The integrated stress response (ISR) pathway is essential for adaption of various stresses and is related to mitochondrion-to-nucleus communication. Mitochondrial dysfunction-induced reactive oxygen species (ROS) was demonstrated to activate general control nonderepressible 2 (GCN2)–eukaryotic translation initiation factor 2α (eIF2α)–activating transcription factor-4 (ATF4) pathway-mediated cisplatin resistance of human gastric cancer cells. However, whether or how ISR activation per se could enhance chemoresistance remains unclear. In this study, we used eIF2α phosphatase inhibitor salubrinal to activate the ISR pathway and found that salubrinal reduced susceptibility to cisplatin. Moreover, salubrinal up-regulated ATF4-modulated gene expression, and knockdown of ATF4 attenuated salubrinal-induced drug resistance, suggesting that ATF4-modulated genes contribute to the process. The ATF4-modulated genes, xCT (a cystine/glutamate anti-transporter), tribbles-related protein 3 (TRB3), heme oxygenase 1 (HO-1), and phosphoenolpyruvate carboxykinase 2 (PCK2), were associated with a poorer prognosis for gastric cancer patients. By silencing individual genes, we found that xCT, but not TRB3, HO-1, or PCK2, is responsible for salubrinal-induced cisplatin resistance. In addition, salubrinal increased intracellular glutathione (GSH) and decreased cisplatin-induced lipid peroxidation. Salubrinal-induced cisplatin resistance was attenuated by inhibition of xCT and GSH biosynthesis. In conclusion, our results suggest that ISR activation by salubrinal up-regulates ATF4-modulated gene expression, increases GSH synthesis, and decreases cisplatin-induced oxidative damage, which contribute to cisplatin resistance in gastric cancer cells.

Previous studies have reported inconsistent results regarding the associations between metabolic syndrome (MetS) and obesity-related indices and bone mineral density (BMD). However, no previous studies have reported these associations among hemodialysis (HD) patients. The aims of this study were to investigate associations between MetS and its components and BMD T-score in HD patients and also between obesity-related indices and BMD T-score in HD patients with and without MetS. MetS was defined according to the Adult Treatment Panel III for Asians, and BMD T-score was calculated using dual-energy X-ray absorptiometry. Eight obesity-related indices were evaluated, including lipid accumulation product (LAP), visceral adiposity index (VAI), body adiposity index, conicity index (CI), body roundness index (BRI), abdominal volume index (AVI), waist-to-height ratio (WHtR), waist–hip ratio, and body mass index (BMI). One hundred and sixty-four patients undergoing HD were enrolled, and the prevalence of MetS was 61.6%. MetS was significantly associated with high lumbar spine and total hip T-scores. Regarding the MetS components, abdominal obesity and low HDL-C were significantly associated with high lumbar spine, femoral neck, and total hip T-scores; hypertriglyceridemia was significantly associated with high lumbar spine and total hip T-scores; hyperglycemia was significantly associated with a high lumbar spine T-score, whereas high blood pressure was not associated with T-score at any site. In the patients with MetS, BMI, WHtR, AVI, and BRI were significantly associated with T-score at all sites, and high CI, VAI, and LAP were also related to a high lumbar T-score. However, these indices were not associated with T-score at any site in patients without MetS. This study demonstrated positive associations between MetS and its five components and BMD T-score among HD patients. MetS, abdominal obesity, hypertriglyceridemia, and low HDL-cholesterol were associated with low risk of osteoporosis among the HD patients. Furthermore, we found that some obesity-related indices were associated with BMD T-score among HD patients with MetS but not in those without MetS. Our study highlights the importance of BMI, WHtR, AVI, and BRI in predicting the risk of osteoporosis among HD patients with MetS. In clinical practice, they can be easily calculated through simple anthropometric measurements and routine laboratory examinations and be used to quickly and conveniently assess the risk of osteoporosis among HD patients.

Type 2 diabetes mellitus (DM) is an increasing global health issue. Peripheral artery occlusive disease (PAOD) is a common complication of diabetes, and it is a complex and costly disease. The association between type 2 DM and obesity is well known, however, the relationship between obesity and PAOD in patients with type 2 DM has yet to be elucidated. Therefore, the aim of this study was to examine associations between obesity-related indices and PAOD in patients with type 2 DM. A total of 1872 outpatients with type 2 DM were recruited from two hospitals in southern Taiwan. An ankle–brachial index (ABI) < 0.9 in either leg was considered to indicate the presence of PAOD. The following obesity-related indices were investigated: conicity index (CI), waist–hip ratio (WHR), body roundness index (BRI), waist-to-height ratio (WHtR), abdominal volume index, a body shape index (ABSI), visceral adiposity index (VAI), lipid accumulation product (LAP), body adiposity index, body mass index and triglyceride–glucose index. Overall, 4.1% of the enrolled patients had an ABI < 0.9. High values of the following obesity-related indices were significantly associated with a low ABI: WHtR (p = 0.045), VAI (p = 0.003), CI (p = 0.042), BRI (p = 0.021) and ABSI (p = 0.043). Furthermore, WHR (area under the curve (AUC) = 0.661), CI (AUC = 0.660) and LAP (AUC = 0.642) had the best performance (all p < 0.001) to predict PAOD. In conclusion, high WHtR, BRI, CI, VAI and BAI values were associated with a low ABI in the enrolled patients, and WHR, CI and LAP were the most powerful predictors of PAOD.

