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Clinical trials have confirmed that chimeric antigen receptor (CAR) T cell therapies are revolutionizing approaches for treating several relapsed or refractory hematological tumors. Cytokine release syndrome (CRS) is an adverse event with high incidence during CAR-T treatment. A further understanding of the characteristics and related risk factors of CRS is important for effective management. A total of 142 patients with relapsed or refractory acute lymphocyte leukemia (ALL), lymphoma, or multiple myeloma (MM) received lymphodepletion chemotherapy followed by infusion of CAR-T cells. The characteristics of CRS at different time points after treatment were monitored and risk factors were analyzed. The incidence of CRS for ALL, lymphoma, and multiple myeloma were 82%, 90%, and 90% respectively. Fever was observed on a median of day 3 for ALL, day 1 for lymphoma, and day 8.5 for MM after CAR-T cell infusion, and the duration was different between grade 1–2 CRS and grade 3–5 CRS. Disease types, peak concentration of IL-6, and CRP were associated with CRS. For patients with ALL, numbers of lymphoblast in bone marrow before lymphodepletion, peak concentration of IL-6, and CRP were independent risk factors of CRS. Clinical stage of lymphoma patients and high tumor burden in marrow of MM patients were independent risk factors of CRS. In conclusion, the characteristics and risk factors of CRS in different B-cell hematological tumors are different and should be managed individually during CAR-T cell therapy.

Herein, we report a general strategy for the rational design of an efficient organic photocatalyst, and we describe a robust method for the direct C(sp 3 )−H carbamoylation of saturated aza-heterocycles under mild conditions by using a naphthalimide (NI)-based organic photocatalyst. This protocol provides a concise and practical approach for the rapid installation of a valuable amide bond onto pharmaceutically useful saturated aza-heterocycles to access a wide range of cyclic α-amino amides. A series of mechanism investigations have demonstrated this transformation undergoes a visible-light photocatalytic, oxidative Ugi reaction process.

IntroductionChimeric antigen receptor T (CAR-T) cells are effective in treating hematological malignancies. However, in patients receiving CAR-T therapy, data characterizing cardiac disorders are limited.Methods126 patients with hematologic malignancies receiving CAR-T cell therapy were analyzed to determine the impact of CAR-T therapy on occurrence of cardiac disorders, including heart failure, arrhythmias, myocardial infarction, which were defined by the Common Terminology Criteria for Adverse Events (CTCAE). Parameters related to cardiac disorders were detected including myocardial enzyme, NT-proBNP and ejection fraction (EF). Cardiovascular (CV) events included decompensated heart failure (HF), clinically significant arrhythmias and CV death.ResultsThe median age of patients was 56 years (6 to 72 years). 58% patients were male, 62% had multiple myeloma, 20% had lymphoma and 18% had ALL. 33 (26%) patients had cardiac disorders, most of which were grade 1-2. 13 patients (10%) were observed with cardiac disorders grade 3-5, which comprised 5(4%) patients with new-onset HF, 2 (2%) patients with new-onset arrhythmias, 4 (3%) patients with the acute coronary syndrome, 1(1%) patient with myocardial infarction and 1(1%) patient with left ventricular systolic dysfunction. There were 9 CV events (7%) including 6 decompensated heart failure, 1 clinically significant arrhythmias and 2 CV deaths. Among the 33 patients with cardiac disorders, the patients with cardiac disorders CTCAE grade 3-5 had higher grade CRS (grade ≥ 3) than those with cardiac disorders CTCAE grade ≤ 2 (P <0.001). More patients with cardiac disorders CTCAE grade 3-5 were observed in the cohort who did not receive corticosteroids and/or tocilizumab therapy timely comparing with those who received corticosteroids and/or tocilizumab therapy timely (P =0.0004).ConclusionsCardiac disorders CAR-T cell therapy were common and associated with occurrence of CRS. However, most cases were mild. For patients with CRS grade 3-5, timely administration of corticosteroids and/or tocilizumab can effectively prevent the occurrence and progression of cardiac disorders.

