Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

Inflammatory cytokines and two subtypes of breast cancer: A two-sample mendelian randomization study.

BACKGROUND: Breast cancer is a common cancer type that leads to cancer-related deaths among women. HER2-positive breast cancer, in particular, is associated with poor prognosis due to its high aggressiveness, increased risk of recurrence, and metastasis potential. Previous observational studies have explored potential associations between inflammatory cytokines and the risk of two breast cancer subtypes (HER2-positive and HER2-negative), but the results have been inconsistent. To further elucidate the causal relationship between inflammatory cytokines and the two breast cancer subtypes, we conducted a two-sample Mendelian randomization (MR) study. METHODS: We employed a two-sample bidirectional MR analysis using publicly available genome-wide association study (GWAS) statistics. After obtaining instrumental variables, we conducted MR analyses using five different methods to ensure the reliability of our results. Additionally, we performed tests for heterogeneity and horizontal pleiotropy. Subsequently, we conducted a reverse MR study by reversing exposure and outcome variables. RESULTS: Evidence from our IVW analysis revealed that genetically predicted levels of IL-5 [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.04-1.35, P = 0.012], IL-7 (OR: 1.11, 95% CI: 1.01-1.22, P = 0.037), and IL-16 (OR: 1.13, 95% CI: 1.02-1.25, P = 0.025) were associated with an increased risk of HER2-positive breast cancer. Conversely, IL-10 (OR: 1.14, 95% CI: 1.03-1.26, P = 0.012) was associated with an increased risk of HER2-negative breast cancer. These results showed no evidence of heterogeneity or horizontal pleiotropy (P > 0.05). Results from the reverse MR analysis indicated no potential causal association between breast cancer and inflammatory cytokines (P > 0.05). CONCLUSION: Our findings demonstrate that IL-5, IL-7, and IL-16 are risk factors for HER2-positive breast cancer, with varying degrees of increased probability of HER2-positive breast cancer associated with elevated levels of these inflammatory cytokines. Conversely, IL-10 is a risk factor for HER2-negative breast cancer. Reverse studies have confirmed that breast cancer is not a risk factor for elevated levels of inflammatory cytokines. This series of results clarifies the causal relationship between different types of inflammatory cytokines and different subtypes of breast cancer. Based on this research, potential directions for the mechanism research of different inflammatory cytokines and different subtypes of breast cancer have been provided, and potential genetic basis for identifying and treating different subtypes of breast cancer have been suggested.

Identification of CDT1 as a prognostic marker in human lung adenocarcinoma using bioinformatics approaches.

Background: Lung cancer has the highest cancer-related mortality worldwide. Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC). Chromatin licensing and DNA replication factor 1 (CDT1), a key regulator of cell cycle control and replication in eukaryotic cells, has been implicated in various cancer-related processes. Given its significant role in cancer, the focus on CDT1 in this study is justified as it holds promise as a potential biomarker or therapeutic target for cancer treatment. However, its prognostic value in lung adenocarcinoma (LUAD) remains unclear. Methods: Bioinformatics analysis was conducted using data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were utilized to predict biological processes and signaling pathways, respectively. The LinkedOmics database was employed to identify differentially expressed genes (DEGs) associated with CDT1. Nomograms and Kaplan-Meier plots were generated to assess the survival rates of patients with lung adenocarcinoma (LUAD). To determine the RNA and protein expression levels of CDT1 in LUAD and adjacent normal tissues, quantitative polymerase chain reaction (qPCR) and immunohistochemistry techniques were employed, respectively. Results: CDT1 was upregulated in the vast majority of cancer tissues, based on pan-cancer analysis in TCGA and GEO datasets, as to lung cancer, the level of CDT1 expression was much higher in LUAD tissue than in healthy lung tissue. Our clinical data supported these findings. In our study, we used a specific cutoff value to dichotomize the patient samples into high and low CDT1 expression groups. The Kaplan-Meier survival curve revealed poor survival rates in CDT1 high expression group than the low expression group. To determine if CDT1 expression was an independent risk factor in LUAD patients, univariate and multivariate Cox regression analyses were performed. The result showed that CDT1 was a potential novel prognosis factor for LUAD patients, whose prognosis was poorer when CDT1 expression was higher. Based on functional enrichment analysis, highly expressed DEGs of CDT1-high patients were predicted to be involved in the cell cycle. According to our analysis of immune infiltration, CDT1 exhibited a strong correlation with specific immune cell subsets and was found to be a significant predictor of poor survival in patients with LUAD. Conclusions: Our research found that CDT1 was upregulated in LUAD and that high CDT1 expression predicted poor prognosis. We comprehensively and systematically analyzed the expression level in the datasets as well as in our own clinical samples, we also evaluated the prognostic and diagnostic value of CDT1, and finally, the potential mechanisms of CDT1 in the progression of LUAD. These results suggested that CDT1 may be a prognostic marker and therapeutic target for LUAD.

