Berberine attenuates 5-fluorouracil-induced intestinal mucosal injury by modulating the gut microbiota without compromising its anti-tumor efficacy.

Background: 5-Fluorouracil (5-Fu), a prominent chemotherapeutic agent for colorectal cancer (CRC) treatment, is often associated with gastrointestinal toxicities, particularly diarrhea. Our previous study demonstrated that berberine (BBR) ameliorates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota in rats. Nevertheless, the precise molecular mechanism underlying BBR's protective effect on intestinal mucosa remains elusive, and its impact on the anti-tumor efficacy of 5-Fu warrants further investigation. Methods: The effect of BBR on 5-Fu-induced intestinal mucosal injury was investigated using a tumor-bearing murine model, employing H&E staining, 16 S rDNA sequencing, transcriptome sequencing, Western blot analysis, cell experiments and constructing a pseudo-germ-free tumor xenograft model. Result: Our findings demonstrate that BBR alleviates intestinal mucosal damage, reduces the levels of inflammatory factors (IL-6, TNF-α, and IL-1ß), and inhibits epithelial cell apoptosis in 5-Fu-treated mice without compromising 5-Fu's anti-tumor efficacy. Moreover, 16 S rDNA sequencing indicated that BBR significantly increases the abundance of Akkermansia and decreases the abundance of pathogenic bacteria Escherichia/Shigella at the genus level. Mechanistically, transcriptome sequencing and Western blot analysis confirmed that BBR upregulates PI3K/AKT/mTOR expression in the intestinal mucosa. However, this effect was not observed in tumor tissues. Notably, BBR did not demonstrate a direct protective effect on 5-Fu-treated CCD841 and SW480 cells. Additionally, BBR had no effect on the PI3K/AKT/mTOR pathway in the intestinal tissue of the 5-Fu-treated mouse model with a depleted gut microbiota. Conclusion: This study indicates that BBR alleviates 5-Fu-induced intestinal mucosal injury by modulating the gut microbiota and regulating the PI3K/AKT/mTOR signaling pathway without compromising the anti-tumor efficacy of 5-Fu.

Risk evaluation for diabetic retinopathy in Chinese renal-biopsied type 2 diabetes mellitus patients.

AIM: To investigate diabetic retinopathy (DR) prevalence in Chinese renal-biopsied type 2 diabetes mellitus (T2DM) patients with kidney dysfunction, and to further evaluate its relationship with diabetic nephropathy (DN) incidence and the risk factors for DR development in this population. METHODS: A total of 84 renal-biopsied T2DM patients were included. Fundus and imaging examinations were employed for DR diagnosis. Demographic information and clinical measures along with renal histopathology were analyzed for comparisons between the DR and non-DR groups. Risk factors on DR development were analyzed with multiple logistic regression. RESULTS: DR prevalence was 50% in total. The incidences of DN, non-diabetic renal disease (NDRD) and mixed-type pathology were 47.6%, 19.0% and 33.3% in the DR group respectively, while 11.9%, 83.3% and 4.8% in the non-DR group. Systolic blood pressure, ratio of urinary albumin to creatine ratio, urinary albumin, 24-hours urinary protein, the incidence and severity of DN histopathology were found statistically increased in the DR group. Multiple logistic regression analysis showed histopathological DN incidence significantly increased the risk of DR development [odds ratio (OR)=21.664, 95% confidential interval (CI) 5.588 to 83.991, P<0.001 for DN, and OR=45.475, 95%CI 6.949 to 297.611, P<0.001 for mixed-type, respectively, in reference to NDRD)], wherein DN severity positively correlated. CONCLUSION: Renal histopathological evidence indicates DN incidence and severity increases the risk of DR development in Chinese T2DM patients inexperienced of regular fundus examinations.

SLC4A4 as a novel biomarker involved in immune system response and lung adenocarcinoma progression.

