IFNγ at the early stage induced after cryo-thermal therapy maintains CD4+ Th1-prone differentiation, leading to long-term antitumor immunity.

Introduction: Recently, more and more research illustrated the importance of inducing CD4+ T helper type (Th)-1 dominant immunity for the success of tumor immunotherapy. Our prior studies revealed the crucial role of CD4+ Th1 cells in orchestrating systemic and durable antitumor immunity, which contributes to the satisfactory outcomes of the novel cryo-thermal therapy in the B16F10 tumor model. However, the mechanism for maintaining the cryo-thermal therapy-mediated durable CD4+ Th1-dominant response remains uncovered. Additionally, cryo-thermal-induced early-stage CD4+ Th1-dominant T cell response showed a correlation with the favorable prognosis in patients with colorectal cancer liver metastasis (CRCLM). We hypothesized that CD4+ Th1-dominant differentiation induced during the early stage post cryo-thermal therapy would affect the balance of CD4+ subsets at the late phase. Methods: To understand the role of interferon (IFN)-γ, the major effector of Th1 subsets, in maintaining long-term CD4+ Th1-prone polarization, B16F10 melanoma model was established in this study and a monoclonal antibody was used at the early stage post cryo-thermal therapy for interferon (IFN)-γ signaling blockade, and the influence on the phenotypic and functional change of immune cells was evaluated. Results: IFNγ at the early stage after cryo-thermal therapy maintained long-lasting CD4+ Th1-prone immunity by directly controlling Th17, Tfh, and Tregs polarization, leading to the hyperactivation of Myeloid-derived suppressor cells (MDSCs) represented by abundant interleukin (IL)-1ß generation, and thereby further amplifying Th1 response. Discussion: Our finding emphasized the key role of early-phase IFNγ abundance post cryo-thermal therapy, which could be a biomarker for better prognosis after cryo-thermal therapy.

Natural Killer Cells Reprogram Myeloid-Derived Suppressor Cells to Induce TNF-α Release via NKG2D-Ligand Interaction after Cryo-Thermal Therapy.

In our previous studies, a novel cryothermal therapy (CTT) was developed to induce systemic long-term anti-tumor immunity. Natural killer (NK) cells were found to play an important role in CTT-induced long-term immune-mediated tumor control at the late stage after CTT, but the underlying mechanism is unclear. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that have potent immunosuppressive effects on T cells and weaken the long-term benefits of immunotherapy. Consequently, overcoming MDSC immunosuppression is essential for maintaining the long-term efficacy of immunotherapy. In this study, we revealed that NK cells considerably diminish MDSC accumulation at the late stage after CTT, boost T cell production, increase T cell activation, and promote MDSC maturation, culminating in Th1-dominant CD4+ T cell differentiation and enhancing NK and CD8+ T cell cytotoxicity. Additionally, NK cells activate ERK signaling in MDSCs through NKG2D-ligand interaction to increase the activity of tumor necrosis factor (TNF)-α converting enzyme (TACE)-cleaved membrane TNF-α. Furthermore, Increased TACE activity releases more soluble TNF-α from MDSCs to promote MDSC maturation. In our studies, we propose a novel mechanism by which NK cells can overcome MDSC-induced immunosuppression and maintain CTT-induced persistent anti-tumor immunity, providing a prospective therapeutic option to improve the performance of cancer immunotherapy.

ROR2-Related Skeletal Dysplasia Reveals Disrupted Chondrocyte Polarity through Modulation of BMP/TGF-ß Signaling.

Genetic studies have shown that Robinow syndrome (RS), a rare skeletal dysplasia, is caused by ROR2 mutation. However, the cell origin and molecular mechanisms underlying this disease remain elusive. We established a conditional knockout system by crossing Prx1cre and Osxcre with Ror2 flox/flox mice. and conducted histological and immunofluorescence analyses to investigate the phenotypes during skeletal development. In the Prx1cre line, we observed RS-like skeletal abnormities, including short stature and an arched skull. Additionally, we found inhibition of chondrocyte differentiation and proliferation. In the Osxcre line, loss of ROR2 in osteoblast lineage cells led to reduced osteoblast differentiation during both embryonic and postnatal stages. Furthermore, ROR2 mutant mice exhibited increased adipogenesis in the bone marrow compared to their littermate controls. To further explore the underlying mechanisms, bulk RNA-seq analysis of Prx1cre; Ror2 flox/flox embryos was performed, results revealed decreased BMP/TGF-ß signaling. Immunofluorescence analysis further confirmed the decreased expression of p-smad1/5/8, accompanied by disrupted cell polarity in the developing growth plate. Pharmacological treatment using FK506 partially rescued the skeletal dysplasia and resulted in increased mineralization and osteoblast differentiation. By modeling the phenotype of RS in mice, our findings provide evidence for the involvement of mesenchymal progenitors as the cell origin and highlight the molecular mechanism of BMP/TGF-ß signaling in skeletal dysplasia.