Improved [68Ga]Ga-PSMA-11 image qualities reconstructed by total variation regularized expectation maximization on total-body PET/CT.

Background: Total variation regularized expectation maximization (TVREM) reconstruction algorithm on the image quality of gallium (68GA) prostate-specific membrane antigen-11 ([68Ga]Ga-PSMA-11) total-body positron emission tomography/computed tomography (PET/CT). Methods: Images of a phantom with small hot sphere inserts and the total-body PET/CT scans of 51 prostate cancer patients undergoing [68Ga]Ga-PSMA-11 were reconstructed using TVREM with 5 different penalization factors between 0.09 and 0.45 and for 20-, 40-, 60-, 120-, and 300-second acquisition, respectively. As a comparison, the same data were also reconstructed using the ordered subset expectation maximization (OSEM) with 3 iterations, 20 subsets, and 300 second acquisition. The contrast recovery coefficients (CRC) and background variability (BV) of the phantom, the tumor-to-background ratios (TBR), the contrast recovery (CR) ratio, the image noise of the liver, and maximum standard uptake value (SUVmax) of the lesions were calculated to evaluate the image quality. The clinical performance of the images was evaluated by 2 radiologists with a 5-point scale (1-poor, 5-excellent). Results: The TVREM reconstructions groups fwith 120 second acquisition and the penalization of 0.27 to 0.45 showed the best performance in terms of CR, TBR, image noise, and the gain of SUVmax compared to that obtained in the OSEM 300 second group. Even the image noise of the TVREM 120 second group with a penalization factor of 0.27 and 0.36 was comparable to the OSEM 300 second group; the lesions' SUVmax increased by 28% whereas the image noise decreased by 5% and 14%, respectively. The TVREM 120 second group with a penalization factor of 0.36 (5.00±0.00) had the highest qualitative score that equaled OSEM and TVREM for the 300 second (P>0.05) group. Conclusions: Our study has shown the potential of the TVREM reconstruction algorithm with optimized penalization factors to achieve comparable [68Ga]Ga-PSMA-11 total-body PET/CT image quality with a shorter acquisition time, compared with the conventional OSEM reconstruction algorithm.

GPER governs the immune infiltration of gastric cancer and activates the NF-κB/ROS/Apoptosis pathway in gastric mucosal epithelium.

BACKGROUND: Gastric cancer (GC) is with high mortality and morbidity. The GC morbidity of males is twice as high as that of females. G-protein estrogen receptor (GPER) bears on this phenomenon. METHODS: Networks and experiments assessed the GPER expression in different validity and content. The evidence-based practice involved accessing the clinical relevance of GPER by UALCAN and Kaplan-Meier plotter. Enrichment analyses contributed to guide further experimental validations. Activation of the NF-κB/ROS/Apoptosis pathway was analyzed by WB, immunofluorescence (IF), microplate reader and flow cytometry. TISIDB and TIMER identified the immune infiltration investigations, with credibility boosted by the Kaplan-Meier plotter. RESULTS: The appraisers revealed that GPER significantly decreased in GC at both gene and protein levels with highly approved prognosis value (P < 0.05). GPER was a significant fate determinant governing the inner part of gastric glands. NF-κB pathway and the following ROS in gastric cells were activated after MNU stimulation (20 µM, 24 h), and the GPER antagonist G15 strengthened the effect of MNU. Furthermore, GPER expression positively correlated with immune cells and various immune markers in GC patients, with highly approved clinical relevance. For example, type-2 helper cells enriched GC patients had a lower survival rate in the GPER-high expression group (P < 0.05). CONCLUSION: We demonstrated that GPER governs the GC progression by activating the NF-κB/ROS/Apoptosis pathway in gastric cells and regulating the immune environment around them.

