Efficacy and safety of tislelizumab plus lenvatinib as first-line treatment in patients with unresectable hepatocellular carcinoma: a multicenter, single-arm, phase 2 trial.

BACKGROUND: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. METHODS: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. RESULTS: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. CONCLUSIONS: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04401800).

Phosphine-Catalyzed (4 + 2) Annulation of Allenoates Bearing Acidic Hydrogen with 1,1-Dicyanoalkenes.

α-succinimide-substituted allenoates were employed as phosphine acceptors in phosphine-catalyzed (4 + 2) annulation with 1,1-dicyanoalkenes. They served as C4 synthons in the annulation reaction under mild reaction conditions and produced hexahydroisoindole derivatives in moderate to high yields with good to excellent diastereoselectivities.

Cleaner tillage and irrigation options for food-water-energy-carbon synergism in wheat-maize cropping systems.

The conventional wheat-maize systems in the North China Plain are energy and water intensive with high carbon emissions. It is imperative to find cleaner production technologies for sustainable food-water-energy-carbon synergism. Here, a three-year field experiment was performed to explore the effects of two tillage modes and four irrigation regimes during wheat season on crop yield, economic profile, water use efficiency, energy utilization, and carbon footprint in typical wheat-maize cropping systems in the North China Plain. Pre-sowing irrigation resulted in the lowest crop yield and benefit profile. Pre-sowing + anthesis irrigation decreased economic benefit and water use efficiency with higher carbon footprint. Pre-sowing + jointing + anthesis irrigation led to the greatest energy consumption and greenhouse gas emissions. However, pre-sowing + jointing irrigation increased yield by 2.3-8.7%, economic benefit by 4.0-11.1%, water use efficiency by 7.4-10.9%, and net energy by 6.5-12.0% but reduced carbon footprint by 9.8-14.3% compared to pre-sowing + anthesis irrigation and pre-sowing + jointing + anthesis irrigation. The corresponding metrics in rotary tillage improved by 9.6%, 13.9%, 7.0%, and 14.2%, respectively, relative to subsoiling, whereas carbon footprint decreased by 12.4-17.2%. Besides, rotary tillage coupled with additional jointing irrigation obtained the highest value based on a Z-score method, which was recommended as a cleaner management practice to improve benefit return and water use efficiency with lower energy consumption and carbon footprint. This work provides valuable insights into food-water-energy-carbon nexus for ensuring food security and achieving environmental sustainability in the wheat-maize cropping systems.

Effects of gait adaptation training on augmented reality treadmill for patients with stroke in community ambulation.

Gait adaptability is essential for stroke survivors to achieve efficient and safe community ambulation. However, conventional treadmill rehabilitation is only a repetitive practice of leg movement. This study compared the effects of augmented reality treadmill-based gait adaptation training with regular treadmill programs for patients with stroke. Forty patients with stroke (n = 40) were randomly assigned to the gait adaptation training {n = 20, age: 49.85 [standard deviation (SD) 8.44] years; onset of stroke: 107.80 (SD 48.31) days} and regular training [n = 20, age: 50.75 (SD 8.05) years, onset of stroke: 111.60 (SD 49.62) days] groups. Both groups completed three sessions of training per week for 5 weeks (15 sessions). The primary outcomes were the 10-m walk test and success rate of obstacle avoidance, while secondary outcomes included the Berg balance scale, component timed-up-and-go, and fall rate in a 6-month follow-up period. Assessments were performed before and after the intervention. The paired t-test was applied to compare the differences within groups and independent sample t-test was performed to compare the differences between groups. The 10-m walk test, success rate of obstacle avoidance, Berg balance scale, and component timed-up-and-go all significantly improved in the both groups (P < .001). The success rate of obstacle avoidance [P = .02, 95% confidence interval (CI): -21.07, -1.64], Berg Balance Scale (P = .02, 95% CI: -8.03, -0.67), 'turning around time' (P = .04, 95% CI: 0.08, 2.81), 'stand-to-sit' (P = .03, 95% CI: 0.16, 2.41) and 'total time' (P = .048, 95% CI: 0.04, 10.32) improved significantly in gait adaptation training group after intervention, while the 10-m walk test (P = .09, 95% CI: -0.17, 0.01), timed 'sit-to-stand' (P = .09, 95% CI: -0.14, 2.04), and 'linear walking' (P = .09, 95% CI: -0.27, 3.25) in gait adaptation training group did not show statistical difference compared to the regular training group. Total fall rate during the follow-up period was statistically decreased in the gait adaptation training group (P = .045). Both interventions improved mobility outcomes, with augmented reality treadmill-based gait adaptation indicating greater improvement in obstacle avoidance, balance, turning, and stand-to-sit. Augmented reality treadmill-based gait adaptation training emerges as an effective and promising intervention for patients with stroke in early rehabilitation.

