Mucinous histology is a negative predictor of neoadjuvant chemoradiotherapy for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. METHODS: A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality. RESULTS: Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18-0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22-0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16-1.12) after NCRT. CONCLUSION: MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant.

Role of N6-methyladenosine in tumor neovascularization.

Tumor neovascularization is essential for the growth, invasion, and metastasis of tumors. Recent studies have highlighted the significant role of N6-methyladenosine (m6A) modification in regulating these processes. This review explores the mechanisms by which m6A influences tumor neovascularization, focusing on its impact on angiogenesis and vasculogenic mimicry (VM). We discuss the roles of m6A writers, erasers, and readers in modulating the stability and translation of angiogenic factors like vascular endothelial growth factor (VEGF), and their involvement in key signaling pathways such as PI3K/AKT, MAPK, and Hippo. Additionally, we outline the role of m6A in vascular-immune crosstalk. Finally, we discuss the current development of m6A inhibitors and their potential applications, along with the contribution of m6A to anti-angiogenic therapy resistance. Highlighting the therapeutic potential of targeting m6A regulators, this review provides novel insights into anti-angiogenic strategies and underscores the need for further research to fully exploit m6A modulation in cancer treatment. By understanding the intricate role of m6A in tumor neovascularization, we can develop more effective therapeutic approaches to inhibit tumor growth and overcome treatment resistance. Targeting m6A offers a novel approach to interfere with the tumor's ability to manipulate its microenvironment, enhancing the efficacy of existing treatments and providing new avenues for combating cancer progression.

The Role and Therapeutic Potential of Pyroptosis in Colorectal Cancer: A Review.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The unlimited proliferation of tumor cells is one of the key features resulting in the malignant development and progression of CRC. Consequently, understanding the potential proliferation and growth molecular mechanisms and developing effective therapeutic strategies have become key in CRC treatment. Pyroptosis is an emerging type of regulated cell death (RCD) that has a significant role in cells proliferation and growth. For the last few years, numerous studies have indicated a close correlation between pyroptosis and the occurrence, progression, and treatment of many malignancies, including CRC. The development of effective therapeutic strategies to inhibit tumor growth and proliferation has become a key area in CRC treatment. Thus, this review mainly summarized the different pyroptosis pathways and mechanisms, the anti-tumor (tumor suppressor) and protective roles of pyroptosis in CRC, and the clinical and prognostic value of pyroptosis in CRC, which may contribute to exploring new therapeutic strategies for CRC.

The deubiquitinase OTUD1 deubiquitinates TIPE2 and plays a protective role in sepsis-induced lung injury by targeting TAK1-mediated MAPK and NF-κB signaling.

Ovarian tumor domain-containing protease 1 (OTUD1) is a critical negative regulator that promotes innate immune homeostasis and is extensively involved in the pathogenesis of sepsis. In this study, we performed a powerful integration of multiomics analysis and an experimental mechanistic investigation to elucidate the immunoregulatory role of OTUD1 in sepsis at the clinical, animal and cellular levels. Our study revealed the upregulation of OTUD1 expression and the related distinctive alterations observed via multiomics profiling in clinical and experimental sepsis. Importantly, in vivo and in vitro, OTUD1 was shown to negatively regulate inflammatory responses and play a protective role in sepsis-induced pathological lung injury by mechanistically inhibiting the activation of the transforming growth factor-beta-activated kinase 1 (TAK1)-mediated mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in the present study. Subsequently, we probed the molecular mechanisms underlying OTUD1's regulation of NF-κB and MAPK pathways by pinpointing the target proteins that OTUD1 can deubiquitinate. Drawing upon prior research conducted in our laboratory, it has been demonstrated that tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) performs a protective function in septic lung injury and septic encephalopathy by suppressing the NF-κB and MAPK pathways. Hence, we hypothesized that TIPE2 might be a target protein of OTUD1. Additional experiments, including Co-IP, immunofluorescence co-localization, and Western blotting, revealed that OTUD1 indeed has the ability to deubiquitinate TIPE2. In summary, OTUD1 holds potential as an immunoregulatory and inflammatory checkpoint agent, and could serve as a promising therapeutic target for sepsis-induced lung injury.

Clinically Applicable Pan-Origin Cancer Detection for Lymph Nodes via Artificial Intelligence-Based Pathology.

INTRODUCTION: Lymph node metastasis is one of the most common ways of tumour metastasis. The presence or absence of lymph node involvement influences the cancer's stage, therapy, and prognosis. The integration of artificial intelligence systems in the histopathological diagnosis of lymph nodes after surgery is urgent. METHODS: Here, we propose a pan-origin lymph node cancer metastasis detection system. The system is trained by over 700 whole-slide images (WSIs) and is composed of two deep learning models to locate the lymph nodes and detect cancers. RESULTS: It achieved an area under the receiver operating characteristic curve (AUC) of 0.958, with a 95.2% sensitivity and 72.2% specificity, on 1,402 WSIs from 49 organs at the National Cancer Center, China. Moreover, we demonstrated that the system could perform robustly with 1,051 WSIs from 52 organs from another medical centre, with an AUC of 0.925. CONCLUSION: Our research represents a step forward in a pan-origin lymph node metastasis detection system, providing accurate pathological guidance by reducing the probability of missed diagnosis in routine clinical practice.

Tumour-derived exosome SNHG17 induced by oestrogen contributes to ovarian cancer progression via the CCL13-CCR2-M2 macrophage axis.

Oestrogen is known to be strongly associated with ovarian cancer. There was much work to show the importance of lncRNA SNHG17 in ovarian cancer. However, no study has revealed the molecular regulatory mechanism and functional effects between oestrogen and SNHG17 in the development and metastasis of ovarian cancer. In this study, we found that SNHG17 expression was significantly increased in ovarian cancer and positively correlated with oestrogen treatment. Oestrogen could promote M2 macrophage polarization as well as ovarian cancer cells SKOV3 and ES2 cell exosomal SNHG17 expression. When exposure to oestrogen, exosomal SNHG17 promoted ovarian cancer cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro, and tumour growth and lung metastasis in vivo by accelerating M2-like phenotype of macrophages. Mechanically, exosomal SNHG17 could facilitate the release of CCL13 from M2 macrophage via the PI3K-Akt signalling pathway. Moreover, CCL13-CCR2 axis was identified to be involved in ovarian cancer tumour behaviours driven by oestrogen. There results demonstrate a novel mechanism that exosomal SNHG17 exerts an oncogenic effect on ovarian cancer via the CCL13-CCR2-M2 macrophage axis upon oestrogen treatment, of which SNHG17 may be a potential biomarker and therapeutic target for ovarian cancer responded to oestrogen.

Oxymatrine alleviates high-fat diet/streptozotocin-induced non-alcoholic fatty liver disease in C57BL/6 J mice by modulating oxidative stress, inflammation and fibrosis.

Non-alcoholic fatty liver disease (NAFLD) represents a complex complication of type 2 diabetes mellitus (T2DM). Oxymatrine (OMT) is an alkaloid extracted from Sophora flavescens with broad pharmacological effects. However, there is currently a lack of research on OMT in the field of NAFLD. The present study aimed to explore the effects and underlying mechanisms of oxymatrine in treating T2DM with NAFLD. The T2DM mice model was induced by high-fat diet (HFD) combined with streptozotocin (STZ) injection in male C57BL/6 J mice. Animals were randomly divided into four groups (n = 8): Control group, DC group, OMT-L group (45 mg/kg i.g.), and OMT-H group (90 mg/kg, i.g.). The drug was administered once a day for 8 weeks. In addition, HepG2 hepatocytes were incubated with palmitic acid (PA) to establish a fatty liver cell model. Treated with OMT, the body weight and fasting blood glucose (FBG) of DC mice were reduced and the liver organ coefficient was significantly optimized. Meanwhile, OMT markedly enhanced the activities of key antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and also reduced malondialdehyde (MDA) levels. These biochemical alterations were accompanied by noticeable improvements in liver histopathology. Furthermore, OMT down-regulated the expression of NOD-like receptor protein 3 (NLRP3), interleukin-1ß (IL-1ß), transforming growth factor-ß1 (TGF-ß1) and collagen I significantly, highlighting its potential in modulating inflammatory and fibrotic pathways. In conclusion, OMT improved liver impairment effectively in diabetic mice by suppressing oxidative stress, inflammation and fibrosis. These results suggest that OMT may represent a novel therapy for NAFLD with diabetes.