Modified Gegen Qinlian decoction ameliorated ulcerative colitis by attenuating inflammation and oxidative stress and enhancing intestinal barrier function in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified Gegen Qinlian decoction (MGQD), which was first documented in Treatise on Febrile Disease, is recognized as a classic prescription to treat ulcerative colitis (UC). However, its protective mechanism against UC remains to be fully elucidated. AIM OF THE STUDY: To explore the impact and the potential molecular mechanism of MGQD on dextran sodium sulfate (DSS)-induced UC mice and tumor necrosis factor alpha (TNF-α)-induced Caco-2 cell monolayer model of intestinal barrier. MATERIALS AND METHODS: The chemical components of MGQD and MGQD drug containing serum (MGQD-DS) were characterized by LC-MS/MS. The therapeutic effect of MGQD on DSS-induced UC was evaluated based on body weight, disease activity index (DAI), colon length, colonic histopathological injury, inflammatory cytokines, oxidative stress response and intestinal barrier function. Cell Counting Kit (CCK)-8 assay was applied to detect the effect of MGQD-DS on the viability of Caco-2 cells. Additionally, TNF-α-induced Caco-2 cell monolayer model of intestinal barrier was established in vitro. The Caco-2 cell monolayers were administered blank serum or MGQD-DS to observe the effects of MGQD-DS on transepithelial electrical resistance (TEER), permeability of fluorescein isothiocyanate (FITC)-dextran, inflammatory cytokines, oxidative stress indicators and intestinal epithelial barrier (IEB). RESULTS: MGQD significantly improved symptoms and pathological damage in UC mice by downregulating the expression of interleukin (IL)-1ß and malondialdehyde (MDA), attenuating the loss of goblet cells and the destruction of intestinal epithelial ultrastructure, and upregulating the expression of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), zonula occludens-1 (ZO-1), Occludin, Claudin-1 and E-cadherin. In vitro, MGQD-DS significantly reduced the flux of FITC-dextran, increased the TEER, inhibited the expression of IL-21, IL-17A and MDA, and promoted the expression of IL-4, IL-10, transforming growth factor-ß (TGF-ß), SOD, CAT, GSH, Occludin and E-cadherin in TNF-α-induced Caco-2 cell monolayer model of intestinal barrier. CONCLUSION: MGQD can ameliorate DSS-induced UC mice and TNF-α-induced Caco-2 cell monolayer model of intestinal barrier, and the protective effect is related to its inhibition of inflammation, alleviation of oxidative stress, and repair of intestinal barrier damage.

Exploration of various roles of hypoxia genes in osteosarcoma.

Osteosarcoma is a primary malignant tumor that often metastasizes in orthopedic diseases. Although multi-drug chemotherapy and surgical treatment have significantly improved the survival and prognosis of patients with osteosarcoma, the survival rate is still very low due to frequent metastases in patients with osteosarcoma. In-depth exploration of the relationship between various influencing factors of osteosarcoma is very important for screening promising therapeutic targets. This study used multivariate COX regression analysis to select the hypoxia genes SLC2A1 and FBP1 in patients with osteosarcoma, and used the expression of these two genes to divide the patients with osteosarcoma into high-risk and low-risk groups. Then, we first constructed a prognostic model based on the patient's risk value and compared the survival difference between the high expression group and the low expression group. Second, in the high expression group and the low expression group, compare the differences in tumor invasion and inflammatory gene expression between the two groups of immune cells. Finally, the ferroptosis-related genes with differences between the high expression group and the low expression group were screened, and the correlation between these genes was analyzed. In the high-risk group, immune cells with higher tumor invasiveness, macrophages M0 and immune cells with lower invasiveness included: mast cell resting, regulatory T cells (Tregs) and monocytes. Finally, among genes related to ferroptosis, we found AKR1C2, AKR1C1 and ALOX15 that may be related to hypoxia. These ferroptosis-related genes were discovered for the first time in osteosarcoma. Among them, the hypoxia gene FBP1 is positively correlated with the ferroptosis genes AKR1C1 and ALOX15, and the hypoxia gene SLC2A1 is negatively correlated with the ferroptosis genes AKR1C2, AKR1C1 and ALOX15. This study constructed a prognostic model based on hypoxia-related genes SLC2A1 and FBP1 in patients with osteosarcoma, and explored their correlation with immune cells, inflammatory markers and ferroptosis-related genes. This indicates that SLC2A1 and FBP1 are promising targets for osteosarcoma research.