BACKGROUND: Altered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD) immunotherapy and prognosis was not entirely clear. METHODS: We analyzed SLC4A4 expression in LUAD tissues and cell lines using quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of SLC4A4 overexpression on angiogenesis, cell migration, invasion, and epithelial-mesenchymal transition were examined. Public databases helped construct a risk model evaluating SLC4A4's expression on LUAD prognosis and immunotherapy response. Additionally, a xenograft model, flow cytometry, and enzyme-linked immunosorbent assay further explored SLC4A4's role in tumor immune microenvironment infiltration. RESULTS: Upregulation of SLC4A4 promoted apoptosis in the LUAD cell line and significantly inhibited the migration and invasive ability of cancer cells (P<0.01). A total of 10 key genes (including SIGLEC6, RHOV, PIR, MOB3B, MIR3135B, LPAR6, KRT8, ITGA2, CPS1, and C6) were screened according to SLC4A4 expression, immune score and stromal score, and a prognostic model with good outcome was constructed (AUC values of which in the training cohort at 1,3, and 5 years reached 0.73, 0.73, and 0.72, respectively). Importantly, we demonstrated that high expression of SLC4A4 was able to increase the proliferation level and cytokine secretion of CD8+ T cells for the purpose of promoting the immune system response to LUAD. CONCLUSION: Our study revealed that SLC4A4 can serve as a prognostic indicator for LUAD, providing new insights into the treatment and diagnosis of LUAD.

OcBSA: An NGS-based bulk segregant analysis tool for outcross populations.

Constructing inbred lines for self-incompatible species and species with long generation times is challenging, making the use of F1 outcross/segregating populations the main strategy for genetic studies of such species. However, there is a lack of dedicated algorithms/tools for rapid quantitative trait locus (QTL) mapping using the F1 populations. To this end, we have designed and developed an algorithm/tool called OcBSA specifically for QTL mapping of F1 populations. OcBSA transforms the four-haplotype inheritance problem from the two heterozygous diploid parents of the F1 population into the two-haplotype inheritance problem common in current genetic studies by removing the two haplotypes from the heterozygous parent that do not contribute to phenotype segregation in the F1 population. Testing of OcBSA on 1800 simulated F1 populations demonstrated its advantages over other currently available tools in terms of sensitivity and accuracy. In addition, the broad applicability of OcBSA was validated by QTL mapping using seven reported F1 populations of apple, pear, peach, citrus, grape, tea, and rice. We also used OcBSA to map the QTL for flower color in a newly constructed F1 population of potato generated in this study. The OcBSA mapping result was verified by the insertion or deletion markers to be consistent with a previously reported locus harboring the ANTHOCYANIN 2 gene, which regulates potato flower color. Taken together, these results highlight the power and broad utility of OcBSA for QTL mapping using F1 populations and thus a great potential for functional gene mining in outcrossing species. For ease of use, we have developed both Windows and Linux versions of OcBSA, which are freely available at: https://gitee.com/Bioinformaticslab/OcBSA.

A randomized trial evaluating the association between related gene polymorphism and nausea and vomiting induced by cisplatin multi-day chemotherapy.

PURPOSE: We aim to investigate the correlation between gene polymorphisms and cisplatin chemotherapy-induced nausea and vomiting (CINV), which was prevented by olanzapine or aprepitant triple antiemetic regimen. METHODS: Before chemotherapy, the blood samples of 89 malignant tumor patients who received multi-day chemotherapy with cisplatin were collected for sequencing and typing. As there were duplicate patients enrolled in different chemotherapy cycles, there were a total of 190 cases. The patients were divided into two groups randomly, who received the triple antiemetic regimen of olanzapine or aprepitant combined with 5-HT3RA and dexamethasone. The main evaluation indicators were the total protection (TP) rate in the acute phase (0-24 h), the delayed phase (25-120 h) and the overall phase (0-120 h). RESULTS: Univariate analysis was performed on genetic loci that reached H-W balance with TP. In the olanzapine group, increased TP in the acute phase was associated with HTR3A rs1176719 non-GG (P < 0.05) genotype etc. Increased TP in the delayed phase was associated with HTR3A rs1176719 non-GG (P < 0.05) genotype etc. In the aprepitant group, increased TP in the acute phase was associated with the MTHFR rs1801131 TT (P < 0.05) genotype etc. Increased TP in the delayed phase was associated with HTR3A rs1062613 CC (P < 0.05) genetype ect. Multivariate Logistic regression analysis showed that HTR3B rs7943062GG (P < 0.05) genotype etc. were correlated with increased TP in the delayed phase. MTHFR rs1801131TT genotype was associated with increased TP in the acute phase (P < 0.05) and delayed phase (P < 0.05). CONCLUSION: This study found that gene polymorphisms, including HTR3B (rs1062613, rs1176719, rs2276303), HTR3B (rs45460698, rs7943062), HTR3C (rs6766410), ERCC1 (rs3212986), ERCC4 (rs744154) and MTHFR(rs1801131), may be independent prognostic factors for CINV.

