Sepsis may directly lead to multiple organ failure, which is among the leading causes of mortality in critically ill patients. According to data released by the Global Sepsis Alliance, the number of mortalities due to sepsis exceeded the combined number for prostate cancer, breast cancer and AIDS in 2012. To date, studies have reported that resveratrol has marked positive effects including anti-inflammatory, anti-oxidative and pro-microcirculatory functions in sepsis-induced organ injury, significantly improving the survival time and mortality of sepsis animals. The present systematic review sought to further clarify the efficacy and safety of resveratrol in the treatment of sepsis. Studies on resveratrol application in the treatment of sepsis-induced organ injury in animal models were reviewed by searching various Chinese and other language databases (PubMed, Embase, CNKI, WanFang and WeiPu) and by manually searching the references of related articles. The selection and evaluation of the studies was performed by two independent reviewers. A total of 260 related studies were initially identified. Following application of the exclusion factors and inclusion criteria, 11 studies were included. Meta-analysis revealed that resveratrol exerted significant protective effect in sepsis-induced animal models of organ injury, through anti-inflammatory, anti-oxidant and pro-microcirculatory functions compared with in the placebo group. While nuclear factor κB (NF-κB) and nuclear factor E2-related factor 2 (NRF-2) are the two major signaling pathways to have been associated with the anti-inflammatory and anti-oxidative effects of resveratrol, these factors were not quantified for mean values, therefore not suitable for systematic evaluation. For related factors, the results of meta-analysis were as follows: For tumor necrosis factor-α (TNF-α), the standardized mean difference (SMD) was-13.50 [95% confidence interval (CI):-22.08,-4.91; P=0.002]; for malondialdehyde (MDA), the SMD was-3.10 (95% CI:-5.27,-0.93; P=0.005); for mean arterial pressure the SMD was 1.34 (95% CI: 0.07, 2.62; P=0.04); for interleukin (IL)-6 the SMD was-9.57 (95% CI:-20.90, 1.75; P=0.10); and for IL-10 the SMD was 0.80 (95% CI:-0.73, 2.34; P=0.31). It was concluded that resveratrol exerted significant anti-inflammatory and anti-oxidative effects through NF-κB and NRF-2 signaling pathways in animal models of sepsis-induced multiple organ injury, manifesting as significant downregulation of TNF-α and MDA expression and improved microcirculation, therefore ameliorating septic damage to the body, which may ultimately improve survival ratios.

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Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Based on the in vitro and in vivo characterization studies of dasatanib, several metabolites were identified. Dasatinib and its metabolite 20 were the major circulating species identified which represented 25.5% and 12.5% of total radioactivity in human plasma respectively. Here, we report the identification of HND-01, a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) which was achieved by modifying metabolite 20 of dasatinib. Bruton’s tyrosine kinase (BTK) is a non-receptor kinase and a key regulator of the B-cell receptor (BCR) signaling pathway. BCR is critical for proliferation and survival of leukemic cells in many B cell malignancies, including chronic lymphocytic leukemia (CLL). BTK is a key target for the development of small molecule inhibitors in B cell malignancies. There are several covalent BTK inhibitors including ibrutinib that have been approved. These covalent inhibitors bind with high affinity to Cys-481 in the active site of BTK. However, some patients develop acquired resistance to ibrutinib due to Cys-481 mutation in the BTK binding site. The acquired resistance to covalent inhibitors can be overcome with the design of new reversible BTK inhibitors. The reversible BTK inhibitors will bind to different sites other than the cysteine residue of BTK and inactivate BTK. These drugs would potentially be active in the presence or absence of the cysteine-to-serine mutation. HND-01, a novel and potent reversible BTK inhibitor inhibits wild type & C481S mutant BTK with IC50 values of 0.157 nM for WTBTK and 0.032 nM for C481SBTK. HND-01 inhibits K562 cell proliferation (IC50 0.183 nM) and it is more stable than dasatinib in human liver microsomes (in vitro clearance; 142 mL/min/kg for HND-01 vs 211 mL/min/kg for dasatinib). In an established human lymphoma efficacy model (TMD-8 model), HND-01 showed stronger tumor inhibition (80.6%) than Ibrutinib (58%). These data demonstrates that HND-01 is a BTK inhibitor that is more potent with potential desirable ADME properties than ibrutinib. HND-01 was filled for international patents, China patent application # 202080030953.6, US patent application #17/636,476, EU application # EP 20853834.8, and Canada application # CA 3148436. Citation Format: Jing Zhang, Ahmed A. Samatar, Yue Tan, Shiqing Pi, Zhigang Zhou, Yan Xu, Daihong Yang. Hnd-01: a potent inhibitor of wild type mutant BTK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3099.

Midshaft (mid)-clavicle fractures are the most common type of clavicle fractures. The Kirschner wire (KW) and anatomic plate (AP) are two commonly used surgical treatment methods for mid-clavicle fractures, of which the use of an AP appears to be a more effective option. The present study performed a meta-analysis of a number of published studies on the treatment of mid-clavicle fractures with APs and KWs, in order to compare the advantages and disadvantages of the two treatments, so as to select a more effective treatment approach. The articles were obtained from several databases, including Cochrane Library, PubMed, Embase, CNKI, Wanfang, VIP and Chinese Biomedical Literature Database. The search period was from database establishment to June, 2021. Research was obtained by two authors who individually searched the aforementioned databases. For controversial studies, decisions were made by two authors (JZ and LW). A total of 20 studies involving 1,739 patients were included in the meta-analysis, including eight randomized controlled studies and 12 cohort trials. The results of the meta-analysis suggested that: Compared with the KW group, the AP group exhibited significant differences in incision length [standardized mean difference (SMD)=2.40; 95% confidence interval (CI), 1.93-2.86], constant function score (6 months; SMD=1.59; 95% CI, 1.29-1.89) and fracture healing time (SMD=-1.48; 95% CI, -2.09 to -0.87) (P<0.05). However, no significant differences were observed in the duration of the surgery (SMD=1.19; 95% CI, -0.19-2.57) and intraoperative blood loss (SMD=0.10; 95% CI, -3.13-3.32) (P>0.05). Compared with the KW group, significant differences were observed in post-operative efficacy (OR, 4.81; 95% CI, 3.10-7.46) and the incidence of post-operative complications (OR, 0.16; 95% CI, 0.05-0.55) in the AP group (P<0.05). On the whole, the AP and KW are two common materials for the clinical surgical treatment of mid-clavicle fractures. The present study confirmed that there was no significant difference between the two treatments as regards the duration of surgery and intraoperative blood loss; however, for post-operative shoulder joint function recovery, fracture healing state and healing time, the AP was significantly more effective than the KW. The post-operative complication rate of the AP group was significantly lower than that of the KW group. However, further prospective, large-sample randomized controlled studies are required to provide more concrete evidence for verification.