Synthesis, growth inhibitory activity against tumor cells, and structure-activity relationship of CGK733 and its analogs.

CGK733 was reported as a compound that inhibited ATM/ATR kinase activities and blocked their checkpoint signaling pathways with great selectivity. However, this paper was subsequently retracted, and the truth about the activity of CGK733 remains unclear. We synthesized various analogs of CGK733 with a modification of the carboxylic acid moiety and/or the aniline derivative moiety to accumulate knowledge of the structure-activity relationship of this compound. Growth inhibitory activity of CGK733 and novel 35 analogs against HeLa S3 cells was evaluated, and the structure-activity relationship revealed that analogs with the 2-naphthyl or 4-fluorophenyl group instead of the benzhydryl group have activity comparable to CGK733 and that the 3-nitro group on the aniline moiety significantly affects the activity.

Predictive factors and clinical impact of ICU-acquired weakness on functional disability in mechanically ventilated patients with COVID-19.

BACKGROUND: Patients with critical COVID-19 often require invasive mechanical ventilation (IMV) and admission to the intensive care unit (ICU), resulting in a higher incidence of ICU-acquired weakness (ICU-AW) and functional decline. OBJECTIVE: This study aimed to examine the causes of ICU-AW and functional outcomes in critically ill patients with COVID-19 who required IMV. METHODS: This prospective, single-center, observational study included COVID-19 patients who required IMV for ≥48 h in the ICU between July 2020 and July 2021. ICU-AW was defined as a Medical Research Council sum score <48 points. The primary outcome was functional independence during hospitalization, defined as an ICU mobility score ≥9 points. RESULTS: A total of 157 patients (age: 68 [59-73] years, men: 72.6%) were divided into two groups (ICU-AW group; n = 80 versus non-ICU-AW; n = 77). Older age (adjusted odds ratio [95% confidence interval]: 1.05 [1.01-1.11], p = 0.036), administration of neuromuscular blocking agents (7.79 [2.87-23.3], p < 0.001), pulse steroid therapy (3.78 [1.49-10.1], p = 0.006), and sepsis (7.79 [2.87-24.0], p < 0.001) were significantly associated with ICU-AW development. In addition, patients with ICU-AW had significantly longer time to functional independence than those without ICU-AW (41 [30-54] vs 19 [17-23] days, p < 0.001). The development of ICU-AW was associated with delayed time to functional independence (adjusted hazard ratio: 6.08; 95% CI: 3.05-12.1; p < 0.001). CONCLUSIONS: Approximately half of the patients with COVID-19 requiring IMV developed ICU-AW, which was associated with delayed functional independence during hospitalization.

Sex Differences in the Oxygenation of the Left and Right Prefrontal Cortex during Moderate-Intensity Exercise.

INTRODUCTION: Differences in cognitive performance with exercise between men and women have previously been reported. In this study, we evaluated between-sex differences in oxygenation of the prefrontal cortex (PFC) with moderate-intensity aerobic exercise (AE), which could contribute to noted differences in cognitive function. METHOD: The subjects were ten men (age, 21.5 ± 0.5 years; height, 171.7 ± 4.8 cm; weight, 65.6 ± 5.6 kg) and ten women (age, 21.4 ± 0.5 years; height, 157.6 ± 4.9 cm; weight, 51.3 ± 6.5 kg). They completed our AE protocol, consisting of a 30-min leg-ergometer cycling at an intensity of 50% peak oxygen uptake, with an initial 4-min rest period for baseline measurement. Measures of the dynamics of cerebral oxygenation included: oxygenated hemoglobin (O2Hb) in the left and right PFC (LR-PFC) and deoxygenated hemoglobin (HHb). The 30-min exercise period was subdivided into six 5-min phases, with the average and peak values determined in each phase. RESULTS: A significant interaction was found between LR-PFC HHb and sex (p < 0.001), with significantly higher values in men than in women in phases 3-6 (p < 0.05). CONCLUSION: We report a significant sex effect of HHb in the LR-PFC.

Low Muscle Mass is Associated with Walking Function in Patients with Acute Ischemic Stroke.

BACKGROUND: Muscle mass might be a possible predictor for walking function in patients with stroke; however, evidence is limited. OBJECTIVE: To investigate whether skeletal muscle mass is associated with walking function at discharge during the acute phase. METHODS: In this observational cohort study, we assessed skeletal muscle mass in patients with acute ischemic stroke using the noninvasive and portable multifrequency bio-impedance device. This device can easily be used in bedridden patients. Appendicular skeletal muscle mass was converted to skeletal muscle index (SMI) standardizing by height squared (kg/m2). The primary outcome was walking function assessed by the modified Rankin Scale score at acute phase hospital discharge. Logistic regression analysis was used to determine the association between skeletal muscle mass and walking function. RESULTS: Of the 107 patients enrolled, low SMI (SMI: male <7.0 kg/m2, female <5.7 kg/m2) was identified in 29.9% (19.7% in men, 48.6% in women). Logistic regression analysis showed that low SMI [OR: 4.02, 95% confidence interval (CI): 1.38-11.7, p = 0.001] independently associated with walking function at discharge. Further, patients with mild and moderate severity had significant difficulty in walking when they had low SMI (p = 0.039). CONCLUSIONS: Low skeletal muscle mass at the onset of ischemic stroke is an independent predictor of walking function at discharge during the acute phase. Our findings highlight the importance of detecting skeletal muscle mass in patients with acute ischemic stroke.

Acute moderate-intensity exercise improves 24-h sleep deprivation-induced cognitive decline and cerebral oxygenation: A near-infrared spectroscopy study.

We evaluated the effects of moderate-intensity exercise in improving the decline in cognitive performance induced by a 24-h period of acute sleep deprivation (SD). We hypothesized that the positive effect of exercise is mediated by increased oxygenation (measured using near-infrared spectroscopy) of the dorsolateral prefrontal cortex (DLPFC). Cognitive performance was measured using the reaction time and interference scores of the Stroop colour and word test, in 12 healthy adults (eight males, 21.1 ± 0.3 years-old), at pre- and post-exercise. Cognitive scores were compared under two conditions: rested wakefulness (RW) and 24-h SD. The exercise consisted of 20-min of ergometer cycling at an intensity of 60 % VO2peak. Oxygenation to the DLPFC increased, at 12 min after exercise onset, compared to the baseline and was maintained until the end of the exercise in both RW and SD conditions (P < 0.01). The change in RT correlated with sleepiness (P < 0.05), with no correlation for the interference score and oxygenation. Taken together, moderate-intensity exercise reverses SD-induced cognitive decline.