Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial.

OBJECTIVE: To evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy. DESIGN: Randomised, double blind, placebo controlled, phase 3 study. SETTING: 146 medical centres across Asia, Europe, and North America, between 13 December 2018 and 28 February 2023. PARTICIPANTS: 1657 patients aged ≥18 years with human epidermal growth factor receptor 2 negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, regardless of programmed death-ligand 1 (PD-L1) expression status, who had not received systemic anticancer therapy for advanced disease. INTERVENTIONS: Patients were randomly (1:1) assigned to receive either tislelizumab 200 mg or placebo intravenously every three weeks in combination with chemotherapy (investigator's choice of oxaliplatin and capecitabine, or cisplatin and 5-fluorouracil) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator's choice of chemotherapy. Treatment continued until disease progression or unacceptable toxicity. MAIN OUTCOME MEASURES: The primary endpoint was overall survival, both in patients with a PD-L1 tumour area positivity (TAP) score of ≥5% and in all randomised patients. Safety was assessed in all those who received at least one dose of study treatment. RESULTS: Of 1657 patients screened between 13 December 2018 and 9 February 2021, 660 were ineligible due to not meeting the eligibility criteria, withdrawal of consent, adverse events, or other reasons. Overall, 997 were randomly assigned to receive tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). Tislelizumab plus chemotherapy showed statistically significant improvements in overall survival versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5% (median 17.2 months v 12.6 months; hazard ratio 0.74 (95% confidence interval 0.59 to 0.94); P=0.006 (interim analysis)) and in all randomised patients (median 15.0 months v 12.9 months; hazard ratio 0.80 (0.70 to 0.92); P=0.001 (final analysis)). Grade 3 or worse treatment related adverse events were observed in 54% (268/498) of patients in the tislelizumab plus chemotherapy arm versus 50% (246/494) in the placebo plus chemotherapy arm. CONCLUSIONS: Tislelizumab added to chemotherapy as primary treatment for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5%, and in all randomised patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03777657.

Effect of temperature on anisotropic bending elasticity of dsRNA: an all-atom molecular dynamics simulation.

Employing all-atom molecular dynamics simulations, we examined the temperature-dependent behavior of bending elasticity in double-stranded RNA (dsRNA). Specifically, we focused on the bending persistence length and its constituent components, namely, the tilt and roll stiffness. Our results revealed a near-linear decrease in these stiffness components as a function of temperature, thereby highlighting the increased flexibility of dsRNA at elevated temperatures. Furthermore, our data revealed a significant anisotropy in dsRNA bending elasticity, which diminished with increasing temperature, attributable to marked disparities in tilt and roll stiffness components. We delineated the underlying biophysical mechanisms and corroborated our findings with extant literature. These observations offer salient implications for advancing our understanding of nucleic acid elasticity, and are pertinent to potential medical applications.

Second-line tislelizumab versus chemotherapy in Japanese patients with advanced or metastatic esophageal squamous cell carcinoma: subgroup analysis from RATIONALE-302.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with limited second-line systemic therapy options, and represents an increasing disease burden in Japan. In the phase 3 RATIONALE-302 study, the anti-programmed cell death protein 1 antibody, tislelizumab, significantly improved overall survival (OS) versus chemotherapy as second-line treatment for advanced/metastatic ESCC. Here, we report the Japanese patient subgroup results. METHODS: Patients with advanced/metastatic ESCC, with disease progression during/after first-line systemic therapy were randomized 1:1 to open-label tislelizumab 200 mg every 3 weeks or investigator's choice of chemotherapy (paclitaxel/docetaxel). Efficacy and safety were assessed in all randomized Japanese patients. RESULTS: The Japanese subgroup comprised 50 patients (n = 25 per arm). Tislelizumab improved OS versus chemotherapy (median: 9.8 vs. 7.6 months; HR 0.59; 95% CI 0.31, 1.12). Among patients with programmed death-ligand 1 score ≥ 10%, median OS was 12.5 months with tislelizumab (n = 10) versus 2.9 months with chemotherapy (n = 6) (HR 0.31; 95% CI 0.09, 1.03). Tislelizumab improved progression-free survival versus chemotherapy (median: 3.6 vs. 1.7 months, respectively; HR 0.50; 95% CI 0.27, 0.95). Objective response rate was greater with tislelizumab (32.0%) versus chemotherapy (20.0%), and responses were more durable (median duration of response: 8.8 vs. 2.6 months, respectively). Fewer patients experienced ≥ grade 3 treatment-related adverse events with tislelizumab (24.0%) versus chemotherapy (47.8%). Tislelizumab demonstrated an improvement in health-related quality of life versus chemotherapy. CONCLUSIONS: As second-line therapy for advanced/metastatic ESCC, tislelizumab improved OS versus chemotherapy, with a favorable safety profile, in the Japanese patient subgroup, consistent with the overall population. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov: NCT03430843.

