Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis.

BACKGROUND: The association between tumor-infiltrating lymphocyte (TIL) levels and the response to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC) remains unclear. AIM: To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients. METHODS: A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31, 2023. The correlation between TIL levels and the NAT pathologic complete response (pCR) in TNBC patients was assessed using a systematic review and meta-analysis. Subgroup analysis, sensitivity analysis, and publication bias analysis were also conducted. RESULTS: A total of 32 studies were included in this meta-analysis. The overall meta-analysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup (48.0% vs 27.7%) (risk ratio 2.01; 95% confidence interval 1.77-2.29; P < 0.001, I 2 = 56%). Subgroup analysis revealed that the between-study heterogeneity originated from differences in study design, TIL level cutoffs, and study populations. Publication bias could have existed in the included studies. The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols (all P ≤ 0.01), and there was no significant between-protocol difference in the statistics among the different NAT protocols (P = 0.29). Additionally, sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded. CONCLUSION: TILs can serve as a predictor of the response to NAT treatment in TNBC patients. TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs, and this predictive capability is consistent across different NAT regimens.

Salvage surgery and conversion surgery for patients with non-small cell lung cancer: A narrative review.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths. With the development of screening, patient selection and treatment strategies, patients' survival outcomes and living quality significantly improved. However, some patients still have local recurrence or residual tumors after receiving definitive therapies. Salvage surgery has been regarded as an effective option for recurrent or residual NSCLC, but its effectiveness remains undetermined. Furthermore, conversion surgery is a special type of salvage surgery for tumors converted from "initially unresectable" to "potentially resectable" status due to a favorable response to systemic treatments. Although conversion surgery is a promising curative procedure for advanced NSCLC, its concept and clinical value remain unfamiliar to clinicians. In this narrative review, we provided an overview of the safety and efficacy of salvage surgery, especially salvage surgery after sublobar resection in early-stage NSCLC. More importantly, we highlighted the concept and value of conversion surgery after systemic treatment in advanced NSCLC to gain some insights into its role in the treatment of lung cancer.

[Chemical composition and pharmacological effects of Cinnamomum camphora chvar. borneol essential oil: a review].

Cinnamomum camphora chvar. borneol, a rare camphor tree variant recently identified in China, is distinguished by its high concentration of D-borneol, also known as " plant gold" due to its significant value. The essential oil extracted from this variant,rich in monoterpenes and sesquiterpenes, demonstrates a broad spectrum of pharmacological activities, including analgesic, antiinflammatory, antioxidant, cognition-enhancing, anti-bacterial, and insecticidal effects. These properties, underscored by extensive research, highlight the oil's potential in the biomedical, chemical, and food sectors as a valuable commodity. Nonetheless, the safety profile of this valuable oil remains poorly characterized, with its chemical composition and therapeutic efficacy subject to variations in the factors like geographic origin, harvesting timing, part used for extraction, and processing techniques. Such variability poses challenges to its clinical application and hampers the efficient exploitation of this resource. This review synthesizes current studies on C. camphora chvar. borneol essential oil and provides a detailed examination of its chemical and pharmacological profiles. In this study, we discuss existing research gaps and propose strategies for advancing its clinical use and industrial application, aiming to provide a foundational reference for future investigations and the resolution of its commercial and therapeutic challenges.

Prognostic factors for patients with pathologic T1-T2N+ esophageal squamous cell carcinoma: A retrospective study with external validation.

BACKGROUND: Lymph node metastasis is significantly associated with a worse prognosis in patients with localized early-stage esophageal squamous cell carcinoma. This study aimed to explore the prognostic factors and develop a nomogram for predicting survival in patients with pathologic T1-2N+ esophageal squamous cell carcinoma. METHODS: Between 2014 and 2022, patients with pT1-2N+ esophageal squamous cell carcinoma who underwent esophagectomy with lymphadenectomy at 2 institutes were reviewed and assigned to training and external validation cohorts. Independent prognostic factors were identified via univariate and multivariate Cox regression analyses. The nomogram model was developed and evaluated by the area under the receiver operating characteristic curve and calibration curve. RESULTS: In total, 268 patients with a median age of 65 years (range, 40-82) were included and assigned to training (n = 190) and external validation (n = 78) cohorts. The Cox proportional hazards model demonstrated that body mass index (P = .031), surgical approach (P < .001), T stage (P = .015), and Clavien-Dindo classification (P < .001) were independent prognostic factors in the training cohort. The nomogram showed good discrimination, with an area under the receiver operating characteristic curve for 1-year, 3-year, and 5-year of 0.810, 0.789, and 0.809 in the training cohort and 0.782, 0.679, and 0.698 in the validation cohort. The calibration curve showed that the predicted survival probability was in good agreement with the actual survival probability. CONCLUSION: Lower body mass index, left surgical approach, T2 stage, and Clavien-Dindo classification grade III to V were related to worse prognosis in patients with pT1-T2N+ esophageal squamous cell carcinoma. The developed nomogram may predict individual survival accurately.

Synthesis, Fluorescence, and Bioactivity of Novel Isatin Derivatives.

The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1PTP with IC50 of 11 ± 3 µM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 µM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.

Clinical outcomes and biomarker exploration of first-line PD-1 inhibitors plus chemotherapy in patients with low PD-L1-expressing of gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial. METHODS: We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis. RESULTS: Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029). CONCLUSIONS: PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy.

Small molecule targeted therapies for endometrial cancer: progress, challenges, and opportunities.

Endometrial cancer (EC) is a common malignancy among women worldwide, and its recurrence makes it a common cause of cancer-related death. Surgery and external radiation, chemotherapy, or a combination of strategies are the cornerstone of therapy for EC patients. However, adjuvant treatment strategies face certain drawbacks, such as resistance to chemotherapeutic drugs; therefore, it is imperative to explore innovative therapeutic strategies to improve the prognosis of EC. With the development of pathology and pathophysiology, several biological targets associated with EC have been identified, including PI3K/Akt/mTOR, PARP, GSK-3ß, STAT-3, and VEGF. In this review, we summarize the progress of small molecule targeted therapies in terms of both basic research and clinical trials and provide cases of small molecules combined with fluorescence properties in the clinical applications of integrated diagnosis and treatment. We hope that this review will facilitate the further understanding of the regulatory mechanism governing the dysregulation of oncogenic signaling in EC and provide insights into the possible future directions of targeted therapeutic regimens for EC treatment by developing new agents with fluorescence properties for the clinical applications of integrated diagnosis and treatment.

Echinatin suppresses cutaneous squamous cell carcinoma by targeting GSTM3-mediated ferroptosis.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers for which effective drugs are urgently needed. Echinatin, a natural compound extracted from Glycyrrhiza plants, has shown promising antitumour effects. However, the efficacy and the direct target of echinatin in cSCC remain unclear. PURPOSE: This study conducted a systematic investigation of the antitumour effects of echinatin on cSCC and the underlying mechanisms involved. STUDY DESIGN AND METHODS: Three cSCC cell lines, a xenograft model, and a UV-induced cSCC mouse model were used to investigate the potential protective effects of echinatin. The interactions between echinatin and glutathione S-transferase mu3 (GSTM3) and between echinatin and peroxiredoxin-2 (PRDX2) were evaluated by a proteome microarray assay, pull-down LC‒MS/MS analysis, surface plasmon resonance, and molecular docking. The potential mechanisms of GSTM3-mediated echinatin activity were analysed by using western blotting, lentivirus infection and small interfering RNA (siRNA) transfection. RESULTS: In this study, we found that echinatin inhibited the proliferation and migration of cSCC cells but had no cytotoxic effect on primary human keratinocytes. Furthermore, echinatin significantly inhibited tumour growth in vivo. Mechanistically, our data showed that echinatin could directly bind to GSTM3 and PRDX2. Notably, echinatin inhibited GSTM3 and PRDX2 levels by promoting their proteasomal degradation, which led to the disruption of ROS production. We then revealed that echinatin increased mitochondrial ROS production by inhibiting GSTM3. Moreover, echinatin triggered ferroptosis by inhibiting GSTM3-mediated ferroptosis negative regulation (FNR) proteins. In addition, echinatin regulated GSTM3-mediated ROS/MAPK signalling. CONCLUSION: Echinatin has good antitumour effects both in vitro and in vivo. Moreover, our findings indicate that GSTM3 and PRDX2 could function as viable targets of echinatin in cSCC. Consequently, echinatin represents a novel treatment for cSCC through the targeting of GSTM3-mediated ferroptosis.

