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Abstract Background The relationship between serum albumin and prognosis in critically ill patients has been studied, however, there is a paucity of exploration into non-linear relationships, particularly in critically ill patients undergoing dialysis. This study intends to investigate the association between serum albumin (ALB) and 28 day mortality in critically ill patients undergoing dialysis. Methods We conducted a multi-center retrospective cohort study of patients undergoing dialysis by utilising data from the eICU Collaborative Research Database from 208 distinct ICUs across the United States between 2014 and 2015. The study focused on mortality within 28 days of ICU admission. We employed univariate analysis, multi-factor logistic regression, subgroup analysis, curve-fitting, and threshold effect analysis to examine the correlation between ALB levels and 28 day mortality. Results Among the 2,315 patients with a median age of 63 years, 205 (8.86%) died within 28 days of ICU admission. When ALB level was

Abstract Copper (Cu)-based catalysts show promise for electrocatalytic CO2 reduction (CO2RR) to multi-carbon alcohols, but thermodynamic constraints lead to competitive hydrocarbon (e.g., ethylene) production. Achieving selective ethanol production with high Faradaic efficiency (FE) and current density is still challenging. Here we show a multivalent Cu-based catalyst, Cu-2,3,7,8-tetraaminophenazine-1,4,6,9-tetraone (Cu-TAPT) with Cu2+ and Cu+ atomic ratio of about 1:2 for CO2RR. Cu-TAPT exhibits an ethanol FE of 54.3 ± 3% at an industrial-scale current density of 429 mA cm−2, with the ethanol-to-ethylene ratio reaching 3.14:1. Experimental and theoretical calculations collectively unveil that the catalyst is stable during CO2RR, resulting from suitable coordination of the Cu2+ and Cu+ with the functional groups in TAPT. Additionally, mechanism studies show that the increased ethanol selectivity originates from synergy of multivalent Cu sites, which can promote asymmetric C–C coupling and adjust the adsorption strength of different carbonaceous intermediates, favoring hydroxy-containing C2 intermediate (*HCCHOH) formation and formation of ethanol.

Background Perioperative chemotherapy is the standard of care for patients with locally advanced gastric and gastroesophageal junction cancer. Recent evidence demonstrated the addition of programmed cell death protein 1 (PD-1) inhibitors enhanced therapeutic efficacy. However, the mechanisms of response and resistance remain largely undefined. A detailed multiomic investigation is essential to elucidate these mechanisms.Methods We performed whole-exome sequencing, whole-transcriptome sequencing, multiplex immunofluorescence and single-cell RNA sequencing on matched pretreatment and post-treatment samples from 30 patients enrolled in an investigator-initiated Phase 2 clinical trial (NCT04908566). All patients received neoadjuvant PD-1 inhibitors in combination with chemotherapy. A major pathologic response (MPR) was defined as the presence of no more than 10% residual viable tumor cells following treatment.Results Before treatment, the positive ratio of CD3+T cells in both the tumor parenchyma and stroma was significantly higher in the non-MPR group compared with the MPR group (p=0.042 and p=0.013, respectively). Least absolute shrinkage and selection operator regression was employed for feature gene selection and 13 genes were ultimately used to construct a predictive model for identifying MPR after surgery. The model exhibited a perfect area under curve (AUC) of 1.000 (95% CI: 1.000 to 1.000, p

BackgroundPulmonary rehabilitation (PR) has been shown to effectively support postsurgical recovery in patients with lung cancer (LC) at various stages. While digital PR programs offer a potential solution to traditional challenges, such as time and space constraints, their efficacy and feasibility for patients undergoing LC surgery remain unclear. ObjectiveThis systematic review aims to assess the feasibility and effectiveness of digital PR programs for individuals undergoing LC surgery. MethodsA systematic review was conducted, retrieving data from 6 English and 4 Chinese databases from their inception to January 1, 2024. References in related studies were also manually reviewed. The primary outcomes assessed were physical capacity, lung function, and the incidence of postoperative pulmonary complications (PPCs). The secondary outcomes were compliance, hospital stay, chest tube duration, anxiety, depression, and quality of life. Where applicable, recruitment and withdrawal rates were also evaluated. Meta-analysis and descriptive analysis were used to assess the outcomes. ResultsA total of 5 randomized controlled trials and 6 quasi-experimental studies (n=1063) were included, with 4 studies being included in the meta-analyses. Our meta-analyses revealed that digital PR reduced the decline in 6-minute walk distance (6-MWD) by an average of 15 m compared with routine PR programs from admission to discharge, demonstrating a clinically significant improvement in physical capacity (mean difference –15.00, 95% CI –25.65 to –4.34, P=.006). Additionally, digital PR was associated with a reduction (26/58, 45%) in the likelihood of PPCs (risk ratio 0.45, 95% CI 0.30-0.66, P

Abstract Objective α-HBDH serves as a biomarker of myocardial damage and is implicated in adverse outcomes across various critical illnesses. Our study aimed to assess the correlation between α-HBDH levels, and severity and recurrence of acute ischemic stroke (AIS). Methods We enrolled patients with mild-to-moderate AIS within 72 h of onset. Based on the baseline score of the National Institutes of Health Stroke Scale (bNIHSS) at registration, patients were categorized into mild (bNIHSS ≤ 4 points) and moderate AIS groups (4 180 U/L) groups. Multivariate logistic regression analysis and Cox proportional hazard regression analysis were employed to evaluate the relationship between α-HBDH levels and bNIHSS scores as well as the risk of recurrent AIS within 90 days. Results We observed a significant association between higher baseline levels of α-HBDH and increased bNIHSS scores, indicating a more severe AIS (odds ratio = 24.449; 95% confidence interval [CI], 8.749–68.324; p

AimAlthough a growing number of studies have shown that elevated uric acid (UA) levels are associated with multiple cardiovascular risk factors and progression of coronary artery disease, the causal relationship between UA and the occurrence of myocardial infarction (MI) remains uncertain. The aim of this study was to investigate the relationship between UA and the risk of MI.MethodsWe screened 23,080 patients in the National Health and Nutrition Examination Survey (NHANES) database for 2009-2018 and explored the association between UA and MI risk using multivariate logistic regression model. In addition, a two-way two-sample Mendelian randomization (TSMR) analysis was performed to examine the causal relationship of UA on MI, and inverse variance-weighted (IVW) results were used as the primary outcome in this study. Sensitivity analysis and horizontal multiple validity test were also performed to verify the reliability of the results.ResultsAfter multivariable adjustment, individuals with the severe elevation of UA levels have a significantly increased risk of MI (OR=2.843, 95%CI: 1.296-6.237, P=0.010). In TSMR analysis, the IVW method demonstrated a significant association between UA and increased risk of MI (OR=1.333, 95%CI: 1.079-1.647, P=0.008). Results from the MR-Egger intercept test, Cochran’s Q test, and MR-PRESSO test all suggest the reliability of the IVW analysis. Reverse TSMR analysis did not indicate a causal relationship between genetic susceptibility to MI and UA levels (IVW: OR=1.001, 95%CI: 0.989-1.012, P=0.922).ConclusionBased on cross-sectional study and Mendelian randomization analysis, it has been demonstrated that UA is an independent risk factor for MI. Elevated levels of UA increase the risk of MI, particularly in cases of severe elevation.

Cyclophosphamide (CTX) is an anticancer medication that suppresses host immunity as well as adversely affects mucosal inflammation and gut microflora dysbiosis. The gut microflora is recognized as a substantial factor in host metabolism and immunological homeostasis. To improve immunity and inhibit cytotoxic and homeostatic imbalances triggered by CTX, it is essential to monitor immunoregulators. In this research, we assessed the impact of Octopus peptide hydrolysate (OPH) on immune modulation, intestinal integrity, and gut microbial composition in CTX-induced immune-deficient mice. The results revealed that OPH increased body weight, and immunological organ indices, and improved the histological changes in the colon, thymus, and spleen. The OPH stimulated the secretion of cytokines (IL-1β, IL-6, and TNF-α) and antibodies (IgM and IgA) while reducing the ratio of lipopolysaccharide (LPS) and diamine oxidase (DAO) in the serum. OPH further enhanced goblet cell and mucus production, upregulated the expression of gut tight-junction proteins (Occludin, Zonula Occludin-1, Mucin-2, and Claudin-1), and activated the TLR4/NF-κB cascade (p-IκBα, P65/p-p65). In addition, OPH treatment declined the Bacteroidetes/Firmicutes ratio, enhanced the relative ratio of Alistipes/Lachnospiraceae, and reversed the ecological equilibrium of the gut microflora. The findings revealed that OPH serves as a prebiotic to prevent CTX-mediated disruption in the intestinal barrier and boosts gut mucosal immunity by attenuating gut microflora imbalance, implying that OPH could be used as an immunological ingredient in nutritious foods to regulate the immune system and protect the gut from inflammatory diseases.