A modified Blumgart method using a homemade crochet needle facilitates pancreaticojejunostomy in laparoscopic pancreaticoduodenectomy: a retrospective cohort study.

BACKGROUND: Among the safest procedures for anastomosis in pancreaticoduodenectomy, Blumgart pancreaticojejunostomy is associated with low rates of postoperative pancreatic fistula (POPF) and postoperative complications. However, this technique is difficult to perform during laparoscopic pancreaticoduodenectomy (LPD). This study presents a modified Blumgart method using a homemade crochet needle to facilitate laparoscopic pancreaticojejunostomy and evaluates its safety and reliability. METHODS: From February 2019 to October 2022, 96 LPD surgeries with the new technique were performed by the same surgeons in the Second Affiliated Hospital of Zhejiang University School of Medicine. The operative details (operative time, pancreaticojejunostomy time, POPF rate, postoperative complication rate, mortality rate) were analyzed along with clinical and pathological indicators (pancreatic duct diameter, pancreatic texture, and histopathological findings). RESULTS: There were 54 men and 42 women with a mean age of 63.38 ± 10.41 years. The intraoperative bleeding volume, operative time and postoperative length of hospital stay were 198.43 ± 132.97 mL, 445.30 ± 87.05 min and 13.68 ± 4.02 days, respectively. The operation time of pancreaticojejunostomy was 66.28 ± 10.17 min. Clinically relevant POPFs (grades B and C) occurred in 14.6% of patients. Only one patient had postoperative abdominal hemorrhage and was cured after reoperation. There were no operative or in-hospital deaths. With our proposed modification, the pancreatic duct and jejunal orifice are aligned correctly during duct-to-mucosa (DTM) after the application of external traction through the homemade crochet needle. The space between the posterior wall of pancreatic remnant and jejunal loop can be exposed by adjusting the tension of the external threads, which can facilitate DTM. CONCLUSIONS: A modified Blumgart method using a homemade crochet needle could be technically feasible and safe during LPD. A randomized control trial is needed to confirm these findings.

Synthesis of 3,4-Disubstituted Maleimide Derivatives via Phosphine-Catalyzed Isomerization of α-Succinimide-Substituted Allenoates Cascade γ'-Addition with Aryl Imines.

3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ'-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ'-addition reaction of allenoates is seldom reported.

Phosphine-Catalyzed γ'-Carbon 1,6-Conjugate Addition of α-Succinimide Substituted Allenoates with Para-Quinone Methides: Synthesis of 4-Diarylmethylated 3,4-Disubstituted Maleimides.

In this paper, an interesting γ'-carbon 1,6-conjugate addition for phosphine-catalyzed α-succinimide substituted allenoates has been disclosed. A wide array of substrates was found to participate in the reaction, resulting in the production of diverse 4-diarylmethylated 3,4-disubstituted maleimides with satisfactory to outstanding yields. Furthermore, a plausible mechanism for the reaction was proposed by the investigators.

Response of the cultivation suitability of Pu'er tea (Camellia sinensis var. assamica) to climate conditions and change in China.