Flow-mediated dilation (FMD) is used to noninvasively assess the health of blood vessels and it has been shown to have a similar predictive ability for cardiovascular disease to traditional risk factors. Skin perfusion pressure (SPP) refers to the blood pressure required to restore capillary or microcirculatory flow after controlled occlusion and the return of flow. SPP has been shown to be an important measurement when making clinical decisions for patients with limb ischemia and to be a predictor of the likelihood of wound healing. Peripheral artery disease is common in hemodialysis (HD) patients. However, little is known about the association between FMD or SPP and peripheral artery disease. The aim of this study was to evaluate the association between FMD and SPP with brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) in HD patients in Taiwan, an area with a high rate of ESRD. This study was conducted at a regional hospital in southern Taiwan. ABI and baPWV values were measured using an ABI automated device. FMD and SPP were measured using ultrasound and a microvasculature blood flow monitor, respectively. Eighty patients were enrolled in this study. Compared to the patients with an ABI ≥ 0.95, those with an ABI < 0.95 had lower SPP of the feet (dorsal and plantar portions, both p < 0.001). After multivariable adjustments, low triglycerides (p = 0.033) and high calcium–phosphate product (p = 0.018) were significantly associated with low FMD. Further, low ABI (p = 0.001) and low baPWV (p = 0.036) were significantly associated with low SPP of dorsal portions. Old age (p = 0.005), low high-density lipoprotein cholesterol (p = 0.016), and low ABI (p = 0.002) were significantly associated with low SPP of plantar portions. This study demonstrated an association between FMD and SPP with peripheral artery disease in HD patients. Patients with low ABI and baPWV had a high risk of low SPP of the feet. However, there was no significant correlation between FMD and ABI or baPWV.

Background: Carpal tunnel syndrome (CTS) diagnosis has traditionally relied on electrodiagnosis (EDX) to confirm the diagnosis and to assess severity. Ultrasound has shown potential in measuring median nerve cross-sectional area (CSA) for CTS diagnosis, and magnetic resonance imaging (MRI) can be used for wrist soft-tissue evaluation. This study explored the correlation between CTS diagnosis and median nerve CSA measured on MRI at different wrist levels. Methods: A retrospective review of an electronic medical record database identified patients who underwent both wrist MRI and EDX within a 90-day interval between January 2000 and December 2022. Median nerve CSA was measured on axial T2-weighted images at 3 levels: proximal to the carpal tunnel inlet (the distal radioulnar joint [DRUJ]), the inlet, and the outlet. Continuous variables are presented as means ± standard deviations. A logistic regression model was constructed to evaluate the diagnostic accuracy of median nerve CSA, at the 3 anatomical levels, in identifying CTS. Empirical cut point estimation determined optimal cutoffs and corresponding areas under the receiver operating characteristic curve (AUCs). Results: Sixty-eight patients (76 wrists; mean age, 51.4 ± 14.2 years; male-to-female ratio, 26 to 50; 59 White patients, 8 Hispanic patients, and 1 Asian patient) were included. The mean median nerve CSA in the EDX-negative group compared with the EDX-positive group was 10.6 ± 3.4 versus 11.7 ± 4.0 mm ² (p = 0.248) at the DRUJ level, 11.1 ± 3.1 versus 14.4 ± 5.1 mm ² (p = 0.007) at the inlet level, and 9.8 ± 2.4 versus 11.0 ± 5.2 mm ² (p = 0.833) at the outlet level. The inlet CSA cutoff for CTS was 11.3 mm ² (AUC = 0.67), with a sensitivity of 74% and a specificity of 60%. Conclusions: MRI-based measurements of median nerve CSA, particularly at the inlet level, suggest that relying solely on CSA measurements may not be an optimal diagnostic strategy for CTS in patients with equivocal clinical symptoms. Even with MRI and highly standardized measurement protocols, only poor-to-fair diagnostic accuracy was achieved. This study raises questions about the diagnosis of CTS based on CSA measurements. Level of Evidence: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence.