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Grapheme-color synesthesia is a consistent and automatic perception of non-physical color when presented with a grapheme. Many previous studies focused on the synesthetic visual system, but other cognitive functions in grapheme-color synesthetes have remained unclear. Therefore, the objective of the present study was to investigate the characteristics of cognitive processing for motor execution and inhibition during Go/No-go paradigms in grapheme-color synesthesia using event-related potentials (ERPs). Six grapheme-color synesthetes and 24 non-synesthetes performed visual, auditory, and somatosensory Go/No-go paradigms. Omission errors were higher in grapheme-color synesthetes than non-synesthetes. Group-trial interactions (i.e., synesthetes–non-synesthetes × Go–No-go) were observed for the latency of the visual N2 component and amplitude of the somatosensory N2 component. Latencies of auditory and somatosensory P3 components were shorter in grapheme-color synesthetes than non-synesthetes. These findings suggest that grapheme-color synesthetes have specific cognitive processing in motor execution and inhibition as well as synesthetic color perception. Our data advance understanding of cognitive processing in grapheme-color synesthesia.

Soft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi‐pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3β, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3β in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3β (tyrosine 216‐phosphorylated) was higher in synovial sarcoma (SYO‐1, HS‐SY‐II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3β activity by pharmacological agents (AR‐A014418, SB‐216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis. These effects were associated with G0/G1‐phase cell cycle arrest and decreased expression of cyclin D1, cyclin‐dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3β inhibitors attenuated the growth of SYO‐1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3β in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4‐mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3β as a new and promising therapeutic target for these STS types. This study shows that deregulated activity of GSK3β in synovial sarcoma and fibrosarcoma is responsible for tumor cell proliferation through cyclin D1/CDK4‐mediated cell cycle progression, and for tumor cell invasion via enhanced extracellular matrix degradation. The present results therefore suggest that targeting of GSK3β in tumor cells is a promising therapeutic strategy for soft tissue sarcomas.

The maternal restraint stress animal model is based on a long-term stress paradigm administered to pregnant maternal animals, and these offspring have been shown to exhibit a variety of biochemical defects including obesity. This study aimed to investigate whether maternal restraint stress affects obesity-associated changes in offspring intestinal microbiota and the adipogenic differentiation of mesenchymal stem cells (MSCs). Pregnant mice were subjected to restraint stress three times daily from gestational Day12 to delivery. Changes in the composition of the intestinal microbiota of mothers (during pregnancy and lactation) and their lactating offspring exposed to maternal restraint stress were analyzed using next-generation sequencing. Maternal stress altered the maternal microbiota, with reduced Bacteroidetes and increased Firmicutes. While similar trends were observed in offspring, these changes were not statistically significant. However, maternal stress notably reduced microbial diversity in the offspring’s intestinal microbiota. Bone marrow-derived MSCs from offspring at weaning were analyzed for adipogenic transcription factors and hormone receptor expression using quantitative PCR. Maternal stress enhanced the adipogenic phenotype of offspring MSCs, as evidenced by increased expression of adipogenic markers (PPARγ, leptin receptor) and a reduced osteogenic phenotype. In vitro induction further confirmed the higher adipocyte differentiation potential in stressed offspring MSCs compared to controls. Our results revealed that maternal restraint stress altered the maternal intestinal microbiota, leading to reduced microbial diversity in offspring, predisposing their MSCs toward an adipocyte phenotype. These finding suggest that modulating the intestinal microbiota of stressed pregnant women may improve the susceptibility to obesity in their children.

Recently, immune checkpoint inhibitor (ICI), such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies, has provided clinical benefits in various cancer types including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, firstly showed an improvement in the overall survival (OS) in patients with AGC in the ATTRACTION-2 trial. Recently, chemotherapy plus nivolumab, as a first-line treatment for AGC, showed both OS and progression-free survival (PFS) benefits in patients with PD-L1 combined positive score (CPS) [greater than or equal to]5 in the global CheckMate-649 trial, and demonstrated PFS benefit irrespective of CPS status in the Asian ATTRACTION-4 trial. Based on these results, chemotherapy plus nivolumab in a first-line treatment was approved worldwide. However, the approval requirements and recommendations are different according to the approval agent or country. Thus, this review summarized the clinical trials of chemotherapy plus anti-PD1 antibody as a first-line treatment and focused on the role of nivolumab combined with chemotherapy mainly from the viewpoint of the Japanese experience. Keywords: immune checkpoint inhibitors, chemotherapy, programmed cell death-1, human epidermal growth factor receptor 2

In patients with impaired renal function, S‐1–related toxicities increase due to higher exposure of 5‐fluorouracil (5‐FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S‐1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty‐three patients with various renal functions received S‐1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration‐time curve (AUC) of 5‐FU. Thirty patients with BSA of 1.14‐1.84 m2 and CLcr of 23.8‐96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S‐1–related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5‐FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S‐1. Our previously developed S‐1 dosage formula based on renal function was prospectively evaluated. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S‐1.