CircP50 functions through the phosphorylation- and acetylation-activated p53 pathway to mediate inorganic arsenic-induced apoptosis in A549 cells.

As a class I carcinogen, arsenic has been reported to cause diseases accompanied by circRNAs regulating proliferation and apoptosis at the molecular level, but whether circP50 (circBase ID: hsa_circ_0008012) does the same has not been demonstrated. The aim of this study is to provide the basis for anti-lung cancer mechanism research, by studying the expression of circP50 under arsenic-induced conditions, and the effect and mechanism on the proliferation and apoptosis of A549 cells based on the circP50 knockdown models. To explore whether the circP50 is responsive to arsenic exposure, the qRT-PCR was applied to discover that the relative expression of circP50 in A549 cells increased only with increasing NaAsO2 dose and independent of its metabolites. We further determined the mechanism of circP50 by establishing circP50 knockdown models. The results of cell viability and EdU assays indicated the proliferation of A549 cells. According to the western blotting, phosphorylation of p53 at Ser15, Ser376, and Ser392 and acetylation of p53 at Lys370 and Lys382 were inhibited, resulting in the deficiency of p53 expression. Subsequently, the expression of genes downstream of p53 was reduced, including p21, PUMA, Caspase3, and Bcl-xS. Furthermore, the expressions of IKB-α, p65, and p50 decreased, but C-myc expression did not change significantly, referring to the NF-κB pathway was not dominant. The results suggest that circP50 mainly functions through the p53 pathway to mediate apoptosis in response to arsenic exposure.

Long-Term Survival of a Lynch Syndrome Patient With Eight Primary Tumors: A Case Report.

With the modern technological developments in the diagnosis and treatment of cancer, the survival rate of cancer patients has increased. On the other hand, the incidence of multiple primary tumors is increasing annually. Lynch syndrome (LS), an autosomal dominant disorder with germline mutations in DNA mismatch repair genes, increases the risk of cancer in patients carrying those mutations. In this report, we present an extremely rare case of an 81-year-old male patient with eight primary malignancies and LS. The patient is still alive having survived for more than 41 years since the initial discovery of the first tumor. The eighth and most recently diagnosed primary cancer was a malignant peripheral nerve sheath tumor. Although there have been numerous reports of malignancies in LS, malignant peripheral nerve sheath tumors have not been reported previously with LS. Here, we report, to the best of our knowledge, the first case of a malignant peripheral nerve sheath tumor with LS.

Identification and Validation in a Novel Quantification System of Ferroptosis Patterns for the Prediction of Prognosis and Immunotherapy Response in Left- and Right-Sided Colon Cancer.

