Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

Calcipotriol abrogates TGF-ß1/pSmad3-mediated collagen 1 synthesis in pancreatic stellate cells by downregulating RUNX1.

RUNX1 with CBFß functions as an activator or repressor of critical mediators regulating cellular function. The aims of this study were to clarify the role of RUNX1 on regulating TGF-ß1-induced COL1 synthesis and the mechanism of calcipotriol (Cal) on antagonizing COL1 synthesis in PSCs. RT-qPCR and Western Blot for determining the mRNAs and proteins of RUNX1 and COL1A1/1A2 in rat PSC line (RP-2 cell). Luciferase activities driven by RUNX1 or COL1A1 or COL1A2 promoter, co-immunoprecipitation and immunoblotting for pSmad3/RUNX1 or CBFß/RUNX1, and knockdown or upregulation of Smad3 and RUNX1 were used. RUNX1 production was regulated by TGF-ß1/pSmad3 signaling pathway in RP-2 cells. RUNX1 formed a coactivator with CBFß in TGF-ß1-treated RP-2 cells to regulate the transcriptions of COL1A1/1A2 mRNAs under a fashion of pSmad3/RUNX1/CBFß complex. However, Cal effectively abrogated the levels of COL1A1/1A2 transcripts in TGF-ß1-treated RP-2 cells by downregulating RUNX1 production and hindering the formation of pSmad3/RUNX1/CBFß complexes. This study suggests that RUNX1 may be a promising antifibrotic target for the treatment of chronic pancreatitis.

Photosynthetic Fixation of CO2 in Alkenes by Heterogeneous Photoredox Catalysis with Visible Light.

Light-driven fixation of CO2 in organics has emerged as an appealing alternative for the synthesis of value-added fine chemicals. Challenges remain in the transformation of CO2 as well as product selectivity due to its thermodynamic stability and kinetic inertness. Here we develop a boron carbonitride (BCN) with the abundant terminal B/N defects around the mesoporous walls, which essentially enhances surface active sites as well as charge transfer kinetics, boosting the overall rate of CO2 adsorption and activation. In this protocol, anti-Markovnikov hydrocarboxylation of alkenes with CO2 to an extended carbon chain is achieved with good functional group tolerance and specific regioselectivity under visible-light irradiation. The mechanistic studies demonstrate the formation of CO2 radical anion intermediate on defective boron carbonitride, leading to the anti-Markovnikov carboxylation. Gram-scale reaction, late-stage carboxylation of natural products and synthesis of anti-diabetic GPR40 agonists reveal the utility of this method. This study sheds new insight on the design and application of metal-free semiconductors for the conversion of CO2 in an atom-economic and sustainable manner.

Graves' disease overlapping with chronic hepatitis B and methimazole-induced liver injury and autoimmune hepatitis: a case report.

BACKGROUND: Liver injury related to Graves' Disease (GD) includes hepatotoxicity of thyroid hormone excess, drug-induced liver injury, and changes resulting from concomitant liver disease. Methimazole (MMI) has been shown to induce several patterns of liver injury. However, the diagnosis and treatment of autoimmune hepatitis (AIH) overlapping with either GD or chronic hepatitis B are challenging. CASE PRESENTATION: A 35-year-old man from China presented with a two-year history of GD and a 10-day history of progressive jaundice. He had taken MMI for two months and discontinuing treatment due to liver toxicity 1 year ago and for another 6 days 20 days prior to hospitalization. The patient was diagnosed with GD overlapping with chronic hepatitis B and MMI-induced liver injury with early stage of acute-on-chronic liver failure on admission. However, the elevated aminotransferase and bilirubin levels could not be controlled after correction of liver failure and effective control of HBV replication and hyperthyroidism by daily oral entecavir and one-time oral administration of 131-iodine. The patient underwent liver biopsy on the 43rd day of hospitalization, showing HBsAg expression on the membrane of hepatocytes and typical histopathological characteristics of AIH. He was finally diagnosed with GD overlapping with chronic hepatitis B and MMI-induced liver injury and AIH. The elevated aminotransferase and bilirubin completely returned to normal by 3-month glucocorticoid therapy and continuous entecavir treatment and there was no recurrence during a 6-month follow-up, suggesting that AIH in this patient is different from classical AIH or GD-associated AIH. CONCLUSIONS: GD together with AIH is a complex and difficult subject. It needs to be clarified whether MMI or HBV can act as a trigger for AIH in this patient.

