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Transforming growth factor β (TGFβ) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGFβ therapies for potential combination with cancer immunotherapy agents. Inhibition of TGFβ signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of TGFβ receptor and not considered to be a liability associated with pan-TGFβ neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGFβ neutralizing mAb (pan-TGFβ mAb; neutralizes TGFβ1, 2, and 3) after 5 weekly intravenous doses of 10, 30, and 100 mg/kg, followed by a 4-week recovery period, in mice and cynomolgus monkeys. Mortality was observed due to acute bleeding and cardiovascular toxicity in mice at ≥ 30 mg/kg and prolonged menstruation in female monkeys at 100 mg/kg. Additional findings considered to be on-target exaggerated pharmacology included generalized bleeding and cardiovascular toxicity in mice and monkeys; histopathologic changes in the teeth, tongue, and skin in mice; and abnormal wound healing and microscopic pathology in the bone in monkeys. Importantly, our data indicate that the cardiovascular toxicities associated with the inhibition of TGFβ signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGFβ inhibiting mAb. [ABSTRACT FROM AUTHOR]

Aims The study aims to demonstrate the antimicrobial and disinfectant resistance phenotypes and genotypes of Escherichia coli isolates obtained from giant pandas ( Ailuropoda melanoleuca). Methods and Results Antimicrobial testing was performed according to the standard disk diffusion method. The minimal inhibitory concentrations ( MICs) of disinfectants were determined using the agar dilution method. All isolates were screened for the presence of antimicrobial and disinfectant resistance genes and further analysed for genetic relatedness by pulse-field gel electrophoresis ( PFGE). Results showed that 46·6% of the isolates were resistant to at least one antimicrobial. Escherichia coli isolates showed resistance to fewer antimicrobials as panda age increased. Among antimicrobial-resistant E. coli isolates, the antimicrobial resistance genes bla CTX-M (88·2%) and sul1 (92·3%) were most prevalent. The disinfectant resistance genes emrE, ydgE/ydgF, mdfA and sugE(c) were commonly present (68·2-98·9%), whereas qac and sugE(p) were relatively less prevalent (0-21·3%). The frequencies of resistance genes tended to be higher in E. coli isolated in December than in July, and PFGE profiles were also more diverse in isolates in December. The qacEΔ1 and sugE(p) genes were higher in adolescent pandas than in any other age groups. PFGE revealed that antimicrobial resistance correlated well with sampling time and habitat. Conclusions This study demonstrated that antimicrobial and disinfectant resistance was common in giant panda-derived E. coli, and the antimicrobial resistance was associated with sampling time and habitat. Escherichia coli could serve as a critical vector in spreading disinfectant and antimicrobial resistance. Significance and Impact of the Study This is the first study that demonstrated the phenotypic and genetic characterizations of antimicrobial and disinfectant resistance in E. coli isolates from more than 60 giant pandas. Frequent transfer of pandas to other cages may lead to the dissemination of antimicrobial resistance. The study highlights the need for regularly monitoring the antimicrobial and disinfectant resistance in bacteria from giant pandas. [ABSTRACT FROM AUTHOR]

Preoperative elevations in the levels of serum amyloid A ( SAA) or C-reactive protein ( CRP) have been reported to be prognostic indicators in several malignancies. The aim of this study is to evaluate the serum levels of SAA and CRP in the prognosis of esophageal squamous cell carcinoma ( ESCC). In total, 252 patients with ESCC who had undergone surgery with curative-intent were retrospectively recruited. The specificity, sensitivity, and prognostic value of SAA or CRP levels were measured as the area under the receiver operating characteristic ( ROC) curve ( AUC). The clinical value of SAA and CRP levels as prognostic indicators was evaluated using Cox's proportional hazards model. The 1-, 3-, and 5-year overall survival ( OS) rates for the entire cohort of patients with ESCC were 71.0%, 61.0%, and 43.0%, respectively. The correlation between the levels of SAA and CRP was significant ( r2 = 0. 685, P < 0.001). The ROC analysis showed that the levels of CRP were associated with a significantly lower overall accuracy than were the SAA levels ( AUC, 0.615 vs. 0.880; P < 0.001). For the complete cohort, the median OS was 52.0 months longer in patients with low preoperative serum levels of SAA (72.0 months) compared with patients who had high SAA levels (20.0 months, P < 0.001). The median OS among patients with low CRP levels was also longer compared with the patients who had high CRP levels (72.0 vs. 51.0 months, respectively; P < 0.001). Subgroup analyses showed that the preoperative elevated levels of SAA could find significant differences in OS for stage I, stage II, and stage III ( P < 0.001, P = 0.001, and P < 0.001, respectively), whereas the increased levels of CRP could only find a difference in OS for stage II cancers. After a multivariate analysis, preoperative elevated level of SAA was found to be an independently and significant prognostic factor ( P < 0.001). Our study indicates that the preoperative levels of SAA and CRP can act as prognostic factors, and that elevated levels of these proteins are associated with negative effects on the survival of patients with ESCC. SAA showed a higher prognostic value than CRP in both cohort and subgroup analysis. [ABSTRACT FROM AUTHOR]

Collagenase Clostridium Histolyticum (CCH) is the first medical therapy approved by the FDA to treat Peyronie's Disease (PD). CCH men were older than the IFN cohort (56.9 vs 54.7 years, p=0.03), had a shorter duration of PD (2.3 vs 2.7, p<0.0001), and had a larger pre-treatment curvature (62.3 vs 48.3, p<0.0001). These data would suggest that CCH should be considered preferentially over IFN as an injection therapy for PD. [Extracted from the article]