Elevated pretreatment serum apolipoprotein E level associated with poor prognosis of patients with COVID-19 during the omicron BA.5 and BF.7 wave.

The SARS-CoV-2 virus is responsible for the human disease known as COVID-19. This virus is capable of generating a spectrum of infections ranging from moderate to severe. Serum apolipoprotein E (ApoE) inhibits inflammation by preserving immune regulatory function. Nonetheless, the relationship between serum ApoE and clinical prognosis in omicron remains elusive. A cohort of 231 patients was observed for 65 days, with death as the primary outcome. Based on their ApoE levels, the patients were categorized into patients with elevated ApoE levels and those with lower ApoE levels. To do statistical comparisons, the log-rank test was utilized, and the Kaplan-Meier method was utilized to estimate survival rates. Cox hazard models, both univariate and multivariate, were employed to examine the prognostic relevance. According to our research, omicron had significantly greater ApoE levels. In mild-to-moderate and severe cases, the study identified a statistically significant variation in ApoE levels. Additionally, there was a drop in overall survival that is statistically significant (OS, p < 0.0001) for patients with greater ApoE levels. Multiple Cox proportional hazards regression analysis indicates that an elevated ApoE level was determined to be an adverse and independent prognostic factor of OS in patients with omicron. Taken together, our study found that the level of serum ApoE at the time of initial diagnosis was substantially connected to the severity and prognosis of omicron. Consequently, we propose that ApoE might be a poor prognostic factor in individuals afflicted with the omicron variant.

Hsa-circRNA-103809 Promotes Hepatocellular Carcinoma Development via MicroRNA-1270/PLAG1 Like Zinc Finger 2 Axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in the worldwide. A great number of reports manifested that circular RNA hsa-circRNA-103809 (circRNA-103809) could work in several cancers. AIMS: This study aimed to explore the function and mechanism of circRNA-103809 in HCC. METHODS: Gene expressions were detected by quantitative real-time polymerase chain reaction. Colony formation, cell counting kit-8, transwell and wound healing assays were implemented to check the role of circRNA-103809 in HCC. Subcellular fractionation analysis was designed to figure out the cellular location of circRNA-103809. Luciferase reporter assay and RNA pull down assay were employed to verify the relationships among RNAs. RESULTS: CircRNA-103809 was highly expressed in HCC cell lines. After interfering circRNA-103809, the proliferation, migration, invasion and epithelial-to-mesenchymal transition process were all hindered in HCC cells. Significantly, circRNA-103809 competed with PLAG1 like zinc finger 2 (PLAGL2) for binding with microRNA-1270 (miR-1270), which formulated a competing endogenous RNA network in HCC. Thereafter, we verified the tumor-facilitating effect of circRNA-103809/miR-1270/PLAGL2 axis on biological behaviors of HCC cells. CONCLUSION: Hsa-circRNA-103809 promoted development of HCC via sequestering miR-1270 and up-regulating PLAGL2.

Comparison of safety between self-expanding metal stents as a bridge to surgery and emergency surgery based on pathology: a meta-analysis.