Predictive value of 18 F-FDG PET/CT and serum tumor markers for tumor mutational burden in patients with non-small cell lung cancer.

PURPOSE: To investigate the correlations between metabolic parameters (MPs) of 18 F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT), serum tumor markers (STMs), and tumor mutational burden (TMB) in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this retrospective study, we enrolled 129 patients with NSCLC (males, 78; females, 51) who underwent baseline TMB and STM tests and 18 F-FDG PET/CT scans before treatment between March 2018 and September 2022. Patients were categorized into TMB-high (TMB ≥10 mutations/Mb; n = 27 [20.9%]) and non-TMB-high (TMB <10 mutations/Mb; n = 102 [79.1%]) groups. Binary logistic regression analyses were performed to determine independent predictors of TMB-high. Univariate and multivariate linear regression analyses were performed to determine independent predictors of TMB level on a log scale. Subgroup analyses for adenocarcinoma (ADC), ADC with EGFR+, ADC with EGFR-, and squamous cell carcinoma (SCC) were performed. RESULTS: For ADC, all MPs (SULpeak , SULmax , SULmean , MTV, and TLG) were significantly higher in the TMB-high group than the non-TMB-high group; smoker (odds ratio [OR] = 27.08, p = 0.018), EGFR+ (OR = 0.03, p = 0.033), KRAS+ (OR = 7.98, p = 0.083), high CEA (OR = 33.56, p = 0.029), and high CA125 (OR = 13.68, p = 0.030) were independent predictors of TMB-high; and all MPs showed significant positive linear correlations with TMB on a log scale, with SULpeak as an independent predictor. However, no significant correlation was observed for SCC. CONCLUSION: MPs and STMs can predict the TMB level for patients with ADC, and may serve as potential substitutes for TMB with increased value and easy implementation in guiding immunotherapy through noninvasive methods.

Mitochondrial energy metabolism correlates with an immunosuppressive tumor microenvironment and poor prognosis in esophageal squamous cell carcinoma.

Background: Reprogramming of mitochondrial energy metabolism (MEM) is an important hallmark of tumorigenesis and cancer progression. Currently, there are no studies that have examined MEM in the tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC), and relevant drug targets have not yet been identified. Methods: The ESCC single-cell transcriptome sequencing dataset, GSE145370, was analyzed, using the AUCell R package to screen for MEM-related genes in high-scoring cell populations. Monocle was used to infer cell differentiation and CellChat to analyze intercellular communication networks. Finally, transcription levels of prognostic genes were analyzed using a complementary DNA microarray from 15 patients with ESCC. Results: A total of 121 MEM-related genes were differentially expressed in seven cell populations in the TME, and four high-scoring cell populations were identified. As a result, the MEM state of T cells is significantly different from that of macrophages and epithelial cells, and signaling communication between T cells and macrophages is the strongest. These findings suggest that immunosuppression is related to metabolic reprogramming. Additionally, marker genes of high-scoring cells and the top10 receptor-ligand pairs may become new targets for rebuilding immune cell metabolism. Furthermore, the 4-MEM gene risk signature had good predictive power for overall survival and drug sensitivity. MAP1LC3A, APOE, APPL1, and NDUFA are novel potential immunotherapeutic targets for remodeling the TME. Finally, teal-time quantitative PCR was used to verify APOE and MAP1LC3A expression. Conclusion: MEM heterogeneity was observed in the immunosupressive TME of ESCC. Prognostic models based on MEM-related genes are helpful for screening early treatment patient groups and realizing personalized treatment. APOE and MAP1LC3A are potential target genes for the development of anti-ESCC drugs based on MEM-related genes.

Low Dose Olanzapine in the Prevention and Treatment of Carboplatin Induced Nausea and Vomiting: A Prospective Clinical Randomized Controlled Trial.

OBJECTIVE: This study aimed to determine the effectiveness and safety of 5 mg olanzapine (OLZ) in preventing vomiting and nausea caused by carboplatin chemotherapy. METHODS: All patients with malignant tumors (n = 113) who underwent Carboplatin (AUC ≥ 5) treatment were randomly categorized into two groups: the standard group (n = 57) and the OLZ regimen (n = 56). The major endpoints of the trial were the TC (total control) between two groups during the OP (Overall phase, 0-120 hours), DP (delayed phase, 25-120 hours), and AP (acute phase, 0-24 hours). The secondary endpoints were the CR (complete response) and TP (total protection) during AP, OP, and DP. The time of first vomiting was compared between the two groups using Kaplan-Meier curves. The impact of CINV on the quality of life was assessed by the Functional Living Index-Emesis (FLIE). OLZ-related side effects were also recorded. RESULTS: (1) The primary endpoint TC rates were more favorable in the OLZ regimen group than in the standard group during the AP 87.50% (49/56) vs. 63.15% (36/57) P = 0.003, OP 62.50% (35/56) vs. 31.57% (18/57) P = 0.001, and DP 64.28% (36/56) vs. 33.33% (19/57) P = 0.001. (2) The secondary endpoints TP were 82.14% (46/56) vs. 63.15% (36/57), P = 0.024, 83.92% (47/56) vs. 63.15% (36/57). P = 0.012 during the DP and OP. There was no statistical significance during AP between the two groups. The CR rates were not statistically different between the two groups during the three periods, P > 0.05; (3) The first vomiting time in the OLZ group was delayed compared with the standard group (P = 0.248). The effect on life quality (score ≥ 108) assessed by FLIE was 62.50% vs. 43.48% between the two groups, P < 0.05. The primary side effects of OLZ are fatigue (85%) and somnolence (75%). The primary side effects of the standard group are fatigue (77%) and loss of appetite (85%). CONCLUSION: The 5 mg OLZ-based triple antiemetic regimen is effective and safe in preventing vomiting and nausea induced by Carboplatin.

A novel immune-related prognostic signature based on Chemoradiotherapy sensitivity predicts long-term survival in patients with esophageal squamous cell carcinoma.

Background: There is a heterogenous clinical response following chemoradiotherapy (CRT) in esophageal squamous cell carcinoma (ESCC). Therefore, we aimed to study signaling pathway genes that affect CRT sensitivity and prognosis. Methods: Gene expression analyses were performed in the GEO and TCGA datasets. A immunohistochemistry (IHC) analysis was performed in pretreatment biopsies. Results: MMP13 was found to be highly expressed in the "Pathologic Complete Response (pCR)" and "Complete Remission (CR)" and "Alive" groups. Th17 cells and MMP9/13 showed a negative correlation in immune infiltration analysis. In GSEA analysis, IL-4 and IL-13 signaling pathways were highly enriched in patients exhibiting high MMP expression in pCR and CR groups. IHC results suggested higher MMP13 & IL-4 and lower IL-17A & RORC expression in the CR group compared to the 0.70, and the model could well distinguish high-risk and low-risk subgroups. Conclusion: The above results may provide guidance for developing novel treatment and prognostic strategies in ESCC patients.

ALKBH5-mediated m6A demethylation fuels cutaneous wound re-epithelialization by enhancing PELI2 mRNA stability.