Background: This study aimed to establish a novel quantification system of ferroptosis patterns and comprehensively analyze the relationship between ferroptosis score (FS) and the immune cell infiltration (ICI) characterization, tumor mutation burden (TMB), prognosis, and therapeutic sensitivity in left-sided and right-sided colon cancers (LCCs and RCCs, respectively). Methods: We comprehensively evaluated the ferroptosis patterns in 444 LCCs and RCCs based on 59 ferroptosis-related genes (FRGs). The FS was constructed to quantify ferroptosis patterns by using principal component analysis algorithms. Next, the prognostic value and therapeutic sensitivities were evaluated using multiple methods. Finally, we performed weighted gene co-expression network analysis (WGCNA) to identify the key FRGs. The IMvigor210 cohort, TCGA-COAD proteomics cohort, and Immunophenoscores were used to verify the predictive abilities of FS and the key FRGs. Results: Two ferroptosis clusters were determined. Ferroptosis cluster B demonstrated a high degree of congenital ICI and stromal-related signal enrichment with a poor prognosis. The prognosis, response of targeted inhibitors, and immunotherapy were significantly different between high and low FS groups (HSG and LSG, respectively). HSG was characterized by high TMB and microsatellite instability-high subtype with poor prognosis. Meanwhile, LSG was more likely to benefit from immunotherapy. ALOX5 was identified as a key FRG based on FS. Patients with high protein levels of ALOX5 had poorer prognoses. Conclusion: This work revealed that the evaluation of ferroptosis subtypes will contribute to gaining insight into the heterogeneity in LCCs and RCCs. The quantification for ferroptosis patterns played a non-negligible role in predicting ICI characterization, prognosis, and individualized immunotherapy strategies.

Tinospora cordifolia (Willd.) Miers: Protection mechanisms and strategies against oxidative stress-related diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora cordifolia (Willd.) Miers (Menispermaceae) is a Mediterranean herb, used in Ayurvedic, Siddha, Unani, and folk medicines. The herb is also used in conventional medicine to treat oxidative stress-related diseases and conditions, including inflammation, pain, diarrhea, asthma, respiratory infections, cancer, diabetes, and gastrointestinal disorders. AIM OF THE REVIEW: The taxonomy, botanical classification, geographical distribution, and ethnobotanical uses of T. cordifolia, as well as the phytochemical compounds found in the herb, the toxicology of and pharmacological and clinical studies on the effects of T. cordifolia are all covered in this study. MATERIALS AND METHODS: To gather information on T. cordifolia, we used a variety of scientific databases, including Scopus, Google Scholar, PubMed, and Science Direct. The information discussed focuses on biologically active compounds found in T. cordifolia, and common applications and pharmacological activity of the herb, as well as toxicological and clinical studies on its properties. RESULTS: The findings of this study reveal a connection between the use of T. cordifolia in conventional medicine and its antioxidant, anti-inflammatory, antihypertensive, antidiabetic, anticancer, immunomodulatory, and other biological effects. The entire plant, stem, leaves, root, and extracts of T. cordifolia have been shown to have a variety of biological activities, including antioxidant, antimicrobial, antiviral, antiparasitic, antidiabetic, anticancer, anti-inflammatory, analgesic and antipyretic, hepatoprotective, and cardioprotective impact. Toxicological testing demonstrated that this plant may have medicinal applications. T. cordifolia contains a variety of biologically active compounds from various chemical classes, including alkaloids, terpenoids, sitosterols, flavonoids, and phenolic acids. Based on the reports researched for this review, we believe that chemicals in T. cordifolia may activate Nrf2, which leads to the overexpression of antioxidant enzymes such as CAT, GPx, GST, and GR, and thereby induces the adaptive response to oxidative stress. T. cordifolia is also able to reduce NF-κB signalling by inhibiting PI3K/Akt, activating AMPK and sirtuins, and downregulating PI3K/Akt. CONCLUSIONS: Our findings indicate that the pharmacological properties displayed by T. cordifolia back up its conventional uses. Antimicrobial, antiviral, antioxidant, anticancer, anti-inflammatory, antimutagenic, antidiabetic, nephroprotective, gastroprotective, hepatoprotective, and cardioprotective activities were all demonstrated in T. cordifolia stem extracts. To validate pharmacodynamic targets, further research is needed to evaluate the molecular mechanisms of the known compounds against gastrointestinal diseases, inflammatory processes, and microbial infections, as immunostimulants, and in chemotherapy. The T. cordifolia safety profile was confirmed in a toxicological analysis, which prompted pharmacokinetic assessment testing to confirm its bioavailability.

Alleviation of acute pancreatitis-associated lung injury by inhibiting the p38 mitogen-activated protein kinase pathway in pulmonary microvascular endothelial cells.

