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Chronic kidney disease (CKD) patients accumulate uremic toxins in the body, potentially require dialysis, and can eventually develop cardiovascular disease. CKD incidence has increased worldwide, and preventing CKD progression is one of the most important goals in clinical treatment. In this study, we conducted a series of in vitro and in vivo experiments and employed a metabolomics approach to investigate CKD. Our results demonstrated that ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a major transporter of the uremic toxin indoxyl sulfate. ABCG2 regulates the pathophysiological excretion of indoxyl sulfate and strongly affects CKD survival rates. Our study is the first to report ABCG2 as a physiological exporter of indoxyl sulfate and identify ABCG2 as a crucial factor influencing CKD progression, consistent with the observed association between ABCG2 function and age of dialysis onset in humans. The above findings provided valuable knowledge on the complex regulatory mechanisms that regulate the transport of uremic toxins in our body and serve as a basis for preventive and individualized treatment of CKD.

A bstract We report a new measurement of the e + e − → ϒ( nS ) π + π − ( n = 1 , 2 , 3) cross sections at energies from 10 . 52 to 11 . 02 GeV using data collected with the Belle detector at the KEKB asymmetric-energy e + e − collider. We observe a new structure in the energy dependence of the cross sections; if described by a Breit-Wigner function its mass and width are found to be M = 10752.7 ± 5.9 − 1.1 + 0.7 MeV / c 2 and Γ = 35.5 − 11.3 − 3.3 + 17.6 + 3.9 MeV, where the first error is statistical and the second is systematic. The global significance of the new structure including systematic uncertainty is 5.2 standard deviations. We also find evidence for the e + e − → ϒ (1 S ) π + π − process at the energy 10 . 52 GeV, which is below the B B ¯ threshold.

Background: Although multidrug resistance protein 2 (MRP2) confers chemoresistance in some cancer types, its implication on oesophageal squamous cell carcinoma (ESCC) remains unclear. Methods: We evaluated MRP2 expression by immunohistochemistry and RT–PCR using 81 resected specimens from ESCC patients who did or did not receive neo-adjuvant chemotherapy (NACT), including 5-fluorouracil, doxorubicin, and cisplatin (CDDP). Correlation between MRP2 expression and response to chemotherapy was also examined in 42 pre-therapeutic biopsy samples and eight ESCC cell lines. Results: MRP2-positive immunostaining was more frequently observed in ESCCs with NACT than in those without NACT (27.3 vs 5.4%). The MRP2-positive patients showed poorer prognosis than MRP2-negative patients (5-year survival rate, 25.6 vs 55.7%). Concordantly, ESCC with NACT showed 2.1-fold higher mRNA expression of MRP2 than those without NACT ( P =0.0350). In pre-therapeutic biopsy samples of patients with NACT, non-responders showed 2.9-fold higher mRNA expression of MRP2 than responders ( P =0.0035). Among the panel of ESCC cell lines, TE14 showed the highest MRP2 mRNA expression along with the strongest resistance to CDDP. Inhibition of MRP2 expression by small-interfering RNA reduced chemoresistance to CDDP. Conclusion: Our data suggested that MRP2 is one of molecules, which regulate the sensitivity to chemotherapy including CDDP in advanced ESCC patients.

Background: Circulating tumour DNA (ctDNA) is an emerging candidate biomarker for malignancies and may be useful for monitoring the disease status of gastric cancer. Methods: We performed targeted deep sequencing of plasma cell-free DNA (cfDNA) by massively parallel sequencing in patients with tumours harbouring TP53 mutations. The quantitative values of TP53 -ctDNA during the clinical course were compared with the tumour status. Results: Three out of ten patients with TP53 mutations in primary tumours showed detectable TP53 mutation levels in preoperative cfDNA. Although the cfDNA concentrations were not always reflective of the disease course, the ctDNA fraction correlated with the disease status. Conclusions: ctDNA may serve as a useful biomarker to monitor gastric cancer progression and residual disease.

Background: CD133 and CD44 are putative cancer stem cell (CSC) markers in colorectal cancer (CRC). However, their clinical significance is currently unclear. Here, we evaluated primary CRC cell isolates to determine the significance of several CSC markers, including CD133 and CD44, as predictors of tumourigenesis and prognosis. Methods: CD133- and CD44-positive cells from fresh clinical samples of 77 CRCs were selected by flow cytometric sorting and evaluated for tumourigenicity following subcutaneous transplantation into NOD/SCID mice. Cancer stem cell marker expression was examined in both xenografts and a complementary DNA library compiled from 167 CRC patient samples. Results: CD44 + , CD133 + and CD133 + CD44 + sub-populations were significantly more tumourigenic than the total cell population. The clinical samples expressed several transcript variants of CD44. Variant 2 was specifically overexpressed in both primary tumours and xenografts in comparison with the normal mucosa. A prognostic assay using qRT–PCR showed that the CD44v2 high group ( n =84, 5-year survival rate (5-OS): 0.74) had a significantly worse prognosis ( P =0.041) than the CD44v2 low group ( n =83, 5-OS: 0.88). Conclusions: CD44 is an important CSC marker in CRC patients. Furthermore, CRC patients with high expression of CD44v2 have a poorer prognosis than patients with other CD44 variants.

