid glands. Methods We retrospectively reviewed 508 children treated for CH with eutopic thyroid glands between June 1998 and June 2020 in Jiangxi Newborn Screening Center. All patients were treated with levothyroxine and underwent Diagnostic re-evaluation after 2–3 years of age. Patients were classified as having TCH or permanent CH (PCH) during follow-up. Results Of the 508 patients initially treated for CH with a normally located gland, 335 patients (65.9%) were classified in the TCH group and 173 (34.1%) in the PCH group based on the defined criteria. Multivariate analysis revealed that TCH was associated with a lower levothyroxine dose at 24 months of age (p Conclusions TCH presents a significant portion of patients with CH. The levothyroxine dose requirement at 24 months of age has a predictive role in differentiating TCH from PCH in CH patients with eutopic thyroid glands.

2618 aluminum alloy has been used in aerospace structural parts, but the coarse second phase particles agglomerated in the alloy usually result in poor mechanical properties. In this paper, the morphology and distribution of the second phase particles and the mechanical properties of 2618 aluminum alloy ring were investigated, and the fracture morphology is observed by scanning electron microscope (SEM) and analyzed by energy dispersive X-ray spectroscopy (EDS). The result show that the mechanical properties in the axial direction are lower than those in the circumferential direction. It is evidentially shown that the agglomeration of Al9FeNi intermetallic particles and magnesium oxides in the fracture is the main reason for the poor mechanical properties in the axial direction.

Introducing heating function to oil sorbents opens up a new pathway to the fast cleanup of viscous crude oil spills in situ. The oil sorption speed increases with the rise of the temperature, thus oil sorbents with high heating temperature are desirable. Besides, the oil sorbents also need to be produced environment-friendly. Here we present carbonized melamine-formaldehyde sponges (CMSs) that exhibited superior heating performance and the CMSs could be massively fabricated through a non-polluting pyrolysis process. The conductive CMSs could be heated over 300 °C with a low applied voltage of 6.9 V and keep above 250 °C for 30 min in the air without obvious damage. Such high heating performance enabled heating up the oil spills with a high rate of 2.65 °C·s−1 and 14% improvement of oil sorption coefficient compared with the state-of-the-art value. We demonstrated that one joule-heated CMS could continuously and selectively collect viscous oil spills (9,010 mPa·s) 690 times its own weight in one hour. The CMSs will be a highly competitive sorbent material for the fast remediation of future crude oil spills.

Background Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to improve the anti-cancer effects in combination with radiotherapy. However, the tolerability and safety of adding GM-CSF to radiotherapy in thoracic cancer patients need to be further explored. Methods Between June 2020 and Sep 2020, seven patients with thoracic cancer were treated with concurrent radiotherapy and GM-CSF (200 μg subcutaneously injected q.o.d during the radiotherapy). The primary endpoint was adverse event. Results Of seven enrolled patients, four were non-small cell lung cancer, two were small cell lung cancer, and the other one patient was thymic carcinoma. The total dose of GM-CSF that each patient received was at least 3000 μg. All patients had finished the radiotherapy and GM-CSF injection and suffered one or more any grade adverse events. Only one patient had a grade ≥3 hematological adverse event (lymphocytopenia). Grade ≥3 non-hematological toxicities were not observed during the combination treatment. The highest cell counts of white blood cell, neutrophile granulocyte, and monocyte across the treatment were 22.38×109 /L, 18.65×109 /L, and 1.28×109 /L respectively. Conclusions The combination therapy of radiotherapy and GM-CSF (200 μg subcutaneously q.o.d) is tolerable and safe. Further studies are warranted to confirm the effects and optimal total GM-CSF injection doses in the combination of radiotherapy in thoracic cancer patients.

Background Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) monotherapy is the standard of care in treating advanced non-small cell lung cancer (NSCLC). Nevertheless, whether adding pemetrexed-based chemotherapy to EGFR-TKI targeted therapy furtherly prolongs survival outcomes and improves responses remains controversial. Therefore, we conducted this pooled analysis to compare the efficacy and tolerability between gefitinib plus pemetrexed-based chemotherapy and gefitinib alone in the first-line treatment of advanced NSCLC patients with mutated EGFR. Methods We systematically searched PubMed, Web of Science, Embase, and Cochrane CENTRAL on June 23, 2022. Eligible studies were registered randomized clinical trials comparing gefitinib plus pemetrexed-based chemotherapy with gefitinib alone. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR), disease control rate (DCR), and discontinuation rate (DR) were explored as secondary outcomes. Results Eight studies within five randomized clinical trials were eligible. Gefitinib combined with pemetrexed-based chemotherapy significantly prolonged OS (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.37–0.89, p = 0.0125) and PFS (HR 0.52, 95% CI 0.39–0.70, p < 0.0001) versus gefitinib alone. In subgroup analysis, patients with EGFR exon 19 deletion and exon 21 L858R could benefit from the addition of pemetrexed-based chemotherapy to gefitinib in terms of PFS (EGFR exon 19 deletion: HR 0.50, 95% CI 0.34–0.75, p = 0.0008; EGFR exon 21 L858R: HR 0.46, 95% CI 0.26–0.82, p = 0.0079) but not OS. In addition, ORR was improved after the administration of gefitinib plus pemetrexed-based chemotherapy against gefitinib (odds ratio [OR] 1.91, 95% CI 1.44–2.55, p < 0.0001). Both strategies showed comparable DCRs (OR 1.46, 95% CI 0.94–2.26, p = 0.0952) and DRs (risk ratio [RR] 2.80, 95% CI 0.69–11.44, p = 0.1509). Conclusion Compared with gefitinib alone, combining pemetrexed-based chemotherapy with gefitinib significantly improved OS and PFS in advanced EGFR-mutant NSCLC patients with acceptable tolerability. However, the accurate sub-population who could have OS benefits requires further validation.

