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Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.

ObjectivesTo evaluate through a systematic review of the literature the association between the use of biological disease-modifying antirheumatic drugs (bDMARDs) and surgical site infection or wound healing delay after orthopedic surgery in patients with rheumatoid arthritis (RA).MethodsA systematic review was performed of articles indexed in the Cochrane Library, PubMed, and Web of Science from 1992 to 2012. The search aimed to identify studies describing surgical site infection (SSI) or wound healing delay in patients with RA treated with or without bDMARDs. Articles fulfilling the predefined inclusion criteria were reviewed systematically and their quality appraised.ResultsThere was no Cochrane review on this subject. We found 75 articles through specific searches of PubMed and Web of Science, and hand searching. After inclusion and exclusion by full-text review, 10 articles were found for SSI, and five articles for delayed wound healing. The use of bDMARDs appeared to increase the rate of SSI slightly, especially in large joint-replacement surgery. Delayed wound healing was not increased by the use of bDMARDs. However, the definitions of SSI and delayed wound healing varied between the reviewed articles. Most of the articles focused on tumor necrosis factor-a inhibitors.ConclusionsbDMARDs slightly increase the relative risk of SSI but not that of delayed wound healing after orthopedic surgery and should be used with appropriate caution.Disclosure of InterestNone declared

Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide produced greater reductions in symptoms, physical limitations, and body weight than placebo at 1 year.

Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase and generates phosphatidylinositol-3,4,5-trisphosphate (PI(3, 4, 5)P3). PI(3, 4, 5)P3 is a second messenger essential for the translocation of Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (PDK) 1 and PDK2. Activation of Akt plays a pivotal role in fundamental cellular functions such as cell proliferation and survival by phosphorylating a variety of substrates. In recent years, it has been reported that alterations to the PI3K-Akt signaling pathway are frequent in human cancer. Constitutive activation of the PI3K-Akt pathway occurs due to amplification of the PIK3C gene encoding PI3K or the Akt gene, or as a result of mutations in components of the pathway, for example PTEN (phosphatase and tensin homologue deleted on chromosome 10), which inhibit the activation of Akt. Several small molecules designed to specifically target PI3K-Akt have been developed, and induced cell cycle arrest or apoptosis in human cancer cells in vitro and in vivo . Moreover, the combination of an inhibitor with various cytotoxic agents enhances the anti-tumor efficacy. Therefore, specific inhibition of the activation of Akt may be a valid approach to treating human malignancies and overcoming the resistance of cancer cells to radiation or chemotherapy.

Thermoelectric effects have been applied to power generators and temperature sensors that convert waste heat into electricity. The effects, however, have been limited to electrons to occur, and inevitably disappear at low temperatures due to electronic entropy quenching. Here, we report thermoelectric generation caused by nuclear spins in a solid: nuclear-spin Seebeck effect. The sample is a magnetically ordered material MnCO 3 having a large nuclear spin ( I  = 5/2) of 55 Mn nuclei and strong hyperfine coupling, with a Pt contact. In the system, we observe low-temperature thermoelectric signals down to 100 mK due to nuclear-spin excitation. Our theoretical calculation in which interfacial Korringa process is taken into consideration quantitatively reproduces the results. The nuclear thermoelectric effect demonstrated here offers a way for exploring thermoelectric science and technologies at ultralow temperatures. Thermoelectric effects are limited to electrons to occur, and disappear at low temperatures due to electronic entropy quenching. Here, the authors report thermoelectric generation caused by nuclear spins down to 100 mK due to nuclear-spin excitation in a magnetically ordered material MnCO 3 .

Abstract The performance of superconducting radio-frequency (SRF) cavities depends on the condition of the niobium surface. Recently, various heat treatment methods have been investigated to achieve an unprecedentedly high quality factor (Q) and high accelerating field (E). We report the influence of a new baking process called furnace baking on the Q–E behavior of 1.3 GHz SRF cavities. Furnace baking is performed as the final step of the cavity surface treatment; the cavities are heated in a vacuum furnace for 3 h, followed by high-pressure rinsing and radio-frequency measurement. This method is simpler and potentially more reliable than previously reported heat treatment methods, and it is therefore easier to apply to the SRF cavities. We find that the quality factor is increased after furnace baking at temperatures ranging from 300 $^\\circ$C to 400 $^\\circ$C, while a strong decrease in the quality factor at for a high accelerating field is observed after furnace baking at temperatures ranging from 600 $^\\circ$C to 800 $^\\circ$C. We find significant differences in the surface resistance for various processing temperatures.