BACKGROUND: To explore the long-term oncological safety of using self-expanding metal stents (SEMS) as a bridge to surgery for acute obstructive colorectal cancer by comparing the pathological results of emergency surgery (ES) with elective surgery after the placement of SEMS. METHODS: Studies comparing SEMS as a bridge to surgery with emergency surgery for acute obstructive colorectal cancer were retrieved through the databases of Pubmed, Embase, and Cochrane libraries, and a meta-analysis was conducted based on the pathological results of the two treatments. Risk ratios (OR) or mean differences (MD) with 95% confidence intervals (CI) were calculated for the outcomes under random effects model. RESULTS: A total of 27 studies were included, including 3 randomized controlled studies, 2 prospective studies, and 22 retrospective studies, with a total of 3737 patients. The presence of perineural invasion (RR = 0.58, 95% CI 0.48, 0.71, P < 0.00001), lymphovascular invasion (RR = 0.68, 95% CI 0.47, 0.99, P = 0.004) and vascular invasion (RR = 0.66, 95% CI 0.45, 0.99, P = 0.04) in SEMS group were significantly higher than those in ES group, and there was no significant difference in lymphatic invasion (RR = 0.92, 95% CI 0.77, 1.09, P = 0.33). The number of lymph nodes harvested in SEMS group was significantly higher than that in ES group (MD = - 3.18, 95% CI - 4.47, - 1.90, P < 0.00001). While no significant difference was found in the number of positive lymph nodes (MD = - 0.11, 95% CI - 0.63, 0.42, P = 0.69) and N stage [N0 (RR = 1.03, 95% CI 0.92, 1.15, P = 0.60), N1 (RR = 0.99, 95% CI 0.87, 1.14, P = 0.91), N2 (RR = 0.94, 95% CI 0.77, 1.15, P = 0.53)]. CONCLUSIONS: SEMS implantation in patients with acute malignant obstructive colorectal cancer may lead to an increase in adverse tumor pathological characteristics, and these characteristics are mostly related to the poor prognosis of colorectal cancer. Although the adverse effect of SEMS on long-term survival has not been demonstrated, their adverse effects cannot be ignored. The use of SEMS as the preferred treatment for patients with resectable obstructive colorectal cancer remains to be carefully weighed, especially when patients are young or the surgical risk is not very high.

miR-532 promotes colorectal cancer invasion and metastasis by targeting NKD1.

The aim of this study was to investigate the effect of microRNA-532 (miR-532) on invasion and metastasis of colorectal cancer (CRC) cells, and the underlying mechanism. Human CRC cell line (HCT116) and normal colon (FHC) cells were used for this study. The cells were transfected with naked cuticle homolog 1 (NKD1) overexpression plasmid, miR-532 mimics, miR-532 inhibitor or miR-532 non-homologous sequence using lipofectamine 2000. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to determine the expression of miR-532 in CRC cells, and a combination of scratch and Transwell assays was used to assess the effect of miR-532 on migration and invasion of CRC cells. Western blotting was used to determine the effect of miR-532 on NKD1 expression in CRC cells. Bioinformatics analysis and luciferase reporter gene assay were used to assess the regulatory effect of miR-532 on NKD1. The expression of miR-532 was upregulated in CRC cells relative to normal colon cells (p < 0.05). The HCT116 cells transfected with miR-532 mimics migrated faster than those of miR-532 negative control (miR532-NC) group (p < 0.05). The migration ability of HCT116 cells transfected with miR-532 inhibitor was significantly reduced, when compared with that of miR532-NC group (p < 0.05). The invasive ability of HCT116 cells transfected with miR-532 mimics was significantly higher than that of miR532-NC cells (p < 0.05). However, inhibition of miR-532 expression significantly reduced the invasive ability of HCT116 cells (p < 0.05). Results of bioinformatics showed that miR-532 had specific binding sequence with the 3'UTR region of NKD1. After cloning the sequence into the luciferase reporter plasmid, miR-532 significantly inhibited the expression of NKD1 (p < 0.05). However, miR-532 had no inhibitory effect on mutated NKD1 3'UTR (p > 0.05). Results of Western blotting showed that increased miR-532 expression significantly reduced the expression of NKD1, while decreased miR-532 expression promoted the expression of NKD1 (p < 0.05). Overexpression of NKD1 significantly down-regulated miR-532 overexpression and promoted CRC cell invasion and metastasis (p < 0.05). miR-532 is highly expressed in CRC cells and directly inhibits NKD1 expression, while enhancing invasion and metastasis of CRC cells. It promotes the development of CRC by inhibiting the expression of NKD1.

Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice.

BACKGROUND AND AIMS: Bacterially derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. METHODS: Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis ± IAP supplementation. Liver tissue was assessed for biochemical, inflammatory, and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. RESULTS: Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. CONCLUSIONS: IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.

Effects of hyperlipidaemia on plasma apolipoprotein M levels in patients with type 2 diabetes mellitus: an independent case-control study.

BACKGROUND: Apolipoprotein M (apoM) is mainly enriched in high-density lipoprotein (HDL) cholesterol and is slightly present in low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein cholesterol. apoM is involved in HDL formation and HDL-mediated reverse cholesterol transport. apoM is also associated with hyperlipidaemia and type 2 diabetes mellitus (T2DM). Significantly high plasma apoM levels are detected in hyperlipidaemia mice with a defective LDL receptor. By contrast, low plasma apoM levels are observed in patients with T2DM, which is often accompanied with hyperlipidaemia. However, the underlying mechanism of this condition is poorly understood. This research aims to examine the changes in apoM levels in patients with hyperlipidaemia and to determine the effects of hyperlipidaemia on plasma apoM levels in patients with T2DM. METHODS: This study included patients with hyperlipidaemia (n = 79), patients with T2DM but without hyperlipidaemia (n = 125), patients with T2DM and hyperlipidaemia (n = 98), and healthy controls (n = 105). Their plasma apoM concentrations were measured with enzyme-linked immunosorbent assay. RESULTS: The average plasma apoM concentrations were 18 % higher in the hyperlipidaemia group (26.63 ± 10.35 ng/µL) than in the healthy controls (22.61 ± 10.81 ng/µL, P <0.01). The plasma apoM concentrations were lower in the T2DM without hyperlipidaemia group (18.54 ± 10.33 ng/µL, P <0.01) and the T2DM with hyperlipidaemia group (19.83 ± 7.41 ng/µL, P <0.05) than in the healthy controls. Similar to apoA-I (1.29 ± 0.33 g/L vs. 1.28 ± 0.31 g/L, P >0.05), the plasma apoM concentrations in the T2DM with hyperlipidaemia group did not significantly differ from those in the T2DM without hyperlipidaemia group (P >0.05). Multivariate linear regression analysis showed that hyperlipidaemia (ß = 5.18, P = 0.007) is an independent promoting factor of plasma apoM levels and diabetes (ß = -3.09, P = 0.005) is an inhibiting factor of plasma apoM levels. CONCLUSION: Plasma apoM concentrations are higher in patients with hyperlipidaemia than in healthy controls. Low plasma apoM levels in patients with T2DM are likely caused by diabetes but are not induced by hyperlipidaemia.

Continuous topical irrigation for severely infected wound healing.

BACKGROUND: Management of severely infected wounds is a formidable challenge. The pilot prospective cohort study is to investigate the influence of continuous topical irrigation (CTI) on the outcomes of severely infected wounds. METHODS: This pilot study was performed on 17 patients with a single severely infected wound treated with CTI, compared with a control group of 15 patients treated with standard of care from January 2011-January 2013. Bates-Jensen wound assessment tool severity scores and the clinical outcomes were recorded. Profiles of cytokines and/or proteinase in wound fluid were quantified weekly. RESULTS: Comparing with the control, the CTI-treated patients required fewer days for wound infection clearance (8 ± 2 versus 19 ± 5 d, P < 0.001), had wounds closed earlier (17 ± 4 versus 36 ± 7 d, P < 0.001), and had fewer inhospital stay days (23 ± 5 versus 42 ± 8 d, P < 0.001). Bates-Jensen wound assessment tool severity scorings, proinflammatory cytokines (tumor necrosis factor-α, interleukin 1ß, and interleukin 6), and matrix metalloproteinase-8 were significantly decreased in response to CTI. CONCLUSIONS: This pilot study demonstrates that CTI improves severely infected wound healing through partly inhibiting proinflammatory cytokines and improving tissue regeneration.

Vitamin D prevents the intestinal fibrosis via induction of vitamin D receptor and inhibition of transforming growth factor-beta1/Smad3 pathway.