Cemiplimab has been widely recommended by international guidelines to treat patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). In this study, we conducted a comparative analysis to integrate the efficacy and safety data in the published prospective and retrospective studies for better understanding the application of cemiplimab. The online databases (PubMed, Cochrane CENTRAL, Web of Science, and EMBASE) were searched to find out eligible studies from inception to November 4, 2021. The "R" software and the "meta" package were used to synthesize the objective response rates (ORRs), disease control rates (DCRs), and the incidences of treatment-related adverse events (TRAEs). Overall, three retrospective studies with 398 patients and three prospective studies with 219 patients were enrolled. The pooled ORR and DCR were 53% (95% confidence interval [CI] 46-59) and 70% (95% CI 57-82) for retrospective studies versus 45% (95% CI 39-52) and 68% (95% CI 56-79) for prospective studies. In regard of toxicities, prospective studies reported much higher incidences of any grade (99% vs. 47%) and grade 3-4 TRAEs (43% vs. 15%) against retrospective studies. The most reported TRAE was fatigue, followed by diarrhea and pruritus. In addition, nine treatment-related deaths (four in retrospective studies vs. five in prospective studies) were documented. In both retrospective and prospective clinical practices, cemiplimab could be an effective regimen for locally advanced or metastatic CSCC patients, but toxicities during the treatment deserve further attention.

High tumor mutation load (TMB-H, or TMB ≥ 10) has been approved by the U.S. FDA as a biomarker for pembrolizumab treatment of solid tumors, including non‑small cell lung cancer (NSCLC). Patients with cancer who have immunotherapy-resistant gene mutations cannot achieve clinical benefits even in TMB-H. In this study, we aimed to identify gene mutations associated with immunotherapy resistance and further informed mechanisms in NSCLC. A combined cohort of 350 immune checkpoint blockade-treated patients from Memorial Sloan Kettering Cancer Center (MSKCC) was used to identify genes whose mutations could negatively influence immunotherapy efficacy. An external NSCLC cohort for which profession-free survival (PFS) data were available was used for independent validation. CIBERSORT algorithms were used to characterize tumor immune infiltrating patterns. Immunogenomic features were analysed in the TCGA NSCLC cohort. We observed that PBRM1 mutations independently and negatively influence immunotherapy efficacy. Survival analysis showed that the overall survival (OS) and PFS of patients with PBRM1 mutations (MT) were significantly shorter than the wild type (WT). Moreover, compared with PBRM1-WT/TMB-H group, OS was worse in the PBRM1-MT/TMB-H group. Notably, in patients with TMB-H/PBRM1-MT, it was equal to that in the low-TMB group. The CIBERSORT algorithm further confirmed that the immune infiltration abundance of CD8+ T cells and activated CD4+ memory T was significantly lower in the MT group. Immunogenomic differences were observed in terms of immune signatures, T-cell receptor repertoire, and immune-related genes between WT and MT groups. Nevertheless, we noticed an inverse relationship, given that MT tumors had a higher TMB than the WT group in MSKCC and TCGA cohort. In conclusion, our study revealed that NSCLC with PBRM1 mutation might be an immunologically cold phenotype and exhibited immunotherapy resistance. NSCLC with PBRM1 mutation might be misclassified as immunoresponsive based on TMB.