BACKGROUND: Previous reports have suggested that the p38 mitogen-activated protein kinase signaling pathway is involved in the development of severe acute pancreatitis (SAP)-related acute lung injury (ALI). Inhibition of p38 by SB203580 blocked the inflammatory responses in SAP-ALI. However, the precise mechanism associated with p38 is unclear, particularly in pulmonary microvascular endothelial cell (PMVEC) injury. AIM: To determine its role in the tumor necrosis factor-alpha (TNF-α)-induced inflammation and apoptosis of PMVECs in vitro. We then conducted in vivo experiments to confirm the effect of SB203580-mediated p38 inhibition on SAP-ALI. METHODS: In vitro, PMVEC were transfected with mitogen-activated protein kinase kinase 6 (Glu), which constitutively activates p38, and then stimulated with TNF-α. Flow cytometry and western blotting were performed to detect the cell apoptosis and inflammatory cytokine levels, respectively. In vivo, SAP-ALI was induced by 5% sodium taurocholate and three different doses of SB203580 (2.5, 5.0 or 10.0 mg/kg) were intraperitoneally injected prior to SAP induction. SAP-ALI was assessed by performing pulmonary histopathology assays, measuring myeloperoxidase activity, conducting arterial blood gas analyses and measuring TNF-α, interleukin (IL)-1ß and IL-6 levels. Lung microvascular permeability was measured by determining bronchoalveolar lavage fluid protein concentration, Evans blue extravasation and ultrastructural changes in PMVECs. The apoptotic death of pulmonary cells was confirmed by performing a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analysis and examining the Bcl2, Bax, Bim and cle-caspase3 levels. The proteins levels of P-p38, NFκB, IκB, P-signal transducer and activator of transcription-3, nuclear factor erythroid 2-related factor 2, HO-1 and Myd88 were detected in the lungs to further evaluate the potential mechanism underlying the protective effect of SB203580. RESULTS: In vitro, mitogen-activated protein kinase (Glu) transfection resulted in higher apoptotic rates and cytokine (IL-1ß and IL-6) levels in TNF-α-treated PMVECs. In vivo, SB2035080 attenuated lung histopathological injury, decreased inflammatory activity (TNF-α, IL-1ß, IL-6 and myeloperoxidase) and preserved pulmonary function. Furthermore, SB203580 significantly reversed changes in the bronchoalveolar lavage fluid protein concentration, Evans blue accumulation, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cell numbers, apoptosis-related proteins (cle-caspase3, Bim and Bax) and endothelial microstructure. Moreover, SB203580 significantly reduced the pulmonary P-p38, NFκB, P-signal transducer and activator of transcription-3 and Myd88 levels but increased the IκB and HO-1 levels. CONCLUSION: p38 inhibition may protect against SAP-ALI by alleviating inflammation and the apoptotic death of PMVECs.

Does the time from symptom onset to surgery affect the outcomes of patients with acute appendicitis? A prospective cohort study of 255 patients.

INTRODUCTION: The objective of this study was to evaluate the impact of operative timing on outcomes of acute appendicitis. METHODS: This study examined adult patients who had presented to the hospital with acute appendicitis and had undergone appendectomy from December 2017 to February 2019. Time delay and outcomes of perforated and non-perforated appendicitis were compared. Patients were classified into five groups based on the period from symptom onset to operation: group 1, <24 hours; group 2, ≥24 and <48 hours; group 3, ≥48 and <72 hours; group 4, ≥72 and <96 hours; and group 5, ≥96 hours. The five groups were compared, with risk of perforation assessed in particular. RESULTS: A total of 255 patients were included in the analysis. Symptom duration, operative time, and length of postoperative hospital stay (P < .001) were significantly longer in the perforated group (n = 49) than in the non-perforated group (n = 206). The perforated group also had a higher conversion rate to open procedures (P = .002) and a higher rate of wound infection (P = .034). Group 1 had 53 patients, group 2 had 95 patients, group 3 had 57 patients, group 4 had 32 patients, and group 5 had 18 patients. The incidence of appendiceal perforation and median operative time progressively increased along with symptom duration in the five groups. In multivariate analyses, independent risk factors for appendiceal perforation were male gender (odds ratio = 2.33, 95% confidence interval [CI]: 1.07-5.08) and symptom duration ≥48 hours (relative to ≥24 and <48 hours) (odds ratio = 4.64, 95%CI: 1.76-12.27). Patients with symptom duration ≥72 hours had a significantly longer operative time than those with symptom duration ≥48 and <72 hours (ß = 21.38, 95%CI: 5.66-37.11, P = .008). CONCLUSION: The risk of perforation increased significantly 48 hours after the onset of appendicitis. Symptoms duration ≥72 hours was associated with a longer operative time.