China has abundant coalbed methane (CBM) resources, and most of them are low-permeability and tight reservoirs, with generally low production rate and small recovery factor. Existing technologies face great challenges to meet the demand on CBM in China. It is desirable to develop new methods to improve the production rate and enhance recovery factor. In addition to physical stimulation methods such as hydraulic fracturing and open-hole cave completion, the use of chemical methods to improve physical properties of coal reservoirs has also been a hot research topic in recent years. Coal reservoir acidification and oxidation technology can promote desorption of gas and enlarge permeability of reservoir. But for different coal rank coal reservoirs, the acidification and oxidation agents need to be optimized and their performance evaluated. Laboratory experiments are conducted to compare and analyze the physical properties coal samples from Baode, Mu’ai, and Xinjiang blocks, including coal rank, texture, macroscopic characteristics, quality, porosity, permeability, element, and mineral composition. The optimal concentration of hydrochloric acid is determined through pre-dissolution experiment of coal powder in acid solution. Then a five-factor and three-level orthogonal experiment for acid solution optimization is designed and performed by using Design-Expert software, which identifies the sensitive factors affecting the dissolution. For the coal samples in Baode, Mu’ai, and Xinjiang blocks, the oxidant types and the corresponding acidification and oxidation agent systems are optimized. Applying these acidification and oxidation agent systems to coal samples from Baode, Mu’ai, and Xinjiang blocks, the change of porosity, permeability, and wettability are compared and analyzed. Finally, through numerical simulation, the gas production is predicted for acidification and oxidation in typical well group in Block Mu’ai. Results show that the acid solution has the best dissolution at a concentration of hydrochloric acid of 3 mol/L to 4 mol/L; Top factors played in the experiment are soaking time, acid type, soaking temperature, coal sample type, and acid concentration, in descending order of importance; The optimal oxidant is a hydrogen peroxide solution with a concentration of 3%; the mixed acidification oxidant formula in Baode block is 10% HCl + 2% CH3COOH + 2% HF + 3% H2O2; The optimal mixed acidification oxidant formula in Mu’ai block is 8% HCl + 2% CH3COOH + 4% HF + 3% H2O2; the optimal mixed acidification oxidant formula in Xinjiang block is 12% HCl + 1% CH3COOH + 1% HF + 3% H2O2; The higher the coal rank, the greater the HF content in the optimal acidification oxidant system. Both acidification and oxidation improve the porosity and permeability of coal samples to some extent, and the improvement in low-rank coal is more significant than that in high-rank coal. Acidification and oxidation have different effects on the wettability of coal: Acidification increases the hydrophilicity of coal, whereas oxidation reduce the hydrophilicity of coal; and the hydrophilicity of coal samples treated by the optimized acidification and oxidation system is weakened. Reservoir simulation results show that acidification and oxidation lead to a recovery factor of 64.64% after 10 years of production, which is 19.72% higher than that without acidification and oxidation. The advantage of acidification and oxidation is 0.97% after 18 years of production. However, the acidification and oxidation saved 8 years of production time to achieve a close final recovery factor, which greatly reduces the operating costs. The optimized acidizing oxidation agent systems for CBM reservoirs with low, medium, and high ranks improved the desorption and permeability of the target reservoirs, and increase well production and recovery factor. This research provides technical support for stimulation practices of CBM reservoirs in the aforementioned blocks in China, as well as similar coal reservoirs in the world.

Abstract Chordoma is a relatively rare and locally aggressive malignant tumor. Sirtuin (SIRT)5 plays pivotal roles in various tumors, but the role of SIRT5 in chordoma has not been found. This study was performed to investigate the regulatory effects of SIRT5 on cell proliferation, migration, and invasion and the underlying mechanism in chordoma. A xenograft tumor mouse model was established to assess tumor growth. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA levels of SIRT5 and c-myc. The effects of SIRT5 and c-myc on cell proliferation, migration, and invasion of chordoma cells were detected by cell counting kit-8, colony formation, and Transwell assays. The interaction between SIRT5 and c-myc was evaluated by co-immunoprecipitation (IP) assay. The succinylation of c-myc was analyzed by IP and Western blot. The results showed that SIRT5 expression was upregulated in chordoma tissues and cells. SIRT5 interacted with c-myc to inhibit the succinylation of c-myc at K369 site in human embryonic kidney (HEK)-293T cells. Silencing of SIRT5 suppressed the cell proliferation, migration, and invasion of chordoma cells, while the results were reversed after c-myc overexpression. Moreover, silencing SIRT5 suppressed tumor growth in mice. These findings suggested that SIRT5 promoted the malignant advancement of chordoma by regulating the desuccinylation of c-myc.

Abstract Background There are various recommendations for third-line treatment in mCRC, however, there is no consensus on who is more suitable for particular strategy. Chemotherapy re-use in third-line setting is a common option in clinical practice. This study aimed to investigate the efficacy of third-line chemotherapy re-use by the comparison with that of anti-angiogenic monotherapy, and further find the population more suitable for third-line chemotherapy. Methods Using electronic medical records of patients with mCRC, a retrospective cohort study was conducted. A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting as control group were retrospectively collected. Baseline characteristics were analyzed using the χ² test or the Fisher’s exact test. ROC curve and surv_cutpoint function of ‘survminer’ package in R software were used to calculate the cut-off value. Survival curves were plotted with the Kaplan-Meier method and were compared using the log-rank test. The Cox proportional hazard regression model was used to analyze the potential risk factors. Results A total of 143 patients receiving chemotherapy and 40 patients receiving anti-angiogenic monotherapy in third-line setting were retrospectively collected. Chemotherapy rechallenge was recorded in 93 patients (93/143, 65.0%), and the remaining patients chose new chemotherapeutic drugs that had not been previously used, including irinotecan-based (22/50), oxaliplatin-based (9/50), raltitrexed (9/50), gemcitabine (5/50) and other agents (5/50). The ORR and DCR of third-line chemotherapy reached 8.8%, 61.3%, respectively (anti-angiogenic monotherapy group: ORR 2.6%, DCR 47.4%). The mPFS and mOS of patients receiving chemotherapy were 4.9 and 12.0 m, respectively (anti-angiogenic monotherapy group: mPFS 2.7 m, mOS 5.2 m). Subgroup analyses found that patients with RAS/RAF mutation, longer PFS (greater than 10.6 m) in front-line treatment or larger tumor burden had better prognosis with third-line chemotherapy rather than anti-angiogenic monotherapy. Conclusions Third-line chemotherapy re-use was effective in mCRC. Those with more aggressive characteristics (RAS/RAF mutant, larger tumor burden) or better efficacy of previous chemotherapy (longer PFS) were more appropriate for third-line chemotherapy, rather than anti-angiogenic monotherapy.

Abstract Background Incentive spirometry (IS) as a routine respiratory therapy during the perioperative period has been widely used in clinical practice. However, the impact of IS on patients with perioperative lung cancer remains controversial. This review aimed to evaluate the efficacy of IS in perioperative pulmonary rehabilitation for patients with lung cancer. Methods Cochrane Library, PubMed, Web of Science, Ovid, CINAHL, Chinese National Knowledge Infrastructure, Weipu, and Wanfang Databases were searched from inception to 30 November 2023. Only randomized controlled trials were included in this systematic review. The PRISMA checklist served as the guidance for conducting this review. The quality assessment of the included studies was assessed by the Cochrane risk-of-bias tool. The meta-analysis was carried out utilizing Review Manager 5.4. Furthermore, sensitivity analysis and subgroup analysis were also performed. Results Nine studies recruited 1209 patients met our inclusion criteria. IS combined with other respiratory therapy techniques was observed to reduce the incidence of postoperative pulmonary complications, enhance pulmonary function, curtail the length of hospital stay, and lower the Borg score. Nevertheless, no improvements were found in the six-minute walk distance or quality of life score. Conclusions Although IS demonstrates benefits as a component of comprehensive intervention measures for perioperative patients with lung cancer, it proves challenging to determine the precise impact of IS as a standalone component within the comprehensive intervention measures. Therefore, further researches are required to better understand the effectiveness of IS isolation and its interactions when integrated with additional respiratory therapies for these patients. Clinical trial registration PROSPERO, https://www.crd.york.ac.uk/prospero/ , registry number: CRD42022321044.

