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In human inflammatory sites, PD-1 hi CXCR5 − CD4 + T cells are involved in the formation of ectopic lymphoid-like structures (ELSs) by the secretion of chemokine CXCL13, but how the transcription of CXCL13 is regulated in CD4 + T cells is still unclear. Here we show that Sox4 is a key transcription factor for CXCL13 production in human CD4 + T cells under inflammatory conditions. In vitro TGF-β + , IL-2-neutralizing culture conditions give rise to PD-1 hi CXCR5 − CD4 + T cells that preferentially express CXCL13, and transcriptome analysis and lentiviral overexpression indicate Sox4 association with the CXCL13 transcription. In vivo, Sox4 is significantly upregulated in synovial CD4 + T cells, when compared with blood CD4 + T cells, from patients with rheumatoid arthritis (RA), and further correlates with ELS formation in RA synovium. Overall, our studies suggest that Sox4 contributes to CXCL13 production and ELS formation at inflammatory sites in humans. At inflammatory sites, ectopic lymphoid-like structures (ELS) can be induced through the function of chemokine CXCL13 produced by CD4 + T cells. Here the authors show that a transcription factor, Sox4, induces the expression of CXCL13 in CD4 T cells in vitro, and is associated with ELS formation in patients with rheumatoid arthritis.

Purpose This study evaluated the risk of medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer who received denosumab or zoledronic acid (ZA) for treating bone metastasis. Methods The medical records of patients were retrospectively reviewed. Patients who did not undergo a dental examination at baseline were excluded. The primary endpoint was a comparison of the risk of developing MRONJ between the denosumab and ZA groups. Propensity score matching was used to control for baseline differences between patient characteristics and compare outcomes for both groups. Results Among the 799 patients enrolled, 58 (7.3%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the ZA group (9.6% [39/406] vs. 4.8% [19/393], p  = 0.009). Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.65–5.25; p  < 0.001) and tooth extraction after starting ZA or denosumab (HR, 4.26; 95% CI, 2.38–7.44; p  < 0.001) were significant risk factors for MRONJ. Propensity score–matched analysis confirmed that the risk of developing MRONJ was significantly higher in the denosumab group than in the ZA group (HR, 2.34; 95% CI, 1.17–5.01; p  = 0.016). Conclusion The results of this study suggest that denosumab poses a significant risk for developing MRONJ in patients treated for bone metastasis, and thus these patients require close monitoring.

PurposeSwitch from zoledronic acid (ZA) to denosumab may increase the risk of medication-related osteonecrosis of the jaw (MRONJ) owing to the additive effect of denosumab on the jawbone and residual ZA activities. We evaluated the risk of developing MRONJ in patients who received ZA, denosumab, or ZA-to-denosumab for the treatment of bone metastases.MethodsThe medical charts of patients with cancer who received denosumab or ZA for bone metastases were retrospectively reviewed. Patients who did not undergo a dental examination at baseline were excluded. Primary endpoint was the evaluation of the risk of developing MRONJ in the ZA-to-denosumab group. Secondary endpoints were probability of MRONJ and the relationship between risk factors and the time to the development of MRONJ.ResultsAmong the 795 patients included in this study, 65 (8.2%) developed MRONJ. The incidence of MRONJ was significantly higher in the ZA-to-denosumab group than in the ZA group [7/43 (16.3%) vs. 19/350 (5.4%), p = 0.007]. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment [hazard ratio (HR), 2.41; 95% confidence interval (CI), 1.37–4.39; p = 0.002], ZA-to-denosumab treatment (HR, 4.36; 95% CI, 1.63–10.54, p = 0.005), tooth extraction after starting ZA or denosumab (HR, 4.86; 95% CI, 2.75–8.36; p < 0.001), and concomitant use of antiangiogenic agents (HR, 1.78; 95% CI, 1.06–2.96; p = 0.030) were significant risk factors for MRONJ.ConclusionOur results suggest that switching from ZA to denosumab significantly increases the risk for developing MRONJ in patients with bone metastases.

A pixel in an uncooled microbolometer terahertz (THz) focal plane array (FPA) has a suspended structure above read-out integrated circuit (ROIC) substrate. An optical cavity structure is formed between a thin metallic layer deposited on the suspended structure and a thick metallic layer deposited on the ROIC surface. The geometrical optical cavity length for our previous pixel structure, 3–4 μm, is extended three times, so that responsivity can be increased in the sub-THz region. This modification is carried out by depositing a thick SiN layer on the thick metallic layer. The modified pixel structure is applied to 640 × 480 and 320 × 240 THz-FPAs with 23.5 μm pixel pitch. Minimum detectable powers per pixel (MDP) are evaluated for these FPAs at 4.3, 2.5, 0.6, and 0.5 THz, and the MDP values are found to be improved by a factor of ten at 0.6 and 0.5 THz. The MDP values of the THz-FPAs developed in this work are compared with those of other THz detectors, such as uncooled antenna-coupled CMOS (complimentary metal-oxide semiconductor) THz-FPAs and cooled bolometer arrays. It is found that our THz-FPAs are more sensitive in the sub-THz region than the CMOS THz-FPAs, while they are much less sensitive than the cooled bolometer arrays. These THz-FPAs are incorporated into a 640 × 480 THz camera and 320 × 240 THz camera, and imaging equipment is developed. The equipment consists of a linearly polarized sub-THz source, a collimator lens, a beam homogenizer, two wire grids, a quarter-wave plate, and two THz cameras, and sub-THz images are demonstrated. It should be mentioned for the equipment that imaging of transmission and reflection is realized by moving only the quarter-wave plate, and the reflection image is taken along a direction normal to a sample surface so that the reflection image is hardly deformed.