Qushi Huayu decoction ameliorates non-alcoholic fatty liver disease in rats by modulating gut microbiota and serum lipids.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease. As a clinical empirical prescription of traditional Chinese medicine, Qushi Huayu decoction (QHD) has attracted considerable attention for its advantages in multi-target treatment of NAFLD. However, the intervention mechanism of QHD on abnormal lipid levels and gut microbiota in NAFLD has not been reported. Methods: Therefore, we verified the therapeutic effect of QHD on high-fat diet (HFD)-induced NAFLD in rats by physiological parameters and histopathological examination. In addition, studies on gut microbiota and serum lipidomics based on 16S rRNA sequencing and ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) were conducted to elucidate the therapeutic mechanism of NAFLD in QHD. Results: The changes in gut microbiota in NAFLD rats are mainly reflected in their diversity and composition, while QHD treated rats restored these changes. The genera Blautia, Lactobacillus, Allobaculum, Lachnoclostridium and Bacteroides were predominant in the NAFLD group, whereas, Turicibacter, Blautia, Sporosarcina, Romboutsia, Clostridium_sensu_stricto_1, Allobaculum, and Psychrobacter were predominant in the NAFLD+QHD group. Lipid subclasses, including diacylglycerol (DG), triglycerides (TG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidic acid (PA), phosphatidylserine (PS), lysophosphatidylinositol (LPI), and phosphatidylglycerol (PG), were significantly different between the NAFLD and the control groups, while QHD treatment significantly altered the levels of DG, TG, PA, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and platelet activating factor (PAF). Finally, Spearman's correlation analysis showed that NAFLD related differential lipid molecules were mainly associated with the genera of Bacteroides, Blautia, Lachnoclostridium, Clostridium_sensu_stricto_1, and Turicibacter, which were also significantly correlated with the biological parameters of NAFLD. Discussion: Taken together, QHD may exert beneficial effects by regulating the gut microbiota and thus intervening in serum lipids.

Residual circulating tumor DNA after adjuvant chemotherapy effectively predicts recurrence of stage II-III gastric cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker for predicting relapse in multiple solid cancers. However, the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer (GC). Here, we aimed to evaluate the predictive value of ctDNA in this context. METHODS: From 2016 to 2019, 100 patients with stage II/III resectable GC were recruited in this prospective cohort study (NCT02887612). Primary tumors were collected during surgical resection, and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma was defined as ctDNA-positive only if one or more variants detected in the plasma were presented in at least 2% of the primary tumors. RESULTS: Compared with ctDNA-negative patients, patients with positive postoperative ctDNA had moderately higher risk of recurrence [hazard ratio (HR) = 2.74, 95% confidence interval (CI) = 1.37-5.48; P = 0.003], while patients with positive post-ACT ctDNA showed remarkably higher risk (HR = 14.99, 95% CI = 3.08-72.96; P < 0.001). Multivariate analyses indicated that both postoperative and post-ACT ctDNA positivity were independent predictors of recurrence-free survival (RFS). Moreover, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and serial cancer antigen. A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C-index (0.78; 95% CI = 0.71-0.84) than the model without ctDNA (0.71; 95% CI = 0.64-0.79; P = 0.009). CONCLUSIONS: Residual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC, and the combination of tissue-based and circulating tumor features could achieve better risk prediction.

A Mechanism Study on the (+)-ESI-TOF/HRMS Fragmentation of Some PPI Prazoles and Their Related Substances.