Objective To determine senescence‐associated changes in the gingival tissues of aged mice and gingival fibroblast cultures. Materials and Methods The production of senescence‐associated β‐galactosidase (SA‐β‐gal) and mRNA expression of p16, p21, interleukin (IL)‐1β, and tumor necrosis factor α (TNF‐α) were evaluated in gingival tissues, gingival fibroblasts of 10‐ and 20‐month‐old C57BL/6NCrl mice, and multiple‐passaged and hydrogen peroxide‐stimulated human gingival fibroblasts (HGFs). Changes in molecular expression in HGF cultures due to senescent cell elimination by the senolytic drug ABT‐263 (Navitoclax) were analyzed. Results Compared to 10‐week‐old mice, the 20‐month‐old mice had higher numbers of M1 macrophages. The proportion of cells expressing SA‐β‐gal were also higher in 20‐ month‐old mice than in 10‐week‐old‐mice. Gingival fibroblasts in 20‐month‐old mice expressed less collagen 1a1, collagen 4a1, and collagen 4a2 mRNA than those in 10‐week‐old mice. Compared to control cells, H2O2 treated HGF cells expressed higher levels of SA‐β‐gal and p16, p21, IL‐1β, and TNF‐α. Furthermore, ABT‐263 suppressed HGF cell expression of cytokines after senescence induction. Conclusions Senescence‐associated changes were observed in the gingival tissues of aged mice and HGF cultures. In addition, the potential of senolytic drugs to modify aging‐related changes in the gingiva was shown.

We recently found that polyvinylpyrrolidone (PVP)-protected metal nanoparticles dispersed in water/butanol mixture spontaneously float to the air/water interface and form two-dimensional assemblies due to classical surface excess theory and Rayleigh–Bénard–Marangoni convection induced by butanol evaporation. In this study, we found that by leveraging this principle, a unique structure is formed where hetero gold nanospheres (AuNPs)/gold nanostars (AuNSs) complexes are dispersed within AuNP two-dimensional assemblies, obtained from a mixture of polyvinylpyrrolidone-protected AuNPs and AuNSs that interact electrostatically with the AuNPs. These structures were believed to form as a result of AuNPs/AuNSs complexes formed in the water/butanol mixture floating to the air/water interface and being incorporated into the growth of AuNP two-dimensional assemblies. These structures were obtained by optimizing the amount of mixed AuNSs, with excessive addition resulting in the formation of random three-dimensional network structures. The AuNP assemblies dispersed with AuNPs/AuNSs complexes exhibited significantly higher Raman (surface-enhanced resonance Raman scattering: SERRS) activity compared to simple AuNP assemblies, while the three-dimensional network structure did not show significant SERRS activity enhancement. These results demonstrate the excellent SERRS activity of AuNP two-dimensional assemblies dispersed with hetero AuNPs/AuNSs complexes.

BackgroundSubgroup analyses of randomized trials suggest the superiority of immune checkpoint inhibitor-based therapy over chemotherapy in patients with mismatch-repair deficient (dMMR) and/or microsatellite instability-high (MSI-high) advanced gastric or gastroesophageal junction adenocarcinoma. However, these subgroups are small and studies examining prognostic features within dMMR/MSI-high patients are lacking.MethodsWe conducted an international cohort study at tertiary cancer centers and collected baseline clinicopathologic features of patients with dMMR/MSI-high metastatic or unresectable gastric cancer treated with anti-programmed cell death protein-1 (PD-1)-based therapies. The adjusted HRs of variables significantly associated with overall survival (OS) were used to develop a prognostic score.ResultsOne hundred and thirty patients were included. At a median follow-up of 25.1 months, the median progression-free survival (PFS) was 30.3 months (95% CI: 20.4 to NA) and 2-year PFS rate was 56% (95% CI: 48% to 66%). Median OS was of 62.5 months (95% CI: 28.4 to NA) and 2-year OS rate was 63% (95% CI: 55% to 73%). Among the 103 Response Evaluation Criteria in Solid Tumors-evaluable patients, objective response rate was 66% and disease control rate 87% across lines of therapy. In the multivariable models, Eastern Cooperative Oncology Group Performance Status of 1 or 2, non-resected primary tumor, presence of bone metastases and malignant ascites were independently associated with poorer PFS and OS. These four clinical variables were used to build a three-category (ie, good, intermediate, and poor risk) prognostic score. Compared with patients with good risk, patients with intermediate risk score had numerically inferior PFS and OS (2-year PFS rate: 54.3% versus 74.5%, HR 1.90, 95% CI: 0.99 to 3.66; 2-year OS rate: 66.8% versus 81.2%, HR 1.86, 95% CI: 0.87 to 3.98), whereas patients with poor risk score had significantly inferior PFS and OS (2-year PFS rate: 10.6%, HR 9.65, 95% CI: 4.67 to 19.92; 2-year OS rate: 13.3%, HR 11.93, 95% CI: 5.42 to 26.23).ConclusionsOverall outcomes with anti-PD-1-based therapies are favorable in MSI-high gastroesophageal adenocarcinomas. However, within this overall favorable subgroup a more accurate prognostication using baseline clinical characteristics might identify patients at higher risk of rapid disease progression who may deserve intensified immunotherapy combination strategies.