BACKGROUND AND AIMS: Vitamin D deficiency in patients with inflammatory bowel disease (IBD) is associated with greater disease activity and lower quality of life. Intestinal fibrosis is a main complication of IBD. However, the effect of vitamin D on intestinal fibrosis remains unclear. We investigated the prophylactic effect and the underlying mechanism of vitamin D on the intestinal fibrosis in vitamin D-deficient mice with chronic colitis. METHODS: Vitamin D-deficient mice were randomized into two groups receiving the vitamin D-deficient or vitamin D-sufficient diet from weaning (week 4). Intestinal fibrosis was induced by six-weekly 2,4,6-trinitrobenzene sulfonic acid administrations from week 8. At week 14, the productions of extracellular matrix (ECM) and total collagen were measured in the colons, and TGF-ß1/Smad3 signal transduction was examined in isolated colonic subepithelial myofibroblasts (SEMF). The expression of vitamin D receptor (VDR), α-SMA and Collagen I in normal SEMF and VDR-null SEMF exposed to TGF-ß1 and/or 1,25(OH)2D3 was measured. RESULTS: Vitamin D significantly reduced the histological scoring, ECM and collagen productions in the colons and decreased the levels of TGF-ß1, Smad-3, p-Smad3 and Collagen I in SEMF. 1,25(OH)2D3-induced VDR expression and decreased TGF-ß1-stimulated α-SMA and Collagen I expressions in SEMF. Knocking down VDR expression in SEMF abolished the effect of 1,25(OH)2D3. CONCLUSIONS: Vitamin D has prophylactic effect on intestinal fibrosis in the vitamin D-deficient mice with chronic colitis, which may be associated with the inhibited activation of TGF-ß1/Smad3 pathway in the SEMF via VDR induction.

Intestinal alkaline phosphatase promotes gut bacterial growth by reducing the concentration of luminal nucleotide triphosphates.

The intestinal microbiota plays a pivotal role in maintaining human health and well-being. Previously, we have shown that mice deficient in the brush-border enzyme intestinal alkaline phosphatase (IAP) suffer from dysbiosis and that oral IAP supplementation normalizes the gut flora. Here we aimed to decipher the molecular mechanism by which IAP promotes bacterial growth. We used an isolated mouse intestinal loop model to directly examine the effect of exogenous IAP on the growth of specific intestinal bacterial species. We studied the effects of various IAP targets on the growth of stool aerobic and anaerobic bacteria as well as on a few specific gut organisms. We determined the effects of ATP and other nucleotides on bacterial growth. Furthermore, we examined the effects of IAP on reversing the inhibitory effects of nucleotides on bacterial growth. We have confirmed that local IAP bioactivity creates a luminal environment that promotes the growth of a wide range of commensal organisms. IAP promotes the growth of stool aerobic and anaerobic bacteria and appears to exert its growth promoting effects by inactivating (dephosphorylating) luminal ATP and other luminal nucleotide triphosphates. We observed that compared with wild-type mice, IAP-knockout mice have more ATP in their luminal contents, and exogenous IAP can reverse the ATP-mediated inhibition of bacterial growth in the isolated intestinal loop. In conclusion, IAP appears to promote the growth of intestinal commensal bacteria by inhibiting the concentration of luminal nucleotide triphosphates.

A novel approach to maintain gut mucosal integrity using an oral enzyme supplement.

OBJECTIVE: To determine the role of intestinal alkaline phosphatase (IAP) in enteral starvation-induced gut barrier dysfunction and to study its therapeutic effect as a supplement to prevent gut-derived sepsis. BACKGROUND: Critically ill patients are at increased risk for systemic sepsis and, in some cases, multiorgan failure leading to death. Years ago, the gut was identified as a major source for this systemic sepsis syndrome. Previously, we have shown that IAP detoxifies bacterial toxins, prevents endotoxemia, and preserves intestinal microbiotal homeostasis. METHODS: WT and IAP-KO mice were used to examine gut barrier function and tight junction protein levels during 48-hour starvation and fed states. Human ileal fluid samples were collected from 20 patients postileostomy and IAP levels were compared between fasted and fed states. To study the effect of IAP supplementation on starvation-induced gut barrier dysfunction, WT mice were fasted for 48 hours +/- IAP supplementation in the drinking water. RESULTS: The loss of IAP expression is associated with decreased expression of intestinal junctional proteins and impaired barrier function. For the first time, we demonstrate that IAP expression is also decreased in humans who are deprived of enteral feeding. Finally, our data demonstrate that IAP supplementation reverses the gut barrier dysfunction and tight junction protein losses due to a lack of enteral feeding. CONCLUSIONS: IAP is a major regulator of gut mucosal permeability and is able to ameliorate starvation-induced gut barrier dysfunction. Enteral IAP supplementation may represent a novel approach to maintain bowel integrity in critically ill patients.