Abstract Background Increasing evidence has showed that inflammatory biomarkers, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and fibrinogen can be used as predictors in the prognosis of esophageal squamous cell carcinoma (ESCC). The aim of this study was to explore prognostic value of these biomarkers and evaluate the clinicopathological and prognostic significance of combined score based on plasma fibrinogen and platelet-lymphocyte ratio (F-PLR score). Methods A total of 506 patients with ESCC were enrolled in this study. Harrell’s concordance index (c-index) was used to determine the optimal cut-off values of these markers and evaluate their prognostic significance. The relationship between factors with survival rates (including overall survival [OS] and disease-free survival [DFS]) was explored by Kaplan-Meier curve, univariate analysis and multivariate cox hazard analysis. Results Our result indicated that high F-PLR score was significantly associated with longer tumor length and deeper depth of tumor invasion (p

Postoperative pulmonary complications (PPCs) are associated with high mortality rates after lung cancer surgery. Although some studies have discussed the different risk factors for PPCs, the relationship between these factors and their impact on PPCs remains unclear. Hence, this study aimed to systematically summarize the incidence and determine the risk factors for PPCs.We conducted a systematic search of five English and four Chinese databases from their inception to April 1, 2023. A total of 34 articles (8 cohort studies and 26 case-control studies) (n = 31696, 5833 with PPCs) were included in the analysis. The primary outcome was the incidence of PPC. The secondary outcome was the odds ratio (OR) of PPCs based on the identified risk factors calculated by RevMan 5.4. A narrative descriptive summary of the study results was presented when pooling the results or conducting a meta-analysis was not possible.The pooled incidence of PPCs was 18.4 %. This meta-analysis demonstrated that TNM staging (OR 4.29, 95 % CI 2.59–7.13), chronic obstructive pulmonary disease (COPD) (OR 2.47, 95 % CI 1.80–3.40), smoking history (OR 2.37, 95 % CI 1.33–4.21), poor compliance with respiratory rehabilitation (OR 1.64, 95 % CI 1.17–2.30), male sex (OR 1.62, 95 % CI 1.28–2.04), diabetes (OR 1.56, 95 % CI 1.07–2.27), intraoperative bleeding volume (OR 1.44, 95 % CI 1.02–2.04), Eastern Cooperative Oncology Group score (ECOG) > 1 (OR 1.37, 95 % CI 1.04–1.80), history of chemotherapy and/or radiotherapy (OR 1.32, 95 % CI 1.03–1.70), older age (OR 1.18, 95 % CI 1.11–1.24), and duration of surgery (OR 1.07, 95 % CI 1.04–1.10) were significantly associated with a higher risk of PPCs. In contrast, the peak expiratory flow rate (PEF) (OR 0.99, 95 % CI 0.98–0.99) was a protective factor. Clinicians should implement targeted and effective interventions to prevent the occurrence of PPCs.

Abstract Background Podoplanin (PDPN) is a highly conserved, mucin-type protein specific to the lymphatic system. Overexpression of PDPN is associated with the progression of various solid tumors, and plays an important roles in the tumor microenvironment by regulating the immune system. However, the role of PDPN-mediated signal activation in the progression of melanoma is still unknown. Methods PDPN expression was first analyzed in 112 human melanoma tissue microarrays and melanoma cell lines. Functional experiments including proliferation, clone formation, migration, and metastasis were utilized to identify the suppressive effects of PDPN. The Ph.D.TM-12 Phage Display Peptide Library was used to obtain a PDPN antagonist peptide, named CY12-RP2. The immunofluorescence, SPR assay, and flow cytometry were used to identify the binding specificity of CY12-RP2 with PDPN in melanoma cells. Functional and mechanistic assays in vivo and in vitro were performed for discriminating the antitumor and immune activation effects of CY12-RP2. Results PDPN was overexpressed in melanoma tissue and cells, and inhibited melanoma cells proliferation, migration, and metastasis by blocking the EMT and Wnt/β-catenin pathway. PDPN antagonistic peptide, CY12-RP2, could specifically bind with PDPN, suppressing melanoma various functions inducing apoptosis in both melanoma cells and 3D spheroids. CY12-RP2 also enhanced the anti-tumor capacity of PBMC, and inhibited melanoma cells growth both in xenografts and allogeneic mice model. Moreover, CY12-RP2 could inhibit melanoma lung metastasis, and abrogated the immunosuppressive effects of PDPN by increasing the proportion of CD3 + CD4 + T cells, CD3 + CD8 + T cells, CD49b + Granzyme B + NK cells, and CD11b + CD86 + M1-like macrophages and the levels of IL-1β, TNF-α, and IFN-γ. Conclusions This study has demonstrated the important role of PDPN in the progression of melanoma and formation of immunosuppressive environment, and provided a potential approach of treating melanoma using the novel CY12-RP2 peptide. Graphical Abstract In melanoma, PDPN is overexpressed in the cancer cells, and promotes melanoma cells growth and metastasis through activating the Wnt/β-catenin pathway. Treatment with the PDPN antagonistic peptide CY12-RP2 could not only inhibit the melanoma growth and metastasis both in vitro and in vivo through Wnt/β-catenin pathway blockade, but also abrogate the immunosuppressive effects of PDPN through modulating immune cells.

Abstract Background Mitophagy is a process of selectively degrading damaged mitochondria, which has been found to be related to immunity, tumorigenesis, tumor progression, and metastasis. However, the role of mitophagy-related genes (MRGs) in the tumor microenvironment (TME) of ovarian cancer (OV) remains largely unexplored. Methods We analyzed the expression, prognosis, and genetic alterations of 29 MRGs in 480 OV samples. Unsupervised clustering was used to classify OV into two subtypes (clusters A and B) based on MRG changes. We compared the clinical features, differential expressed genes (DEGs), pathways, and immune cell infiltration between the two clusters. We constructed a mitophagy scoring system (MRG_score) based on the DEGs and validated its ability to predict overall survival of OV patients. Results We found that patients with high MRG_scores had better survival status and increased infiltration by immune cells. Further analysis showed that these patients may be more sensitive to immune checkpoint inhibitor (ICI) treatment. Additionally, the MRG_score significantly correlated with the sensitivity of chemotherapeutic drugs and targeted inhibitors. Conclusion Our comprehensive analysis of MRGs in the TME, clinical features, and patient prognosis revealed that the MRG_score is a potentially effective prognostic biomarker and predictor of treatment. This study provides new insights into the role of MRGs in OV and identifies patients who may benefit from ICI treatment, chemotherapy, or targeted treatment.

Abstract The HIV-1 Tat protein hijacks the Super Elongation Complex (SEC) to stimulate viral transcription and replication. However, the mechanisms underlying Tat activation and inactivation, which mediate HIV-1 productive and latent infection, respectively, remain incompletely understood. Here, through a targeted complementary DNA (cDNA) expression screening, we identify PRMT2 as a key suppressor of Tat activation, thus contributing to proviral latency in multiple cell line latency models and in HIV-1-infected patient CD4+ T cells. Our data reveal that the transcriptional activity of Tat is oppositely regulated by NPM1-mediated nucleolar retention and AFF4-induced phase separation in the nucleoplasm. PRMT2 preferentially methylates Tat arginine 52 (R52) to reinforce its nucleolar sequestration while simultaneously counteracting its incorporation into the SEC droplets, thereby leading to its functional inactivation to promote proviral latency. Thus, our studies unveil a central and unappreciated role for Tat methylation by PRMT2 in connecting its subnuclear distribution, liquid droplet formation, and transactivating function, which could be therapeutically targeted to eradicate latent viral reservoirs.