OsMKK1 is a novel element that positively regulates the Xa21-mediated resistance response to Xanthomonas oryzae pv. oryzae in rice.

KEY MESSAGE: OsMKK1, a MAPK gene, positively regulates rice Xa21-mediated resistance response and also plays roles in normal growth and development process of rice. The mitogen-activated protein kinase (MAPK) cascade was highly conserved among eukaryotes, which played crucial roles in plant responses to pathogen infection. Bacterial blight is the most devastating bacterial disease. Xa21 confers broad-spectrum resistance to Xanthomonas oryzae pv. Oryzae (Xoo). This study identified that the transcription level of OsMKK1 was up-regulated in resistant response against Xoo, thus overexpression (OsMKK1-OX) and RNA interference (OsMKK1-RNAi) transgenic rice lines under the background of Xa21 was constructed. Compared with recipient control plants 4021, the OsMKK1-OX lines significantly enhanced disease resistance to Xoo, on the contrary, the resistance of OsMKK1-RNAi lines was weakened, demonstrated that OsMKK1 played a positive role in Xa21-mediated disease resistance pathway. A number of pathogenesis-related proteins, including PR1A, PR2 and PR10A showed enhanced expression in OsMKK1-OX lines, supported that these PR genes may be regulated by OsMKK1 to participate in the defense responses. In addition, the agronomic traits of OsMKK1 transgenic plants were affected. Overall, these results revealed the role of OsMKK1 in Xa21-mediated resistance against Xoo and in the normal growth and development process in rice.

Pro-aromatic Dihydroquinazolinones - From Multigram Synthesis to Reagents for Gram-scale Metallaphotoredox Reactions.

Dihydroquinazolinone (DHQZ) has recently been harnessed as a ketone-derived pro-aromatic reagent extensively employed in (metalla)photoredox reactions as versatile group transfer agents. In this work, we outline a column chromatography-free protocol for the multigram-scale synthesis of pro-aromatic DHQZs as well as its use in a gram-scale nickel/photoredox dual-catalyzed cross-coupling in single-batch, photoflow, and simultaneous multiple smaller batches. While the single-batch approach leveraged moderate yields, a simple plug-flow photoreactor also exhibited amenable productivity (up to 45 % yield) despite the use of a heterogeneous base. Meanwhile, performing the metallaphotoredox-catalyzed reaction in multiple smaller batches in an improvised photoreactor facilitated high yields of up to 59 % and good reproducibility, implying a convenient alternative in the absence of photoflow setups.

Evaluation of lifestyle behaviors, anxiety and depression in patients with hematologic disorders.

Patients with hematologic disorders may experience anxiety and depression due to their immunocompromised status and potential side effects of therapies. Healthy lifestyle behaviors might enhance the mental health. To evaluate the association of both separate and clustering pattern lifestyle behaviors with anxiety and depression in hematological patients, healthcare providers can develop future initiatives that respond to the specific needs of this population. A total of 185 patients with hematologic disorders were enrolled in this cross-sectional study. Linear regression analysis was performed to measure the association of separate lifestyles with anxiety and depression. Latent class analysis was further conducted to identify homogeneous and mutually exclusive lifestyle classes, and the logistic regression was then used to assess the relationship between class memberships and symptoms of anxiety and depression. The study found sleep quality was correlated with anxiety and depression. Nevertheless, no association of anxious and depressive symptoms with sitting and exercise, dietary habits, toxicant exposure, drinking, and smoking, in either the overall patient population or patients classified by hematologic neoplasms. Two latent classes of lifestyle behaviors were further identified, but the class memberships were independent of anxiety and depression. The study suggested that promoting sleep quality was a viable intervention for patients with hematologic disorders. However, the clustering pattern of lifestyles may not be a reliable indicator of psychological issues.

Optimization of mammalian expression vector by cis-regulatory element combinations.