Clinicopathological characteristics and typing of multilocular cystic renal neoplasm of low malignant potential.

BACKGROUND: Up until now, no research has been reported on the association between the clinical growth rate of multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) and computed tomography (CT) imaging characteristics. Our study sought to examine the correlation between them, with the objective of distinguishing unique features of MCRNLMP from renal cysts and exploring effective management strategies. AIM: To investigate optimal management strategies of MCRNLMP. METHODS: We retrospectively collected and analyzed data from 1520 patients, comprising 1444 with renal cysts and 76 with MCRNLMP, who underwent renal cyst decompression, radical nephrectomy, or nephron-sparing surgery for renal cystic disease between January 2013 and December 2021 at our institution. Detection of MCRNLMP utilized the Bosniak classification for imaging and the 2016 World Health Organization criteria for clinical pathology. RESULTS: Our meticulous exploration has revealed compelling findings on the occurrence of MCRNLMP. Precisely, it comprises 1.48% of all cases involving simple renal cysts, 5.26% of those with complex renal cysts, and a noteworthy 12.11% of renal tumors coexisting with renal cysts, indicating a statistically significant difference (P = 0.001). Moreover, MCRNLMP constituted a significant 22.37% of the patient population whose cysts demonstrated a rapid growth rate of ≥ 2.0 cm/year, whereas it only represented 0.66% among those with a growth rate below 2.0 cm/year. Of the 76 MCRNLMP cases studied, none of the nine patients who underwent subsequent nephron-sparing surgery or radical nephrectomy following renal cyst decompression experienced recurrence or metastasis. In the remaining 67 patients, who were actively monitored over a 3-year postoperative period, only one showed suspicious recurrence on CT scans. CONCLUSION: MCRNLMP can be tentatively identified and categorized into three types based on CT scanning and growth rate indicators. In treating MCRNLMP, partial nephrectomy is preferred, while radical nephrectomy should be minimized. After surgery, active monitoring is advisable to prevent unnecessary nephrectomy.

Use of MRI Radiomics Models in Evaluating the Low HER2 Expression in Breast Cancer.

Objective: To investigate the magnetic resonance imaging (MRI) radiomics models in evaluating the human epidermal growth factor receptor 2(HER2) expression in breast cancer. Materials and Methods: The MRI data of 161 patients with invasive ductal carcinoma (non-special type) of breast cancer were retrospectively collected, and the MRI radiomics models were established based on the MRI imaging features of the fat suppression T2 weighted image (T2WI) sequence, dynamic contrast-enhanced (DCE)-T1WIsequence and joint sequences. The T-test and the least absolute shrinkage and selection operator (LASSO) algorithm were used for feature dimensionality reduction and screening, respectively, and the random forest (RF) algorithm was used to construct the classification model. Results: The model established by the LASSO-RF algorithm was used in the ROC curve analysis. In predicting the low expression state of HER2 in breast cancer, the radiomics models of the fat suppression T2WI sequence, DCE-T1WI sequence, and the combination of the two sequences showed better predictive efficiency. In the receiver operating characteristic (ROC) curve analysis for the verification set of low, negative, and positive HER2 expression, the area under the ROC curve (AUC) value was 0.81, 0.72, and 0.62 for the DCE-T1WI sequence model, 0.79, 0.65 and 0.77 for the T2WI sequence model, and 0.84, 0.73 and 0.66 for the joint sequence model, respectively. The joint sequence model had the highest AUC value. Conclusions: The MRI radiomics models can be used to effectively predict the HER2 expression in breast cancer and provide a non-invasive and early assistant method for clinicians to formulate individualized and accurate treatment plans

RENAL PROTECTIVE EFFECT AND CLINICAL ANALYSIS OF VITAMIN B 6 IN PATIENTS WITH SEPSIS.