Interleukin-6 participates in human pancreatic stellate cell activation and collagen I production via TGF-ß1/Smad pathway.

Pancreatic stellate cells (PSCs) play a key role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor-ß1 (TGF-ß1) is a major regulator of PSC activation and extracellular matrix production. Interleukin-6 (IL-6) has shown to participate in TGF-ß1 production and rat PSC activation. This study aimed to investigate whether IL-6 promotes human PSC activation and collagen 1(Col1) production through the TGF-ß1/Smad pathway. Our results showed that the expression of IL-6 and IL-6R in activated PSCs and macrophages (Mφs) were enhanced in the pancreas of ACP compared to healthy controls and that the mRNA expression of IL-6, IL-6R, TGF-ß1, α-SMA or Col1a1 were significantly increased in the pancreas of ACP, showing positive correlations between elevated IL-6 levels and either TGF-ß1 or α-SMA or Col1a1 levels and between elevated TGF-ß1 levels and α-SMA or Col1a1 levels. In in vitro studies, we identified that IL-6R expression or IL-6 and TGF-ß1 secretions were significantly increased in, respectively, Mφs and PSCs by ethanol (EtOH) or lipopolysaccharide (LPS) stimulation while EtOH- or LPS-induced α-SMA or Col1a1 mRNA and protein production in PSCs were partially blocked by IL-6 antibody. IL-6-induced TGF-ß1 production in PSCs was antagonized by si-IL-6R RNA or by an inhibitor of STAT3. Additionally, IL-6-promoted α-SMA or Col1a1 protein production was blocked by TGF-ß1 antibody and IL-6-induced phosphorylation of Smad2/3 and transcription of α-SMA and Col1a1 mRNA were antagonized by si-TGF-ß1 RNA. Our findings indicate that IL-6 contributes to PSC activation and Col1 production through up-regulation of TGF-ß1/Smad2/3 pathway.

Mean platelet volume: a new predictor of ischaemic stroke risk in patients with nonvalvular atrial fibrillation.

BACKGROUND: Mean platelet volume (MPV) has been identified as an individual risk factor for stroke and thrombosis. Concurrently, ischaemic stroke caused by nonvalvular atrial fibrillation (AF) has attracted increasing attention. The aim of this study was to investigate the association between MPV and the risk of ischaemic stroke in AF patients not receiving anticoagulant therapy. METHODS: A total of 370 patients with nonvalvular AF were enrolled. Patients were divided into a control group and a stroke group according to the presence of ischaemic stroke. RESULTS: The MPV level and CHA2DS2-VASc scores of the stroke group were higher than those of the control group (all p < 0.001). The ischaemic stroke event rates were significantly increased in the highest MPV tertile when compared to the lowest MPV tertile (56.9% vs. 30.3%, p < 0.001). Multivariate logistic regression analysis showed that CHA2DS2-VASc, MPV and D-dimer (D2) were predictors of ischaemic stroke [all p < 0.05]. The receiver operating characteristic (ROC) curve analysis indicated that an MPV value of 11.65 fL could predict ischaemic stroke with a sensitivity of 67.3% and specificity of 58.5%, while a CHA2DS2-VASc score cutoff value 3.5 had a sensitivity of 52.1% and specificity of 87.3%. The predictive value of the combined model of CHA2DS2-VASc+MPV was higher than others (comparison calculated by using MedCalc software). The sensitivity of the CHA2DS2-VASc score combined with MPV for predicting ischaemic stroke was 72.1%, and the specificity was 81.5%. CONCLUSIONS: MPV could be a new predictor of ischaemic stroke risk in patients with AF. Moreover, the CHA2D2S2-VASc combined with MPV can improve predictive value with higher sensitivity and it could be a powerful tool for stratifying patients in terms of ischaemic stroke risk.

Myocardial injury and pericarditis after combined left atrial and coronary sinus ablation in Wolff-Parkinson-White syndrome: a case report.