BACKGROUND: Impaired wound re-epithelialization contributes to cutaneous barrier reconstruction dysfunction. Recently, N6-methyladenosine (m6A) RNA modification has been shown to participate in the determination of RNA fate, and its aberration triggers the pathogenesis of numerous diseases. Howbeit, the function of m6A in wound re-epithelialization remains enigmatic. METHODS: Alkbh5‒/‒ mouse was constructed to study the rate of wound re-epithelialization after ALKBH5 ablation. Integrated high-throughput analysis combining methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq was used to identify the downstream target of ALKBH5. In vitro and in vivo rescue experiments were conducted to verify the role of the downstream target on the functional phenotype of ALKBH5-deficient cells or animals. Furthermore, the interacting reader protein and regulatory mechanisms were determined through RIP-qPCR, RNA pull-down, and RNA stability assays. RESULTS: ALKBH5 was specifically upregulated in the wound edge epidermis. Ablation of ALKBH5 suppressed keratinocyte migration and resulted in delayed wound re-epithelialization in Alkbh5‒/‒ mouse. Integrated high-throughput analysis revealed that PELI2, an E3 ubiquitin protein ligase, serves as the downstream target of ALKBH5. Concordantly, exogenous PELI2 supplementation partially rescued keratinocyte migration and accelerated re-epithelialization in ALKBH5-deficient cells, both in vitro and in vivo. In terms of its mechanism, ALKBH5 promoted PELI2 expression by removing the m6A modification from PELI2 mRNA and enhancing its stability in a YTHDF2-dependent manner. CONCLUSIONS: This study identifies ALKBH5 as an endogenous accelerator of wound re-epithelialization, thereby benefiting the development of a reprogrammed m6A targeted therapy for refractory wounds.

MOTS-c: A potential anti-pulmonary fibrosis factor derived by mitochondria.

Pulmonary fibrosis (PF) is a serious lung disease characterized by diffuse alveolitis and disruption of alveolar structure, with a poor prognosis and unclear etiopathogenesis. While ageing, oxidative stress, metabolic disorders, and mitochondrial dysfunction have been proposed as potential contributors to the development of PF, effective treatments for this condition remain elusive. However, Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), a peptide encoded by the mitochondrial genome, has shown promising effects on glucose and lipid metabolism, cellular and mitochondrial homeostasis, as well as the reduction of systemic inflammatory responses, and is being investigated as a potential exercise mimetic. Additionally, dynamic expression changes of MOTS-c have been closely linked to ageing and ageing-related diseases, indicating its potential as an exercise mimetic. Therefore, the review aims to comprehensively analyze the available literature on the potential role of MOTS-c in improving PF development and to identify specific therapeutic targets for future treatment strategies.

αCGRP deficiency aggravates pulmonary fibrosis by activating the PPARγ signaling pathway.

In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.

A Surrogate Endpoint for Overall Survival in Locally Advanced and Resectable Esophageal Squamous Cell Carcinoma: A Reanalysis of Data From the NEOCRTEC5010 Trial.

PURPOSE: This study aimed to investigate disease-free survival (DFS) as a surrogate endpoint for overall survival (OS) in patients with locally advanced and resectable esophageal squamous cell carcinoma. METHODS AND MATERIALS: We re-analyzed patient data from the NEOCRTEC5010 randomized controlled trial (N = 451 patients) to compare their OS with that of an age- and sex-matched cohort from the general population of China. We used expected survival and the standardized mortality ratio, respectively, in our analysis of data collected from a neoadjuvant chemoradiation therapy (NCRT) plus surgery group and a surgery-only group. Published data from 6 randomized controlled trials and 20 retrospective studies were used to examine the correlation between DFS and OS at the trial level. RESULTS: The annual hazard rate of disease progression decreased to 4.9% and 8.1% within 3 years in the NCRT and surgery groups, respectively. Patients who were disease-free at 36 months had a 5-year OS of 93.9% (95% CI, 89.7%-98.4%) in the NCRT group with a standardized mortality ratio of 1.1 (95% CI, 0.7-1.8; P = .5639). In contrast, the 5-year OS was only 12.9% (95% CI, 7.3%-22.6%) for patients in the NCRT group who exhibited disease progression within 36 months. At the trial level, DFS and OS were correlated with treatment effect (R2 = 0.605). CONCLUSIONS: Disease-free status at 36 months is a valid surrogate endpoint for 5-year OS in patients with locally advanced and resectable esophageal squamous cell carcinoma. Patients who were disease-free at 36 months showed a favorable OS, which was indistinguishable from that of the age- and sex-matched comparison group from the general population; otherwise, their 5-year OS was extremely poor.