The regulation of gene expression in mammalian cells by combining various cis-regulatory features has rarely been discussed. In this study, we constructed expression vectors containing various combinations of regulatory elements to examine the regulation of gene expression by different combinations of cis-regulatory elements. The effects of four promoters (CMV promoter, PGK promoter, Polr2a promoter, and EF-1α core promoter), two enhancers (CMV enhancer and SV40 enhancer), two introns (EF-1α intron A and hybrid intron), two terminators (CYC1 terminator and TEF terminator), and their different combinations on downstream gene expression were compared in various mammalian cells using fluorescence microscopy to observe fluorescence, quantitative real-time PCR (qRT-PCR), and western blot. The receptor binding domain (RBD) sequence from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein was used to replace the eGFP sequence in the expression vector and the RBD expression was detected by qRT-PCR and western blot. The results showed that protein expression can be regulated by optimizing the combination of cis-acting elements. The vector with the CMV enhancer, EF-1α core promoter, and TEF terminator was found to express approximately threefold higher eGFP than the unmodified vector in different animal cells, as well as 2.63-fold higher recombinant RBD protein than the original vector in HEK-293T cells. Moreover, we suggest that combinations of multiple regulatory elements capable of regulating gene expression do not necessarily exhibit synergistic effects to enhance expression further. Overall, our findings provide insights into biological applications that require the regulation of gene expression and will help to optimize expression vectors for biosynthesis and other fields. Additionally, we provide valuable insights into the production of RBD proteins, which may aid in developing reagents for diagnosis and treatment during the COVID-19 pandemic.

Benign prostatic hyperplasia associated with white matter hyperintensities in men.

PURPOSE: Benign prostatic hyperplasia (BPH) describes common noncancerous prostate enlargement. BPH is usually associated with lower urinary tract symptoms and an increased risk of cerebrovascular diseases, such as stroke and its recurrence. White matter hyperintensities (WMHs), markers of cerebral injury, increase the risk of stroke, cognitive impairment, dementia, and death. The relationship between BPH and WMHs remains unclear. This study aimed to determine the association between BPH and WMHs. METHODS: A total of 788 male patients from the First Affiliated Hospital of Kunming Medical University from July 2019 to September 2021 were enrolled in this cross-sectional study. BPH was assessed by abdominal ultrasound, and three independent neuroradiologists rated the presence or absence of WMHs. Multiple imputations of chained equations were used to handle missing data. Logistic regression was used to assess the relationship between BPH and WMHs. RESULTS: Patients with BPH presented an increased risk of WMHs with a crude odds ratio (OR) of 2.76 (95% CI, 2.02-3.79) and an adjusted OR of 1.75 (95% CI, 1.24-2.48) after controlling for potential confounding factors in the multivariate logistic regression. CONCLUSION: We found that BPH was closely associated with WMHs in male Chinese individuals.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study.

BACKGROUND: The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma. METHODS: This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0-1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60-80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750-800 mg/m2 intravenously on days 1-5] or capecitabine [1000 mg/m2 orally twice daily on days 1-14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442. FINDINGS: Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0-69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6-21·8) in the tislelizumab group and 9·8 months (IQR 5·8-19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8-20·1) and in the placebo group was 10·6 months (9·3-12·1; stratified hazard ratio 0·66 [95% CI 0·54-0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related. INTERPRETATION: Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis. FUNDING: BeiGene.

Association of lifestyle behaviors with health-related quality of life among patients with hematologic diseases.

PURPOSE: Health-related quality of life (HRQoL) is a multi-dimensional construct used to assess the impact of health status on quality of life, and it is known to be affected by lifestyle behaviors. This study focused on multiple lifestyle behaviors among patients with hematologic diseases, including physical activity, dietary intake, sleep quality, occupational exposure, alcohol consumption and smoking. The main objective was to investigate the association of both individual and clustering of health behaviors with HRQoL among the population with hematologic diseases based on a comprehensive lifestyle survey. METHODS: A total of 539 patients with hematologic diseases aged over 18 years were enrolled in this cross-sectional study. Latent class analysis was used to identify homogeneous, mutually exclusive lifestyle classes, and multinomial logistic regression was then performed to explore the association of lifestyle classes membership with HRQoL. Meanwhile, multiple linear regression and quantile regression were used to identify the relationship between individual lifestyle behaviors and HRQoL. RESULTS: A three-class model was selected based on conceptual interpretation and model fit. We found no association between multiple lifestyle behaviors and HRQoL in the 3-class model, either in the whole patients or in subgroups stratified by hematological malignancies. Further research on each lifestyle found that physical activity, dietary intake, occupational exposure, alcohol consumption or smoking were independent of HRQoL. Sleep quality was positively associated with HRQoL. CONCLUSION: Our findings suggested that clustering of lifestyle behaviors may not be an indicator to reflect the health quality of patients with hematologic diseases. Sleep represents a viable intervention target that can confer health benefits on the hematologic patients.