Abstract Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster, Dicer-2 (DmDcr-2)-mediated RNAi pathway plays important roles in defending against viral infections and protecting genome integrity. During the maturation of siRNAs, two cofactors can regulate DmDcr-2’s functions: Loqs-PD that is required for dsRNA processing, and R2D2 that is essential for the subsequent loading of siRNAs into effector Ago2 to form RISC complexes. However, due to the lack of structural information, it is still unclear whether R2D2 and Loqs-PD affect the functions of DmDcr-2 simultaneously. Here we present several cryo-EM structures of DmDcr-2/R2D2/Loqs-PD complex bound to dsRNAs with various lengths by the Helicase domain. These structures revealed that R2D2 and Loqs-PD can bind to different regions of DmDcr-2 without interfering with each other. Furthermore, the cryo-EM results demonstrate that these complexes can form large oligomers and assemble into fibers. The formation and depolymerization of these oligomers are associated with ATP hydrolysis. These findings provide insights into the structural mechanism of DmDcr-2 and its cofactors during siRNA processing.

Abstract Background MCD (MYD88L265P/CD79Bmut) diffuse large B‐cell lymphoma has a poor prognosis. There is no published clinical research conclusion regarding zanubrutinib or orelabrutinib for the initial treatment of MCD DLBCL. Aims This study aimed to analyse the efficacy and safety of Bruton's tyrosine kinase inhibitor (BTKi) (zanubrutinib or orelabrutinib) therapy for newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut. Materials and Methods Twenty‐three newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut from June 2020 to June 2022 received BTKi combined with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) or rituximab + lenalidomide (R2). A control group of 17 patients with MYD88mut and/or CD79Bmut DLBCL who received the standard R‐CHOP therapy was also assessed. We retrospectively analysed clinical characteristics, safety, overall response rate (ORR), complete response (CR) rate and progression‐free survival (PFS) of the two groups. Results The main clinical features were a high International Prognostic Index (IPI) score (≥3, 22/40, 55%) and a high rate of extranodal involvement (27/40,67.5%). Among the 23 DLBCL patients, 18 received BTKi + R‐CHOP, and five elderly DLBCL patients were treated with BTKi + R2. Compared with those in the control group (ORR 70.6%, CRR 52.9%, 1‐year PFS rate 41.2%), improved ORR, CRR and PFS results were observed in the BTKi + R‐CHOP group (100%, 94.4% and 88.9%, p = 0.019, 0.007, and 0.0001). In subgroup analyses based on genetic subtypes, cell origin, dual expression or IPI score, patients in the BTKi + R‐CHOP group had better PFS than patients in the control group. In the BTKi + R‐CHOP group, no significant difference was found in ORR, CRR and PFS based on subtype analysis, while BTKi‐type subgroups exhibited statistically significant differences in 1‐year PFS (p = 0.028). There were no significant differences in grade 3–4 haematological toxicity (p = 1) and grade 3–4 non‐haematological toxicity (p = 0.49) between the BTKi + R‐CHOP and R‐CHOP treatment groups. In the BTKi + R2 group, the ORR was 100%, the CRR was 80%, and the 1‐year PFS rate was 80%. The incidences of grade 3–4 haematologic toxicity and non‐haematological toxicity were both 40%. No bleeding or cardiovascular events of grade 3 or higher occurred in any patients. Discussion The efficacy of BTKi combined with R‐CHOP was similar to previous reports, which was significantly better than R‐CHOP alone. It is necessary to fully consider that 14 patients in the BTKi + R‐CHOP group received a BTKi as maintenance therapy when evaluating efficacy. Meanwhile, the addition of a BTKi may improve the prognosis of non‐GCB, DEL or high‐IPI‐score DLBCL patients with MYD88mut and/or CD79Bmut. In our study, five elderly DLBCL patients with MYD88mut and/or CD79Bmut were achieved better ORR, CRR, PFS than the historical data of R‐miniCHOP treatment and Ibrutinib + R2 treatment. However, the efficacy and benefit of BTKis for this type of DLBCL need to be further analysed using a larger sample size. Conclusion This study suggests that newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut may benefit from BTKis according to real‐world clinical data.

Abstract Seeking new cathode chemistry with high onset potential and compatibility with electrolytes has become a challenge for aqueous Zn ion batteries. Anion intercalation in graphite (4.5 V vs Li+/Li) possesses the potentiality but usually shows a competitive relationship with oxygen evolution reaction (OER) in aqueous solutions. Herein, a decoupled design is proposed to optimize a full utilization of perchlorate ion intercalation in graphite cathode by pH adjustment. Benefiting from the decoupled design, high Coulombic efficiency is obtained by decelerating the kinetic of OER in acidic media. The decoupled Zn‐graphite battery exhibits a wide potential window of 2.01 V, as well as an attractive energy density of 231 Wh kg−1. In addition, a Zn‐graphite battery with SO42− insertion is assembled, which demonstrates the capability of the proposed decoupled strategy to integrate novel electrode chemistries for high‐performance aqueous Zn‐based energy storage systems.

Abstract Background Postoperative adjuvant chemotherapy (AC) is now well-accepted as standard for high-risk stage II and stage III colorectal cancer (CRC) patients, however the optimal time to initiate AC remains elusive. Methods A comprehensive literature search was performed using the PubMed and Embase databases. The Hazard ratio (HR) with the corresponding 95% confidence interval (CI) was used as an effect measure to evaluate primary endpoints. All analyses were conducted using Stata software version 12.0 with the Random-effects model. Results A total of 30 studies were included in our study. Upon comparison on overall survival (OS), we identified that delaying the initiation of AC for > 8 weeks after operation was significantly associated with poor OS (HR: 1.37; 95% CI: 1.27—1.48; P 8 weeks was not undermined by subgroup analysis based on region, tumor site, sample size and study quality. No obvious differences were observed in survival between AC within 5–8 weeks and ≤ 4 weeks (HR: 1.03; 95% CI: 0.96 -1.10; P = 0.46). Moreover, two studies both highlighted that the survival benefit of AC was still statistically significant when AC was applied 5–6 months after surgery compared with the non-chemotherapy group. Conclusions Delaying the initiation of AC for > 8 weeks after surgery was significantly associated with poor OS. AC started within 8 weeks after surgery brought more benefits to CRC patients. There were no obvious differences in survival benefits between AC within 5–8 weeks and ≤ 4 weeks. Compared to patients not receiving AC after surgery, a delay of approximately 5–6 months was still useful to improve prognosis.

Accurate inflow turbulence wind profile is a key premise of large eddy simulation (LES) methodology for super tall buildings. This paper presents an improved method for narrow band synthesis random flow generation to produce a more accurate inflow turbulence of LES based on superposition of harmonics. The proposed method considers time correlation by adopting time parameters, and an accurate expression of wind speed spectrum energy by a modified spectrum integral equation is used. These improvements could generate a more accurate turbulence intensity for the atmospheric boundary layer. A simple numerical example is applied to verify the spectrum characteristic, time correlation and spatial correlation of atmospheric numerical boundary layer. Meanwhile, the effects of the introduced parameters are investigated and the method is applied to the LES of the Commonwealth Advisory Aeronautical Research Council building (CAARC). The improved method could increase the accuracy of simulated turbulence intensity. Compared with the results of CAARC model obtained from the wind tunnel test, the improved method in this study decreases the errors of root-mean-square (rms) of the based bending moment from 5.3% to 4.1% in the along-wind direction and from 5.6% to 1.3% in the cross-wind direction.