Fragmentation mechanisms of some prazoles and their related substances were newly investigated in this paper via positive mode ESI-TOF HRMS1 and HRMS2. Some novel fragmentation rules or ions were found or detected in the research. The pyridine and the benzoimidazole ring remained in most cases during the ionization, and heterolytic fragmentations often occurred near the -S(O)nCH2- linker to give the [1,3]-H migration ion or [1,7]-H migration ion rearranging across the benzoimdazole ring. Smiles rearrangement ionizations also frequently occurred, initiated by the attack of the lone pair electrons from the pyridine ring, and the sulfones gave special N-(2-benzoimdazolyl) pyridine ions (11b and 12c) by a direct extraction from SO2, and the thioethers gave similar framework ions (8c, 9c and 10c) via the rearrangement and a further homolytic cleavage of SH radicals. However, the sulfoxides were seldom detected in the corresponding Smiles rearrangement ions during our measurement, and the N'-oxides of the pyridines did not undergo the Smiles rearrangement ionization due to the absence of the lone pair electrons. The 5/6-membered chelating ions with Na+ or K+ were frequently detected as the molecular and further fragment ions. Some novel and interesting fragment ions containing bivalent (8b and 9b), tetravalent (4b, 5c and 6c) or hexavalent (15b and 16b) sulfurs were first reported here.

Exosomes: Potential key players towards novel therapeutic options in diabetic wounds.

Diabetic wounds are usually difficult to heal, and wounds in foot in particular are often aggravated by infection, trauma, diabetic neuropathy, peripheral vascular disease and other factors, resulting in serious foot ulcers. The pathogenesis and clinical manifestations of diabetic wounds are complicated, and there is still a lack of objective and in-depth laboratory diagnosis and classification standards. Exosomes are nanoscale vesicles containing DNA, mRNA, microRNA, cyclic RNA, metabolites, lipids, cytoplasm and cell surface proteins, etc., which are involved in intercellular communication and play a crucial role in vascular regeneration, tissue repair and inflammation regulation in the process of diabetic wound healing. Here, we discussed exosomes of different cellular origins, such as diabetic wound-related fibroblasts (DWAF), adipose stem cells (ASCs), mesenchymal stem cells (MSCs), immune cells, platelets, human amniotic epithelial cells (hAECs), epidermal stem cells (ESCs), and their various molecular components. They exhibit multiple therapeutic effects during diabetic wound healing, including promoting cell proliferation and migration associated with wound healing, regulating macrophage polarization to inhibit inflammatory responses, promoting nerve repair, and promoting vascular renewal and accelerating wound vascularization. In addition, exosomes can be designed to deliver different therapeutic loads and have the ability to deliver them to the desired target. Therefore, exosomes may become an innovative target for precision therapeutics in diabetic wounds. In this review, we summarize the latest research on the role of exosomes in the healing of diabetic wound by regulating the pathogenesis of diabetic wounds, and discuss their potential applications in the precision treatment of diabetic wounds.

Peroxy radical chemistry during ozone photochemical pollution season at a suburban site in the boundary of Jiangsu-Anhui-Shandong-Henan region, China.

Ambient peroxy radical (RO2⁎ = HO2 + RO2) concentrations were measured at a suburban site in a major prefecture-level city (Huaibei) in the boundary of Jiangsu-Anhui-Shandong-Henan region, which is the connecting belt of air pollution in the Beijing-Tianjin-Hebei region and the Yangtze River Delta. Measurements were carried out during the period of September to October 2021 to elucidate the formation mechanism of O3 pollution. The observed maximum concentration of peroxy radicals was 73.8 pptv. A zero-dimensional box model (Framework for 0-Dimensional Atmospheric Modeling, F0AM) based on Master Chemical Mechanism (MCM3.3.1) was used to predict radical concentrations for comparison with observations. The model reproduced the daily variation of peroxy radicals well, but discrepancies still appear in the morning hours. As in previous field campaigns, systematic discrepancies between modelled and measured RO2⁎ concentrations are observed in the morning for NO mixing ratios higher than 1 ppbv. Between 6:00 and 9:00 am, the model significantly underpredicts RO2⁎ by a mean factor of 7.2. This underprediction can be explained by a missing RO2⁎ source of 1.2 ppbv h-1 which originated from the photochemical conversion of an alkene-like chemical species. From the model results it shows that the main sources of ROx (= OH + HO2 + RO2) are the photolysis of oxygenated volatile organic compounds (OVOCs, 33 %), O3 and HONO (25 %), and HCHO (24 %). And the major sinks of ROx transitioned from a predominant reaction of radicals with NOx in the morning to a predominant peroxy self- and cross-reaction in the late afternoon. The introduction of an alkene-like species increased RO2 radical concentration and resulted in 14 % increase in net daily integrated ozone production, indicating the possible significance of the mechanism of alkene-like species oxidation to peroxy radicals. This study provides important information for subsequent ozone pollution control policies in Jiangsu-Anhui-Shandong-Henan region.

Loss of signal transducer and activator of transcription 3 in osteoblasts impaired the bone healing in inflammatory microenvironment.

INTRODUCTION: This study aimed to investigate the effect of Stat3 on the osteoblast-mediated bone healing in the inflammatory lesion. METHODS: The conditional knockout of Stat3 in osteoblasts (Stat3 CKO) was generated via the Cre-loxP recombination system using Osterix-Cre transgenic mice. The calvarial bone inflammatory lesions were established on both Stat3 CKO and wild-type mice, then harvested to assess the bone healing. In response to lipopolysaccharide (LPS) stimulation, osteoblasts from Stat3 CKO and wild-type mice were subjected to examine the formation of calcium deposits, the expression of osteogenic markers (i.e., Runx2, OPN, COL1A1), and osteoclast-related markers (i.e., RANKL, OPG). The EdU and transwell assays were performed to assess the proliferation and migration of the cells. RESULTS: A decrease in bone mass and an increase in osteolysis were found in the inflammatory lesions on Stat3 CKO mice when compared with the control. More osteoclastic-like cells and an increased expression of RANKL were observed in Stat3 CKO mice. Both mRNA and protein expressions of Stat3 and osteogenic markers in the lesions were significantly decreased in Stat3 CKO mice. After co-cultured with osteogenic medium, the Stat3-deficient osteoblasts were found with a significant decrease in calcium deposits and the expression of osteogenic markers, and with a significant increased expression of RANKL. The impaired ossification of Stat3-deficient osteoblasts was even more pronounced with the presence of lipopolysaccharides in vitro. The most decrease in cell proliferation and migration was found in Stat3-deficient osteoblasts in response to LPS. CONCLUSIONS: Loss of Stat3 in osteoblasts impaired bone healing in an inflammatory microenvironment.

[Characteristics of O3 Production in the Western Suburb of Hefei in Summer Based on the Observation of Total Peroxy Radical].

In August 2020, the observations of total peroxy radical concentrations were carried out in the western suburb site of Hefei using a peroxy radical chemical amplifier (PERCA) instrument. The ozone production and its sensitivity were characterized with the measured O3 and its precursors. The results showed that the daily variation in total peroxy radical concentrations exhibited an obvious convex tend, with the highest value at approximately 12:00; the average peak peroxy radical concentration was 43.8×10-12; and the concentrations of the peroxy radical and ozone were driven by strong solar radiation and high temperature. The photochemical ozone production rate could be determined with peroxy radical and NO concentration. The average ozone peak production rate in summer was 10.6×10-9 h-1, which was more sensitive to NO concentration. Based on the ratio of the radical loss rate due to reactions with NOx to the radical loss rate (Ln/Q), the characteristics of O3 production in the western suburb of Hefei in summer were analyzed. The results showed that O3 production sensitivity varied greatly during the day. The summer O3 production regime shifted from the VOC-sensitive chemistry in the early morning to NOx-sensitive chemistry in the afternoon, and this regime transition typically occurred in the morning.

Loss of Stat3 in Osterix+ cells impairs dental hard tissues development.

BACKGROUND: Mutations in the signal transducers and activators of transcription 3 (STAT3) gene result in hyper-IgE syndrome(HIES), a rare immunodeficiency that causes abnormalities in immune system, bones and teeth. However, the role of Stat3 in development of dental hard tissues was yet to investigate. METHODS: In this study, a transgenic mouse of conditional knockout of Stat3 in dental mesenchymal cells (Osx-Cre; Stat3fl/fl, Stat3 CKO) was made. The differences of postnatal tooth development between control and Stat3 CKO mice were compared by histology, µCT and scanning electron microscopy. RESULT: Compared with the control, Stat3 CKO mice were presented with remarkable abnormal tooth phenotypes characterized by short root and thin dentin in molars and incisors. The enamel defects were also found on mandibular incisors. showed that Ki67-positive cells significantly decreased in dental mesenchymal of Stat3 CKO mice. In addition, ß-catenin signaling was reduced in Hertwig's epithelial root sheath (HERS) and odontoblasts of Stat3 CKO mice. CONCLUSIONS: Our results suggested that Stat3 played an important role in dental hard tissues development, and Stat3 may regulate dentin and tooth root development through the ß-catenin signaling pathway.