Lean adipose tissue macrophage derived exosome confers immunoregulation to improve wound healing in diabetes.

Chronic non-healing wounds, a prevalent complication of diabetes, are associated with increased mortality in diabetic patients. Excessive accumulation of M1 macrophages in diabetic wounds promotes inflammation and results in dysregulated tissue repair. Adipose tissue macrophages (ATMs) derived from healthy lean donors have the ability to improve glucose tolerance and insulin sensitivity, as well as modulate inflammation. MicroRNAs (miRs), which can be packaged into exosomes (Exos) and secreted from cells, serve as essential regulators of macrophage polarization. Here, we revealed that ATMs isolated from lean mice secrete miRs-containing Exos, which modulate macrophage polarization and promote rapid diabetic wound healing when administered to diabetes-prone db/db mice. The miRs sequence of tissue samples from wounds treated with Exos secreted by lean ATMs (ExosLean) revealed that miR-222-3p was up-regulated. Further analyses showed that inhibiting miR-222-3p using a miR inhibitor impaired the macrophage-reprogramming effect of ExosLean. In the excisional skin wound mouse model, locally inhibiting miR-222-3p disrupted healing dynamics and failed to modulate macrophage polarization. Mechanistic studies revealed a connection between miR-222-3p, Bcl2l11/Bim, an inflammatory response effector, macrophage polarization, and diabetic wound healing. In summary, ExosLean act as positive regulators of macrophage polarization by regulating miR levels in wounds and accelerating wound healing, and thus have important implications for wound management in diabetes.

Association of malnutrition with all-cause and cardiovascular mortality in patients with mild to severe chronic kidney disease undergoing coronary angiography: a large multicenter longitudinal study.

PURPOSE: Evidence on the prognostic impact of malnutrition was focused on patients with advanced kidney disease. The relationships between malnutrition and all-cause and cardiovascular mortality in patients with different severity of chronic kidney disease (CKD) have not been adequately addressed. We aimed to reveal the prevalence of malnutrition and its prognostic value in patients with different severity of CKD undergoing coronary angiography (CAG). METHODS: This was a multicenter, longitudinal, and retrospective cohort study of 12,652 patients with non-dialysis dependent CKD (defined as estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) undergoing CAG from five tertiary hospitals between January 2007 and December 2020. The controlling nutritional status (CONUT) score was applied to assess nutritional status. Cox regression models and competing risk Fine and Gray models were used to examine the relationships between malnutrition, all-cause and cardiovascular mortality. Further stratified analysis was performed according to baseline CKD severity (mild, moderate and severe, defined by eGFR < 30, 30-44 and 45-59 ml/min/1.73 m2). RESULTS: During a median follow-up of 5.5 years (interquartile range: 3.2 to 8.6 years), 3801 patients (30.0%) died, and 2150 (17.0%) definitely died of cardiovascular disease. After controlling for confounders, patients had higher all-cause mortality (mild, moderate, and severe vs. absent: HR 1.27, 95 CI % [1.17-1.39]; HR 1.54, 95 CI % [1.39-1.71]; HR 2.22, 95 CI % [1.78-2.77], respectively; P for trend < 0.001) and cardiovascular mortality (mild, moderate and severe vs. absent: HR 1.35, 95 CI % [1.21-1.52]; HR 1.67, 95 CI % [1.45-1.92]; HR 2.10, 95 CI % [1.55-2.85], respectively; P for trend < 0.001) with the severity of malnutrition. In further stratified analysis, a similar prognostic impact of malnutrition was observed in patients with mild to moderate CKD, while mild malnutrition did not seem to have a consistent effect on severe CKD patients. CONCLUSION: Malnutrition is common among patients with mild to severe CKD undergoing CAG and is strongly associated with increased risk of all-cause and cardiovascular mortality. Malnutrition seems to have a modestly stronger impact on mortality in patients with mild to moderate CKD. This study was registered at Clinicaltrials.gov as NCT05050877.