Abstract Background Which antimicrobial agents provide the optimal efficacy, safety, and tolerability for the empirical treatment of complicated intra-abdominal infection (cIAI) remains unclear but is paramount in the context of evolving antimicrobial resistance. Therefore, updated meta-analyses on this issue are warranted. Methods We systematically searched four major electronic databases from their inception through October 2022. Randomized controlled trials examining antimicrobial agents for cIAI treatment were included. Two reviewers independently assessed the quality of included studies utilizing the Cochrane Collaboration’s risk of bias tool as described in the updated version 1 of the Cochrane Collaboration Handbook and extracted data from all manuscripts according to a predetermined list of topics. All meta-analyses were conducted using R software. The primary outcome was clinical success rate in patients with cIAIs. Results Forty-five active-controlled trials with low to medium methodological quality and involving 14,267 adults with cIAIs were included in the network meta-analyses. The vast majority of patients with an acute physiology and chronic health evaluation II score

Abstract Objectives The current study compared the safety and efficacy of long-term dual antiplatelet therapy (DAPT, aspirin plus clopidogrel) and intensive rosuvastatin with short-term DAPT for acute ischemic stroke (AIS). Methods A total of 220 patients were enrolled 72 h after the onset of mild to moderate AIS, and divided into a control group treated with 21-day DAPT and a study group treated with intensive rosuvastatin with 7-day DAPT on a voluntary basis. The primary outcome was recurrent ischemic stroke and hemorrhage during a 90-day follow-up period in an intention-to-treat analysis. The secondary outcome was clinical efficacy with respect to alleviating existing focal nerve defect symptoms. A Cox proportional-hazards model was used to evaluate treatment differences. Results Clinical efficacy was evident in 87.3% of patients in the study group, compared with 84.3% in the control group (p = 0.042). Recurrent ischemic stroke occurred in 9 patients (7.6%) in the study group and in 9 (8.8%) in the control group (p = 0.767). Hemorrhage occurred in 6 patients (5.1%) in the study group and in 15 (14.7%) in the control group (p = 0.023). In comparisons of levels of ALT, AST, LDH, and CK in the two groups before and 2 weeks after therapy, only CK differed significantly (p

Abstract Background The prognosis of patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer remains poor. Given the robust development of immunotherapy and targeted therapy during the last decades, we aimed to investigate if the combination of traditional second-line chemotherapy with sintilimab and apatinib could bring survival benefits for these patients. Methods In this single-center, single-arm, phase II trial, patients with previously treated advanced gastric or GEJ adenocarcinoma received specific dose level of intravenous paclitaxel or irinotecan (investigator’s choice), 200 mg intravenous sintilimab on day 1, and 250 mg oral apatinib once daily continuously in each cycle until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were objective response rate and progression-free survival. The secondary endpoints were mainly overall survival and safety. Results From May 2019 to May 2021, 30 patients were enrolled. At the data cutoff date (March 19, 2022), the median follow-up duration was 12.3 months and 53.6% (95% CI, 33.9–72.5%) patients achieved objective response. The median progression-free survival and overall survival were 8.5 months (95% CI, 5.4–11.5) and 12.5 months (95% CI, 3.7–21.3), respectively. Grade 3–4 adverse events included hematological toxicities, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, hyperbilirubinemia and proteinuria. The most frequent grade 3–4 adverse event was neutropenia (13.3%). No serious treatment-related adverse events or treatment-related deaths occurred. Conclusion Sintilimab plus apatinib and chemotherapy demonstrates promising anti-tumor activity with manageable safety profile in patients with previously treated advanced gastric or GEJ cancer. Trial registration ClinicalTrials.gov: NCT05025033, 27/08/2021.

Abstract This article summarizes the drug therapy progress of advanced hepatocellular carcinoma, biliary tract cancer, and pancreatic cancer in 2022, including chemotherapy, molecular targeted therapy, and immunotherapy, to provide reference information for current clinical treatment and future clinical research, and to better improve prognosis and quality of life in patients with hepatobiliary and pancreatic cancer.

Nowadays, malignant brain tumors are still mostly lethal diseases with poor prognosis and a clinical median survival rate of fewer than 2 years after therapeutic intervention. It is difficult to achieve complete remission of brain tumors due to blood-brain barrier (BBB) and a lack of efficient drug delivery systems to targeted transportation of brain tumor medicines. Nanoparticle delivery systems have shown merits including stability and high carrier capacity for the transportation of different drugs to treat brain tumors. The application of mRNA nanomedicines brings in great promise not only in COVID-19, but also for malignant brain tumor immunotherapy. The appropriate delivery system facilitates mRNA delivery efficiency and enhances the immune response successfully, for optimal treatment outcomes on malignant brain tumors. Herein, we do an updated review on the development of mRNA nanomedicines for malignant brain cancer treatment. We focus on how to design mRNA-loaded nanoparticle-based delivery systems with optimized pharmacokinetics and pharmacodynamics for efficient therapy of brain cancers. In addition, we point out the challenges and solutions for further development of mRNA nanomedicines for brain cancer therapy. We hope this review would stimulate interest among researchers with different backgrounds and expedite the translation from bench to bedside for the mRNA nanomedicines.

Federated learning (FL), as a paradigm for addressing challenges of machine learning (ML) to be applied in private distributed data provides a novel and promising scheme to promote ML in multiple independently distributed healthcare institutions. However, the non-IID and unbalanced nature of the data distribution can decrease its performance, even resulting in the institutions losing motivation to participate in its training. This paper explored the problem with an in-hospital mortality prediction task under an actual multi-center ICU electronic health record database that preserves the original non-IID and unbalanced data distribution. It first analyzed the reason for the performance degradation of baseline FL under this data scenario, and then proposed a personalized FL (PFL) approach named POLA to tackle the problem. POLA is a personalized one-shot and two-step FL method capable of generating high-performance personalized models for each independent participant. The proposed method, POLA was compared with two other PFL methods in experiments, and the results indicate that it not only effectively improves the prediction performance of FL but also significantly reduces the communication rounds. Moreover, its generality and extensibility also make it potential to be extended to other similar cross-silo FL application scenarios.

Abstract Background With increasing incidence and mortality, colorectal cancer (CRC) seriously endangers human health. LARP6, a member of La-related protein (LARP) family, is a RNA binding protein and probably associates with CRC progression, but its specific roles and mechanisms in CRC still remain unknown. Method Quantitative real-time PCR (qPCR), western blot, and immunohistochemistry were employed to examine LARP6 expression in CRC tissues. Using the stable LARP6 overexpression or interference CRC cell lines, the effect of LARP6 on CRC progression were evaluated. High-throughput RNA immunoprecipitation sequencing (RIP-seq) and a series of relevant experiments were conducted to explain how LARP6 functions. SPSS software was used for statistical analysis. Result In this study, we found that LARP6 expression is downregulated in CRC and correlates with patients’ overall survival and relapse-free survival. Furthermore, altered LARP6 expression influences CRC cells invasion and metastasis. Mechanically, we discovered that LARP6 bind ZNF267 mRNA and regulated its stability and translation. LARP6 inhibited expression of SGMS2, a downstream target of ZNF267, resulting in ceramide and sphingomyelin imbalance in CRC cells. Interestingly, LARP6 also enhances autophagy activity of CRC cells, and the effect was at least partially determined by the inhibition of SGMS2-mediated sphingomyelin synthesis. Conclusion Our study showed how LARP6/ZNF267/SGMS2 axis influence CRC progression, which contributes to further understanding of the molecular mechanisms underlying CRC development.

Abstract Paediatric pneumonia is a respiratory infection that affects infants and young children under the age of 3. This disease is the leading cause of infant and child mortality in developing countries because of the weak immune system of young children. The difficulty and length of time required to identify the pathogen and causative agent are the main reasons for this high mortality rate. In addition, the identification of certain causative agents is particularly important for the treatment of paediatric pneumonia. In this study, we explored the possible mechanisms by which pathogenic Enterococcus faecalis induced pneumonia in vivo. The potential virulence factors of bacteria isolated from the intestines of paediatric pneumonia patients were determined. Taken together, the results suggested that lysophosphatidic acid (LTA) from pathogenic E. faecalis decreases the expression of platelet-activating factor receptor (PAFR), which in turn disrupts the function of intestinal tight junctions (Occ and Ccldn1), leading to the entry of LE-LTA into the bloodstream because of the disruption of the intestinal barrier. Although LTA can enter circulation, it cannot directly infiltrate the lungs, which indicates that lung inflammation in mice is not caused by the direct entry of LE-LTA into the lungs. We further found that LTA activates immune cells, such as CD8 + T cells and type 2 innate lymphocytes, in vivo. Interleukin-6 and interleukin-17 can produce large amounts of inflammatory factors and thus promote the development of pneumonia. In conclusion, our findings demonstrate that the LTA of pathogenic E. faecalis in the intestine is a virulence factor that can cause paediatric pneumonia. This study found that intestinal bacterial virulence factors can induce immune responses in the lungs and blood. These findings could provide further insight into the mechanism of infectious diseases in the lung that are caused by bacteria in the intestine.