Rice MPK17 Plays a Negative Role in the Xa21-Mediated Resistance Against Xanthomonas oryzae pv. oryzae.

Rice bacterial blight, caused by Xanthomonas oryzae pv. oryzae (Xoo), is one of the most serious diseases affecting rice production worldwide. Xa21 was the first disease resistance gene cloned in rice, which encodes a receptor kinase and confers broad resistance against Xoo stains. Dozens of components in the Xa21-mediated pathway have been identified in the past decades, however, the involvement of mitogen-activated protein kinase (MAPK) genes in the pathway has not been well described. To identify MAPK involved in Xa21-mediated resistance, the level of MAPK proteins was profiled using Western blot analysis. The abundance of OsMPK17 (MPK17) was found decreased during the rice-Xoo interaction in the background of Xa21. To investigate the function of MPK17, MPK17-RNAi and over-expression (OX) transgenic lines were generated. The RNAi lines showed an enhanced resistance, while OX lines had impaired resistance against Xoo, indicating that MPK17 plays negative role in Xa21-mediated resistance. Furthermore, the abundance of transcription factor WRKY62 and pathogenesis-related proteins PR1A were changed in the MPK17 transgenic lines when inoculated with Xoo. We also observed that the MPK17-RNAi and -OX rice plants showed altered agronomic traits, indicating that MPK17 also plays roles in the growth and development. On the basis of the current study and published results, we propose a "Xa21-MPK17-WRKY62-PR1A" signaling that functions in the Xa21-mediated disease resistance pathway. The identification of MPK17 advances our understanding of the mechanism underlying Xa21-mediated immunity, specifically in the mid- and late-stages.

Ultrasound Technique Based on Liposome Nanovesicles in the Evaluation of Abnormal Pregnancy Outcomes in Diabetic Women.

Gestational diabetes mellitus (GDM) refers to the first occurrence or detection of glucose tolerance abnormalities during pregnancy, including cases that may have existed before pregnancy but have not been detected. It is one of the common complications during pregnancy. In recent years, the incidence of GDM is on the rise. The most common complication of GDM is macrosomia, which often causes dystocia, neonatal asphyxia, birth injury and postpartum bleached blood. Early diagnosis, appropriate treatment and maintenance of reasonable and stable blood glucose concentration can significantly reduce the incidence of complications. The purpose of this study was to investigate the application of ultrasound technique based on liposome nano-vesicles in the assessment of abnormal pregnancy outcomes in diabetic pregnant women. Objective: To investigate the value of ultrasound in the examination of fetal growth in pregnant women with gestational diabetes mellitus. Methods a total of 100 pregnant women with gestational diabetes admitted to the hospital were selected as the research objects, and the clinical data of ultrasound examination were retrospectively analyzed. According to the newborn weight, they were divided into control group (normal fetus group) and observation group (giant fetus group). The growth of fetuses in the two groups was compared, and the predictive value of each measurement index to the weight of giant fetus was analyzed.Multiple regression analysis showed that LL, AC and FL played a decisive role in fetal weight, with statistically significant differences (P<0.05). Conclusion Ultrasonography is of great value in predicting fetal growth in pregnant women with gestational diabetes mellitus and can be widely used.

Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study.