Background Difficult resection of tumors from regions with complex local anatomy, such as the pelvis and sacrum, is likely to result in inadequate surgical margins (intralesional or marginal); this is because three-dimensional osteotomy is difficult particularly around the acetabulum. Additionally, removal of the joint makes reconstruction very difficult; thus, retention of good function also becomes difficult. In musculoskeletal oncology, computer navigation systems are still not widely used to prevent tumor-positive margins. We performed wide excision with guidance from a computer navigation system and reconstruction using frozen bone autografts for malignant pelvic bone tumors in two patients, and we obtained excellent functional and oncological outcomes. Here we present these patients and discuss our approach. Case presentation Case 1: A 12-year-old girl presented with Ewing sarcoma of the left pelvis (PI-II). We performed wide excision assisted by a computer navigation system with the osteotomy of the load surface of acetabulum and reconstruction using a frozen bone autograft. At the final follow-up, she showed excellent function and was alive without the disease. Moreover, she did not have osteoarthritis of the left hip joint. Case 2: A 71-year-old woman presented with dedifferentiated chondrosarcoma of the right pelvis (PII-III). We performed wide excision assisted by a computer navigation system with osteotomy avoiding load surface of the acetabulum and reconstruction using a frozen bone autograft; there was no tumor at the load surface. At the final follow-up, she showed good function, was alive without the disease, and did not have osteoarthritis of the left hip joint. Conclusions Wide excision assisted by a computer navigation system and reconstruction using a frozen bone autograft are very useful for the management/treatment of extremely difficult cases such as malignant pelvic bone tumors, particularly those including the acetabulum.

•The prognosis was updated to the latest in order to prolong the follow-up period of the prognosis.•The hypothesis for poorer prognosis in sarcopenic patients with pancreatic ductal adenocarcinoma compared to those who are not sarcopenic was added.•Data related to NLR/PLR/LMR were deleted.•Data about immunonutrition were added.•A breakdown of other diagnoses of 18 non-sarcopenic patients was added. It has been reported that sarcopenia is associated with higher postoperative complication rates in various surgeries and with a poorer prognosis in various carcinomas. However, many of these reports did not strictly follow the definition of sarcopenia. Therefore, we prospectively evaluated the influence of sarcopenia, as defined by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), on complications after pancreaticoduodenectomy (PD) and on the prognosis of pancreatic head carcinoma. We prospectively investigated 180 patients who underwent PD at Chiba University Hospital from January 2016 to March 2020. The skeletal muscle mass, grip strength, and gait speed of the patients were measured preoperatively. Sarcopenia was defined in accordance with the EWGSOP2 definition. We evaluated the frequency and severity of postoperative complications in infectious, non-infectious, and overall complications. We analyzed the prognosis of 83 patients with pancreatic head carcinoma who underwent PD. There were no differences in the severity and frequency of infectious, non-infectious, and overall complications between patients with and without sarcopenia. In patients with pancreatic head carcinoma, the recurrence-free and overall survival rates were significantly lower in patients with sarcopenia than in those without sarcopenia (P = 0.017 and P = 0.011, respectively). In multivariate analysis, sarcopenia was an independent risk factor for poor recurrence-free survival and overall survival (HR, 4.48; 95% CI, 1.68–11.98; P = 0.003 and HR, 3.25; 95% CI, 1.19–8.86; P = 0.021, respectively). Sarcopenia, as defined by EWGSOP2, did not affect complications after PD. Sarcopenia is an important prognostic factor for surgically resected pancreatic head carcinoma.