Global research trends between gut microbiota and lung cancer from 2011 to 2022: A bibliometric and visualization analysis.

Background: An increasing number of studies have found that the gut microbiota was related to the occurrence and development of lung cancer. Nonetheless, publication trends and research hotspots in this field remain unknown. The study aimed to perform a bibliometric analysis to systematically identify publication trends and research hotspots in the field of gut microbiota and lung cancer research within a 12-year panorama. Methods: Publications related to the gut microbiota and lung cancer between 1 January 2011 and 25 October 2022 were retrieved from the Web of Science Core Collection (WoSCC) database. The online analytic tool of the WoSCC was used to analyze various bibliometric parameters. The bibliometrics website, CiteSpace, and VOSviewer were used to identify research trends and hotspots. Results: A total of 375 publications related to the gut microbiota and lung cancer were extracted from WoSCC and identified for analysis. The number of annual publications has grown rapidly since 2018 and reached a peak in 2022. China was the most prolific country in this field, with 120 publications, followed by the United States (114), with the highest H-index of 31. Additionally, France ranked the highest with an average of 133 citations, while the leading institution and journal were the Unicancer and the International Journal of Molecular Sciences, respectively. Interestingly, Routy Bertrand was the most prolific author and also the most cited author in terms of H-index and citations. Reference and keyword burst detection indicated that the research hotspots mainly included 1) the gut microbiota directly affects the efficacy of immunotherapy for lung cancer, 2) the application of different gut bacteria on lung cancer, and 3) the mechanism of the gut microbiota on lung cancer. Conclusion: The findings of this study revealed the general publication trends and evolving research hotspots in the field of gut microbiota and lung cancer at a global level. The research hotspots focused on the clinical application of the gut microbiota combined with immunotherapy in lung cancer and its mechanism. The findings of this study provide new perspectives on the field, which may shed light on a beneficial impact on further etiological studies, diagnosis, and treatment for lung cancer.

Identification on surrogating overall survival with progression-free survival of first-line immunochemotherapy in advanced esophageal squamous cell carcinoma-an exploration of surrogate endpoint.

BACKGROUND: Overall survival (OS) is the gold standard to assess novel therapeutics to treat cancer. However, to identify early efficacy and speed up drug approval, trials have used progression-free survival (PFS) as a surrogate endpoint (SE). Herein, we aimed to examine if PFS could function as an OS surrogate in advanced Esophageal Squamous Cell Carcinoma (ESCC) treated with first-line immunochemotherapy. METHODS: Two hundred ninety-two advanced ESCC patients treated using inhibitors of PD-1/PD-L1 + chemotherapy or chemotherapy alone were collected. In addition, six phase III randomized clinical trials were eligible for inclusion. Bayesian normal-induced-copula-estimation model in retrospective patient data and regression analysis in the published trial data were used to determine the PFS-OS correlation. RESULTS: PFS correlated moderately with OS in the retrospective cohort (Kendall's Tau = 0.684, τ = 0.436). In trial-level, treatments effects for PFS correlated weakly with those for OS in intention-to-treat population (R2 = 0.436, adj.R2 = 0.249, P > 0.05) and in PD-L1-enriched population (R2 = 0.072). In arm-level, median PFS also correlated weakly with median OS. Moreover, analysis of the retrospective cohort demonstrated that the annual death risk after progression in the continued immunotherapy group was considerably lower than that in the discontinued group. CONCLUSION: In trials of anti-PD-1 agents to treat advanced ESCC, the current results provide only weak support for PFS as an OS surrogate; OS cannot be substituted completely by PFS in these cases. The results also suggest that qualified patients with advanced ESCC might benefit from continuous immunotherapy beyond progression to achieve a decreased risk of death.