Crop cultivation suitability plays a vital role in determining the distribution, quality, and production of crop and can be greatly affected by climate change. Therefore, evaluating crop cultivation suitability under climate change and identifying the factors influencing it can optimize crop cultivation layout and improve production and quality. Based on comprehensive datasets including geographical distribution points, climate data, soil characteristics, and topography, our study employed the MaxEnt model to simulate the potential distribution of Pu'er tea (Camellia sinensis var. assamica) cultivation suitability in Yunnan Province from 1961 to 2020. Furthermore, we assessed the consistency between the simulated suitable areas and the actual production of Pu'er tea. The results showed that precipitation of the warmest quarter, precipitation of the driest month, and average temperature in January were the three dominant environmental variables affecting the cultivation distribution of Pu'er tea. The high suitable areas for Pu'er tea cultivation in Yunnan Province were mainly distributed in the western and southern regions, accounting for 13.89% of the total area of Yunnan Province. The medium suitable areas are mainly distributed in the central and western regions of Yunnan Province, accounting for 20.07% of the total area of Yunnan Province. Over the past 60 years, the unsuitable area for Pu'er tea has increased, while the suitable area has shown a trend of migration to the southwest. Changes in precipitation and temperature were found to be the main drivers of the changes in the distribution of suitable areas for Pu'er tea. We also found a mismatch between the cultivation suitability and the actual production of Pu'er tea. Our study provides an accurate assessment and zoning analysis of the suitability of Pu'er tea cultivation in Yunnan Province, which can help optimize the layout of Pu'er tea cultivation and reduce potential climate risks.

Downregulation of circ-STK39 suppresses pancreatic cancer progression by sponging mir-140-3p and regulating TRAM2-mediated epithelial-mesenchymal transition.

BACKGROUND: Pancreatic cancer (PC) is amongst the most lethal gastrointestinal tumors, which is the seventh leading reason of cancer-related mortality worldwide. Previous studies have indicated that circular RNAs (circRNAs), which is a new type of endogenous noncoding RNA (ncRNA), can mediate tumor progression in diverse tumor types including PC. Whereas precise roles regarding circRNAs and their underlying regulatory mechanisms in PC remain unknown. METHODS: In the current study, we employed next generation sequencing (NGS) to characterize abnormally expressed circRNAs among PC tissues. Next, we assessed expression levels of one identified circRNA, circ-STK39, in PC cell lines and tissues. Then, using bioinformatics analysis, luciferase reporter, Transwell migration, EdU and CCK-8 assays, we examined the regulatory mechanisms and targets of circ-STK39. Finally, our group explored the circ-STK39 role in PC tumor growth and metastasis in vivo. RESULTS: Our team discovered that circ-STK39 expression increased in PC tissues and cells, suggesting that circ-STK39 may have a role in PC progression. Downregulation of circ-STK39 inhibited PC proliferation and migration. Bioinformatics and luciferase reporter outcomes demonstrated that TRAM2 and miR-140-3p were circ-STK39 downstream targets. TRAM2 overexpression reversed the miR-140-3p overexpression effects upon migration, proliferation and the epithelial-mesenchymal transition (EMT). CONCLUSION: In this regard, we showed that circ-STK39 downregulation led to decreased migration, proliferation and the EMT of PC via the miR-140-3p/TRAM2 axis.

Organocatalytic cascade nucleophilic/aza-Michael addition reactions: metal-free catalytic strategy for the synthesis of hydantoins.

Lewis base-catalyzed cascade nucleophilic/aza-Michael addition reaction of N-alkoxy ß-oxo-acrylamides with isocyanates has been developed to afford various highly functionalized hydantoin derivatives in 80-98% yields under mild reaction conditions. The intriguing features of this method include metal-free reaction conditions, low catalyst loading, broad substrate scope and short reaction time.

Profiling risk factors for separation of infection complications in patients with gastrointestinal and nodal diffuse large B-cell lymphoma.

OBJECTIVE: To identify risk factors for infection complications in patients with gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) and nodal DLBCL (N-DLBCL) during treatment, respectively. METHODS: Total 51 GI-DLBCL patients and 80 N-DLBCL patients were included after retrieving clinical data from a single medical center in the past ten years. Logistic regression analysis was utilized to analyze patients' data, including baseline demographics, treatments and laboratory values, to determine independent risk factors of infection in these patients. RESULTS: Total 28 of 51 patients (54.9%) in the GI-DLBCL group and 52 of 80 patients (65%) in the N-DLBCL group were observed infection events during treatment. A multivariate logistic regression model revealed that Ann-arbor stage IV (P = 0.034; odds ratio [OR]: 10.635; 95% confidence interval [CI]: 1.152-142.712), extra-nodal lesions ≥ 2 (P = 0.041; OR: 23.116; 95%CI: 1.144-466.949) and high serum lactate dehydrogenase (LDH) at the time of diagnosis (LDH > 252U/L; P = 0.033; OR: 6.058; 95%CI: 1.159-31.659) were independent risk factors for the development of infection in patients with GI-DLBCL after systemic treatment. In the N-DLBCL group, high serum C-reactive protein (CRP) (P = 0.027; OR: 1.104; 95%CI: 1.011-1.204) and a low platelet count (P = 0.041; OR: 0.991; 95%CI: 0.982-1.000) at routine blood tests just before infection occurred were identified as significant risk factors related to infection events during treatment. CONCLUSIONS: Discordant independent risk factors induced infection may be present during the treatment in patients with GI-DLBCL and N-DLBCL. Close monitoring these risk factors is likely an effective strategy to prevent microbial infections in these patients.

Wrapping gastroduodenal artery stump with the teres hepatis ligament to prevent postpancreatectomy hemorrhage after pancreaticoduodenectomy.

BACKGROUND: Gastroduodenal artery (GDA) stump erosion hemorrhage is a fatal complication after pancreaticoduodenectomy. This study aimed to determine whether GDA stump wrapping with the teres hepatis ligament during pancreaticoduodenectomy decreased the incidence of postpancreatectomy hemorrhage (PPH). METHODS: We reviewed 307 patients who had undergone pancreaticoduodenectomy between March 2019 and June 2022. The patients were divided into two groups according to application of GDA stump wrapping with the teres hepatis ligament: GDA wrapping group (165 patients) and no-wrapping group (142 patients). The perioperative data were compared between the groups. RESULTS: The clinical characteristics were balanced between the two groups. Grades B and C PPH and GDA-stump-related hemorrhage were significantly reduced in the GDA wrapping group compared with the no-wrapping group (PPH B/C, 13.4% vs 6.1%, P = 0.029; GDA hemorrhage, 5.6% vs 0.6%, P = 0.014). No difference was observed in the incidence of clinically relevant postoperative pancreatic fistula, biliary leak, intra-abdominal abscess, delayed gastric emptying, 90-day mortality, and postoperative hospital stay between the two groups. CONCLUSION: Wrapping GDA stump with the teres hepatis ligament reduced the incidence of GDA-stump-related PPH. Therefore, the wrapping technique is a simple and effective strategy to prevent PPH. Prospective studies are needed to confirm the benefit of this procedure.

Physical therapy for end-stage hemophilic arthropathy: a case report.

This report introduces a young adult who has been in bed for more than ten years with end-stage hemophilic arthropathy. He didn't have access to factor VIII (FVIII) in the early stage of hemophilia due to the high costs of clotting replacement therapy. As a result, he is experiencing some difficulties, such as joint contracture, muscular atrophy, severe pain, and poor function of cardiopulmonary. He came to visit us for a comprehensive rehabilitation program, and, finally, he achieved the basic goal of self-care in daily life.

The Viral Protein Poly(A) Polymerase Catalytic Subunit Interacts with Guanylate-Binding Proteins 2 to Antagonize the Antiviral Ability of Targeting Ectromelia Virus.

The recent spread of the monkeypox virus among humans has heightened concerns regarding orthopoxvirus infections. Consequently, conducting a comprehensive study on the immunobiology of the monkeypox virus is imperative for the development of effective therapeutics. Ectromelia virus (ECTV) closely resembles the genetic and disease characteristics of monkeypox virus, making it a valuable research tool for studying orthopoxvirus-host interactions. Guanylate-binding proteins (GBPs), highly expressed interferon-stimulated genes (ISGs), have antagonistic effects against various intracellular pathogenic microorganisms. Our previous research has shown that GBP2 has a mild but statistically significant inhibitory effect on ECTV infection. The presence of a significant number of molecules in the poxvirus genome that encode the host immune response raises questions about whether it also includes proteins that counteract the antiviral activity of GBP2. Using IP/MS and co-IP technology, we discovered that the poly(A) polymerase catalytic subunit (PAPL) protein of ECTV is a viral regulatory molecule that interacts with GBP2. Further studies have shown that PAPL antagonizes the antiviral activity of GBP2 by reducing its protein levels. Knocking out the PAPL gene of ECTV with the CRISPR/Cas9 system significantly diminishes the replication ability of the virus, indicating the indispensable role of PAPL in the replication process of ECTV. In conclusion, our study presents preliminary evidence supporting the significance of PAPL as a virulence factor that can interact with GBP2.

LncRNA CRNDE promotes cell proliferation, migration and invasion of ovarian cancer via miR-423-5p/FSCN1 axis.

