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Background In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported. Materials and Methods Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ–Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated. Results The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, −5.54; 95% CI, −10.93 to −0.16) and pain (LSM difference, −2.94; 95% CI, −5.86 to −0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95). Conclusion The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer. ClinicalTrials.gov ID NCT03189719 [ABSTRACT FROM AUTHOR]

It is known that there are abnormalities of tight junction functions, cell migration and mitochondrial metabolism in human endometriosis and endometrial carcinoma. In this study, we investigated the effects of growth factors and their inhibitors on the epithelial permeability barrier, cell migration and mitochondrial metabolism in 2D and 2.5D cultures of human endometrioid endometrial carcinoma Sawano cells. We also investigated the changes of bicellular and tricellular tight junction molecules and ciliogenesis induced by these inhibitors. The growth factors TGF-β and EGF affected the epithelial permeability barrier, cell migration and expression of bicellular and tricellular tight junction molecules in 2D and 2.5D cultures of Sawano cells. EW-7197 (a TGF-β receptor inhibitor), AG1478 (an EGFR inhibitor) and SP600125 (a JNK inhibitor) affected the epithelial permeability barrier, cell migration and mitochondrial metabolism and prevented the changes induced by TGF-β and EGF in 2D and 2.5D cultures. EW-7197 and AG1478 induced ciliogenesis in 2.5D cultures. In conclusion, TGF-β and EGF promoted the malignancy of endometrial cancer via interplay among the epithelial permeability barrier, cell migration and mitochondrial metabolism. EW-7197 and AG1478 may be useful as novel therapeutic treatments options for endometrial cancer. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the effect of optimization of the intraocular lens (IOL) power calculation formula SRK/T and Barrett Universal II (BU II) in long eyes (≥ 26 mm: group L) and short eyes (≤ 22 mm: group S) using axial length calculated from segmented refractive indices (SRI). Setting: Multicenter study at five sites in Japan. Design: Retrospective observational study. Methods: This study included 461 eyes of 461 patients (mean age 73.8 ± 8.4 years) who underwent cataract surgery. The predicted refractive error (PRE) was compared between the SRI (ARGOS) and the equivalent refractive index (ERI) biometers (IOLMasterTM 700). The patients were randomly divided into two groups, a learning group and a validation group. The optimization constants were determined in the learning group, and the optimization constants were subsequently applied to the validation group and compared with the ERI biometer results. Results: Using both SRK/T and BU II, the validation group's PRE using optimization constants for the SRI biometer in group L was significantly smaller than that using the ERI biometer (p< 0.001, p< 0.01). In group L, the arithmetic PRE of Barrett UII formula with SRI showed a significant improvement after optimization compared to before optimization (p< 0.0001). In group S, the arithmetic PRE of SRK/T and Barrett UII formula with SRI showed a significant improvement (p< 0.0001, p< 0.0001). Conclusion: In long and short eyes, the current study revealed that optimization of the SRK/T and Barrett formula constants for the SRI biometer was beneficial to achieve accurate refractive outcomes after cataract surgery. [ABSTRACT FROM AUTHOR]

Neurovascular coupling (NVC) is the functional hyperemia of the brain responding to local neuronal activity. It is mediated by astrocytes and affected by subcortical ascending pathways in the cortex that convey information, such as sensory stimuli and the animal condition. Here, we investigate the influence of the raphe serotonergic system, a subcortical ascending arousal system in animals, on the modulation of cortical NVC and cerebral blood flow (CBF). Raphe serotonergic neurons were optogenically activated for 30 s, which immediately awakened the mice from non-rapid eye movement sleep. This caused a biphasic cortical hemodynamic change: a transient increase for a few seconds immediately after photostimulation onset, followed by a large progressive decrease during the stimulation period. Serotonergic neuron activation increased intracellular Ca2+ levels in cortical pyramidal neurons and astrocytes, demonstrating its effect on the NVC components. Pharmacological inhibition of cortical neuronal firing activity and astrocyte metabolic activity had small hypovolemic effects on serotonin-induced biphasic CBF changes, while blocking 5-HT1B receptors expressed primarily in cerebral vasculature attenuated the decreasing CBF phase. This suggests that serotonergic neuron activation leading to animal awakening could allow the NVC to exert a hyperemic function during a biphasic CBF response, with a predominant decrease in the cortex. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Although metabolic dysfunction‐associated steatotic liver disease (MASLD) patients with a Fib‐4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, a more convenient method identifying high‐risk populations requiring follow‐up is needed. We explored the utility of serum levels of growth differentiation factor‐15 (GDF15), a cell stress‐responsive cytokine related to metabolic syndrome, for stratifying the risk of clinical events in MASLD patients. Methods: Serum GDF15 levels were measured in 518 biopsy‐performed MASLD patients, 216 MASLD patients for validation, and 361 health checkup recipients with MASLD. Results: In the biopsy‐MASLD cohort, multivariate analysis indicated that the serum GDF15 level was a risk factor for liver cancer, independent of the fibrosis stage or Fib‐4 index. Using a GDF15 cutoff of 1.75 ng/mL based on the Youden index, high‐GDF15 patients, regardless of fibrosis status, had a higher liver cancer incidence rate. While patients with a Fib‐4 index <1.3 or low‐GDF15 rarely developed liver cancer, high‐GDF15 patients with a Fib‐4 index >1.3 developed liver cancer and decompensated liver events at significantly higher rates and had poorer prognoses. In the validation cohort, high‐GDF15 patients had significantly higher incidences of liver cancer and decompensated liver events and poorer prognoses than low‐GDF15 patients, whether limited to high‐Fib‐4 patients. Among health checkup recipients with MASLD, 23.0% had a Fib‐4 index >1.3, 2.7% had a Fib‐4 index >1.3 and >1.75 ng/mL GDF15. Conclusions: Serum GDF15 is a biomarker for liver cancer with high predictive capability and is useful for identifying MASLD patients requiring regular surveillance. [ABSTRACT FROM AUTHOR]

Despite continuing advances in the development of effective new therapies, including immunotherapies, the prognosis of pancreatic cancer remains extremely poor. Gap junction proteins have become attractive targets for potential cancer therapy. However, the role of gap junction beta‐4 (GJB4) protein remains unexplored in pancreatic cancer. Through bioinformatic analyses we discovered pancreatic cancer tissues showed higher levels of GJB4 transcripts compared to normal pancreatic tissues and this had a negative effect on overall survival in patients that had pancreatic cancer. The high expression of nuclear GJB4 was identified as a negative prognostic factor in such patients. Knockdown of GJB4 in cultured pancreatic cancer cells resulted in G0/G1 arrest followed by decreased cell proliferation and suppression of metastatic potential. The overexpression of GJB4 accelerated cell proliferation, migration, and invasion in a SUIT‐2 cell line, whereas MET inhibitor canceled the acceleration. GJB4 suppression with siRNA significantly inhibited tumor growth in a mouse xenograft model. Mechanistically, suppression of GJB4 inhibited MET–AKT activities. Such data suggest that targeting the GJB4–MET axis could represent a promising new therapeutic strategy for pancreatic cancer. [ABSTRACT FROM AUTHOR]