A sequential and general strategy has been successfully developed for the synthesis of spiropyrazolone scaffolds. This intriguing transformation of the asymmetric multicomponent catalysis process was realized with the combination of Michael addition/chlorination/nucleophilic substitution in a one-pot sequence, giving rise to a series of spiropyrazolones with fully substituted cyclopropanes and spiro-dihydrobenzofurans containing continuous stereogenic centers in good yields with excellent stereoselectivities.

SUMMARY Plants deploy various immune receptors to recognize pathogen‐derived extracellular signals and subsequently activate the downstream defense response. Recently, increasing evidence indicates that the endoplasmic reticulum (ER) plays a part in the plant defense response, known as ER stress‐mediated immunity (ERSI), that halts pathogen infection. However, the mechanism for the ER stress response to signals of pathogen infection remains unclear. Here, we characterized the ER stress response regulator NAC089, which was previously reported to positively regulate programed cell death (PCD), functioning as an ERSI regulator. NAC089 translocated from the ER to the nucleus via the Golgi in response to Phytophthora capsici culture filtrate (CF), which is a mixture of pathogen‐associated molecular patterns (PAMPs). Plasma membrane localized co‐receptor BRASSINOSTEROID INSENSITIVE 1‐associated receptor kinase 1 (BAK1) was required for the CF‐mediated translocation of NAC089. The nuclear localization of NAC089, determined by the NAC domain, was essential for immune activation and PCD. Furthermore, NAC089 positively contributed to host resistance against the oomycete pathogen P. capsici and the bacteria pathogen Pseudomonas syringae pv. tomato (Pst) DC3000. We also proved that NAC089‐mediated immunity is conserved in Nicotiana benthamiana. Together, we found that PAMP signaling induces the activation of ER stress in plants, and that NAC089 is required for ERSI and plant resistance against pathogens.

Background Acute myeloid leukemia (AML) is a highly heterogeneous malignancy with various outcomes, and therefore needs better risk stratification tools to help select optimal therapeutic options. Methods In this study, we identify miRNAs that could predict clinical outcome in a heterogeneous AML population using TCGA dataset. Results We found that MiR-363 is a novel prognostic factor in AML patients undergoing chemotherapy. In multivariable analyses, high miR-363 remained predictive for shorter OS (HR = 2.349, P = 0.012) and EFS (HR = 2.082, P = 0.001) independent of other well-known prognostic factors. More importantly, allogeneic hematopoietic stem cell transplantation (allo-HSCT) overcame the adverse outcomes related to high miR-363 expression. In gene expression profiling, high miR-363 expression was positively correlated with the amounts of leukemogenic transcription factors, including Myb, RUNX3, GATA3, IKZF3, ETS1 and MLLT3. Notably, we found that the in silico predicted target genes (EZH2, KLF6 and PTEN) of miR-363 were downregulated in association with high miR-363 expression. Conclusions In summary, miR-363 expression may help identify patients in need of strategies to select the optimal therapy between chemotherapeutic and allo-HCST regimens. AML patients with high miR-363 expression may be highly recommended for early allo-HSCT regimen.

BackgroundBlood pressure variability (BPV) is a modifiable risk factor for stroke. This study was performed to determine the prognostic role of BPV in patients with acute hemorrhagic stroke.MethodsThe data of 131 hospitalized hypertensive patients with spontaneous intracerebral hemorrhage (sICH) were collected. All patients underwent examinations using several neurological scales (Glasgow Coma Scale, National Institutes of Health Stroke Scale, and modified Rankin scale [mRS]) and BP measurements at different time points.ResultsSex, age, hematoma volume, and neurological scores were not significantly different between patients with a favorable and unfavorable prognosis for sICH. However, significant differences were found in hypertension, diabetes, metabolic syndrome, atrial fibrillation, smoking, and stroke history. The standard deviation (SD), coefficient of variation (CV), and maximum–minimum range (Max–Min) of diastolic BP and the mean, SD, CV, and Max–Min of systolic BP significantly differed between the groups. Statistical analysis also demonstrated correlations between the 90-day mRS score and BPV and between systolic BPV and the 90-day mRS score.ConclusionHigh systolic or diastolic BPV within 24 hours of hemorrhagic stroke onset is associated with the 90-day neurological prognosis. The 24-hour BPV plays a critical role in the neurological outcome of hemorrhagic stroke.