BACKGROUND: Radiofrequency catheter ablation is an established procedure with a high success rate for treating Wolff-Parkinson-White (WPW) syndrome. Rare complications post-ablation may nonetheless occur particularly associated with coronary sinus. Identifying and avoiding these complications remains a challenge. CASE PRESENTATION: A 66-year-old woman with WPW syndrome was admitted to the hospital due to frequent attacks of paroxysmal tachycardia. During electrophysiological study, an accessory pathway was thought to connect the posterior wall of the left ventricle. The patient underwent Radiofrequency (RF) catheter ablation. The procedure was time-consuming because of combined left atrial and coronary sinus ablation. The total amount of radiofrequency application energy in the coronary sinus was 6800 J. After the operation, widespread concave ST-segment elevation, significantly increased value of serum troponin I and mild pericardial effusion were identified, but the patient did not show any symptoms. Therefore, the patient was suspected to have myocardial injury and pericarditis caused by ablation-related injury. The patient was uneventfully discharged five days after the procedure with a significantly decreased value of troponin I. The reexamined electrocardiogram was normal after three weeks. CONCLUSIONS: To the best of our knowledge, this is the first study to report on myocardial injury and pericarditis after combined left atrial and coronary sinus ablation in WPW syndrome. Our findings underscore the need for detailed mapping and careful ablation with low energy, as well as the merits of identifying myocardial infarction after coronary sinus ablation.

The preablation monocyte/ high density lipoprotein ratio predicts the late recurrence of paroxysmal atrial fibrillation after radiofrequency ablation.

BACKGROUND: The monocyte/high-density lipoprotein ratio (MHR) has emerged as a promising alternative biomarker in the fields of cardiovascular disease and atrial fibrillation (AF). This retrospective study was aimed to explore the predictive value of the MHR for the late recurrence of AF after radiofrequency ablation. METHODS: From April 2015 to October 2018, patients with paroxysmal AF who had undergone radiofrequency catheter ablation at Subei People's Hospital of Jiangsu Province were enrolled in our study. All the participants were observed until November 2019 after the procedure. During the postoperative follow up, the patients were categorized into the recurrence group and maintenance of sinus rhythm group based on who had experienced AF recurrence. RESULTS: One hundred twenty-five patients were diagnosed with paroxysmal AF, with an average age of 61.2 ± 9.3 years. Forty-seven patients had developed late recurrence during a mean follow up of 25.1 ± 12.0 months. The AF recurrence event rates were significantly increased in the highest MHR tertile compared with those in the lowest MHR tertile (22.0% vs. 57.1%; P < 0.05). On multivariate logistic regression analysis, the preablation MHR (OR = 1.34; 95% CI = 1.12 ~ 1.60; P = 0.001) and left atrial diameter (LAD) (OR = 1.21, 95% CI = 1.08 ~ 1.35; P = 0.001) were independent risk factors predicting the recurrence of AF after radiofrequency ablation. Furthermore, receiver operating characteristic (ROC) curve analysis revealed that the area under the curve (AUC) of the MHR was 0.712 (95% CI = 0.618 ~ 0.806; P = 0.000) and that of LAD was 0.739 (95% CI = 0.653 ~ 0.814; P = 0.000). Z-test found no significant difference between the MHR and LAD regarding the AUC (Z = 0.451; P = 0.652). CONCLUSION: An elevated preablation MHR was associated with an increased risk of the postoperative recurrence of AF. Additionally, the MHR independently predicted the late recurrence of paroxysmal AF after radiofrequency ablation, with the same predictive value as LAD.

Effects of GST variants on the risk odds of hematological malignancy: A meta-analysis.

BACKGROUND: Whether glutathione S-transferases (GST) polymorphisms influence the risk odds of hematological malignancy remains controversial. Therefore, we performed this meta-analysis to better analyze correlations between GST polymorphisms and hematological malignancy. METHODS: Literature retrieve was conducted in PubMed, MEDLINE, and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Sixty-two studies were enrolled for analyses. Significant associations with hematological malignancy were observed for GSTM1 (P < 0.0001, OR = 1.25, 95% CI, 1.14-1.38), GSTP1 (P = 0.002, OR = 1.20, 95% CI, 1.07-1.34), and GSTT1 (P < 0.0001, OR = 1.57, 95% CI, 1.39-1.76) polymorphisms in overall analyses. Further subgroup analyses by ethnicity revealed that GSTM1 and GSTT1 polymorphisms were both significantly correlated with hematological malignancy in Caucasians, East Asians, and West Asians, whereas GSTP1 polymorphism was only significantly correlated with hematological malignancy in Caucasians and West Asians. When we stratified data according to type of disease, positive results were found for all investigated polymorphisms in patients with certain types of acute leukemia. Moreover, GSTP1 polymorphism was also found to be significantly associated with chronic leukemia and lymphoma. CONCLUSIONS: Our findings indicated that GSTM1, GSTT1, and GSTP1 polymorphisms may serve as potential genetic biomarkers of hematological malignancy in certain ethnicities.

Metal-Free Dehydrogenation of N-Heterocycles by Ternary h-BCN Nanosheets with Visible Light.

An efficient metal-free catalytic system has been developed based on hexagonal boron carbon nitride (h-BCN) nanosheets for the dehydrogenation of N-heterocycles with visible light; hydrogen gas is released in the process, and thus no proton acceptor is needed. This acceptorless dehydrogenation of hydroquinolines, hydroisoquinolines, and indolines to the corresponding aromatic N-heterocycles occurred in excellent yield under visible-light irradiation at ambient temperature. With h-BCN as the photocatalyst and water as the solvent, this environmentally benign protocol shows broad substitution tolerance and high efficiency.

Access to Thiazole via Copper-Catalyzed [3+1+1]-Type Condensation Reaction under Redox-Neutral Conditions.

A new strategy for thiazoles via copper-catalyzed [3+1+1]-type condensation reaction from oximes, anhydrides and potassiumthiocyanate (KSCN) is developed herein. The transformation has good functional group tolerance and various thiazoles were formed smoothly in good to excellent yields under mild reaction conditions. This process involves copper-catalyzed N-O/C-S bond cleavages, activation of vinyl sp2 C-H bond, and C-S/C-N bond formations which are under redox-neutral conditions as well as operational simplicity.

Retinoic acid signaling pathway in pancreatic stellate cells: Insight into the anti-fibrotic effect and mechanism.

Pancreatic stellate cells (PSCs) are activated following loss of cytoplasmic vitamin A (retinol)-containing lipid droplets, which is a key event in the process of fibrogenesis of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDCA). PSCs are the major source of cancer-associated fibroblasts (CAFs) that produce stroma to induce PDAC cancer cell growth, invasion, and metastasis. As an active metabolite of retinol, retinoic acid (RA) can regulate target gene expression in PSCs through its nuclear receptor complex (RAR/RXR or RXR/RXR) or transcriptional intermediary factor. Additionally, RA also has extranuclear and non-transcriptional effects. In vitro studies have shown that RA induces PSC deactivation which reduces extracellular matrix production through multiple modes of action, such as inhibiting TßRⅡ, PDGFRß, ß-catenin and Wnt production, downregulating ERK1/2 and JNK phosphorylation and suppressing active TGF-ß1 release. RA alone or in combination with other reagents have been demonstrated to have an effective anti-fibrotic effect on cerulein-induced mouse CP models in vivo studies. Clinical trial data have shown that repurposing all-trans retinoic acid (ATRA) as a stromal-targeting agent for human pancreatic cancer is safe and tolerable, suggesting the possibility of using RA for the treatment of CP and PDCA in humans. This review focuses on RA signaling pathways in PSCs and the effects and mechanisms of RA in PSC-mediated fibrogenesis as well as the anti-fibrotic and anti-tumor effects of RA targeting PSCs or CAFs in vitro and in vivo, highlighting the potential therapies of RA against CP and PDAC.

Metal-Free Heterogeneous Photocatalysis for Carbocarboxylation of Alkenes: Efficient Synthesis of γ-Amino Carboxylic Derivatives.

A metal-free heterogeneous protocol is established herein for the synthesis of value-added γ-amino acid scaffolds via carbocarboxylation of alkenes with CO2 and alkylamines under visible light irradiation. The protocol shows broad substrate scope under mild reaction conditions and good stability of the catalyst for recycle tests. Moreover, the methodology could be feasible to the late-stage derivatization of several natural products, enriching the chemical arsenal for practical application.

Vitamin D3 analogue calcipotriol inhibits the profibrotic effects of transforming growth factor- ß1 on pancreatic stellate cells.

OBJECTIVE: To evaluate the inhibitory effect of vitamin D3 analogue calcipotriol (Cal) on the fibrosis of pancreatic stellate cells (PSCs) induced by TGF-ß1 and the rationality of Cal use in alcoholic chronic pancreatitis (ACP). MATERIAL AND METHODS: Double-labeling immunofluorescence was used for the identification of VDR+PSCs in the pancreas of healthy controls (HC) and ACP patients. Van Gieson staining for examination of collagen fibers. RT-qPCR and Western Blot for determining the mRNAs and proteins of VDR, TGF-ß1 and COL1A1 in the pancreas of ACP or in vitro PSCs. ELISA or LC-MS/MS for detection of serum TGF-ß1 and COL1A1 or 25(OH)D3. The PSC line (RP-2 cell) was used for the determination of proteomic alterations in Cal plus TGF-ß1 versus TGF-ß1 and to examine the effect of VDR gene knockdown. RESULTS: Enhanced expression of VDR was detected in RP-2 cells stimulated with alcohol (ALC) plus Cal versus Cal alone and in PSCs in the pancreas of ACP versus HC. The increased VDR+PSCs were positively correlated with the levels of COL1A1 mRNAs or areas of collagen deposition in the pancreas of ACP. TGF-ß1 was overexpressed in the pancreas of ACP and ALC-treated RP-2 cells while 25(OH)D3 level in serum was significantly decreased in ACP versus HC. Through a VDR-dependent mechanism, Cal antagonized 16 profibrotic proteins in TGF-ß1-induced RP-2 cells that included 7 extracellular matrix components, 2 cytoskeletal proteins, 2 fibrosis-associated factors (RUNX1 and TRAF2), TIMP-1, CCN1, integrin α11, an adhesion scaffold protein (TGFB1i1) and an enzyme mediating TGF-ß1-induced fibrogenesis (ENPP1). CONCLUSION: This study suggests that Cal administration may be a potential antifibrotic strategy via inhibiting TGF-ß1-mediated PSC action during the development of ACP.

Vitamin D: A Potential Star for Treating Chronic Pancreatitis.

Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas. The incidence of CP is increasing worldwide but the effective therapies are lacking. Hence, it is necessary to identify economical and effective agents for the treatment of CP patients. Vitamin D (VD) and its analogues have been confirmed as pleiotropic regulators of cell proliferation, apoptosis, differentiation and autophagy. Clinical studies show that VD deficiency is prevalent in CP patients. However, the correlation between VD level and the risk of CP remains controversial. VD and its analogues have been demonstrated to inhibit pancreatic fibrosis by suppressing the activation of pancreatic stellate cells and the production of extracellular matrix. Limited clinical trials have shown that the supplement of VD can improve VD deficiency in patients with CP, suggesting a potential therapeutic value of VD in CP. However, the mechanisms by which VD and its analogues inhibit pancreatic fibrosis have not been fully elucidated. We are reviewing the current literature concerning the risk factors for developing CP, prevalence of VD deficiency in CP, mechanisms of VD action in PSC-mediated fibrogenesis during the development of CP and potential therapeutic applications of VD and its analogues in the treatment of CP.

Ambroxol Chaperone Therapy for Gaucher Disease Type I-Associated Liver Cirrhosis and Portal Hypertension: A Case Report.

BACKGROUND: Gaucher Disease (GD) is a rare autosomal recessive inherited disease caused by the deficiency of glucocerebrosidase and characterized by a broad spectrum of clinical manifestations, including hepatosplenomegaly, bone infiltration, and cytopenia. Moreover, it is even involved in the central nervous system. GD is classified into three phenotypes on the ground of neurologic involvement: type 1 (GD1), the commonly adult-onset, non-neuropathic variant; type 2 (GD2), the acute neuropathic form; and type 3 (GD3), the severe chronic neuro-visceral form. Recently, several studies have shown a promising outcome of ambroxol chaperone therapy for the treatment of GD, but its therapeutic role in GD1-associated liver cirrhosis and portal hypertension was not verified. CASE PRESENTATION: A 36-year-old male patient was admitted for esophageal varices lasting for one year with a 34-year history of liver and spleen enlargement. The patient was diagnosed with GD1 with cirrhosis and portal hypertension based on the identification of Gaucher cells and advanced fibrosis in the liver biopsy tissue and two known pathogenic mutations on the glucocerebrosidase (GBA) gene. The patient received 660 mg/d of ambroxol for up to two years. At his six-month follow- up, the patient exhibited a remarkable increase in GBA activity (+35.5%) and decrease in liver stiffness (-19.5%) and portal vein diameter (-41.2%) as examined by ultrasound elastography and computer tomography, respectively. At two-year follow-up, the liver stiffness was further reduced (-55.5%) in comparison with untreated patients. CONCLUSION: This case report suggests that long-term treatment with high dose ambroxol may play a role in the reduction of hepatic fibrosis in GD1.

An aerobic [2 + 2 + 2] cyclization via chloropalladation: from 1,6-diynes and acrylates to substituted aromatic carbocycles.

A Pd-catalyzed aerobic [2 + 2 + 2] cyclization of 1,6-diynes and acrylates proceeding through a chloropalladation process has been developed. Polysubstituted five-membered aromatic carbocycles/heterocycles were obtained in good to excellent yields. The results of the mechanistic study are consistent with the proposed reaction mechanism.