Piezoelectric Bioactive Glasses Composite Promotes Angiogenesis by the Synergistic Effect of Wireless Electrical Stimulation and Active Ions.

Insufficient angiogenesis frequently occurs after the implantation of orthopedic materials, which greatly increases the risk of bone defect reconstruction failure. Therefore, the development of bone implant with improved angiogenic properties is of great importance. Mimicking the extracellular matrix clues provides a more direct and effective strategy to modulate angiogenesis. Herein, inspired by the bioelectrical characteristics of the bone microenvironment, a piezoelectric bioactive glasses composite (P-KNN/BG) based on the incorporation of polarized potassium sodium niobate is constructed, which could effectively promote angiogenesis. It is found that P-KNN/BG has exceptional wireless electrical stimulation performance and sustained active ions release. In vitro cell experiments reveal that P-KNN/BG enhances endothelial cell adhesion, migration, and differentiation via activating the eNOS/NO signaling pathway, which might be contributed to cell membrane hyperpolarization induced by wireless electrical stimulation increase the influx of active ions into the cells. In vivo chick chorioallantoic membrane experiment demonstrates that P-KNN/BG shows excellent pro-angiogenic capacity and biocompatibility. This work broadens the current understanding of bioactive materials with bionic electrical properties, which brings new insights into the clinical treatment of bone defect repair.

Contact Angle Measurement on Curved Wetting Surfaces in Multiphase Lattice Boltzmann Method.

Contact angle is an essential physical quantity that characterizes the wettability of a substrate. Although it is widely used in the studies of surface wetting, capillary phenomena, and moving contact lines, the contact angle measurements in simulations and experiments are still complicated and time-consuming. In this paper, we present an efficient scheme for the measurement of contact angle on curved wetting surfaces in lattice Boltzmann simulations. The measuring results are in excellent agreement with the theoretical predictions without considering the gravity effect. A series of simulations with various drop sizes and surface curvatures confirm that the present scheme is grid-independent. Then, the scheme is verified in gravitational environments by simulating the deformations of sessile and pendent droplets on the curved wetting surface. The numerical results are highly consistent with experimental observations and support the theoretical analysis that the microscopic contact angle is independent of gravity. Furthermore, the method utilizes only the microscopic geometry of the contact angle and does not depend on the droplet profile; therefore, it can be applied to nonaxisymmetric shapes or moving contact lines. The scheme is applied to capture the dynamic contact angle hysteresis on homogeneous or chemically heterogeneous curved surfaces. Importantly, the accurate contact angle measurement enables the dynamic mechanical analysis of moving contact lines. The present measurement is simple and efficient and can be extended to implementations in various multiphase lattice Boltzmann models.

Clinical Benefit of First-Line Programmed Death-1 Antibody Plus Chemotherapy in Low Programmed Cell Death Ligand 1-Expressing Esophageal Squamous Cell Carcinoma: A Post Hoc Analysis of JUPITER-06 and Meta-Analysis.