Background: MicroRNAs (miRNAs) are involved in essential biological activities, and have been reported to exhibit differential expression profiles in various cancers. Our previous study demonstrated that intercellular adhesion molecule-2 ( ICAM2 ) inhibition induces radiosensitisation in oral squamous cell carcinoma (OSCC) cells. Thus, we hypothesised that certain miRNAs play crucial roles in radioresistance in OSCC by regulating ICAM2 expression. Methods: Because predicted target gene analyses revealed that microRNA-125b (miR-125b) potentially regulates ICAM2 mRNA expression, we examined the association between miR-125b and radioresistance. The expression of miR-125b was investigated by real-time quantitative reverse transcriptase–PCR. For a functional analysis, miR-125b was transfected to OSCC-derived cells. Results: A downregulated expression of miR-125b was found in OSCC-derived cell lines and OSCC samples. The miR-125b-transfected cells showed a decreased proliferation rate, enhanced radiosensitivity to X-ray irradiation and diminished ICAM2 mRNA expression. Moreover, miR-125b expression correlated with OSCC tumour staging and survival. Conclusion: These findings suggested that the downregulated miR-125b expression was associated with proliferation and radioresistance mechanisms, probably through ICAM2 signalling. Thus, controlling the expression or activity of miR-125b might contribute to suppressing proliferation and overcoming radioresistance in OSCC.

Aims/hypothesis The aim of the study was to clarify whether a therapeutic intervention focused on lifestyle modification affected the incidence of vascular complications in patients with established diabetes. Methods A total of 2,033 eligible Japanese men and women aged 40-70 years with type 2 diabetes from 59 institutes were randomised to a conventional treatment group (CON), which continued to receive the usual care, and a lifestyle intervention group (INT), which received education on lifestyle modification regarding dietary habits, physical activities and adherence to treatment by telephone counselling and at each outpatient clinic visit, in addition to the usual care. Randomisation and open-label allocation were done by a central computer system. Primary analysis regarding measurements of control status and occurrence of macro- and microvascular complications was based on 1,304 participants followed for an 8 year period. Results Although status of control of most classic cardiovascular risk factors, including body weight, glycaemia, serum lipids and BP, did not differ between groups during the study period, the incidence of stroke in the INT group (5.48/1,000 patient-years) was significantly lower than in the CON group (9.52/1,000 patient-years) by Kaplan-Meier analysis (p = 0.02 by logrank test) and by multivariate Cox analysis (HR 0.62, 95% CI 0.39-0.98, p = 0.04). The incidence of CHD, retinopathy and nephropathy did not differ significantly between groups. Lipoprotein(a) was another significant independent risk factor for stroke. Conclusions/interpretation These findings suggest that lifestyle modification had limited effects on most typical control variables, but did have a significant effect on stroke incidence in patients with established type 2 diabetes. Clinical Trial Registration: UMIN-CTR C000000222 Funding: The Ministry of Health, Labour and Welfare, Japan