Ovarian cancer seriously threatens the health of women. LncRNA CRNDE is known to be upregulated in ovarian cancer. However, the mechanism by which CRNDE regulates the progress of ovarian cancer is largely unknown. MTT assay was applied to measure the cell viability. Colony formation assay was used to measure the cell proliferation. Cell migration was tested by wound healing, and Transwell assay was performed to detect cell invasion. In addition, the expression of miR-423-5p, CRNDE and FSCN1 were detected by RT-qPCR and western blotting, respectively. Meanwhile, dual-luciferase reporter assay and RIP assay were performed to explore the correlation between miR-423-5p and CRNDE (or FSCN1). CRNDE and FSCN1 were upregulated in ovarian cancer cells (SKOV3, CAOV-3, IGROV1, A2780 and C13K), while miR-423-5p was downregulated. Moreover, silencing of FSCN1/CRNDE significantly decreased proliferation, migration and invasion of ovarian cancer cells (SKOV3 and CI3K) via suppressing MMP-2 and MMP-9. In addition, CRNDE could sponge miR-423-5p, and FSCN1 was confirmed to be the direct target of miR-423-5p. Furthermore, CRNDE knockdown-induced inhibition of FSCN1 was notably reversed by miR-423-5p downregulation. Knockdown of CRNDE inhibited cell proliferation, migration and invasion of ovarian cancer via miR-423-5p/FSCN1 axis. Thus, CRNDE may serve a new target for ovarian cancer.

The role of AURKA/miR-199b-3p in hepatocellular carcinoma cells.

BACKGROUND: Previous studies proved that AURKA functions as an oncogene in several cancers. This article aimed to probe the miRNA-induced regulatory mechanism of AURKA in hepatocellular carcinoma (HCC). METHODS: Differentially expressed genes in TCGA-LIHC dataset were screened by bioinformatics methods. Levels of miR-199b-3p and AURKA mRNA were examined by qRT-PCR. Western blot was utilized to evaluate protein levels of AURKA, p-AKT, and AKT. Dual-luciferase assay was introduced to explore their interaction. MTT, colony formation, scratch healing, transwell, and flow cytometry assays were introduced into cell proliferation, migration, invasion, and apoptosis assessment. The impact of miR-199b-3p/AURKA axis on HCC tumor growth was determined in a tumor xenograft model. RESULTS: We found that AURKA was highly expressed in HCC and was coupled to poor prognosis of HCC. As manifested by cellular assays, compared to the normal cells HL-7702, AURKA presented notably high expression in HCC cell lines. Overexpressed AURKA evidently impelled the proliferation, colony formation, migration, and invasion of HCC cells while suppressing apoptosis. The regulatory gene upstream of AURKA was predicted to be miR-199b-3p by bioinformatics method, and there was a markedly negative correlation between the two. Overexpressed miR-199b-3p constrained HCC cell proliferation, migration, and invasion while fostering apoptosis, which could be counteracted by upregulating AURKA. MiR-199b-3p repressed the tumor growth in vivo by targeting AURKA and affected PI3K/AKT signaling pathway. CONCLUSION: To summarize, this study implied the regulatory mechanism of miR-199b-3p/AURKA axis in HCC, and supplied optional therapeutic targets for HCC patients.

Identification of Immune-Related Markers in Hepatocellular Carcinoma Based on Gene Co-expression Network.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death throughout the world, with constant increasing morbidity and mortality. Existing studies suggest that immunotherapy is beneficial to the treatment of advanced HCC. At present, it is imperative to identify biomarkers suitable for HCC immunotherapy. In this paper, the mRNA expression data of HCC were downloaded from The Cancer Genome Atlas, and Stromal Score, Immune Score and ESTIMATE Score of each sample were calculated. Weighted gene co-expression network analysis clustered the pretreated genes into eight modules. The brown module that was remarkably associated with Immune Score was identified by module eigengene-immune trait analysis, in which genes were mainly enriched in immune-related pathways. Four hub genes (CCR5, CD53, ITGB2, and TYROBP) related to tumor immunity, were screened out by intramodular gene connectivity combined with protein-protein interaction network topology analysis. Kaplan-Meier survival analysis presented a correlation between high expression of CCR5 and CD53, and better prognoses of HCC patients. TIMER analysis revealed a positive correlation between expression of each hub gene and immune cell infiltration level, and a positive correlation between the expression of each hub gene and the expression of immunosuppressive factors CTLA4 and PDCD1. Gene set enrichment analysis displayed that there was an evident difference in the activation of cytokines and the activation of immune signal transduction-related pathways between high- and low-expression groups of each hub gene. In conclusion, this study identified four potential genetic markers associated with HCC immunity and assessed their association with HCC patient's prognosis and immune microenvironment. The study results are expected to provide theoretical guidance for immunotherapy of HCC patients.