The Global Leadership Initiative on Malnutrition criteria for diagnosis of malnutrition and outcomes prediction in emergency abdominal surgery.

OBJECTIVES: Malnutrition has adverse postoperative outcomes, especially in emergency surgery. Among the numerous tools for nutritional assessment, this study aims to investigate malnutrition diagnosed by Global Leadership Initiative on Malnutrition criteria and the Global Leadership Initiative on Malnutrition predictive value for outcomes after emergency abdominal surgery. METHODS: This was a prospective observational study. Among the 468 patients undergoing emergency abdominal surgery admitted to a department of emergency surgery from June 2020 to December 2021, 53 patients were not eligible for enrollment, and 19 patients had missing data. Thus, the final number of participants was 396. Muscle mass was evaluated by skeletal muscle index at the third lumbar vertebra on computed tomography scans, and the lower quartile was defined as the threshold of muscle mass reduction. The associations of Global Leadership Initiative on Malnutrition, Global Leadership Initiative on Malnutrition (muscle mass reduction excluded), and skeletal muscle index with in-hospital mortality, postoperative complications, and postoperative stay were evaluated using χ2. In addition, confounding factors were screened, regression models were established, and the Global Leadership Initiative on Malnutrition predictive value was analyzed for clinical outcome. Ethical approval was obtained from the appropriate department. RESULTS: Malnutrition was observed in 19.9% of the total 396 patients based on the Global Leadership Initiative on Malnutrition and in 12.4% on the Global Leadership Initiative on Malnutrition (muscle mass reduction excluded). Sarcopenia by skeletal muscle index was found in 24.7% of patients. Univariate analysis indicated that in-hospital mortality, postoperative complications, infective complication rate, and postoperative hospital stay were significantly higher in malnourished and sarcopenic patients. Multivariate analysis found that malnutrition diagnosed by the Global Leadership Initiative on Malnutrition was predictive for complications, infective complications, and postoperative stay (total postoperative complications: odds ratio = 3.620; 95% CI, 1.635-8.015; P = 0.002; infective complications: odds ratio = 3.127; 95% CI, 1.194-8.192; P = 0.020; and postoperative stay: regression coefficient = 2.622; P = 0.022). The Global Leadership Initiative on Malnutrition (muscle mass reduction excluded) identified postoperative complications and postoperative stay (total postoperative complications: odds ratio = 3.364; 95% CI, 1.247-9.075; P = 0.017 and postoperative stay: regression coefficient = 3.547; P = 0.009). Sarcopenia by skeletal muscle index was a risk factor for postoperative complications (odds ratio = 3.366; 95% CI, 1.587-7.140; P = 0.002). CONCLUSION: The Global Leadership Initiative on Malnutrition and Global Leadership Initiative on Malnutritison (muscle mass reduction excluded) had predictive value for adverse clinical outcomes due to malnutrition in patients undergoing emergency abdominal surgery.

Phellinus igniarius polysaccharides induced mitochondrial apoptosis of hepatic carcinoma by enhancing reactive oxygen species-mediated AKT/p53 signalling pathways.

Phellinus igniarius (PI) has various kinds of biological activities, such as antitumour activities, and polysaccharides are one of its main components. In this study, polysaccharides from PI (PIP) were prepared, purified, analysed for their structure and investigated for their antitumour activity and mechanism in vitro. PIP consists of 12138 kDa of carbohydrates containing 90.5 ± 1.6% neutral carbohydrates. PIP consists of glucose, galactose, mannose, xylose, D-fructose, L-guluronic acid, glucosamine hydrochloride, rhamnose, arabinose and D-mannoturonic acid. PIP can significantly inhibit HepG2 cell proliferation, induce cell apoptosis and also inhibited migration and invasion in a concentration-dependent manner. PIP increased reactive oxygen species (ROS), increased the expression of p53, and induced cytochrome c release into the cytoplasm to activate caspase-3. PIP is a promising potential candidate for the therapeutic treatment of hepatic carcinoma via the ROS-mediated mitochondrial apoptosis pathway.