Abstract Background Liuwei Dihuang Pill (LP) was verified to alleviate postmenopausal osteoporosis (PMOP) development. Nevertheless, the major constituent of LP and the related network pharmacology study remain unexplored. Methods Protein–protein interaction was established to identify the downstream target of LP in PMOP, and the related signaling pathway was investigated by bioinformatics analysis. MC3T3-E1 cells were added to ferric ammonium citrate (FAC) to mimic osteoporosis in vitro. The osteoblasts were identified by Alizarin red staining. Western blot was applied to evaluate protein levels. In addition, Cell Counting Kit-8 (CCK8) assay was applied to assess cell viability, and cell apoptosis was assessed by flow cytometry. Results Quercetin was the major constituent of LP. In addition, quercetin significantly reversed FAC-induced inhibition of osteogenic differentiation in MC3T3-E1 cells. In addition, quercetin notably abolished the FAC-induced upregulation of Bax, Caspase-3, FOS, JUN, TGFB1 and PPARD. In contrast, Bcl-2, p-mTOR/mTOR, p-AKT/AKT and p-PI3K/PI3K levels in MC3T3-E1 cells were reduced by FAC, which was restored by quercetin. Meanwhile, FAC notably inhibited the viability of MC3T3-E1 cells via inducing apoptosis, but this impact was abolished by quercetin. Furthermore, quercetin could reverse pcDNA3.1-FOS-mediated growth of FAC-treated osteoblasts by mediating PI3K/AKT/mTOR signaling. Conclusion Quercetin alleviated the progression of PMOP via activation of PI3K/AKT/mTOR signaling. Hence, this study would shed novel insights into discovering new methods against PMOP.

Current mesenchymal stem cell (MSC) transplantation practices are limited by the loss or reduced performance of MSCs. Here the authors develop a bead-jet printer for intraoperative formulation and printing of MSCs-laden Matrigel beads to improve skeletal muscle and hair follicle regeneration.

Background: There are multiple recommendations on the third-line therapy of metastatic colorectal cancer (mCRC); however, no consensus has been reached. Objectives: This study aimed to explore the patient demographics and the real-world third-line treatment landscape of mCRC. Design: A retrospective real-world cohort study. Methods: Electronic medical records of mCRC patients from Tianjin Medical University Cancer Institute and Hospital between 2013 and 2020 were collected. Upon descriptive, comparative, and survival analyses, a retrospective study was conducted to describe demographics and clinical outcomes of mCRC patients receiving third-line treatment. Results: Among 218 mCRC patients receiving third-line therapy, 65.5% received chemotherapy combined with or without targeted drugs, followed by anti-angiogenic monotherapy (18.4%), anti-epidermal growth factor receptor drugs (6.9%) and immunotherapy (6.4%). The overall response rate and disease control rate reached 10.2% and 59.2%, respectively; and median progression-free survival (PFS) and overall survival were 4.0 m and 10.7 m, respectively. After Cox multivariate analysis, we found that therapeutic regime was an independent prognostic factor. Compared to patients receiving anti-angiogenic monotherapy, those receiving chemotherapy combined with or without targeted drugs exhibited better prognosis. For patients whose PFS were longer in the front-line treatment, the PFS of third-line therapy was also relatively longer ( p = 0.023). Multiple types of therapies (>3, p = 0.002) or multiple drugs (>5, p = 0.024) in the whole-course management of mCRC are indicators of longer survival. Conclusion: Chemotherapy combined with or without targeted therapy remained dominated third-line choice and showed favorable efficacy compared with anti-angiogenic monotherapy. With the application of more types and quantities of effective drugs, patients would achieve better survival.

Objective: The aim of this research was to identify whether exosomes were involved in impairing adipogenesis in cancer-associated cachexia (CAC) by detecting the adipodifferentiation capacity and the expressions of adipogenic proteins in gastric cancer (GC)-associated adipocytes. Methods: Western blotting and RT-PCR were used to investigate the expressions of C/EPBβ, C/EPBα, PPARγ, and UCP1 in adipose mesenchymal stem cells (A-MSCs) to evaluate the function of exosomal miR-155. BALB/c nude mice were intravenously injected in vivo with GC exosomes with different levels of miR-155 to determine changes in adipodifferentiation of A-MSCs. Results: Exosomes derived from GC cells suppressed adipogenesis in A-MSCs as characterized by decreased lipid droplets. Similarly, A-MSCs co-cultured with GC exosomes exhibited increased ATP production through brown adipose differentiation characterized by highly dense mitochondria and enhanced UCP1 expression (P < 0.05). Mechanistically, exosomal miR-155 secreted from GC cells suppressed adipogenesis and promoted brown adipose differentiation by targeting C/EPBβ, accompanied by downregulated C/EPBα and PPARγ and upregulated UCP1 (P < 0.05). Moreover, overexpression of miR-155 in GC exosomes improved CAC in vivo, which was characterized by fat loss, suppressed expressions of C/EPBβ, C/EPBα, and PPARγ in A-MSCs, and high expression of UCP1 (P < 0.05). Decreasing the level of miR-155 in injected GC exosomes abrogated the improved CAC effects. Conclusions: GC exosomal miR-155 suppressed adipogenesis and enhanced brown adipose differentiation in A-MSCs by targeting C/EPBβ of A-MSCs, which played a crucial role in CAC.

Background: Lymphocyte-activation gene 3 (LAG-3), a checkpoint molecule contributing to immune suppressive microenvironment, is regarded as a promising target in cancer treatment. SHR-1802 is a novel anti-LAG-3 monoclonal antibody. Objectives: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SHR-1802. Design: A phase I dose-escalation and expansion trial of SHR-1802 in patients with advanced solid tumors. Methods: Patients with confirmed advanced solid tumors who failed previous standard-of-care or for whom no effective therapy was available were enrolled to receive SHR-1802 once every 21-day cycle. Dose escalation was performed in an accelerated titration design followed by a 3 + 3 scheme at escalating doses from 0.3 to 10 mg/kg. On the basis of results from dose-escalation phase, one or two dose levels were expanded to establish the recommended phase II dose (RP2D). The primary end points were dose-limiting toxicity (DLT) and RP2D. Results: Between 01 July 2020, and 07 September 2021, 28 patients were enrolled. No DLTs were observed, and all doses investigated were well tolerated. Treatment-related adverse events occurred in 20 patients (71.4%), all grade 1 or 2, with the most common ones being anemia (14.3%), asthenia (14.3%), electrocardiogram QT prolonged (14.3%), followed by increased blood fibrinogen (10.7%), infusion-related reaction (10.7%), and hypoalbuminemia (10.7%). No adverse event-related discontinuation occurred. Three patients died from adverse events, but none of the deaths were deemed related to study treatment. SHR-1802 exposure enhanced with the increasing doses in a greater than dose-proportional manner over the investigated dose range. The disease control rate was 32.0% (95% CI 14.9%–53.5%). The median progression-free survival was 2.0 months (95% CI 1.2–6.1). Conclusions: SHR-1802 demonstrated a tolerable safety profile and preliminary antitumor activity in patients with advanced solid tumors. Further studies with larger sample size and in combination forms are warranted for future clinical application. Registration ClinicalTrials.gov: NCT04414150

ABSTRACT Biodiversity is vital for ecosystem functions and services, and many studies have reported positive, negative, or neutral biodiversity-ecosystem functioning (BEF) relationships in plant and animal systems. However, if the BEF relationship exists and how it evolves remains elusive in microbial systems. Here, we selected 12 Shewanella denitrifiers to construct synthetic denitrifying communities (SDCs) with a richness gradient spanning 1 to 12 species, which were subjected to approximately 180 days (with 60 transfers) of experimental evolution with generational changes in community functions continuously tracked. A significant positive correlation was observed between community richness and functions, represented by productivity (biomass) and denitrification rate, however, such a positive correlation was transient, only significant in earlier days (0 to 60) during the evolution experiment (180 days). Also, we found that community functions generally increased throughout the evolution experiment. Furthermore, microbial community functions with lower richness exhibited greater increases than those with higher richness. Biodiversity effect analysis revealed positive BEF relationships largely attributable to complementary effects, which were more pronounced in communities with lower richness than those with higher richness. This study is one of the first studies that advances our understanding of BEF relationships and their evolutionary mechanisms in microbial systems, highlighting the crucial role of evolution in predicting the BEF relationship in microbial systems. IMPORTANCE Despite the consensus that biodiversity supports ecosystem functioning, not all experimental models of macro-organisms support this notion with positive, negative, or neutral biodiversity-ecosystem functioning (BEF) relationships reported. The fast-growing, metabolically versatile, and easy manipulation nature of microbial communities allows us to explore well the BEF relationship and further interrogate if the BEF relationship remains constant during long-term community evolution. Here, we constructed multiple synthetic denitrifying communities (SDCs) by randomly selecting species from a candidate pool of 12 Shewanella denitrifiers. These SDCs differ in species richness, spanning 1 to 12 species, and were monitored continuously for community functional shifts during approximately 180-day parallel cultivation. We demonstrated that the BEF relationship was dynamic with initially (day 0 to 60) greater productivity and denitrification among SDCs of higher richness. However, such pattern was reversed thereafter with greater productivity and denitrification increments in lower-richness SDCs, likely due to a greater accumulation of beneficial mutations during the experimental evolution.