Rationale: Albuminuria is an early clinical feature in the progression of diabetic nephropathy (DN). Podocyte insulin resistance is a main cause of podocyte injury, playing crucial roles by contributing to albuminuria in early DN. G protein-coupled receptor 43 (GPR43) is a metabolite sensor modulating the cell signalling pathways to maintain metabolic homeostasis. However, the roles of GPR43 in podocyte insulin resistance and its potential mechanisms in the development of DN are unclear. Methods: The experiments were conducted by using kidney tissues from biopsied DN patients, streptozotocin (STZ) induced diabetic mice with or without global GPR43 gene knockout, diabetic rats treated with broad-spectrum oral antibiotics or fecal microbiota transplantation, and cell culture model of podocytes. Renal pathological injuries were evaluated by periodic acid-schiff staining and transmission electron microscopy. The expression of GPR43 with other podocyte insulin resistance related molecules was checked by immunofluorescent staining, real-time PCR, and Western blotting. Serum acetate level was examined by gas chromatographic analysis. The distribution of gut microbiota was measured by 16S ribosomal DNA sequencing with faeces. Results: Our results demonstrated that GPR43 expression was increased in kidney samples of DN patients, diabetic animal models, and high glucose-stimulated podocytes. Interestingly, deletion of GPR43 alleviated albuminuria and renal injury in diabetic mice. Pharmacological inhibition and knockdown of GPR43 expression in podocytes increased insulin-induced Akt phosphorylation through the restoration of adenosine 5'-monophosphate-activated protein kinase α (AMPKα) activity. This effect was associated with the suppression of AMPKα activity through post-transcriptional phosphorylation via the protein kinase C-phospholipase C (PKC-PLC) pathway. Antibiotic treatment-mediated gut microbiota depletion, and faecal microbiota transplantation from the healthy donor controls substantially improved podocyte insulin sensitivity and attenuated glomerular injury in diabetic rats accompanied by the downregulation of the GPR43 expression and a decrease in the level of serum acetate. Conclusion: These findings suggested that dysbiosis of gut microbiota-modulated GPR43 activation contributed to albuminuria in DN, which could be mediated by podocyte insulin resistance through the inhibition of AMPKα activity.

Background: Weekly and triweekly cisplatin-based concurrent chemoradiotherapy (CCRT) have been used in the treatment of nasopharyngeal carcinoma (NPC). Objective: This study aimed to compare the benefits and risks between the two treatments. Methods: We systematically searched electronic databases for prospective and retrospective clinical studies of NPC patients who received weekly compared with triweekly cisplatin-based CCRT. The primary endpoints comprised overall, failure-free, distant metastasis-free, and locoregional recurrence-free survivals (OS, FFS, DMFS, and LRFS). Secondary endpoints were toxicities. Results: Six studies were included in the systematic review, of which four with 1515 NPC patients were eligible for further pooled analysis. There were no significant differences between weekly and triweekly groups in terms of 5-year OS (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.51-1.79), FFS (OR 1.09, 95% CI 0.67-1.76), DMFS (OR 1.25, 95% CI 0.54-2.92), and LRFS (OR 0.83, 95% CI 0.55-1.25). For grade ≥ 3 toxicities, the weekly group had higher risks of anemia (risk ratio [RR] 2.96, 95% CI 1.12-7.81) and thrombocytopenia (RR 2.75, 95% CI 1.54-4.90), but a lower incidence of vomiting (RR 0.34, 95% CI 0.18-0.63) versus the triweekly group. Conclusion and Relevance: Both weekly and triweekly schedules could be recommended to NPC patients during CCRT. Additionally, hematologic adverse events in weekly strategy and non-hematologic adverse events in triweekly strategy are of higher concern.

Background: Cardiovascular disease (CVD) is the leading cause of death in haemodialysis (HD) patients. Vascular calcification (VC) is dramatically accelerated and is strongly associated with CVD events and mortality in HD patients. VC coexists with osteoporosis in many studies. Fibroblast growth factor 21 (FGF21) as an adipocytokines is a new hypoglycemic strategy and is inversely related to bone mineral density.Methods: To evaluate the contribution of FGF21 to VC in HD patients, we preliminary sreened 802 HD patients of two large HD centers in China. At last 388 HD patients were entered this cross-sectional study. We detected circulating FGF21 levels and measured the whole thoracic aorta calcification scores (TACS) and calcification scores of the three segments of thoracic aorta (TA), including ascending thoracic aorta (ATACS), aortic arch (AoACS), and descending thoracic aorta (DTACS) of our 388 HD patients. In addition, we pre-incubated human aortic endothelial cells (HAECs) with FGF21 in the presence or absence of parathyroid hormone (PTH) in vitro.Results: The median serum FGF21 level in HD patients was 11-fold higher than that in healthy controls. Ln(FGF21) was positively correlated with Ln(TACS+1), Ln(ATACS+1), Ln(AoACS+1) and Ln(DTACS+1) respectively in HD patients. Serum FGF21 was independently associated with TACS and ATACS, AoACS, and DTACS. FGF21 combined with age, calcium and intact parathyroid hormone demonstrated a high area under the curve (AUC=0.84) with optimal sensitivity (84%) and specificity (71%) for the prediction of VC in HD patients. Our vitro results showed that FGF21 enhanced the calcification effect of PTH on HAECs by increasing calcium deposition and endothelial-to-mesenchymal transition (EndMT).Conclusions: Circulating FGF21 was notably higher and was a potential predictor and promoter of VC in HD patients.Trial registration Chinese Clinical Trial Registry, identifier: ChiCTR1900028249. Registered 16 December 2019-Retrospectively registered,http://www.medresman.org.cn/uc/project/projectedit.aspx?proj=5981