Many individuals with obstructive airway disease (OAD), including chronic obstructive pulmonary disease (COPD) and asthma, remain undiagnosed, despite the potential for reducing disease burden through early detection and treatment. OCEAN aimed to determine the prevalence of, and characteristics associated with, impaired lung function in a Japanese population, with the goal of improving strategies for early OAD detection. OCEAN was an observational, cross-sectional study in sequentially recruited Japanese individuals ≥40 years of age undergoing routine health examinations. Participants completed screening questionnaires and spirometry testing. Airflow limitation was defined as forced expiratory volume in 1 second/forced vital capacity (FEV /FVC) <0.7 by pre-bronchodilator spirometry. Preserved ratio impaired spirometry (PRISm) was defined as FEV /FVC ≥0.7 and FEV <80% predicted. The primary endpoint was prevalence of spirometry-based airflow limitation and PRISm. The characteristics of study participants were reported as secondary endpoints. Overall, 2518 individuals were included; 79% were <60 years of age (mean 52.0 years). Airflow limitation and PRISm were observed in 52 (2.1%) and 420 (16.7%) participants, respectively. FEV in the PRISm group was between that in the no airflow limitation/PRISm and airflow limitation groups, FVC was similar in the PRISm and airflow limitation groups. The PRISm group had higher mean body mass index and a higher proportion of comorbid metabolic disease compared with the airflow limitation group. The prevalence of airflow limitation and PRISm was highest among current smokers (3.9% and 21.3%, respectively) versus former or never smokers. A significant proportion of Japanese individuals <60 years of age attending their annual health examination had impaired lung function (airflow limitation and PRISm); prevalence was highest among current smokers. These findings support screening of current or former smokers ≥40 years of age using patient-reported questionnaires to inform the need for spirometry to confirm an OAD diagnosis.

Different molecular targeted therapies affect immune cell phenotypes and signals differently due to their modes of action[1]. Theoretically, it is possible to use these drugs based on a stratification of rheumatoid arthritis (RA) patients. However, despite innovations in the treatment of RA, precision medicine with the development and application of personalized treatments by molecular targeted therapy is still far from its achievement. At least, precision medicine by a single biomarker is not known to be possible[2]. To investigate the possibility of precision medicine based on the immune phenotype of peripheral blood, we stratified RA patients by comprehensive flow cytometric immunophenotyping and evaluated the response to targeted therapy. This study enrolled 96 healthy controls (HC) and 533 bio-naive RA patients with moderate to severe disease activity acording to CDAI. The Human Immunology Project, a NIH/FOCIS-developed flow cytometric immune cell profiling method on T cells, B cells, NK cells, dendritic cells, and monocytes, was used to stratify the patients using cluster analysis (Ward and UMAP methods). Inverse probability weighting with propensity scores was used to control for patient characteristics and CDAI was used to measure remission achievement after 6 months of targeted molecular therapy for each stratified subgroup. The mean age was 63.5 years old, and the disease activity was CDAI 27.1. In comparison to HC, CD4 T cell differentiation was noticeably affected in RA patients, with elevated effector T cells and effector memory T cells re-expressing CD45RA (TEMRA). Meanwhile, there was no meaningful change in the proportion of Th1, Th17, Treg, and Tfh cells as well as B cells, NK cells, monocytes, and dendritic cells subpopulations. Cluster analysis of the immunophenotypes revealed five main groups of RA patients, with roughly equal numbers of patients in each group. When dimension reduction of their immunophenotypes was performed by UMAP, these groups were clearly separated (Figure 1). One of the five groups had an immunophenotype almost identical to that of healthy controls (cluster 1), two groups were moderately different (clusters 2 and 3), and the last two groups had phenotypes characteristic of RA with little overlap with healthy controls (clusters 4 and 5). These 2 groups were accompanied by a marked increase in TEMRA with increased effector memory T cells (cluster 4) and with increased Th1 (cluster 5). There were few differences in baseline clinical findings such as disease activity and ACPA/RF among the groups. Of note, the clinical efficacy of each targeted therapy was statistically different in each group. In the group with immunophenotypes similar to those of healthy subjects (cluster 1) and the moderately different group (cluster 2), JAK inhibitors and IL-6R antibody treatment were effective, while TNF inhibitors were effective in another moderately different group (cluster 3). CTLA4-Ig and TNF inhibitors were effective in the two groups with phenotypes characteristic of RA (clusters 4 and 5). Immunophenotyping after treatment revealed that the first three groups became comparable to the HC phenotype. However, TEMRA dominancy groups (clusters 4 and 5) remained elevated in TEMRA. Interestingly, CTLA4-Ig decreased the proportion of TEMRA. [Display omitted] RA patients can be stratified into five groups, each of which benefited from different molecular targeted therapies. The increase in CD4 TEMRA in peripheral blood was significant in RA patients, and the proportion was virtually unchanged with treatment. Thus, CD4 TEMRA could be the pathogenic memory cells in RA. Our results may be a milestone in achieving precision medicine. [1]Nakayamada S, Kubo S, et al. Differential effects of biological DMARDs on peripheral immune cell phenotypes in patients with rheumatoid arthritis. Rheumatology (Oxford) 2018; 57(1): 164-74. [2]Lin CMA, et al. Precision medicine: the precision gap in rheumatic disease. Nat Rev Rheumatol 2022; 18(12): 725-33. The author thanks Ms. N. Sakaguchi for the excellent technical assistance, and thanks all medical staff at all participating medical facilities for providing the data. Satoshi Kubo Speakers bureau: Eli Lilly, Bristol-Myers, and GlaxoSmithKline, Grant/research support from: Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Shingo Nakayamada Speakers bureau: Bristol-Myers, AstraZeneca, Pfizer, GlaxoSmithKline, Astellas, Asahi-Kasei, Sanofi, Abbvie, Eisai, Chugai, Gilead, Boehringer Ingelheim, Grant/research support from: Mitsubishi-Tanabe, Yusuke Miyazaki Speakers bureau: Eli Lilly, GlaxoSmithKline, Grant/research support from: GlaxoSmithKline, YUYA FUJITA: None declared, Ryuichiro Kanda: None declared, Katsuhide Kusaka: None declared, Yasuyuki Todoroki: None declared, Hiroko Miyata: None declared, Koshiro Sonomoto: None declared, Shunsuke Fukuyo: None declared, Kentaro Hanami: None declared, Yoshiya Tanaka Speakers bureau: Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, Grant/research support from: Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Behringer-Ingelheim.

