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The reduction behavior of the surface oxide on Cu particles under a reducing gas atmosphere was investigated for a pressureless sinter joining. We conducted x-ray thermodiffraction analysis and simultaneous thermogravimetry, differential thermal analysis, and mass spectroscopy (TG–DTA–MS) under a reducing atmosphere to investigate the reduction and subsequent sintering behaviors of copper particles at different oxygen concentrations. The shear strength of the pressureless sinter joint decreased with increasing oxygen concentration. The thermodiffraction results revealed that the reduction onset of Cu2O started at the same temperature (220°C), whereas the reaction markedly persisted at higher oxygen concentrations. Cu sintering progressed significantly after the reduction due to generation of Cu nanoparticles. The TG–DTA–MS results indicated that H2O formation temperature associated with the reduction depends on the oxygen concentration, consistent with the thermodiffraction results. The surface oxides were found to play an important role in pressureless sinter joining via nanoparticle formation, while the presence of a large amount of oxide delayed the reduction and subsequent sintering.

Methotrexate (MTX)‐associated lymphoproliferative disorder (MTX‐LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its incidence, prognosis, and risk factors remain unclear. In this retrospective study, we evaluated the actual incidence, prognostic impact, and risk factors of MTX‐LPD. Of the 986 patients with RA treated with MTX, 90 patients experienced 95 new malignancies (NMs), with LPD as the most frequent in 26 patients. The cumulative LPD incidences were 1.3% and 4.7% at 5 and 10 years after MTX initiation, respectively. Among the 24 patients who discontinued MTX after developing LPD, 15 showed sustained regression, without difference in overall survival between patients with LPD and without NM. Inflammatory markers and absolute lymphocyte counts were not useful for early LPD development detection, but most of the patients with LPD had persistently elevated erythrocyte sedimentation ratios. Regarding concomitant drugs, tacrolimus increased the risk only if patients were not receiving biological disease‐modifying antirheumatic drugs (bDMARDs). bDMARDs did not increase the risk for any of the drugs or the number of classes used. The number of LPD cases was lower in patients with IL‐6A even after a long period after MTX, although with no statistically significant difference. Thus, approximately 1 in 20 patients with RA developed MTX‐LPD over the 10 years of MTX treatment, but it did not affect the survival of patients with RA. Tacrolimus increased the risk of developing LPD for certain patients and should be used with caution. The cumulative lymphoproliferative disorder (LPD) incidences were 1.3% and 4.7% at 5 and 10 years after methotrexate (MTX) initiation, respectively. Among the 24 LPD patients who discontinued MTX after developing LPD, 15 showed sustained regression.

INTRODUCTION: Signet ring cell carcinoma (SRC) of the gallbladder is a rare type of gallbladder cancer. We report a case of SRC of the gallbladder that was characterized by the diffuse presence of SRC on the gallbladder mucosa and diagnosed after cholecystectomy.CASE PRESENTATION: A 40-year-old man was referred to our department with upper abdominal pain and vomiting. Based on the findings of blood tests, computed tomography, and magnetic resonance imaging, acute cholecystitis was suspected, and emergency laparoscopic cholecystectomy was performed. Intraoperative findings showed mild inflammation. Although the tumor remained within the mucosa, tumor cell infiltration was suspected at the edge of cystic duct pathologically. Although additional endoscopic ultrasound and endoscopic retrograde cholangiography showed that horizontal extension into the residual cholecystic duct was suspected, there was no evidence of invasion into the common bile duct, lymph node metastasis, or distant metastasis. One and a half months after cholecystectomy, the patient underwent extrahepatic bile duct resection, lymph node dissection, and bile duct jejunal anastomosis. The postoperative course was uneventful, and the patient was discharged on the 10th postoperative day. Postoperative pathological analysis showed no obvious residual tumor tissue in the common bile duct or choledochal duct margins, and no metastasis in the submitted lymph nodes. Based on the above, a diagnosis of pT1aN0M0, pStage IA SRC was made. As no lymph node metastasis was observed, it was decided to follow up the patient without initiating postoperative chemotherapy, and the patient has been recurrence-free for 12 months after surgery.CONCLUSIONS: We describe an incidentally discovered case of intramucosal SRC diffusely spreading throughout the gallbladder after cholecystectomy for acute cholecystitis.

