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Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X L ) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-X L inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-X L inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-X L -targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-X L -mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-X L -targeting agent to enter human clinical trials.

Background: Brucellosis is a severe zoonotic disease that is often overlooked, particularly in impoverished countries. Timely identification of focal complications in brucellosis is crucial for improving treatment outcomes. However, there is currently a lack of established indicators or biomarkers for diagnosing these complications. Therefore, this study aimed to investigate potential warning signs of focal complications in human brucellosis, with the goal of providing practical parameters for clinicians to aid in the diagnosis and management of patients., Methods: A multi-center cross-sectional study was conducted in China from December 2019 to August 2021. The study aimed to investigate the clinical characteristics and complications of patients with brucellosis using a questionnaire survey and medical record system. The presence of warning signs for complications was assessed using univariate and multivariate logistic regression models. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used for variable screening and model evaluation., Results: A total of 880 participants diagnosed with human brucellosis were enrolled. The median age of the patients was 50 years [interquartile range (IQR): 41.5-58.0], and 54.8% had complications. The most common organ system affected by complications was the osteoarticular system (43.1%), with peripheral arthritis (30.0%), spondylitis (16.6%), paravertebral abscess (5.0%), and sacroiliitis (2.7%) being the most prevalent. Complications in other organ systems included the genitourinary system (4.7%), respiratory system (4.7%), and hematologic system (4.6%). Several factors were found to be associated with focal brucellosis. These factors included a long delay in diagnosis [odds ratio (OR) = 3.963, 95% confidence interval (CI) 1.906-8.238 for > 90 days], the presence of underlying disease (OR = 1.675, 95% CI 1.176-2.384), arthralgia (OR = 3.197, 95% CI 1.986-5.148), eye bulging pain (OR = 3.482, 95% CI 1.349-8.988), C-reactive protein (CRP) > 10 mg/L (OR = 1.910, 95% CI 1.310-2.784) and erythrocyte sedimentation rate (ESR) elevation (OR = 1.663, 95% CI 1.145-2.415). The optimal cutoff value in ROC analysis was > 5.4 mg/L for CRP (sensitivity 73.4% and specificity 51.9%) and > 25 mm/h for ESR (sensitivity 47.9% and specificity 71.1%)., Conclusions: More than 50% of patients with brucellosis experienced complications. Factors such as diagnostic delay, underlying disease, arthralgia, eye pain, and elevated levels of CRP and ESR were identified as significant markers for the development of complications. Therefore, patients presenting with these conditions should be closely monitored for potential complications, regardless of their culture results and standard tube agglutination test titers., (© 2024. The Author(s).)

Objectives: This systematic review and meta-analysis investigated the accuracy of prenatal fetal ultrasound (US) to detect cleft palate during the second and third trimester (12-36 weeks) of pregnancy in high-risk fetuses., Methods: Pubmed and Embase databases were searched for studies that performed prenatal fetal US (comparator) and postnatal examination (reference standard) in fetuses at high risk for orofacial clefts. Risk of bias among included studies was assessed using the QUADAS-2. Area under the summary receiver operating characteristic (SROC) curve and pooled sensitivity and specificity were calculated., Results: This meta-analysis included 7 studies involving 663 high-risk fetuses. The individual studies showed that prenatal fetal US accurately predicted the possibility of cleft palate in these fetuses. Pooled sensitivity was 87% (95% CI 71%-95%), pooled specificity was 98% (95%CI 90%-100%), and the area under the SROC curve was 0.98 (95% CI 0.97-0.99)., Conclusion: Second and third trimester fetal US has excellent sensitivity and specificity for the detection of cleft palate in high-risk pregnancies., (© 2021 American Institute of Ultrasound in Medicine.)