Assessing Morinidazole for Surgical Site Infection in Class â ¢ Wounds Prevention: A Multicenter, Randomized, Single-Blind, Parallel-Controlled Study.

INTRODUCTION: Surgical site infections are significant postoperative risks, antibiotic prophylaxis is crucial due to the presence of anaerobic bacteria. This study investigated the efficacy and safety of a novel nitroimidazole, morinidazole, in SSI reduction in class Ⅲ wounds, as there is currently a lack of evidence in the existing literature. METHODS: A multicenter randomized clinical trial was conducted from December 2020 to October 2022 in the general surgery departments of 12 tertiary hospitals in China. 459 patients in two treatment groups using morinidazole plus ceftriaxone or ceftriaxone alone. Efficacy and safety were evaluated including SSI incidence, adverse events, and compliance. Statistical analysis employed SAS 9.4 software. Data analysis was performed from February to May 2023. RESULTS: A total of 440 participants (median [IQR] age, 63.0 [54.0, 70.0] years; 282 males [64.09%]; 437 patients were of Han race [99.32%]) were randomized. The experimental group exhibited a significantly lower SSI rate compared with the control group (31 [14.49%] vs 52 [23.01%]; risk difference, 1.76%, 95%CI, 1.08% to 2.88%; P=0.0224). The superficial incisional site infections revealed a marked reduction in the experimental group (12 [5.61%] vs 31 [13.37%]; risk difference,2.68%; 95%CI,1.34%to5.36%; P=0.0042). Non-surgical site infections, severe postoperative complications, and total adverse events showed no statistically significant differences between the groups (P>0.05). CONCLUSION: The significant decrease in SSI rates and superficial incisional infections demonstrates morinidazole as a valuable prophylactic antibiotic. Our findings provided valuable insights for clinical practice, where this new-generation nitroimidazole can play a crucial role in SSI prevention.

Elevated serum beta-2 microglobulin level predicts short-term poor prognosis of patients with de novo acute omicron variant COVID-19 infection.

Background: The devastating coronavirus disease of 2019 (COVID-2019) epidemic has been declared a public health emergency, resulting in a worldwide pandemic. The omicron variety is the most common epidemic mutant strain in the globe. Serum beta-2 microglobulin (ß2-MG) is associated with endothelial cell injury and has value in monitoring the progression of inflammation in infected individuals. Nonetheless, the potential functions of ß2-MG in omicron remain elusive. Methods: To investigate the prognostic value of serum ß2-MG levels at diagnosis, we retrospectively analyzed a cohort of 240 people with omicron. Over the course of 65 days, all patients were monitored, and death was the primary outcome. Patients were allocated to two groups: those with high and low ß2-MG levels. The Kaplan-Meier method was used to examine OS, and the log-rank test was used to compare them. Univariate and multivariate Cox hazard models were used to determine the prognostic significance. Results: Our results revealed that ß2-MG was significantly elevated in omicron. ß2-MG levels in severe patients were higher than in mild-to-moderate patients, and the difference was statistically significant. Timely, interleukin-6 (IL-6) and interleukin-10 (IL-10) were observed to be significantly increased in individuals exhibiting elevated levels of ß2-MG. In addition, patients exhibiting elevated levels of ß2-MG demonstrated a statistically significant decrease in overall survival (OS, P < 0.0001). An elevated ß2-MG level (≥4.72 mg/l) was found to be an independent, adverse prognostic factor for OS in omicron patients, according to multivariate Cox proportional hazards regression analysis (P = 0.001). Conclusion: Serum ß2-MG level at initial diagnosis was significantly correlated with omicron severity and prognosis. Thus, we propose that ß2-MG may be an independent poor additional prognostic factor in patients with omicron.