INTRODUCTION: Benign peritoneal multicystic mesothelioma (BPMM) is a rare mesothelial tumor with a high local recurrence rate and potential for malignant transformation. It predominantly affects women of reproductive age and is often associated with prior abdominal surgery or inflammation. Complete surgical resection is the standard treatment; however, tumor recurrence remains a concern. BPMM occurring outside the pelvis is extremely rare, and lesions requiring colectomy because of adherence to the gastrointestinal tract are infrequent.CASE PRESENTATION: A 63-year-old woman presented with right lower abdominal pain. She had undergone cervical cancer surgery 20 years ago. Contrast-enhanced CT and MRI revealed multiple well-defined cystic lesions adjacent to the ascending colon. Colonoscopy revealed extrinsic compression, and 18F-fluorodeoxyglucose (18F-FDG)-PET/CT showed no abnormal uptake of 18F-FDG. Given the patient’s symptoms, a laparoscopic right hemicolectomy with intracorporeal anastomosis was performed. The cystic lesions were firmly adhered to the appendix, cecum, and ascending colon, requiring en bloc resection. Histopathological and immunohistochemical analyses confirmed a diagnosis of BPMM. The patient had an uneventful postoperative course and was discharged on POD 7. No recurrence was observed during the 1-year follow-up period.CONCLUSIONS: A laparoscopic approach may be a feasible and safe option for complete resection of BPMM as it allows for magnified visualization and careful handling of cystic lesions, avoiding their intraoperative rupture. Given the high recurrence rate of BPMM, close postoperative surveillance is essential. This case illustrates the feasibility of laparoscopic resection for BPMM.

Neurotoxicity is one of the dangerous complications of chimeric antigen receptor (CAR) T-cell therapy, while its pathophysiology remains to be fully understood. Motor weakness not associated with central nervous system (CNS) toxicity has rarely been reported after CAR T-cell therapy. A 42-year-old female with a refractory diffuse large B-cell lymphoma received tisagenlecleucel (tisa-cel) and developed cytokine release syndrome (CRS) on day 3. She was treated with tocilizumab and methylprednisolone, which resolved CRS promptly. On day 7, motor weakness in lower extremities appeared, and she gradually became unable to walk without showing any other symptoms attributed to CNS disturbances. Whereas dexamethasone and tocilizumab were ineffective, neuropathy improved after high dose chemotherapy followed by autologous stem cell transplantation. Nerve conduction study (NCS) in lower extremities showed a decline in compound muscle action potential amplitude along with worsening of motor weakness, which was restored after improvement of symptoms. Based on symptoms and NCS, her motor weakness was thought to be due to disturbance in peripheral nerves. This study reports a patient who developed severe motor weakness due to disturbance in peripheral nerves after tisa-cel therapy. Neurotoxicity of non-CNS origin should also be noted in CAR T-cell therapy.

Background Gasping during resuscitation has been reported as a favorable factor for out-of-hospital cardiac arrest. We examined whether gasping during resuscitation is independently associated with favorable neurological outcomes in patients with refractory ventricular fibrillation or pulseless ventricular tachycardia (VF/pVT) undergoing extracorporeal cardiopulmonary resuscitation ECPR. Methods Data from a 2014 study on advanced cardiac life support for ventricular fibrillation with extracorporeal circulation in Japan (SAVE-J), which examined the efficacy of ECPR for refractory VF/pVT, were analyzed. The primary endpoint was survival with a 6-month favorable neurological outcome in patients who underwent ECPR with or without gasping during resuscitation. Multivariate logistic regression analysis was performed to evaluate the association between gasping and outcomes. Results Of the 454 patients included in the SAVE-J study, data from 212 patients were analyzed in this study after excluding those with missing information and those who did not undergo ECPR. Gasping has been observed in 47 patients during resuscitation; 11 (23.4%) had a favorable neurological outcome at 6 months. Multivariate logistic regression analysis showed that gasping during resuscitation was independently associated with a favorable neurological outcome (odds ratio [OR], 10.58 [95% confidence interval (CI) 3.22–34.74]). The adjusted OR for gasping during emergency medical service transport and on arrival at the hospital was 27.44 (95% CI 5.65–133.41). Conclusions Gasping during resuscitation is a favorable factor in patients with refractory VF/pVT. Patients with refractory VF/pVT with continuously preserved gasping during EMS transportation to the hospital are expected to have more favorable outcomes.