ABSTRACT: Objective: To investigate the protective effect and possible mechanisms of vitamin B 6 against renal injury in patients with sepsis. Methods: A total of 128 patients with sepsis who met the entry criteria in multiple centers were randomly divided into experimental (intravenous vitamin B 6 therapy) and control (intravenous 0.9% sodium chloride therapy) groups based on usual care. Clinical data, the inflammatory response indicators interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor (TNF-α), and endothelin-1 (ET-1), the oxidative stress response indicators superoxide dismutase, glutathione and malondialdehyde, and renal function (assessed by blood urea nitrogen, serum creatinine, and renal resistance index monitored by ultrasound) were compared between the two groups. Results: After 7 d of treatment, the IL-6, IL-8, TNF-α, and ET-1 levels in the experimental group were significantly lower than those in the control group, the oxidative stress response indicators were significantly improved in the experimental group and the blood urea nitrogen, serum creatinine, and renal resistance index values in the experimental group were significantly lower than those in the control group ( P < 0.05). There was no statistical difference between the two groups in the rate of renal replacement therapy and 28 d mortality ( P > 0.05). However, the intensive care unit length of stay and the total hospitalization expenses in the experimental group were significantly lower than those in the control group ( P < 0.05). Conclusion: The administration of vitamin B 6 in the treatment of patients with sepsis attenuates renal injury, and the mechanism may be related to pyridoxine decreasing the levels of inflammatory mediators and their regulation by redox stress.

The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. METHODS: We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. RESULTS: A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. CONCLUSIONS: The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.

B-Myb deficiency boosts bortezomib-induced immunogenic cell death in colorectal cancer.

B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb-defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb-defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb-defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage-associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb-defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.

Chronic infectious unilateral giant thyroid cyst related to diabetes mellitus: A case report.

BACKGROUND: Patients rarely develop complicated infections in thyroid cysts. Here, we describe a patient with chronic infected unilateral giant thyroid cyst related to diabetes mellitus (DM). CASE SUMMARY: A 66-year-old male was admitted due to an evident neck lump for 5 d after approximately 40 years of gradually progressive neck mass and 7 years of DM. Doppler ultrasound and computed tomography scan showed a giant lump in the left thyroid gland lobe. He was diagnosed with a large thyroid nodule complicated by tracheal dislocation and had surgical indications. Surgical exploration revealed evident inflammatory edema and exudation between the left anterior neck muscles, the nodule and glandular tissue. Fortunately, inflammatory lesions did not affect major neck vessels. Finally, a left partial thyroidectomy was performed. Macroscopic observation showed that the cystic thyroid mass consisted of extensive cystic wall calcification and was rich in massive rough sand-like calculi content and purulent matter. Postoperative pathology confirmed benign thyroid cyst with chronic infection. CONCLUSION: The progression of this chronic infectious unilateral giant thyroid cyst may have been related to DM, and identifying blood vessels involvement can prevent serious complications during operation.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

UNVEILING THE PROTECTIVE MECHANISMS OF PUERARIN AGAINST ACUTE LUNG INJURY: A COMPREHENSIVE EXPLORATION OF THE ROLES AND MECHANISMS OF MST1/ERS SIGNALING.

ABSTRACT: Objectives: Puerarin, the principal active constituent extracted from Pueraria, is believed to confer protection against sepsis-induced lung injury. The study aimed to elucidate the role and mechanism of Mst1/ERS in puerarin-mediated protection against acute lung injury (ALI). Methods: Monolayer vascular endothelial cell permeability was assessed by gauging the paracellular flow of FITC-dextran 40,000 (FD40). ELISA was employed for the quantification of inflammatory cytokines. Identification of target proteins was conducted through western blotting. Histological alterations and apoptosis were scrutinized using hematoxylin-eosin staining and TUNEL staining, respectively. The ultrastructure of the endoplasmic reticulum was observed via transmission electron microscopy. Results: Puerarin significantly protected mice from LPS-induced ALI, reducing lung interstitial width, neutrophil and lymphocyte infiltration, pulmonary interstitial and alveolar edema, and lung apoptosis. Puerarin treatment also markedly attenuated levels of TNF-α and IL-1ß in both alveolar lavage fluid and serum. Furthermore, puerarin significantly attenuated LPS-induced increases in Mst1, GRP78, CHOP, and Caspase12 protein expression and blunted LPS-induced decrease in ZO-1 protein expression in lung tissues. Puerarin obviously reduced endoplasmic reticulum expansion and vesiculation. Similarly, puerarin significantly mitigated the LPS-induced reduction in HUVEC cell viability and ZO-1 expression. Puerarin also attenuated LPS-induced increase in apoptosis, TNF-α and IL-1ß, FD40 flux, and Mst1, GRP78, CHOP, and Caspase12 expression in HUVEC cells. Nevertheless, the inhibitory impact of puerarin on vascular endothelial cell injury, lung injury, and endoplasmic reticulum stress (ERS) was diminished by Mst1 overexpression. Conclusion: These findings demonstrated that the Mst1/ERS signaling pathway played a pivotal role in the development of LPS-induced vascular endothelial cell dysfunction and ALI. Puerarin exhibited the ability to attenuate LPS-induced vascular endothelial cell dysfunction and ALI by inhibiting the Mst1/ERS signaling pathway.

Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors Versus Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma with First- or Lower-Order Portal Vein Tumor Thrombosis.

PURPOSE: To compare the efficacy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (TACE-TKI-ICI) versus TKIs plus ICIs (TKI-ICI) for unresectable hepatocellular carcinoma (HCC) with first- or lower-order portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS: A retrospective study was performed in HCC patients with first- or lower-order PVTT receiving TKIs (Lenvatinib or sorafenib) plus ICIs (camrelizumab, sintilimab, or atezolizumab) with or without TACE from four institutions between January 2019 and January 2022. Propensity score-based method was performed to minimize bias by confounding factors. Tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated and compared between the two groups. RESULTS: After inverse probability of treatment weighting, two balanced pseudopopulations were created: 106 patients in the TACE-TKI-ICI group and 109 patients in the TKI-ICI group. The objective response rate was higher in the TACE-TKI-ICI group (50.9% vs. 28.4%, P < 0.001). The median PFS and OS were significantly longer in the TACE-TKI-ICI group than in the TKI-ICI group (PFS: 9.1 vs. 5.0 months, P = 0.005; OS: 19.1 vs. 12.7 months, P = 0.002). In Cox regression, TACE-TKI-ICI treatment was an independent predictor of favorable OS. Treatment-related grade 3/4 AEs were comparable between the two groups (22.6% vs. 17.9%, P = 0.437). CONCLUSION: TACE-TKI-ICI therapy contributed to better tumor control, PFS and OS than TKI-ICI therapy in unresectable HCC patients with first- or lower-order PVTT.

Causal association of rheumatoid arthritis with frailty and the mediation role of inflammatory cytokines: A Mendelian randomization study.

BACKGROUND: Previous observational studies have suggested the association between rheumatoid arthritis (RA) and frailty. However, it remains obscure whether this association is causal. This study aims to investigate the causal association of RA with frailty and the mediation effect of inflammatory cytokines using Mendelian randomization (MR) design. METHODS: Summary-level data for RA (N = 58,284), frailty index (FI) (N = 175,226), Fried frailty score (FFS) (N = 386,565), and 41 inflammatory cytokines (N = 8,293) were obtained from recent genome-wide association studies. Univariable and multivariable MR analyses were conducted to investigate and verify the causal association of RA with frailty. The potential mediation effects of inflammatory cytokines were estimated using two-step MR. RESULTS: Univariable inverse variance weighted MR analysis suggested that genetically determined RA was associated with increased FI (beta=0.021; 95 % CI: 0.012, 0.03; p = 2.2 × 10-6) and FFS (beta=0.011; 95 %CI: 0.007, 0.015; p = 8.811 × 10-8). The consistent results were observed in multivariable MR analysis after adjustment for asthma, smoking, BMI, physical activity, telomere length, and depression. Mediation analysis showed evidence of an indirect effect of RA on FI through monokine induced by interferon-gamma (MIG) with a mediated proportion of 9.8 % (95 %CI: 4.76 %, 19.05 %), on FFS via MIG and stromal cell-derived factor-1 alpha with a mediated proportion of 9.6 % (95 %CI: 0 %, 18.18 %) and 8.44 % (95 %CI: 0 %, 18.18 %), respectively. CONCLUSION: This study provided credible evidence that genetically predicted RA was associated with a higher risk of frailty. Additionally, inflammatory cytokines were involved in the mechanism of RA-induced frailty.