PURPOSE: Pembrolizumab or nivolumab plus chemotherapy was approved as a first-line treatment for high programmed cell death ligand 1 (PD-L1)-expressing esophageal squamous cell carcinoma (ESCC) by the European Medicines Agency, whereas the US Food and Drug Administration approved this regimen regardless of PD-L1 expression. The superiority of programmed death-1 (PD-1) antibody plus chemotherapy over chemotherapy alone in patients with low PD-L1-expressing ESCC remains debatable. METHODS: Post hoc analysis of the Chinese JUPITER-06 study focusing on efficacy stratified by PD-L1 tumor proportion score (TPS; using JS311 antibody) was conducted. Electronic databases were searched to identify eligible randomized controlled trials for meta-analysis. Study-level pooled analyses of hazard ratios (HRs) for overall survival and progression-free survival and odds ratios for objective response rate according to PD-L1 expression were performed. RESULTS: The post hoc analysis of JUPITER-06 showed more prominent clinical benefit with PD-1 antibody plus chemotherapy than with chemotherapy alone in both the high and low PD-L1-expressing subgroups. Five randomized controlled trials were included in the meta-analysis, and two PD-L1 expression scoring criteria, TPS (≥ 1%/< 1%) and combined positive score (CPS, ≥ 10/< 10), were analyzed. Significant overall survival benefit by adding PD-1 antibody to chemotherapy was observed in both the TPS < 1% (HR, 0.74; 95% CI, 0.56 to 0.97) and CPS < 10 (HR, 0.77; 95% CI, 0.66 to 0.89) subgroups. Similarly, significantly prolonged progression-free survival was observed in both the TPS < 1% (HR, 0.66; 95% CI, 0.50 to 0.86) and CPS < 10 (HR, 0.63; 95% CI, 0.47 to 0.84) subgroups. In addition, the objective response rate of the TPS < 1% subgroup was significantly improved (odds ratio, 1.71; 95% CI, 1.27 to 2.29). In all high PD-L1-expressing subgroups, the pooled benefit of PD-1 antibody plus chemotherapy was significantly better than that of chemotherapy. CONCLUSION: This study provided novel evidence supporting the superiority of PD-1 antibody plus chemotherapy to chemotherapy alone in patients with advanced ESCC with low PD-L1 expression. Further studies of predictive biomarkers are warranted.

AKR1B8 deficiency drives severe DSS-induced acute colitis through invasion of luminal bacteria and activation of innate immunity.

Background: Dysfunction of intestinal epithelial cells (IECs) promotes inflammatory bowel disease (IBD) and associated colorectal cancer (CRC). AKR1B8 deficiency impairs the IEC barrier function, leading to susceptibility to chronic colitis induced by dextran sulfate sodium (DSS), yet it remains unclear how acute colitic response is in AKR1B8 deficient mice. Methods: AKR1B8 knockout (KO) and littermate wild type mice were exposed to oral 1.5% DSS in drinking water for 6 days. Disease activity index and histopathological inflammation scores by H&E staining were calculated for colitic severity; permeability was assessed by fluorescein isothiocyanate dextran (FITC-Dextran) probes and bacterial invasion and transmission were detected by in situ hybridization in mucosa or by culture in blood agar plates. Immunofluorescent staining and flow cytometry were applied for immune cell quantification. Toll-like receptor 4 (TLR4) and target gene expression was analyzed by Western blotting and qRT-PCR. Results: AKR1B8 KO mice developed severe acute colitis at a low dose (1.5%) of DSS in drinking water compared to wild type controls. In AKR1B8 KO mice, FITC-dextran was penetrated easily and luminal bacteria invaded to the surface of IEC layer on day 3, and excessive bacteria translocated into the colonic mucosa, mesenteric lymph nodes (MLNs) and liver on day 6, which was much mild in wild type mice. Hyper-infiltration of neutrophils and basophils occurred in AKR1B8 KO mice, and monocytes in spleen and macrophages in colonic mucosa increased markedly compared to wild type mice. TLR4 signaling in colonic epithelial cells of AKR1B8 KO mice was activated to promote great IL-1ß and IL-6 expression compared to wild type mice. Conclusions: AKR1B8 deficiency in IECs drives severe acute colitis induced by DSS at a low dose through activation of the innate immunity, being a novel pathogenic factor of colitis.

Impact of mismatch repair or microsatellite status on the prognosis and efficacy to chemotherapy in metastatic colorectal cancer patients: A bi-institutional, propensity score-matched study.