Small Bowel Refractory Bleeding: A Retrospective Study for Causes and Surgical Management.

INTRODUCTION: Small bowel (SB) bleeding is one of the common gastrointestinal problems, particularly in elders. The study aimed to find the causes of refractory bleeding and overcome the challenges and difficulties of surgical treatment for SB refractory bleeding. METHODS: All patients with SB refractory bleeding who underwent surgical treatment were included in this study. Patients' characteristics, surgical finding, and follow-up assessments were reviewed and analyzed through Hospital Information System records from October 1, 2014, to November 30, 2020. All analyses were performed using SPSS v23.0. RESULTS: The causes of SB bleeding include vascular lesions (angioectasia, arteriovenous malformations, and dieulafoy lesions) 29.6%, tumors (Polyps, gastrointestinal stromal tumor, Adenocarcinoma, and other) 24.5%, diverticular 18.4%, ulcers/erosion 15.3%, inflammatory bowel disease 7.1%, and other 5.1%. Patients (age below 60 y) were highly developed SB bleeding caused by diverticular 26.4% compared with patients (age 60 y or older) 8.9%, whereas bleeding caused by vascular lesions was significantly higher in patients (age 60 y or older) 37.8%. Other causes, such as tumors and inflammatory bowel disease, showed no significant difference related in age. Exploratory laparotomy was the standard method of bowel extrinsic examination. The intraoperative enteroscopy enterotomy (IOE-E) and IOE-combined were performed in 52 patients (1:1). IOE-E shows lower postoperative morbidity and shorter time of operation P <0.05 compared with the IOE-combined approach. CONCLUSIONS: Age and exhaustive patient history can assist in finding out the etiology. IOE-E is safe, and coordination between surgeon and endoscopist is necessary for IOE if an identifiable source cannot be found in endoscopy or exploratory laparotomy alone.

Comparison of postoperative pancreatic fistula between open and laparoscopic surgery in patients with gastric cancer: A meta-analysis.

Background: Open gastrectomy"OG" compared with laparoscopic gastrectomy"LG" in patients with gastric cancer"GC" has been widely discussed over the past years. However, the lack of comparative analysis in postoperative pancreatic fistula "POPF" hinders its severity as surgical procedures developed rapidly. Therefore, there are still moot on whether one of these surgical options is superior in POPF. Objective: To compare the incidence of POPF in patients undergoing OG and LG for gastric cancer "GC". Methods: Articles from January 2011 to August 2021 that compared LG and OG for GC were reviewed. Cohort studies were included in our study. The quality of enrolled studies was evaluated. Outcomes regarding POPF complication and relative operation results were analyzed. Statistical analysis portrayed the Weighted mean difference"WMD"and the odds ratio"OR"with a 95% confidence interval "CI". The curative effect was analyzed using RevMan 5.4.1 software. Results: Totally 7 articles met the inclusion criteria, including 3194 patients with treatment of gastrectomy surgeries for gastric cancer "GC". There was no significant difference observed in POPF incidence (OR, 95% CI = 1.04 [0.74,1.46], P = 0.81) between OG group and LG group in patients undergoing GC gastrectomy. Conclusion: We stringently explored the current incidence of POPF after GC gastrectomy, comparing its incidence during LG and OG, there was no significant difference between OG and LG in the incidence of POPF, and surgeons should give more concern for improvement in surgical techniques. Further research is still needed to explore the risk of causes and surgical techniques should be considered cautiously in a clinical procedure.

The efficacy and safety of low-dose temozolomide maintenance therapy in elderly patients with glioblastoma: a retrospective cohort study.