We demonstrate a cladding-pumped seven-core erbium-doped fibre amplifier. A developed multimode pump light coupler enables the cladding pump. We measure amplification characteristics of all the seven cores and obtain gain of >14dB, noise figure of <9dB in C-band. Total crosstalk for the centre core is -32.7 dB.

BackgroundHyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is not well-characterized in patients with advanced gastric cancer (AGC).MethodsTotal 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as ≥ two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.ResultsThirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached, P < 0.001; median PFS: 0.7 months vs. 2.4 months, P < 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.ConclusionsHPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.

Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1 + CD8 + T cells relative to that of PD-1 + regulatory T (T reg ) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8 + T cells and T reg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1 + CD8 + T cells and enhanced PD-1 + T reg cell–mediated immunosuppression. A profound reactivation of effector PD-1 + CD8 + T cells rather than PD-1 + T reg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies. Checkpoint blockade is effective in only a subset of patients; therefore, biomarkers that can predict efficacy would be clinically highly valuable. Nishkawa and colleagues develop a biomarker based on PD-1 positivity of effector and regulatory T cells in the tumor microenvironment that accurately predicts the effectiveness of checkpoint blockade in patients.

Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population. TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m2 twice daily on days 1–5 and days 8–12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT02500043. The trial, including follow-up of all participants, has been completed. Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8–6·2) in the trifluridine/tipiracil group and 3·6 months (3·1–4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56–0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group). Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need. Taiho Oncology and Taiho Pharmaceutical.

Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody–drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive gastric or gastro-oesophageal junction cancer who received trastuzumab deruxtecan at the recommended doses for expansion. This was an open-label, dose-escalation and dose-expansion phase 1 trial done at eight hospitals and clinics in the USA and six in Japan. Eligible patients were at least 18 years old in the USA and at least 20 years old in Japan and had advanced solid tumours (regardless of HER2 expression in dose escalation or HER2 expression or mutation in dose expansion). The recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan were administered intravenously to patients once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. In this Article, all patients with HER2-positive gastric or gastro-oesophageal junction cancer with previous trastuzumab treatment who received trastuzumab deruxtecan were analysed together. The primary endpoints of the study were safety and preliminary activity (proportion of patients who achieved an objective response as assessed by the investigators). The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion, and for whom both baseline and post-treatment activity data were available. The safety analysis set included all patients who received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. Enrolment for patients with gastric or gastro-oesophageal junction cancer has completed. This trial is registered at ClinicalTrials.gov, number NCT02564900, and ClinicalTrials.jp, number JapicCTI-152978. Between Aug 28, 2015, and Aug 10, 2018, 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer received at least one dose of trastuzumab deruxtecan at the recommended doses for expansion. All patients had at least one treatment-emergent adverse event. The most frequent grade 3 or worse treatment-emergent adverse events included anaemia (13 [30%]) and decreases in neutrophil (nine [20%]), platelet (eight [18%]), and white blood cell (seven [16%]) counts. Serious treatment-emergent adverse events occurred in 11 (25%) patients. There were four pneumonitis cases (three grade 2 and one grade 3). There were no drug-related deaths due to treatment-emergent adverse events. 19 (43·2%; 95% CI 28·3–59·0) of 44 patients had a confirmed objective response. Trastuzumab deruxtecan had a manageable safety profile and showed preliminary activity in heavily pretreated patients with HER2-positive gastric or gastro-oesophageal junction cancer. These results support further investigation of trastuzumab deruxtecan for HER2-positive gastric or gastro-oesophageal junction cancer post-trastuzumab. Daiichi Sankyo Co, Ltd.

This paper proposes a method for detecting and recovering from immobilized states in mobile robots operating in outdoor environments. In recent years, the demand for autonomous mobile robots capable of navigating outdoor environments has been increasing. In particular, the delivery industry anticipates replacing human-driven transport with robots to cover the section between pickup and delivery points. However, achieving autonomous navigation in outdoor environments is significantly more challenging than in indoor settings as robots must coexist with pedestrians and vehicles while complying with traffic regulations, such as obeying pedestrian signals. In this study, we aimed to develop a mobile robot capable of autonomous navigation from a starting point to a target point in a real outdoor environment. We implemented a self-position estimation method using scan matching between the real-time point-cloud data and a loop-closure-corrected three-dimensional point-cloud map. This was integrated with a path-planning system that combines detection and recovery of a robot from immobilized states, prioritized velocity control, and event-based waypoints, enabling safe autonomous navigation that complies with traffic rules in outdoor environments. In addition, we implemented a control architecture that prioritizes asynchronous velocity commands sent in parallel. To enhance the autonomy of mobile robots, a method was proposed in this study in which the robot detects obstacles and recovers from an immobilized state when it becomes stuck after colliding with these obstacles that cannot be captured by obstacle sensors during navigation. To evaluate the effectiveness of the proposed method, we conducted experiments using an autonomous mobile robot developed in this study to recover it from being stuck on a low step that the obstacle sensor could not detect. In the final run in the Tsukuba Challenge 2024, the system successfully performed four tasks of signal recognition and crossings and completed visits to both pickup and delivery destinations. The mobile robot also completed a 2 km course and was awarded the Tsukuba Mayor’s Award.