Chaiqin chengqi decoction alleviates severe acute pancreatitis associated acute kidney injury by inhibiting endoplasmic reticulum stress and subsequent apoptosis.

BACKGROUND: Acute kidney injury (AKI), characterized by an increase of serum creatinine and urea, is a severe complication of severe acute pancreatitis (SAP) with high mortality. Endoplasmic reticulum (ER) stress has been considered as a key pathologic process in AKI. Chaiqin chengqi decoction (CQCQD) is an effective Chinese medicine formula for SAP treatment in China and has been used for many years. Our goal is to explore the role of CQCQD on ER stress of AKI in experimental SAP. MATERIALS & METHODS: SAP was induced in rats by retrograde duct injection of 5% sodium taurocholate (NaTC, 1 ml/kg), sham operation (SO) rats simultaneously received saline infusion. Intraperitoneal injection of 4-PBA (50 mg/kg, once a day for three days before the surgery) or intragastric gavage of CQCQD (1 g/kg, 2 hourly × 3 after disease induction) was used to treat SAP rats. All animals were humanely sacrificed 12 h after disease induction. Histopathology scores of kidney and pancreas; serum biochemical indices and kidney protein levels of ER stress and apoptosis markers were assessed. Tubular epithelial cell line (HK-2) was treated either with TNF-α (10 ng/ml) or IL-6 (10 ng/ml) for 12 h plus either 4-PBA (0.1 M) or CQCQD (1 mg/ml) for in vitro study. Cell viability and markers of ER stress and apoptosis were measured. RESULTS: Ductal perfusion of NaTC caused significant increases in serum lipase, amylase and pancreatic histopathology (inflammatory cell infiltration, interstitial edema, and acinar cell necrosis). Kidney histopathology (tubular dilation, brush border loss, little tubular necrosis, and cast formation), serum creatine and urea levels were raised when compared with the SO group. Moreover, apoptotic cell death markers (caspase-9, cleaved-caspase-3, and TUNEL) and kidney ER stress proteins (BIP, IRE1-α, XBP1s, and CHOP) were elevated after NaTC administration. 4-PBA and CQCQD significantly alleviated histopathological changes of kidney and pancreas, inflammatory cytokines, biochemical markers of AKI, ER stress proteins and apoptotic cell death markers. They also protected HK-2 cells from injury of TNF-α and IL-6, and alleviated both ER stress and apoptosis proteins in vitro. CONCLUSION: CQCQD may alleviate SAP-related AKI by inhibiting ER stress-related apoptosis.

Correlation of MicroRNA 17-92 Cluster Host Gene (MIR17HG) Polymorphisms With Susceptibility and Prognosis for Multiple Myeloma.