Ceramic boron carbonitrides for unlocking organic halides with visible light.

Photochemistry provides a sustainable pathway for organic transformations by inducing radical intermediates from substrates through electron transfer process. However, progress is limited by heterogeneous photocatalysts that are required to be efficient, stable, and inexpensive for long-term operation with easy recyclability and product separation. Here, we report that boron carbonitride (BCN) ceramics are such a system and can reduce organic halides, including (het)aryl and alkyl halides, with visible light irradiation. Cross-coupling of halides to afford new C-H, C-C, and C-S bonds can proceed at ambient reaction conditions. Hydrogen, (het)aryl, and sulfonyl groups were introduced into the arenes and heteroarenes at the designed positions by means of mesolytic C-X (carbon-halogen) bond cleavage in the absence of any metal-based catalysts or ligands. BCN can be used not only for half reactions, like reduction reactions with a sacrificial agent, but also redox reactions through oxidative and reductive interfacial electron transfer. The BCN photocatalyst shows tolerance to different substituents and conserved activity after five recycles. The apparent metal-free system opens new opportunities for a wide range of organic catalysts using light energy and sustainable materials, which are metal-free, inexpensive and stable.

Efficacy and Safety of the Biosimilar IBI301 Plus Standard CHOP (I-CHOP) in Comparison With Rituximab Plus CHOP (R-CHOP) in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A Randomized, Double-Blind, Parallel-Group, Phase 3 Trial.

INTRODUCTION: Patients with diffuse large B-cell lymphoma (DLBCL) have limited access to rituximab. IBI301 is a recombinant chimeric murine/human anti-CD20 monoclonal antibody and is a candidate biosimilar to rituximab. This study aimed to assess the therapeutic equivalence of IBI301 and rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This multicenter, randomized, double-blind, parallel-group, phase 3 trial compared IBI301 and rituximab, both plus the chemotherapy of doxorubicin, cyclophosphamide, vindesine, and prednisone (CHOP), was conducted in 68 centers across China. Eligible patients with untreated CD20 positive (CD20+) DLBCL randomly received IBI301 (375 mg/m2) plus the standard CHOP or rituximab (375 mg/m2) plus the standard CHOP for six cycles of a 21-day cycle. The primary end point was the overall remission rate (ORR). Efficacy equivalence was defined if 95% CIs for the ORR difference between the two groups were within a ± 12.0% margin. RESULTS: Between August 22, 2016, and September 5, 2018, 419 patients were randomly allocated into the IBI301 group (N = 209) and rituximab group (N = 210). In the full analysis set, the ORR was 89.9% and 93.8% in the IBI301 and rituximab groups, respectively, and the ORR difference was -3.9% (95% CI - 9.1%-1.3%), falling within a ± 12.0% margin. The occurrences of treatment-emergent adverse events (TEAEs) (100% vs. 99.0%) and AEs of grade ≥ 3 (87.1% vs. 83.3%) were similar in the two groups (P > 0.05). CONCLUSIONS: IBI301 had a non-inferiority efficacy and a comparable safety compared with rituximab. IBI301 plus CHOP could be suggested as a candidate treatment regimen for untreated patients with CD20+ DLBCL. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov (NCT02867566).

Nanoscale boron carbonitride semiconductors for photoredox catalysis.

The conversion of solar energy to chemical energy achieved by photocatalysts comprising homogeneous transition-metal based systems, organic dyes, or semiconductors has received significant attention in recent years. Among these photocatalysts, boron carbon nitride (BCN) materials, as an emerging class of metal-free heterogeneous semiconductors, have extended the scope of photocatalysts due to their good performance and Earth abundance. The combination of boron (B), carbon (C), and nitrogen (N) constitutes a ternary system with large surface area and abundant activity sites, which together contribute to the good performance for reduction reactions, oxidation reactions and orchestrated both reduction and oxidation reactions. This Minireview reports the methods for the synthesis of nanoscale hexagonal boron carbonitride (h-BCN) and describes the latest advances in the application of h-BCN materials as semiconductor photocatalysts for sustainable photosynthesis, such as water splitting, reduction of CO2, acceptorless dehydrogenation, oxidation of sp3 C-H bonds, and sp2 C-H functionalization. h-BCN materials may have potential for applications in other organic transformations and industrial manufacture in the future.