PURPOSE: Patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) have poor prognosis. For these patients, treatment options are limited after first-line systemic therapy. PATIENTS AND METHODS: In this open-label phase III clinical study, patients with advanced or metastatic ESCC, whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive intravenous tislelizumab, an anti-programmed cell death protein 1 antibody, 200 mg every 3 weeks or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). The primary end point was overall survival (OS) in all patients. The key secondary end point was OS in patients with programmed death-ligand 1 tumor area positivity (TAP) score ≥ 10%. RESULTS: In total, 512 patients across 11 countries/regions were randomly assigned. At final analysis, conducted after 410 death events occurred, OS was significantly longer with tislelizumab versus chemotherapy in all patients (median, 8.6 v 6.3 months; hazard ratio [HR], 0.70 [95% CI, 0.57 to 0.85]; one-sided P = .0001), and in patients with TAP ≥ 10% (median, 10.3 months v 6.8 months; HR, 0.54 [95% CI, 0.36 to 0.79]; one-sided P = .0006). Survival benefit was consistently observed across all predefined subgroups, including those defined by baseline TAP score, region, and race. Treatment with tislelizumab was associated with higher objective response rate (20.3% v 9.8%) and a more durable antitumor response (median, 7.1 months v 4.0 months) versus chemotherapy in all patients. Fewer patients experienced ≥ grade 3 treatment-related adverse events (18.8% v 55.8%) with tislelizumab versus chemotherapy. CONCLUSION: Tislelizumab significantly improved OS compared with chemotherapy as second-line therapy in patients with advanced or metastatic ESCC, with a tolerable safety profile. Patients with programmed death-ligand 1 TAP ≥ 10% also demonstrated statistically significant survival benefit with tislelizumab versus chemotherapy.

Pseudorabies Virus Inhibits Expression of Liver X Receptors to Assist Viral Infection.

Pseudorabies virus (PRV) is a contagious herpesvirus that causes Aujeszky's disease and economic losses worldwide. Liver X receptors (LXRs) belong to the nuclear receptor superfamily and are critical for the control of lipid homeostasis. However, the role of LXR in PRV infection has not been fully established. In this study, we found that PRV infection downregulated the mRNA and protein levels of LXRα and LXRß in vitro and in vivo. Furthermore, we discovered that LXR activation suppressed PRV proliferation, while LXR inhibition promoted PRV proliferation. We demonstrated that LXR activation-mediated reduction of cellular cholesterol was critical for the dynamics of PRV entry-dependent clathrin-coated pits. Replenishment of cholesterol restored the dynamics of clathrin-coated pits and PRV entry under LXR activation conditions. Interestingly, T0901317, an LXR agonist, prevented PRV infection in mice. Our results support a model that PRV modulates LXR-regulated cholesterol metabolism to facilitate viral proliferation.

Desulfurative Ni-Catalyzed Reductive Cross-Coupling of Benzyl Mercaptans/Mercaptoacetates with Aryl Halides.

The C-S activation and sulfur removal from native thiols is challenging, which limits their application as feedstock materials in organic synthesis despite their natural abundance. Herein, we introduce a per-/polyfluoroaryl moiety, which serves as a redox-active scaffold, into sp3-hybridized thiols to activate the C-S bond. Using a Ni catalyst with MgBr2 as an additive, the S group can be removed to yield an aliphatic radical that can react with an aryl halide in a reductive cross-coupling.

Aromatization as an Impetus to Harness Ketones for Metallaphotoredox-Catalyzed Benzoylation/Benzylation of (Hetero)arenes.

Herein we report ketones as feedstock materials in radical cross-coupling reactions under Ni/photoredox dual catalysis. In this approach, simple condensation first converts ketones into prearomatic intermediates that then act as activated radical sources for cross-coupling with aryl halides. Our strategy enables the direct benzylation/benzoylation of (hetero)arenes under mild reaction conditions with high functional group tolerance.

RATIONALE 311: tislelizumab plus concurrent chemoradiotherapy for localized esophageal squamous cell carcinoma.

Definitive chemoradiotherapy is the standard of care for inoperable locoregionally advanced esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have led to a paradigm shift in advanced, metastatic ESCC treatment; however, the effect of incorporating checkpoint inhibitors in the definitive management of ESCC is unclear. Tislelizumab is an anti-PD-1 antibody specifically engineered to minimize FcÉ£R binding on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. The RATIONALE 311 study described here (BGB-A317-311; NCT03957590) is a registrational multicenter, double-blind, placebo-controlled, randomized, Phase III clinical trial designed to evaluate the efficacy and safety of tislelizumab combined with concurrent chemoradiotherapy in patients with inoperable localized ESCC.

Lay abstract Esophageal cancer is a challenging disease that seriously threatens patients' health and life. Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. Most patients who have inoperable stage II­IV ESCC are currently treated with a sequential combination of chemotherapy and radiation therapy, with the hopes of increasing the positive effects seen from either therapy alone. Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have shown encouraging results in patients with ESCC, but it is not known if combining checkpoint inhibitors with simultaneous chemotherapy and radiation therapy will provide additional benefits. The safety and efficacy of tislelizumab, an anti-PD-1 antibody specifically engineered to limit potential resistance to anti-PD-1 therapy, is being investigated in combination with simultaneous chemotherapy and radiation therapy in patients with inoperable stage II­IV ESCC in an actively enrolling clinical trial, RATIONALE 311 (NCT03957590). Our trial in progress article explains the reason RATIONALE 311 was started and provides important enrollment information for doctors. Clinical trial registration: NCT03957590 (ClinicalTrials.gov).