BackgroundThe factors contributing to the efficacy of abatacept in patients with rheumatoid arthritis (RA) remain unknown.ObjectivesWe aimed to identify cellular, transcriptomic, and proteomic features that predict responses or resistance to abatacept.MethodsBlood samples were collected from 22 RA patients treated with abatacept at the initiation and after three months of treatment. Response to treatment was defined based on the EULAR response criteria, and seven patients were classified as responders and the others as non-responders. We quantified gene expression levels in peripheral blood mononuclear cells (PBMCs) by RNA-Seq, 67 plasma protein levels by multiplexed immunoassay, and the expression of surface molecules (CD3, 19, and 56) by flow cytometry, in addition to collecting clinical characteristics. Additionally, three gene expression data sets concerning the efficacy of abatacept[1–3], comprising 37 responders and 50 non-responders in total, were used to replicate the current study. We compared the gene expression of responders versus non-responders in each set and meta-analyzed the results.ResultsAmong the clinical characteristics, the number of monocytes was significantly higher in the non-responders before treatment (p = 0.01). Regarding the transcriptome data, we found 952 differentially expressed genes (DEGs) between the responders and the non-responders before treatment initiation. A cell-type enrichment analysis showed that the DEGs were enriched in monocytes (p = 8.7 × 10-212, Figure 1A). Additionally, gene set enrichment analysis showed enrichment in the gene module, including MYD88 and TIRAP, with the strongest significance among all of the pathways tested. When we estimated the expression of MYD88 and TIRAP in monocytes by deconvolution analysis, the non-responders had higher expression before treatment initiation (p = 0.04 and 0.03, respectively). Among the 67 protein levels, two exhibited a correlation with the expression of the module (p < 0.05). Of these, hepatocyte growth factor (HGF), which is produced by monocytes, was present at significantly higher concentrations in non-responders before treatment (p = 0.02). The analysis of the replication sets identified 1,695 DEGs. These were also enriched for the genes expressed in monocytes (p = 2.9 × 10-90, Figure 1B) but not for the module detected in the current study. Among the DEGs, those expressed in monocytes were enriched for the genes involved in the aerobic electron transport system in mitochondria based on gene set enrichment analysis.ConclusionMonocyte-derived transcriptomic features before treatment underlay the differences in abatacept efficacy. The pathway activated in monocytes was the MYD88/TIRAP-HGF axis in the current study, but that pathway in the replication set was the aerobic electron transport system. Overall, our results highlight the contribution of monocytes as the cells responsible for abatacept-treatment resistance and the heterogeneity of activated pathways within them.Figure 1.Results of cell type enrichment analysis of differentially expressed genes (DEGs) concerning response to abatacept.[Figure omitted. See PDF]References[1]Nakamura, S. et al. Identification of baseline gene expression signatures predicting therapeutic responses to three biologic agents in rheumatoid arthritis: a retrospective observational study. Arthritis Res. Ther. 18, (2016).[2]Triaille, C. et al. Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue. Front. Immunol. 12, (2021).[3]Derambure, C. et al. Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis. Arthritis Res. Ther. 19, (2017).AcknowledgementsThis study received funding from Astellas Pharma Inc.Disclosure of InterestsTakeshi Iwasaki: None declared, Ryu Watanabe Speakers bureau: Asahi Kasei, Chugai, Eli Lilly, GSK, and Sanofi, Grant/research support from: AbbVie, Hiromu Ito Grant/research support from: Bristol Myers, Takayuki Fujii Speakers bureau: Asahi Kasei Pharma, Abbvie, Jansen, Tanabe Mitsubishi Pharma, and Eisai Co LTD, Koichiro Ohmura: None declared, Hiroyuki Yoshitomi: None declared, Koichi Murata Speakers bureau: AbbVie GK, Eisai Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd., and Asahi Kasei Pharma Corp., Grant/research support from: Daiichi Sankyo Co. Ltd, Kosaku Murakami Speakers bureau: Bristol Myers, Ono Pharmaceutical, Akira Onishi Speakers bureau: Pfizer Inc., Bristol-Myers Squibb., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Ono Pharmaceutical Co., UCB Japan Co., Mitsubishi Tanabe Pharma Co., Eisai Co. Ltd., Abbvie Inc., Takeda Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd., Grant/research support from: Pfizer Inc., Bristol-Myers Squibb., Advantest, Ayumi, and the Health Care Science Institute., Employee of: Department of Advanced Medicine for Rheumatic Diseases is supported by Nagahama City, Shiga, Japan, Toyooka City, Hyogo, Japan, and five pharmaceutical companies (Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co. Ltd, UCB Japan Co. Ltd, AYUMI Pharmaceutical Co., and Asahi Kasei Pharma Corp.). It is also supported by grants from Daiichi Sankyo Co. Ltd. Above-mentioned pharmaceutical companies were not involved in the study design, data collection and analysis, manuscript writing, and manuscript submission., Masao Tanaka Speakers bureau: AbbVie GK, Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Pfizer Inc., Tanabe Mitsubishi Pharma Corp., UCB Japan Co., Ltd.., Grant/research support from: AbbVie GK, Eisai Co., Ltd., Kyowa Kirin Co., Ltd. Taisho Pharmaceutical Co., Ltd. Teijin Pharma, Ltd.., Employee of: M.T. belongs to the department financially supported by two local governments in Japan (Nagahama City, Shiga and Toyooka City, Hyogo) and five pharmaceutical companies (Tanabe Mitsubishi Pharma Corp., Chugai Pharmaceutical Co., Ltd., Ayumi Pharmaceutical Corp., Asahi Kasei Pharma Corp. and UCB Japan Co., Ltd.)., Shuichi Matsuda: None declared, Fumihiko Matsuda: None declared, Akio Morinobu Speakers bureau: AbbVie G.K., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Eisai Co. Ltd., Pfizer Inc., Bristol-Myers Squibb., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., and Gilead Sciences Japan., Grant/research support from: AbbVie G.K., Asahi Kasei Pharma Corp., Chugai Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co. Taisho Pharmaceutical Co., Ltd.,and Eisai Co. Ltd. outside the work., Motomu Hashimoto Speakers bureau: Eli Lilly, Chugai, Mitsubishi Tanabe, Bristol Myers, Eisai, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Bristol Myers, Eisai, Daiichi Sankyo, Eli Lilly, Novartis.

Background Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures. This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA. Methods We conducted a prospective longitudinal study in patients with RA. In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm. The BMD in these three regions was reassessed in 2014. We performed multivariate linear regression analysis to identify those factors associated with BMD change. Results The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32–85), 21.3 (12.3–30.0), and 3.2 (0.1–5.9), respectively. Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively. Conclusions Predictive biomarkers for BMD change in RA patients differ at each anatomical site. Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.