Background: Deficient mismatch repair (dMMR) or the microsatellite instability (MSI) phenotype occupied approximately 15-18% of CRC patients. Previous studies showed that dMMR/MSI status is a favorable prognostic factor for stage II/III CRC patients. For metastatic colorectal cancer (mCRC) patients, only 5% of patients have the dMMR/MSI-H phenotype. The relationship between dMMR/MSI, chemosensitivity and survival in mCRC patients of real-world is still not clear. Materials and methods: In this study, we enrolled 77 dMMR/MSI-H mCRC patients and compared their clinicopathological characteristics with those of 510 proficient MMR (pMMR) or microsatellite stable (MSS) mCRC patients. With propensity score matching (PSM) analysis, we further compared the chemosensitivity and survival of dMMR/MSI-H mCRC patients with pMMR/MSS patients. We also analyzed the efficacy of different chemotherapy and target therapy in the dMMR/MSI-H population. Results: In PSM cohort, the objective response rate (ORR) of mCRC patients with dMMR/MSI-H undergoing first-line palliative chemotherapy was 35.2%, which was similar with patients with pMMR/MSS (35.4%, p = 1.00). The median progression-free survival (PFS) of first-line chemotherapy was significantly different (dMMR/MSI-H vs pMMR/MSS = 7.4 months vs 10.2 months; HR = 0.74; 95%CI, 0.57-0.98; p = 0.03). Overall survival (OS) of patients did not significantly differ by status (dMMR/MSI-H vs pMMR/MSS = 40.0 months vs 41.3 months; HR = 1.09; 95%CI, 0.74-1.59; p = 0.68). For second-line palliative chemotherapy, there was no difference in ORR (p = 0.53) or in PFS (HR = 0.88; 95%CI, 0.59-1.33; p = 0.56) between dMMR/MSI-H and pMMR/MSS tumors. We also found that in the overall cohort, the ORR of patients who received oxaliplatin-based and irinotecan-based chemotherapy were 28.8% and 54.5%, respectively, which were not significantly different (p = 0.16). Our results also showed that the use of bevacizumab could lead to a significantly higher ORR in dMMR/MSI-H mCRC patients compared to chemotherapy alone (55.0% vs 22.2%; p = 0.02), whereas cetuximab could not. Conclusion: The dMMR/MSI-H is not a prognostic factor for mCRC patients but is correlated with shorter PFS to first-line palliative chemotherapy.

Multiphase curved boundary condition in lattice Boltzmann method.

The boundary treatment is fundamental for modeling fluid flows especially in the lattice Boltzmann method; the curved boundary conditions effectively improve the accuracy of single-phase simulations with complex-geometry boundaries. However, the conventional curved boundary conditions usually cause dramatic mass leakage or increase when they are directly used for multiphase flow simulations. We find that the principal reason for this is the absence of a nonideal effect in the curved boundary conditions, followed by a calculation error. In this paper, incorporating the nonideal effect into the linear interpolation scheme and compensating for the interpolating error, we propose a multiphase curved boundary condition to treat the wetting boundaries with complex geometries. A series of static and dynamic multiphase simulations with large density ratio verify that the present scheme is accurate and ensures mass conservation.

A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study).

PURPOSE: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. RESULTS: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. CONCLUSIONS: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

Comprehensive profiling of 1015 patients' exomes reveals genomic-clinical associations in colorectal cancer.

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.

Primary tumor resection with or without metastasectomy for left- and right-sided stage IV colorectal cancer: an instrumental variable analysis.

BACKGROUND: Whether primary tumor location (PTL) is predictive of survival benefits following primary tumor resection plus metastasectomy (PMTR) and primary tumor resection (PTR) alone in stage IV colorectal cancer patients is not known. We sought to address this issue by employing instrumental variable analysis to evaluate the efficacy of PMTR and PTR with stratification for primary tumor location in stage IV colorectal cancer patients. PATIENTS AND METHODS: Stage IV colorectal cancer patients diagnosed between January 1, 2005 and December 31, 2015 were identified from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. To account for both measured and unmeasured confounders, the efficacy of PMTR and PTR in the left- and right-sided subgroups was evaluated using instrumental variable analysis, with the health service area as the instrument variable. Overall survival (OS) was the primary outcome of interest. RESULTS: A total of 50,333 eligible patients were analyzed (left-sided, n = 29,402 and right-sided, n = 20,931). OS was significantly better with PMTR than with other treatments (PTR, metastasectomy only, or no surgery) in patients with left-sided tumors (hazard ratio [HR] = 0.37 [95% CI 0.24-0.58], P < 0.001), but not in patients with right-sided tumors (HR = 0.98 [95% CI 0.65-1.47], P = 0.910; interaction test P < 0.001). OS was comparable in patients treated with PTR and those treated with no surgery in both the left-sided (HR = 1.11 [95% CI 0.68-1.81], P = 0.690) and right-sided (HR = 0.85 [95% CI 0.50-1.43], P = 0.530; interaction test P = 0.466) subgroups. CONCLUSIONS: PMTR appears to only benefit patients with left-sided stage IV colorectal cancer but not those with right-sided tumors. PTR does not improve OS, regardless of primary tumor location. When selecting patients for PMTR, primary tumor location should be considered. Overuse of PTR should be avoided.