Aberrant expression of the UPF1 RNA surveillance gene disturbs keratinocyte homeostasis by stabilizing AREG.

The up­frameshift suppressor 1 homolog (UPF1) RNA surveillance gene is a core element in the nonsense­mediated RNA decay (NMD) pathway, which impacts a broad spectrum of biological processes in a cell­specific manner. In the present study, the contribution of the NMD pathway to psoriasis lesions and its moderating effects on the biological processes of keratinocytes was reported. Sanger sequencing for skin scales from two patients with psoriasis identified two mRNA mutations (c.2935_2936insA and c.2030­2081del) in the UPF1 gene. The somatic mutants produced truncated UPF1 proteins and perturbed the NMD pathway in cells, leading to the upregulation of NMD substrates. As the most abundant epidermal growth factor receptor ligand in keratinocytes, it was concluded that amphiregulin (AREG) mRNA is a natural NMD substrate, that is dependent on its 3' untranslated region sequence. Perturbed NMD modulated keratinocyte homeostasis in an AREG­dependent but nonidentical manner, which highlighted the unique characteristics of NMD in keratinocytes. By targeting AREG mRNA post­transcriptionally, the UPF1­NMD pathway contributed to an imbalance between proliferation on the one hand, and apoptosis and abnormal differentiation, migration and inflammatory response on the other, in keratinocytes, which indicated a role of the NMD pathway in the full development of keratinocyte­related morbidity and skin diseases.

Effect of salts formed by neutralization for the enzymatic hydrolysis of cellulose and acetone-butanol-ethanol fermentation.

Neutralization is essential to maintain the pH for enzymatic hydrolysis of cellulose followed by fermentation of biofuels. This study investigated the effect of salts formed during the neutralization on the enzymatic hydrolysis of cellulosic materials and acetone-butanol-ethanol (ABE) fermentation. The results showed that the formed Ca-citrate salt considerably decreased the glucose release by 26.9% and 26.1% from Avicel and sulfuric acid-pretreated hybrid Pennisetum, respectively, which was probably due to the unproductive adsorption of cellulases by Ca-citrate solids. On the other hand, the formed soluble Na and Ca salts severely inhibited ABE fermentation, thereby decreasing the ABE concentration from 12.8 g L-1 to 0-10.7 g L-1 in different degrees, but no or slight inhibition was observed when the Ca salts formed as precipitates. In particular, Ca-sulfate did not show apparent inhibition of both hydrolysis and fermentation. Therefore, the selection of suitable pretreatment and neutralizing reagents is an alternative way to avoid process inhibition in biofuel production from lignocellulosic materials.

Characterization of Chlorella sorokiniana growth properties in monosaccharide-supplemented batch culture.

To reveal growth properties of Chlorella sorokiniana UTEX 1230, four monosaccharides (glucose, fructose, galactose and xylose) were individually supplemented into medium as carbon sources for the cultivation of C. sorokiniana UTEX 1230. Supplementation with glucose increased OD750, biomass and lipid yield but decreased protein abundance per unit dry weight of biomass under all concentrations examined, the maximum OD750, biomass and lipid yield increased 2.04, 6.78 and 12.43 times, respectively, compared with autotrophic controls. A low concentration of glucose (<4 g/L) simultaneously promoted the biosynthesis of chlorophylls and protein abundance per unit culture volume, but decreased the lipid content per unit dry weight of biomass and all supplemented glucose can be exhausted within 7 days. Higher glucose concentrations (≥4 g/L) decreased the biosynthesis of chlorophylls and protein abundance per unit culture volume, but increased the lipid content per unit dry weight of biomass. In glucose supplemented scenario, C. sorokiniana UTEX 1230 growth was light-independent. Supplementation with fructose promoted C. sorokiniana UTEX 1230 growth to a much lesser extent compared with glucose, whereas supplementation with galactose had no effect and supplementation with xylose even inhibited growth. Our findings represent basic experimental data on the effect of monosaccharides and can serve as the basis for a robust cultivation system to increase biomass and lipid yield.