Automatic detection of pulmonary embolism in computed tomography pulmonary angiography using Scaled-YOLOv4.

BACKGROUND: Pulmonary embolism (PE) is a common but fatal clinical condition and the gold standard of diagnosis is computed tomography pulmonary angiography (CTPA). Prompt diagnosis and rapid treatment can dramatically reduce mortality in patients. However, the diagnosis of PE is often delayed and missed. METHODS: In this study, we identified a deep learning model Scaled-YOLOv4 that enables end-to-end automated detection of PE to help solve these problems. A total of 307 CTPA data (Tianjin 142 cases, Linyi 133 cases, and FUMPE 32 cases) were included in this study. The Tianjin dataset was divided 10 times in the ratio of training set: validation set: test set = 7:2:1 for model tuning, and both the Linyi and FUMPE datasets were used as independent external test sets to evaluate the generalization of the model. RESULTS: Scaled-YOLOv4 was able to process one patient in average 3.55 s [95% CI: 3.51-3.59 s]. It also achieved an average precision (AP) of 83.04 [95% CI: 79.36-86.72] for PE detection on the Tianjin test set, and 75.86 [95% CI: 75.48-76.24] and 72.74 [95% CI: 72.10-73.38] on Linyi and FUMPE, respectively. CONCLUSIONS: This deep learning algorithm helps detect PE in real time, providing radiologists with aided diagnostic evidence without increasing their workload, and can effectively reduce the probability of delayed patient diagnosis.

What Motivates Greenhouse Vegetable Farmers to Adapt Organic-Substitute-Chemical-Fertilizer (OSCF)? An Empirical Study from Shandong, China.

This paper reports on a study of the determinants of the adoption behaviour related to Organic-Substitute-Chemical-Fertilizer (OSCF) against the background of Green and Low-carbon Circular Agriculture (GLCA) by analysing a survey of 318 greenhouse vegetable farmers in Shandong Province, China. We use regression analyses to identify policy measures and farmers' psychological cognition of the determinants of adoption behaviour on farmers' psychological cognition. We use three indices for farmers' cognition, including economic value, resource capacity, and ecosystem impact, to examine the differences between training and subsidy. Our findings showed that two policy measures (training and subsidy) had a significant positive impact on vegetable farmers' fertilizer application. Farmers' cognition played a mediating role. We identified and discussed the influence of policy measures on farmers' behaviour and the mediating role of farmers' cognition. Hence, we suggest that local governments should strengthen farmers' training in relation to fertilizer application techniques and enhance farmers' cognition of organic fertilizer as a substitute for chemical fertilizer in terms of economic, resource and environment aspects.

Radiomic-signature changes after early treatment improve the prediction of progression-free survival in patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer.

BACKGROUND: The prognosis of lung cancer varies widely, even in cases wherein the tumor stage, genetic mutation, and treatment regimens are the same. Thus, an effective means for risk stratification of patients with lung cancer is needed. PURPOSE: To develop and validate a combined model for predicting progression-free survival and risk stratification in patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treated with ensartinib. MATERIAL AND METHODS: We analyzed 203 tumor lesions in 114 patients and evaluated average radiomic feature measures from all lesions at baseline and changes in these features after early treatment (Δradiomic features). Combined models were developed by integrating clinical with radiomic features. The prediction performance and clinical value of the proposed models were evaluated using receiver operating characteristic analysis, calibration curve, decision curve analysis (DCA), and Kaplan-Meier survival analysis. RESULTS: Both the baseline and delta combined models achieved predictive efficacy with a high area under the curve. The calibration curve and DCA indicated the high accuracy and clinical usefulness of the combined models for tumor progression prediction. In the Kaplan-Meier analysis, the delta and baseline combined models, Δradiomic signature, and two selected clinical features could distinguish patients with a higher progression risk within 42 weeks. The delta combined model had the best performance. CONCLUSION: The combination of clinical and radiomic features provided a prognostic value for survival and progression in patients with NSCLC receiving ensartinib. Radiomic-signature changes after early treatment could be more valuable than those at baseline alone.