BACKGROUND: Radiotherapy combined with temozolomide chemotherapy (STUPP regimen) is the standard treatment regimen for newly diagnosed glioblastoma (GBM). It is considered feasible to prolong the treatment cycle of temozolomide (TMZ), however, the efficacy and safety of prolonging the treatment cycle of TMZ are still lacking in elderly patients with glioblastoma. This study observed the efficacy and safety of low dose TMZ maintenance therapy in elderly patients with glioblastoma after receiving standard STUPP regimen. METHODS: The clinical data were retrospectively analyzed in 34 patients with glioblastoma aged ≥65 years from April 2017 to April 2021 in Ningbo First Hospital. The patients received conventional radiotherapy (59.4 Gy/28 F/5.5 weeks) and TMZ (75 mg/m2·d) concurrent chemotherapy, followed by sequential TMZ (150-200 mg/m2·d, d1-5, q28d) adjuvant treatment for 6 cycles, and patients with no disease progress or intolerable side effects received low dose TMZ (100 mg/m2·d, d1-5, q28d) maintenance treatment. The patient's progression free survival time (PFS), total survival time (OS) and adverse reactions were observed by telephone, outpatient reexamination and other follow-up methods. Kaplan-Meier method was used to calculate and draw the survival curve for survival analysis. RESULTS: Twenty-four of 34 patients were finally included in the analysis, including 13 males and 11 females (65-74 years old), with a median of 14 cycles (8-38 cycles) of adjuvant TMZ chemotherapy. The median PFS was 11.0 months [95% confidence interval (CI): 8.67-13.33 months] and the median OS was 17.4 months (95% CI: 12.49-22.31 months). The main adverse reactions were digestive tract reactions and hematological toxicity. Three cases of grade III granulocytopenia occurred during the adjuvant treatment, while no grade III or above related adverse reactions occurred during the follow-up TMZ reduction maintenance treatment: leukopenia (5/24), anemia (2/24), decreased blood platelets (2/24), asthenia (5/24), nausea (4/24), and abnormal liver function (3/24). CONCLUSIONS: In general, for elderly patients with good Karnofsky Performance Scale (KPS) scores, further reducing TMZ to maintain chemotherapy after the standard STUPP regimen may improve the PFS and OS to a certain extent, with tolerable adverse reactions and reduced cost. However, prospective randomized grouping study is still needed to determine whether clinical benefits will be achieved.

Lactate Transporter SLC16A3 (MCT4) as an Onco-Immunological Biomarker Associating Tumor Microenvironment and Immune Responses in Lung Cancer.

Purpose: Lactate, a marker of tumor metabolic reprogramming, maintains the acidic microenvironment and also affects the metabolism and function of immune cells. SLC16A3 is responsible for the extracellular transport of lactate, which is a key component of glycolysis. However, the role of SLC16A3 in immune infiltration and immunosuppression of lung cancer is largely unknown. Our study explored the therapeutic and prognostic value of SLC16A3 in predicting immune infiltration and immune checkpoint efficacy of lung cancer. Methods: SLC16A3 expression was evaluated with TCGA database. Kaplan-Meier analysis was performed for survival rates. GO and KEEG enrichment was conducted to determine predictive signaling pathways. We utilized TIMER and CIBERSORT to analyze the correlation between SLC16A3 and immunocyte infiltration as well as immune checkpoint. Interleukin and HIF-1a expression was measured with ELISA kit and flow cytometry separately. Results: In comparison with normal tissues, SLC16A3 expression was significantly upregulated in both lung adenocarcinoma (LUAD) and squamous carcinoma (LUSC), which was closely related to poor prognosis. GO analysis indicated that SLC16A3 involved in different signal pathways in LUAD and LUSC and linked to HIF-1 signaling in LUAD. High SLC16A3 was correlated with immunosuppressive cells (Treg, Th2 and iDC), immune checkpoint (PD1, PD-L1, PVR, Tim-3, ITGAM) and immunosuppressive factors (foxp3, TGF-ß) in LUAD not LUSC. Furthermore, SLC16A3 was identified to tightly interact with IL-8 which may induce microenvironment immune tolerance. Based on the clinical prediction, we performed experiments with LUAD A549 cells and showed reduced IL-8 and HIF-1a when treated with SLC16A3 knockdown. HIF-1a stimulation by dimethyloxalylglycine (DMOG) could restore IL-8 secretion in SLC16A3 downregulated cells. Conclusion: Taken together, our results suggest that SLC16A3 contributes to a worse prognosis in lung cancer and may play an important role in immune microenvironment and evasion through HIF-1a-IL8 axis, which could be a novel therapeutic target for immunotherapy in lung cancer.