Exposure to organochlorine pesticides and polychlorinated biphenyls, adherence to an ideal cardiovascular health, and arterial stiffness among Chinese adults.

This study aimed to assess the relationships between exposure to individual organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and their mixture and arterial stiffness and explore whether adherence to an ideal cardiovascular health (CVH) could mitigate these associations. The cross-sectional study enrolled 1437 Chinese adults between March and May 2019 in Wuhan, China. OCPs and PCBs concentrations were measured using solid phase extraction coupled with gas chromatography-tandem mass spectrometry. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). CVH was determined by three behavioral and four biological metrics and categorized as ideal, intermediate, and poor CVH. We applied generalized linear model and weighted quantile sum (WQS) regression to evaluate the associations of exposure to individual OCPs or PCBs and their mixture with baPWV, respectively. We found that participants with detectable levels of heptachlor epoxide, PCB-153, and PCB-180 had higher baPWV (ß: 34.25, 95% CI 14.28-54.22; ß: 27.64, 95% CI 7.90-47.38; and ß: 30.51, 95% CI 10.68-50.35) than those with undetectable levels. In WQS regression, the mixture of OCPs and PCBs was related to a higher baPWV (ß: 24.93, 95% CI 2.70-47.15). Compared with participants with ideal CVH and undetectable OCPs or PCBs levels, those with poor CVH and detectable OCPs or PCBs levels had the highest increase in baPWV (heptachlor epoxide: ß: 147.94, 95% CI 112.52-183.55; PCB-153: ß: 150.22, 95% CI 115.40-185.04; PCB-180: ß: 147.02, 95% CI 111.66-182.38). Our findings suggested that individual OCPs, PCBs, and their mixture exposure were positively associated with arterial stiffness, and adherence to an ideal CVH may mitigate the adverse effect.

Reverse Lumbar Pedicle Screw in Oblique Lateral Interbody Fusion: A Novel Concept to Restrict Cage Subsidence.

OBJECTIVE: Cage subsidence is a common morbidity after oblique lumbar interbody fusion (OLIF), with risk of compromising clinical and radiographic outcomes. The study aims to describe an innovative reverse lumbar pedicle screw (RLPS) technique in OLIF and compare its effect on restricting cage subsidence with classical lateral fixation (LF) in radiological and clinical evaluation. METHOD: Consecutive patients having undergone single-level OLIF-LF/RLPS from 2018 to 2020 were retrospectively reviewed. In OLIF-RLPS, the upper entry point was determined at the intersection between one horizontal line (1 cm above inferior endplate) and one vertical line (dissecting anterior and middle thirds of the vertebra) while the inferior entry point between one horizontal line (5 mm below superior endplate) and the same vertical line. Trajectories were from vertebrae reverse into contralateral pedicle. Radiological evaluation included disc height (DH) and segmental lordosis (SL); cage subsidence was evaluated by DH loss. Clinical assessment included visual analogue scale (VAS) and Oswestry disability index (ODI). Student t or Mann-Whitney U test was used for continuous variation according to normality analysis while Chi-square test for category variation. RESULTS: A total of 29 patients had been enrolled in the study including 14 cases in the RLPS group and 15 cases in the LF group. The DH in the OLIF-RLPS group had increased from the preoperative 9.07 ± 1.73 mm to 13.73 ± 1.83 mm postoperatively, without significant difference compared with the OLIF-LF group during the perioperative, but decreased to 12.53 ± 1.74 mm in 3 months and maintained at 12.00 ± 1.45 mm in 12 months, significantly higher than the OLIF-LF group (p < 0.05). At the last follow-up, 7.1% (1/14) cases in the OLIF-RLPS group had shown subsidence of grade I, significantly less than 46.7% (7/15) cases in the OLIF-LF group. Pain and disability had improved similarly in two groups, without significant difference detected between two groups at the last follow-up. CONCLUSION: RLPS technique with modified entry points and prolonged trajectory could effectively restrict cage subsidence in OLIF postoperatively compared with traditional lateral fixation.