Exploring wheat-based management strategies to balance agricultural production and environmental sustainability in a wheat-maize cropping system using the DNDC model.

Faced with the great challenge of food demand and environmental pollution, optimizing agricultural practices can potentially balance food security and environmental protection. In this study, the DeNitrification-DeComposition (DNDC) model was applied to explore the effect of wheat-based management strategies on crop productivity and greenhouse gas emissions in the wheat-maize system. The DNDC model was tested against crop yield, daily nitrous oxide (N2O) fluxes, and cumulative N2O emissions determined from field measurements in a typical winter wheat-summer maize cropping system. Model evaluations demonstrated a good agreement between the observations and simulated crop yield (4.4%≤NRMSE≤8.0%), daily N2O fluxes (0.68 ≤ d ≤ 0.88), and cumulative N2O emissions (4.9%≤NRMSE≤11.9%). By adopting sensitivity analysis, the DNDC model then assessed the impacts on crop yield and cumulative N2O emissions of multiple management practices from the winter wheat season. Delaying the sowing date from October 7 to November 4 reduced annual yield by 1.9%, while cumulative N2O emissions were increased by 10.4%. Furthermore, postponing the supplementary irrigation date from April 1 to May 20 decreased annual yield by 2.4% without affecting cumulative N2O emissions. An N fertilizer rate of 120-150 kg N ha-1 was able to reduce N usage and cumulative N2O emissions without sacrificing annual yield. Despite an improvement in the annual yield at the 0-30 cm tillage depth by 2.9%, cumulative N2O emissions increased by 11.6%. The results suggest that sowing in early October, applying supplementary irrigation in early April, an N fertilizer rate of 120-150 kg N ha-1, and no-tillage from the winter wheat season can improve crop yield and mitigate N2O emissions. This is conducive to the synergism of agricultural production and environmental sustainability.

Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus.

Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated researchers to explore novel antidiabetic agents with different mechanisms of action. G-protein Coupled Receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), which is activated by medium-chain and long-chain fatty acids, has emerged as an interesting potential target for the treatment of metabolic disorders. Herein, we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which is susceptible to ß-oxidation and loses its GPR120 agonistic activity in vivo. Among the designed compounds, 14d showed excellent agonistic activity and selectivity and could improve glucose tolerance in normal mice in a dose-dependent manner. In addition, the compound 14d displayed good antidiabetic effects in diet-induced obese (DIO) mice and elevated insulin levels. Molecular simulations illustrated that compound 14d could enter the active site of GPR120 and interact with ARG99, which plays an important role in GPR120 activation. Based on these observations, compound 14d may be a promising lead compound deserving of further biological evaluation and structural modifications.

Prognostic value of immune-related lncRNA pairs in patients with bladder cancer.

BACKGROUND: The characteristics of immune-related long non-coding ribonucleic acids (ir-lncRNAs), regardless of their specific levels, have important implications for the prognosis of patients with bladder cancer. METHODS: Based on The Cancer Genome Atlas database, original transcript data were analyzed. The ir-lncRNAs were obtained using a coexpression method, and their differentially expressed pairs (DE-ir-lncRNAs) were identified by univariate analysis. The lncRNA pairs were verified using a Lasso regression test. Thereafter, receiver operating characteristic curves were generated, and an optimal risk model was established. The clinical value of the model was verified through the analysis of patient survival rates, clinicopathological characteristics, presence of tumor-infiltrating immune cells, and chemotherapy efficacy evaluation. RESULTS: In total, 49 pairs of DE-ir-lncRNAs were identified, of which 21 were included in the Cox regression model. A risk regression model was established on the premise of not involving the specific expression value of the transcripts. CONCLUSIONS: The method and model used in this study have important clinical predictive value for bladder cancer and other malignant tumors.