Background Lateral lymph node dissection (LLND) is an important surgical procedure in the treatment of lower rectal cancer (RC). However, limited data are available regarding the learning curve for robot-assisted LLND (RA-LLND). This study aimed to evaluate the learning curve for prophylactic bilateral RA-LLND for lower RC. Methods We retrospectively analyzed 58 consecutive patients with clinical stage II/III lower RC who had undergone prophylactic bilateral RA-LLND between July 2020 and June 2024. Cumulative sum (CUSUM) analysis was used to evaluate the learning curve for bilateral RA-LLND operative time. Results The mean age of patients was 61.5 years, and mean body mass index was 23.4 kg/m 2 . The proportion of neoadjuvant therapy was 8.6%. Mean prophylactic bilateral RA-LLND operative time was 173.7 min. CUSUM analysis divided the learning curve for prophylactic bilateral RA-LLND operative time into three phases: initial learning phase (20 cases); competence phase (16 cases); and master/proficiency phase (subsequent cases). Mastery of surgical technique was achieved after performing the 36th case. Comparisons of surgical outcomes in terms of operative parameters and complications were made between phases 1 and 2 combined and phase 3. A significant reduction in mean prophylactic bilateral RA-LLND operative time was observed between phases 1 and 2 compared with phase 3 ( P  < 0.01). Mean blood loss was decreased in phase 3 (40.5 ml) compared to phases 1 and 2 combined (148.2 ml, P  < 0.01). The frequencies of overall postoperative complications directly related to LLND and urinary dysfunction were significantly reduced in phase 3 compared to phases 1 and 2 combined ( P  = 0.04, and P  = 0.02, respectively). Conclusions The three phases identified by CUSUM analysis represented characteristics of the learning curve for prophylactic bilateral RA-LLND. These data suggest that 20 cases are required for the early stage of the learning curve, whereas mastery level could be achieved after 36 cases.

Gene expression profiling is a valuable tool for identifying differentially expressed genes in studies of disease subtype and patient outcome for various cancers. However, it remains difficult to assign biological significance to the vast number of genes. There is an increasing awareness of gene expression profile as an important part of the contextual molecular network at play in complex biological processes such as cancer initiation and progression. This study analysed the transcriptional profiles commonly activated at different stages of gastric cancers using an integrated approach combining gene expression profiling of 222 human tissues and gene regulatory dynamic mapping. We focused on an inferred core network with CDKN1A ( p21 WAF1/CIP1 ) as the hub, and extracted seven candidates for gastric carcinogenesis ( MMP7, SPARC, SOD2, INHBA, IGFBP7, NEK6, LUM ). They were classified into two groups based on the correlation between expression level and stage. The seven genes were commonly activated and their expression levels tended to increase as disease progressed. NEK6 and INHBA are particularly promising candidate genes overexpressed at the protein level, as confirmed by immunohistochemistry and western blotting. This integrated approach could help to identify candidate players in gastric carcinogenesis and progression. These genes are potential markers of gastric cancer regardless of stage.