A novel 4-1BB/HER2 bispecific antibody shows potent antitumor activities by increasing and activating tumor-infiltrating T cells.

Resistance to HER2-targeted therapy narrows the efficacy of cancer immunotherapy. Although 4-1BB/CD137 is a promising drug target as a costimulatory molecule of immune cells, no therapeutic drug has been approved in the clinic because of systemic toxicity or limited efficacy. Previously, we developed a humanized anti-HER2 monoclonal antibody (mAb) HuA21 and anti-4-1BB mAb HuB6 with distinct antigen epitopes for cancer therapy. Here, we generated an Fc-muted IgG4 HER2/4-1BB bispecific antibody (BsAb) HK006 by the fusion of HuB6 scFv and HuA21 Fab. HK006 exhibited synergistic antitumor activity by blocking HER2 signal transduction and stimulating the 4-1BB signaling pathway simultaneously and strictly dependent on HER2 expression in vitro and in vivo. Strikingly, HK006 treatment enhanced antitumor immunity by increasing and activating tumor-infiltrating T cells. Moreover, HK006 did not induce nonspecific production of proinflammatory cytokines and had no obvious toxicity in mice. Overall, these data demonstrated that HK006 should be a promising candidate for HER2-positive cancer immunotherapy.

Circumferential approach via dynamic position in OLIF combined with freehand screw pedicle fixation for lumbar tuberculosis requiring multilevel instrumentation: a 3-year retrospective study.

PURPOSE: To advance a modified oblique lumbar interbody fusion (M-OLIF) achieving anterior debridement and posterior freehand instrumentation simultaneously in circumferential approach via dynamic position and compare with traditional combined anterior-posterior surgery (CAPS) in clinical and radiological evaluation. PATIENTS AND METHODS: Innovative freehand instrumentation in floating position was described. Consecutive patients having undergone surgeries for lumbar tuberculosis from 2017 January to 2019 December had been retrospectively reviewed. Patients with follow-ups for at least 36 months were included and divided into M-OLIF or CAPS group according to surgical methods applied. Outcomes included operation time, estimated blood loss, complication profile for safety evaluation; Vascular Analogue Scale (VAS) and Oswestry Disability Index (ODI) for efficacy evaluation; C-reactive protein and Erythrocyte Sedimentation Rate for tuberculosis activity and recurrence evaluation; X-ray and CT scan for radiological evaluation. RESULTS: Totally 56 patients had been enrolled in the study (26 for M-OLIF and 30 for CAPS). Compared with CAPS group, M-OLIF group illustrated significantly decreased estimated blood loss, operation time, hospital stay, and less postoperative morbidities. Meanwhile, M-OLIF group showed earlier improvement in VAS in 3 days and ODI in the first month postoperatively, without obvious discrepancy in further follow-ups. The overall screw accuracy in M-OLIF and CAPS group was 93.8% and 92.3% respectively, without significant difference in perforation distribution. CONCLUSION: M-OLIF was efficient for lumbar tuberculosis requiring multilevel fixation, with reduced operation time and iatrogenic trauma, earlier clinical improvement compared with traditional combined surgery.

Knockout of Erbin promotes pyroptosis via regulating NLRP3/caspase-1/Gasdermin D pathway in sepsis-induced acute kidney injury.

BACKGROUND: This study aims to investigate the correlation between Erbin and sepsis, and the role of Erbin on the pyroptosis pathway in acute kidney injury caused by sepsis and NLRP3/caspase-1/Gasdermin D pathway. METHODS: In the study, lipopolysaccharide (LPS) treatment or cecal ligation and puncture (CLP) surgery on mice were used to stimulate the in vitro and in vivo sepsis-induced renal injury model. The male C57BL/6 of wild-type mice (WT) and Erbin-knockout mice (Erbin-/-, EKO) were randomly divided into four groups (WT + Sham, WT + CLP, EKO + Sham, EKO + CLP). Inflammatory cytokine, renal function, pyroptotic cell numbers and the levels of protein and mRNA expression of pyroptosis, including the NLRP3 (all P < 0.05), were analyzed and found increase in Erbin-/- mice with CLP and LPS-induced HK-2 cells. RESULTS: The inhibited of Erbin shows a renal damaged effect by promoting NLRP3 inflammasome-mediated pyroptosis in SI-AKI. CONCLUSION: This study demonstrated a novel mechanism by which Erbin regulates NLRP3 inflammasome-mediated pyroptosis in SI-AKI.

Effects of Aidi injection on life quality and incidence of adverse reactions in patients with non-small cell lung cancer compared with traditional chemotherapy: a systematic review and meta-analysis.

Objective: Although the clinical application value of Aidi injection when treating non-small cell lung cancer (NSCLC) patients is explained only by the effectiveness of a certain literature or the improvement of a certain evaluation index, and the result is not convincing. To evaluate the effect of Aidi injection on life quality and incidence of adverse reactions in patients with NSCLCcompared with traditional chemotherapy. Methods: PubMed, EMBASE, ScienceDirect, Cochrane Library, China Journal full-text Database (CNKI), VIP full-text Database, Wanfang Database and Chinese Biomedical Literature data (CBM), search relevant Chinese and foreign periodicals, conference papers, degree papers, etc. were searched Database and China Biomedical Literature Database (CBM) to search case-control trials of Aidi injection when treating NSCLC patients. The retrieval period begins with the establishment of the database and ends when the database is closed. Cochrane Handbook 5.3 was adopted to assess the bias risk of each contained literature based on independently extracted data by two researchers. A meta-analysis of the collected data was carried out using RevMan5.3 statistical software. Results: 2306 articles were retrieved by computer database, 1422 articles were harvested by excluding repeated studies, 865 articles were harvested by preliminary reading of article titles and abstracts, and 533 articles were initially contained by excluding unrelated studies, reviews, case reports and uncontrolled articles, and then the full text of the literature was carefully read. Eight clinical controlled studies were finally included, with a total of 784 samples, after excluding 525 literatures with incomplete data and no primary outcome indicators. Data from the contained studies were not noticeably heterogeneous in the meta-analysis of treatment effectiveness. The fixed effect model analysis indicated that the treatment effective rate of the study group was noticeably better, and the difference was statistically significant(P<0.05). The findings of the heterogeneity test were clearly heterogeneous among the contained research data, according to the meta-analysis of the levels of T lymphocyte subsets following treatment. The random effect model analysis indicated that the improvement of the cellular immune function of the research group was obvious, and the difference was statistically significant (P<0.05). According to the meta-analysis of the life quality scores after treatment, data from the contained research were evidently heterogeneous, according to results of the heterogeneity test. The random effect model analysis indicated that the life quality of the study group was noticeably higher, and the difference was statistically significant (P<0.05). The levels of serum vascular endothelial growth factor (VEGF) after treatment were measured by meta. Data from the contained research were evidently heterogeneous, according to results of the heterogeneity test. Random effect model analysis indicated that the level of serum VEGF in the study group was noticeably lower, and the difference was not statistically significant (P>0.05). A meta-analysis was conducted on the incidence of adverse reactions after treatment. The results of the heterogeneity test indicated that data from the contained research were evidently heterogeneous. The incidence was noticeably lower, and the difference was statistically significant (P<0.05). The funnel chart was drawn based on the effective rate of treatment, the level of T lymphocyte subsets, the score of life quality, the level of serum VEGF and the incidence of adverse reactions, and the publication bias analysis was carried out. The results indicated that most of the funnel maps were symmetrical and a small part of them were asymmetrical, suggesting that despite the heterogeneity of the study and the small number of included literatures, a publication bias was apparent in the included literature. Conclusion: Based on routine chemotherapy associated with Aidi injection, the therapeutic effect of NSCLC patients can be noticeably enhanced, the effective rate of treatment can be noticeably promoted, the immune function and life quality can be improved, and the incidence of adverse reactions is low, which is worth popularizing in clinical practice, but several studies and follow-ups are needed to improve methodological quality and to verify the results over a longer period of time.

An Fc-muted bispecific antibody targeting PD-L1 and 4-1BB induces antitumor immune activity in colorectal cancer without systemic toxicity.

BACKGROUND: Resistance to immune checkpoint inhibitor (ICI) therapy narrows the efficacy of cancer immunotherapy. Although 4-1BB is a promising drug target as a costimulatory molecule of immune cells, no 4-1BB agonist has been given clinical approval because of severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy. METHODS: HK010 was generated by antibody engineering, and the Fab/antigen complex structure was analyzed using crystallography. The affinity and activity of HK010 were detected by multiple in vitro bioassays, including enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), flow cytometry, and luciferase-reporter assays. Humanized mice bearing human PD-L1-expressing MC38 (MC38/hPDL1) or CT26 (CT26/hPDL1) tumor transplants were established to assess the in vivo antitumor activity of HK010. The pharmacokinetics (PK) and toxicity of HK010 were evaluated in cynomolgus monkeys. RESULTS: HK010 was generated as an Fc-muted immunoglobulin (Ig)G4 PD-L1x4-1BB bispecific antibody (BsAb) with a distinguished Fab/antigen complex structure, and maintained a high affinity for human PD-L1 (KD: 2.27 nM) and low affinity for human 4-1BB (KD: 493 nM) to achieve potent PD-1/PD-L1 blockade and appropriate 4-1BB agonism. HK010 exhibited synergistic antitumor activity by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously, and being strictly dependent on the PD-L1 receptor in vitro and in vivo. In particular, when the dose was decreased to 0.3 mg/kg, HK010 still showed a strong antitumor effect in a humanized mouse model bearing MC38/hPDL1 tumors. Strikingly, HK010 treatment enhanced antitumor immunity and induced durable antigen-specific immune memory to prevent rechallenged tumor growth by recruiting CD8+ T cells and other lymphocytes into tumor tissue and activating tumor-infiltrating lymphocytes. Moreover, HK010 not only did not induce nonspecific production of proinflammatory cytokines but was also observed to be well tolerated in cynomolgus monkeys in 5 week repeated-dose (5, 15, or 50 mg/kg) and single-dose (75 or 150 mg/kg) toxicity studies. CONCLUSION: We generated an Fc-muted anti-PD-L1x4-1BB BsAb, HK010, with a distinguished structural interaction with PD-L1 and 4-1BB that exhibits a synergistic antitumor effect by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously. It is strictly dependent on the PD-L1 receptor with no systemic toxicity, which may offer a new option for cancer immunotherapy.

Management of vaginal laxity through bilateral wall tightening without mucosal excision.

BACKGROUND: Vaginal tightening or vaginoplasty has been gaining popularity, while validated methods of evaluation and treatment are still lacking. Herein, we describe a bilateral wall tightening technique for vaginal laxity and evaluate the feasibility of this method. METHODS: From April 2020 to September 2021, 25 women with vaginal laxity underwent vaginal tightening, and 22 women were included in this retrospective observational study. The inclusion criteria were as follows: participants with at least one delivery and reported vaginal laxity, but without a history of underlying diseases. Vaginal pressure tests and questionnaires were used to evaluate vaginal laxity and sexual quality before and 6 months after the surgery. RESULTS: The study included 22 women (aged 29-46 years), and the follow-up period was 14.1 ± 3.3 months. The score based on the vaginal laxity questionnaire was improved as a result of surgery (preoperative median: 2.00, interquartile range [IQR]: 1.00-2.00; postoperative median: 5.00, IQR: 5.00-6.25, p < 0.001). The vaginal pressure increased from 2.3 ± 1.8 mm/Hg to 21.4 ± 3.7 mm/Hg. Sexual distress changed from 24.2 ± 8.9-16.1 ± 4.8 after surgery (p < 0.001), and sexual dysfunction with an average score of 20.1 ± 10.6 before surgery improved after the procedure (26.0 ± 10.8, p < 0.001). Women also reported improved scores in desire, arousal, orgasm, and satisfaction. In addition, there were no intraoperative complications or significant events during the follow-up period. CONCLUSIONS: Bilateral vaginal tightening without mucosal excision is a feasible and effective surgical approach for the management of vaginal laxity.

nc-RNA-mediated high expression of CDK6 correlates with poor prognosis and immune infiltration in pancreatic cancer.