BackgroundThe KEYNOTE-811 study exhibited promising preliminary results for HER2-positive metastasis gastric adenocarcinoma; however, long-term survival benefit remains to be determined.MethodsIn this single-center, controlled, retrospective study, patients with histologically confirmed HER2-positive unresectable or metastatic gastric/gastroesophageal adenocarcinoma received either anti-PD-1 antibody combined with trastuzumab and chemotherapy (cohort A) or trastuzumab and chemotherapy treatment (cohort B). The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary end points were objective response rate (ORR), disease control rate (DCR), and duration of response (DoR).ResultsA total of 56 patients were eligible to join the study, with 30 patients in cohort A and 26 patients in cohort B. The median PFS (mPFS) was 16.2 months (95% CI, 15.093–17.307) in cohort A versus 14.5 months (95% CI, 9.491–19.509) in cohort B (p = 0.58). The median OS in cohort A was 28.1 months (95% CI, 17.625–38.575) versus 31.6 months (95% CI, 13.757–49.443) in cohort B (p = 0.534). ORRs were 66.7% and 50% in the two groups, respectively. DCRs were 90% and 84.6% in the two groups. Median DoR was not reached in cohort A and it was 16.3 (95% CI, 8.453–24.207) months in cohort B (p = 0.141). The most common irAEs were grade 1 hypothyroidism (33.3%) in cohort A. No treatment-related deaths occurred in this study.ConclusionsThis retrospective cohort study provided a preliminary picture on the long-term follow-up of combining anti-PD-1 antibody with trastuzumab and chemotherapy in HER2-positive GC, and a trend with longer DoR and ORR was identified. Further studies with larger sample sizes and more in-depth molecular investigation are needed.

Lactobacillus rhamnosus (LBS) is a well-documented probiotic strain in oncology and has a pivotal role in clinical applications. Here, we have investigated the protective effect of Lactobacillus rhamnosus on intestinal mucositis induced by cisplatin (CP) and explored the underlying mechanisms targeting inflammatory proteins, as well as the histological changes in the intestinal tissue of mice, in addition, the bacterial strains that may be related to the health-enhancing properties. BALB/c mice were pre-treated with or without LBS via oral gavage, followed by mucositis induction with cisplatin. Our results revealed that the LBS-treated groups significantly attenuated proinflammatory cytokine levels (IL-1β, IL-6, and TNF-α) compared to the CP group. Furthermore, LBS mitigated the damaged tight junction integrity caused by CP via up-regulating the levels of claudin, occludin, ZO-1, and mucin-2 protein (MUC-2). Finally, the 16S rRNA fecal microbiome genomic analysis showed that LBS administration enhanced the growth of beneficial bacteria, i.e., Firmicutes and Lachnospiraceae, while the relative abundance of the opportunistic bacteria Bacteroides and Proteobacteria decreased. Collectively, LBS was found to beneficially modulate microbial composition structure and functions and enrich the ecological diversity in the gut.

Abstract Objective To compare the survival outcomes and adverse events of patients with locally advanced cervical cancer (LACC) who received platinum monotherapy with concurrent chemoradiation therapy (CCRT) versus platinum-based dual drug therapy with CCRT. Method All relevant literature was screened form the PubMed, EMBASE, Web of Science, The Cochrane Library and other databases from their establishment to October 2020. The main endpoint indicators included overall survival (OS) and progression-free survival (PFS). Grade 3 and above adverse events induced by chemotherapy were also compared. Results This study involved 17 literature and 4,106 patients. There were 2,066 patients treated with CCRT with platinum-based dual drug therapy and 2,040 patients received CCRT with platinum monotherapy. Meta-analysis results showed that, compared to CCRT with platinum monotherapy, OS (HR = 0.68, 95% CI 0.58–0.79) and PFS (HR = 0.67, 95% CI 0.58–0.77) of LACC patients were significantly improved by CCRT with platinum-based dual drug therapy. In addition, CCRT with platinum-based dual drug therapy led to more adverse reactions such as neutropenia (OR = 4.92, 95% CI 3.55–6.84), anemia (OR = 1.99, 95% CI 1.17–3.39), diarrhea (OR = 1.70, 95% CI 1.30–2.22), leukopenia (OR = 2.42, 95%CI 1.84–3.17), thrombocytopenia (OR = 2.87, 95%CI 1.44–5.72), etc. Conclusion CCRT with platinum-based dual drug therapy improved OS and PFS of LACC patients relative to the CCRT with platinum monotherapy. But it also increased the adverse reactions caused by multiple chemotherapy drugs. Thus, it is crucial to select a proper chemotherapy regimen based on the actual tolerance of patients in clinical practice.

Objective: The mainstay treatment of esophageal squamous cell carcinoma (ESCC) involves chemotherapy and immunotherapy. However, alternative therapies are required for patients who are refractory or intolerant to existing therapies. Methods: In this single-arm, multicenter, open-label phase Ib study, 30 patients received an intravenous infusion of SCT200, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, 6.0 mg/kg once a week for 6 weeks, followed by 8.0 mg/kg once every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty patients were enrolled between July 2018 and May 2019. The ORR was 16.7% (95% CI: 5.6%–34.7%). The median PFS and OS were 3.1 months (95% CI: 1.5–4.3) and 6.8 months (95% CI: 4.7–10.1), respectively. A numerical difference without any statistical significance in ORR was observed in patients with different EGFR expressions (≥ 50%: 25.0% vs. < 50%: 0%, P = 0.140) or TP53 mutation abundance (< 10%: 23.8% vs. ≥ 10%: 0%, P = 0.286). Improved median PFS (3.4 vs. 1.4 months, P = 0.006) and OS (8.0 vs. 4.2 months, P = 0.027) were associated with TP53 mutation abundance of < 10%. The most common treatment-related adverse events of grade 3 or 4 (occurring in ≥ 2 patients) were hypomagnesemia [7 (23.3%)] and rash [2 (6.7%)]. No treatment-related death occurred. Conclusions: SCT200 monotherapy as the second- or further-line treatment for advanced ESCC showed favorable efficacy, with an acceptable safety profile. TP53 mutation abundance might serve as a potential predictive biomarker.

Abstract Polymer‐based dielectrics are extensively applied in various electrical and electronic devices such as capacitors, power transmission cables and microchips, in which a variety of distinct performances such as the dielectric and thermal properties are desired. To fulfil these properties, the emerging machine learning (ML) technique has been used to establish a surrogate model for the structure–property linkage analysis, which provides an effective tool for the rational design of the chemical and morphological structure of polymers/nanocomposites. In this article, the authors reviewed the recent progress in the ML algorithms and their applications in the rational design of polymer‐based dielectrics. The main routes for collecting training data including online libraries, experiments and high‐throughput computations are first summarized. The fingerprints charactering the microstructures of polymers/nanocomposites are presented, followed by the illustration of ML models to establish a mapping between the fingerprinted input and the target properties. Further, inverse design methods such as evolution searching strategies and generative models are described, which are exploited to accelerate the discovery of new polymer‐based dielectrics. Moreover, structure–property linkage analysis techniques such as Pearson correlation calculation, decision‐tree‐based methods and interpretable neural networks are summarized to identify the key features affecting the target properties. The future development prospects of the ML‐driven design method for polymer‐based dielectrics are also presented in this review.