Prognostic value of lactate transporter SLC16A1 and SLC16A3 as oncoimmunological biomarkers associating tumor metabolism and immune evasion in glioma.

Background: Hypoxic microenvironment is immunosuppressive and protumorigenic, and elevated lactate is an intermediary in the modulation of immune responses. However, as critical lactate transporters, the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated. Methods: Gene expression in low- and high-grade glioma (LGG and GBM) was evaluated with TCGA database. The TISIDB, TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints. Results: Compared with normal tissues, a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM, and closely related to the poor prognosis only in LGG. Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflammation in glioma. The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis. TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells, which was correlated to tumor-associated macrophages and neutrophils that are immunosuppressive. SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints (especially PD1, PD-L1, PD-L2, Tim-3) and immunosuppressive factors (TGF-ß and IL-10) in glioma. Furthermore, SLC16A3 had a positive correlation to activation markers of tumor-associated neutrophils and chemokines such as CCL2, CCL22, CXCR2, CXCR4 in LGG and CCL7, CCL20 CXCL8 in GBM, which could enhance infiltration of immunosuppressive cells to the tumor microenvironment. Conclusion: In general, our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immunosuppressive cell infiltration, which contributes to immune evasion and a worse prognosis in glioma. Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.

Dual Roles of Lactate in EGFR-TKI-Resistant Lung Cancer by Targeting GPR81 and MCT1.

Lactate is critical in modeling tumor microenvironment causing chemotherapy resistance; however, the role of lactate in tyrosine kinase inhibitor (TKI) resistance has not been fully known. The aim of this study was to evaluate whether lactate could mediate TKI resistance through GPR81 and MCT1 in non-small-cell lung cancer (NSCLC). Here, we showed that lactate enhanced the cell viability and restrained erlotinib-induced apoptosis in PC9 and HCC827 cells. GPR81 and AKT expression were significantly increased with the addition of lactate, and siGPR81 reduced AKT expression resulting in a raised apoptosis rate with erlotinib treatment. Furthermore, we found that lactate also promoted MCT1 exposure, and inhibiting MCT1 with AZD3965 markedly impaired the glycolytic capacity. A significant increase of GPR81 and MCT1 expression was observed in insensitive tissues compared with sensitive ones by immunostaining in NSCLC patients. Our results indicate that lactate adopts dual strategies to promote TKI resistance in NSCLC, not only activating AKT signaling by GPR81, but also giving energy supply through MCT1-mediated input. Targeting GPR81 and MCT1 may provide new therapeutic modalities for TKI resistance in NSCLC.

The Application Value of Spiral CT Lung Densitometry Software in the Diagnosis of Radiation-Induced Lung Injury.

In order to study the application value of spiral CT lung density measurement software in the diagnosis of radioactive lung injury, the average CT values of lung apex, hilum, and diaphragm were measured by Pulmo automatic evaluation software of 16-slice spiral CT in 96 patients with different types of radiation lung injury diagnosed by conventional CT and 80 healthy subjects. The radiation lung injury on CT slices was classified, and the lung density was measured. In 96 patients with different types of radiation lung injury, 56 patients had different degrees of increase in average lung density, which was most obvious in the type of air insufficiency and chronic fibrosis. CT values of lung density in the ground glass stage and patch stage of acute radiation pneumonia had little influence due to the range and time of exposure. The lung density of 35 patients with radiation injury was measured in the normal range. There was a significant difference between normal lung density and abnormal lung density in different types of radiation lung injury (X 2 = 56.718, P < 0.001). The mean lung density of 68 cases was normal and that of 12 cases was abnormal. There was a significant difference in lung density between the lung injury group and the normal group (X 2 = 18.027, P < 0.001). Spiral CT lung density measurement can accurately evaluate the lung density values of different types of radiation lung injury and judge the correlation between lung density and different types of radiation lung injury. It is of great value to diagnose, locate, and master the radiation dose of different types of radiation lung injury.