BACKGROUND: Emerging evidence manifests that cyclin-dependent kinase 6 (CDK6) plays an essential part in the initiation and progression of several types of human cancer, and its descending expression is correlated with an adverse prognosis. However, the precise role of CDK6 in Pancreatic cancer (PC) remains obscure. AIMS: To identify the potential ceRNA regulatory axis of CDK6 in PC and explore its relationship with immune cells and immune checkpoints. MATERIALS & METHODS: Using The Cancer Genome Atlas TCGA and GTEx data analyze the expression and survival of CDK6 in patients in pan-cancer, and cellular experiments were performed to verify the effect of CDK6 on cell function. Using GEPIA and STARBASE databases to analyze prognosis, expression and survival, and identify non coding RNA (ncRNA) that mediates CDK6 overexpression. The TIMER 2.0 database was used for immune correlation analysis. RESULTS: We revealed CDK6 might be an oncogene in PC, and the HOXA11-AS /NR2F1-AS1- miR-454-3p axis was identified as the possible upstream ncRNA-associated pathway of CDK6 in PC. In addition, CDK6 show significant association with three immune checkpoints (PD-L1, PD-L2, and HAVCR2), the infiltration level of immune cells, and immunity biomarkers. DISCUSSION: We discussed some applications of CDK6 in breast cancer, melanoma, and hemorrhagic malignancies. The role of miR-15a-5p, HOXA11-AS and NR2F1-AS1 in tumor development was also discussed based on existing studies. The potential mechanism of CDK6 affecting immune cells in pancreatic cancer was discussed. CONCLUSIONS: Overall, these results established that nc-RNA-mediated high expression of CDK6 is associated with patient outcomes and immune invasion in pancreatic cancer.

Exposure to Metal Mixtures and Overweight or Obesity Among Chinese Adults.

Previous research has investigated the association between individual metal exposure and overweight/obesity (OW/OB). However, there is limited data about metal mixture exposure and OW/OB. This study aimed to explore the individual and joint effects of 21 metals on OW/OB and its metabolic phenotypes. A total of 4042 participants were enrolled in our study, and 51.0% of them were overweight/obese. We quantified 21 metal levels in the urine sample. OW/OB was defined as BMI ≥ 24 kg/m2, while the metabolic phenotypes, including metabolic unhealthy overweight/obesity (MUOW/OB) and metabolic health overweight/obesity (MHOW/OB), were determined by BMI and metabolic state. We used logistic regression to analyze the effect of individual metal exposure on OW/OB and its metabolic phenotypes. Quantile g-computation was applied to evaluate the joint effect of metal exposure on OW/OB and its metabolic phenotypes. In logistic regression, zinc (Zn) was positively associated with OW/OB, with the odds ratio (OR) in the highest quartiles of 2.19 (95% confidence interval (CI), 1.74, 2.77; P trend < 0.001), while arsenic (As) and cadmium (Cd) were negatively associated with OW/OB (OR = 0.70 (0.56, 0.87) and 0.61 (0.48, 0.78), respectively). After adjustment for age, gender, education, cigarette smoking, alcohol drinking, physical activity, meat intake, and vegetable intake, Zn was positively associated with MUOW/OB, while As, Cd, nickel (Ni), and strontium (Sr) were negatively associated with MUOW/OB (all P trend < 0.05). Quantile g-computation showed a significantly negative association between metal mixture exposure and MUOW/OB. Our study suggested that metal mixture exposure might be negatively associated with OW/OB, particularly with MUOW/OB. Zn, As and Cd contributed most to the effect of the mixture. More prospective studies are warranted to confirm these findings and reveal the underlying mechanisms.