Abstract Background Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown. Methods The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining. Results The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance. Conclusions MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

ABSTRACT Central nervous system (CNS) infections can cause significant morbidity and mortality, especially in children. Rapid and accurate pathogenic detection in suspected CNS infections is essential for disease control at the early stage of infection. To evaluate the performance of metagenomic next-generation sequencing (mNGS) of cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) in pediatric patients, we retrospectively analyzed the efficiency of cfDNA mNGS in children with CNS infections (n = 257) or noninfectious neurological disorders (n = 81). The CSF samples of 124 random subjects were used to evaluate the accuracy between mNGS of cfDNA and whole-cell DNA (wcDNA). In total, cfDNA mNGS detected a wide range of microbes with a detection rate of 71.0%, and the sensitivity and total coincidence rate with clinical diagnosis reached 68.9% and 67.5%, respectively. Compared with wcDNA mNGS, cfDNA mNGS had a higher efficacy in detecting viruses (66 versus 13) and Mycobacterium (7 versus 1), with significantly higher reads per million. The dominant causative pathogens were bacteria and viruses in CNS infections, but these presented with different pathogen spectra in different age categories. The best timing for the mNGS test ranged from 1 to 6 days after the start of anti-infection therapy, and the earlier mNGS started, the better was identification of bacterial CNS infections. This study emphasized that cfDNA mNGS had overall superiority to conventional methods on causative pathogen detection in pediatric CNS infections, and it was even better than wcDNA mNGS. Furthermore, research needs to be better validated in large-scale clinical trials to improve the clinical applications of cfDNA mNGS. IMPORTANCE Our study emphasized that cfDNA mNGS had overall superiority to conventional methods on causative pathogen detection in CNS-infected children, and it was even better than wcDNA mNGS. cfDNA mNGS detected a wide range of pathogens with a high total coincidence rate (67.5%) against clinical diagnosis. The best timing for cfDNA mNGS detection ranged from 1 to 6 days, rather than 0 days, after the start of empirical anti-infection therapy. The earlier mNGS started, the better the identifications of bacterial CNS infections. To the best of our knowledge, this research is the first report evaluating the clinical utility of mNGS with different methods (cfDNA versus wcDNA) of extracting DNA from CSF specimens in diagnosing pediatric CNS infections. Meanwhile, this is the largest cohort study that has evaluated the performance of mNGS using cfDNA from CSF specimens in pediatric patients with CNS infections.

Fatty acid oxidation (FAO) plays a vital role in drug resistance in cancer cells. Carnitine palmitoyltransferase 1A (CPT1A), a key enzyme of FAO, is widely recognized as an emerging therapeutic target. Here, we confirmed that CPT1A was heterogeneously expressed in colon cancer cells, with a high expression in oxaliplatin‐resistant cells but low expression in oxaliplatin‐sensitive cells, and expression could be increased by oxaliplatin stimulation. In addition, we verified that CPT1A was more highly expressed in colon cancer tissues than in noncancerous tissues. Silencing CPT1A by siRNA or etomoxir, a specific small‐molecule inhibitor of CPT1A, could reverse the sensitivity of drug‐resistant colon cancer cells to oxaliplatin. Subsequently, the combination of oxaliplatin with CPT1A inhibition promoted apoptosis and inhibited proliferation. In addition, exosomes were generated with the iRGD peptide on the surface, which showed highly efficient targeting compared with control exosomes in vivo. Furthermore, we loaded and therapeutically applied iRGD‐modified exosomes with siCPT1A to specifically deliver siCPT1A into tumours to suppress FAO. As a consequence, iRGD‐modified exosomes showed the significant inhibition of CPT1A in tumour tissues and exhibited the ability to reverse oxaliplatin resistance and inhibit tumour growth by inhibiting FAO with high safety in vivo.

Abstract Background Current treatment options for human epidermal growth factor receptor 2 (HER2)‐overexpressing gastric cancer at third‐line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in‐situ hybridization‐negative patients. Here, we report the efficacy and safety of a novel anti‐HER2 antibody RC48 for patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer. Methods Patients with HER2‐overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second‐line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression‐free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. Results Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%‐33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7‐4.9 months) and 7.9 months (95% CI: 6.7‐9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48‐related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48‐related. Conclusions RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2‐overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.

Abstract Cancer stem cells (CSCs) are an important cause of tumor recurrence and drug resistance. As a new type of cell death that relies on iron ions and is strictly regulated by intracellular and extracellular signals, the role of ferroptosis in tumor stem cells deserves extensive attention. Mass spectrum was applied to screen for ferroptosis-related proteins in gastric cancer (GC). Sphere-formation assay was used to estimate the stemness of gastric cancer stem cells (GCSCs). Exosomal lnc-ENDOG-1:1 (lncFERO) was isolated by ultracentrifugation. Ferroptosis was induced by erastin and was assessed by detecting lipid ROS, mitochondrial membrane potential, and cell death. Furthermore, a series of functional in vitro and in vivo experiments were conducted to evaluate the effects of lncFERO on regulating ferroptosis and chemosensitivity in GCSCs. Here, we showed that stearoyl-CoA-desaturase (SCD1) played a key role in regulating lipid metabolism and ferroptosis in GCSCs. Importantly, exosomal lncFERO (exo-lncFERO) derived from GC cells was demonstrated to promote SCD1 expression by directly interacting with SCD1 mRNA and recruiting heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which resulted in the dysregulation of PUFA levels and the suppression of ferroptosis in GCSCs. Moreover, we found that hnRNPA1 was also involved in lncFERO packing into exosomes in GC cells, and both in vitro and in vivo data suggested that chemotoxicity induced lncFERO secretion from GC cells by upregulating hnRNPA1 expression, leading to enhanced stemness and acquired chemo-resistance. All these data suggest that GC cells derived exo-lncFERO controls GCSC tumorigenic properties through suppressing ferroptosis, and targeting exo-lncFERO/hnRNPA1/SCD1 axis combined with chemotherapy could be a promising CSC-based strategy for the treatment of GC.

Alzheimer's disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive decline and irreversible memory impairment. Currently, several studies have failed to fully elucidate AD's cellular and molecular mechanisms. For this purpose, research on related cellular models may propose potential predictive models for the drug development of AD. Therefore, many cells characterized by neuronal properties are widely used to mimic the pathological process of AD, such as PC12, SH-SY5Y, and N2a, especially the PC12 pheochromocytoma cell line. Thus, this review covers the most systematic essay that used PC12 cells to study AD. We depict the cellular source, culture condition, differentiation methods, transfection methods, drugs inducing AD, general approaches (evaluation methods and metrics), and in vitro cellular models used in parallel with PC12 cells.

BackgroundEsophageal squamous carcinoma (ESCC) is a highly lethal malignancy with poor prognosis. The effect of transcriptome characteristics of patient immune microenvironment (TME) on the efficacy of immunosuppressive agents is still poorly understood.MethodsHere we extracted and isolated immune cells from peripheral blood of patients with PD-1 monoclonal antibody sensitivity and resistance, and conducted deep single-cell RNA sequencing to describe the baseline landscape of the composition, lineage, and functional status of infiltrating immune cells in peripheral blood of patients with esophageal cancer.ResultsThe transcriptome characteristics of immune cells were comprehensively analyzed, and the dynamic changes of cell percentage, heterogeneity of cell subtypes and interactions between cells were explained. Co-expression and pedigree tracking based on T-cell antigen receptors revealed a significant proportion of highly migratory intertissue-effector T cells. GO and KEGG enrichment pathway Analysis of CD8+ effect-T cells ESCC_S group and ESCC_D1,2 group, found that in the up-regulated enrichment pathway, ESCC_S group enriched more PD-L1 and PD-1 checkpoint pathways expressed in tumors (JUN/NFKBIA/FOS/KRAS/IFNG), which also exist in T cell receptor signaling pathways. MT2A, MT1X and MT1E were differentially expressed in ESCC patients with PD-1 monoclonal antibody resistance, which may be related to the resistance of PD-1 mMAB.ConclusionsThis study has an in-depth understanding of the influence of peripheral immune cell infiltration on the sensitivity of monoclonal antibody PD-1 in patients with esophageal cancer, which is helpful to promote the immunotherapy of patients with esophageal cancer.