PURPOSE: To explore the correlation of MIR17HG polymorphism with susceptibility and prognosis of multiple myeloma (MM). PATIENTS AND METHODS: A total of 217 MM patients treated with high-dose melphalan combined with autologous peripheral blood stem-cell transplantation at our hospital were enrolled as the case group, and 220 healthy people were included as the control group. Sequenom MassARRAY iPLEX Gold single nucleotide polymorphism genotyping was used to detect polymorphisms of MIR17HG, including rs7336610, rs17735387, rs4284505, and rs1428. RESULTS: An increased risk of MM was found in patients who carried the rs7336610 T allele and rs4284505 G allele, and the higher the Durie-Salmon and International Staging System stages were, the more MM patients carrying rs7336610 CT + TT genotype and rs4284505 AG + GG genotype (all P < .05). Haplotype AC (rs4284505-rs1428) and CA (rs7336610-rs4284505) evidently reduce MM risk, whereas haplotype GC (rs4284505-rs1428) significantly elevated MM risk (all P < .05). Kaplan-Meier curve analysis demonstrated that rs7336610 CC genotype carriers had higher 5-year survival rate than CT + TT genotype carriers (P = .034), and the AA genotype carriers of rs4284505 had higher 5-year survival rate than AG + GG genotype carriers (P < .001). CONCLUSION: Polymorphisms of MIR17HG rs7336610 and rs1428 were correlated with MM risk and prognosis.

Mesh-preservation approach to treatment of mesh infection after large incisional ventral hernia repair-how I do it.

Mesh infection after large incisional ventral hernia repair is a clinical dilemma in abdominal wall hernia surgery. It is believed foreign material should be removed but it causes secondary trauma to the abdominal wall tissue and might be associated with a higher risk of complications. Currently, there is no consensus on mesh-preservation treatment in cases of mesh infection after hernia repair in general. Herein we present the case of a 27-year-old male who recovered well from mesh infection after large incisional ventral hernia repair by mesh-preservation approach. The path to success is choice of material of prosthetic mesh; surgical approach of hernia repair, sufficient wound irrigation and drainage, and acquiring sterility of the mesh surface by wound care techniques such as local iodophor packing and vacuum sealing drainage. Clinical cohorts are needed to verify the feasibility of mesh-preservation treatment of mesh infection after large incisional hernia repair.

Laparoscopic sphincter-saving surgery for low rectal cancer through marker meeting approach.

Laparoscopic low anterior resection (LAR) with sphincter preservation for ultra-low rectal cancer is always a challenging operation in colorectal surgery. To achieve negative margins, reducing the difficulty and risks of the procedure are major goals for us. The marker meeting approach we reported can help to accomplish this goal. The key technique for the marker meeting approach is to ensure a clear distal margin in a low resection of the rectum by transanal dissection. This procedure allows access to the space around the distal rectum and mesorectum and to pack the gauzes in the distal part of the space as a landmark. Routine laparoscopic LAR was performed to dissect the space until reaching the gauzes packed above and achieve complete mobilization of the rectum and mesorectum. This surgical procedure is simpler and reduces the difficulty of the operation. Therefore, it is expected to reduce the risk of surgery-related complications and positive margins and is suitable to be widely applied and extended in clinical practice. The short-term and long-term clinical outcomes of the marker meeting approach need more research in large samples.

USP49 participates in the DNA damage response by forming a positive feedback loop with p53.

The p53 tumor suppressor is a critical factor in the DNA damage response (DDR), and regulation of p53 stability has a key role in this process. In our study, we identified USP49 as a novel deubiquitinase (DUB) for p53 from a library consisting of 80 DUBs and found that USP49 has a positive effect on p53 transcriptional activity and protein stability. Investigation of the mechanism revealed that USP49 interacts with the N terminus of p53 and suppresses several types of p53 ubiquitination. Furthermore, USP49 rendered HCT116 cells more sensitive to etoposide (Eto)-induced DNA damage and was upregulated in response to several types of cell stress, including DNA damage. Remarkably, USP49 expression was regulated by p53 and USP49 in knockout mice, which are more susceptible to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumors. These findings suggest that USP49 has an important role in DDR and may act as a potential tumor suppressor by forming a positive feedback loop with p53.

Laparoscopic repair of multiple incisional hernias in a single midline incision by double composite mesh.

Laparoscopic repair of ventral incisional hernia with intraperitoneal onlay mesh (IPOM) technique by anti-adhesion mesh has been widely adopted. Due to clinical heterogenicity in location, quantity and size of abdominal incisional hernia, strategy of such repair can be challenging. We hereby present the video of a patient with multiple swiss-cheese hernias in a single long midline incision repaired with double anti-adhesion mesh by IPOM technique. Patient demographics, technical details and clinical tips & tricks are discussed.