Obesity of children and adolescents (OCA) is often accompanied by metabolic syndrome (MetS), which often leads to adult obesity and subsequent complications, yet the entire pathophysiological response is not fully understood. The number and composition of circulating extracellular vesicles (EV) reflect overall patient condition; therefore, we investigated the pathophysiological condition of OCA, including MetS-associated dysmetabolism, using circulating EVs. In total, 107 children and adolescents with or without obesity (boys, n = 69; girls, n = 38; median age, 10 years) were enrolled. Circulating EV number and EV protein composition were assessed via flow cytometry and liquid chromatography tandem-mass spectrometry, respectively. In a multivariate analysis, relative body weight (standardized partial regression coefficient (SPRC) 0.469, P = 0.012) and serum triglyceride level (SPRC 0.548, P < 0.001) were detected as independent parameters correlating with circulating EV number. Proteomic analysis identified 31 upregulated and 45 downregulated EV proteins in OCA. Gene ontology analysis revealed upregulated proteins to be involved in various biological processes, including intracellular protein transport, protein folding, stress response, leukocyte activation, innate immune response, and platelet degranulation, which can modulate lipid and glucose metabolism, skeletal and cardiac muscle development, inflammation, immune response, carcinogenesis, and cancer progression. Notably, several identified EV proteins are involved in neuro-development, neurotransmitter release, and neuro-protective agents in OCA. Circulating EVs were derived from adipocytes, hepatocytes, B cell lymphocytes, and neurons. Circulating EV number is significantly associated with MetS-related dysmetabolism and the EV protein cargo carries a special “signature” that reflects the alteration of various biological processes under the pathophysiological condition of OCA.Key messagesCirculating EV number correlates with physical and laboratory parameters for obesity in children and adolescents.Relative body weight and triglyceride are independent factors for increased circulating EVs.EV composition is significantly changed in obesity of children and adolescents.Identified EV composition changes associated with obesity and involves in metabolism, immune response, and cancer progression.Circulating EVs are partially derived from adipocyte, hepatocytes, B cells, and neurons.

As hematopoietic progenitors supply a large number of blood cells, therapeutic strategies targeting hematopoietic progenitors are potentially beneficial to eliminate unwanted blood cells, such as leukemic cells and immune cells causing diseases. However, due to their pluripotency, targeting those cells may impair the production of multiple cell lineages, leading to serious side effects such as anemia and increased susceptibility to infection. To minimize those side effects, it is important to identify monopotent progenitors that give rise to a particular cell lineage. Monocytes and monocyte-derived macrophages play important roles in the development of inflammatory diseases and tumors. Recently, we identified human monocyte-restricted progenitors, namely, common monocyte progenitors and pre-monocytes, both of which express high levels of CD64, a well-known monocyte marker. Here, we introduce a dimeric pyrrolobenzodiazepine (dPBD)-conjugated anti-CD64 antibody (anti-CD64-dPBD) that selectively induces the apoptosis of proliferating human monocyte-restricted progenitors but not non-proliferating mature monocytes. Treatment with anti-CD64-dPBD did not affect other types of hematopoietic cells including hematopoietic stem and progenitor cells, neutrophils, lymphocytes and platelets, suggesting that its off-target effects are negligible. In line with these findings, treatment with anti-CD64-dPBD directly killed proliferating monocytic leukemia cells and prevented monocytic leukemia cell generation from bone marrow progenitors of chronic myelomonocytic leukemia patients in a patient-derived xenograft model. Furthermore, by depleting the source of monocytes, treatment with anti-CD64-dPBD ultimately eliminated tumor-associated macrophages and significantly reduced tumor size in humanized mice bearing solid tumors. Given the selective action of anti-CD64-dPBD on proliferating monocyte progenitors and monocytic leukemia cells, it should be a promising tool to target cancers and other monocyte-related inflammatory disorders with minimal side effects on other cell lineages.

Introduction Phyllodes tumors of the breast are categorized as benign, borderline, or malignant based on the WHO classification, which provides comprehensive criteria for determination, such as stromal cell density, stromal cell atypia, mitotic count, borderline status, and presence of ectopic stromal components. The present study was conducted to determine whether there is a proliferative marker superior to mitotic count. Methods The cohort comprised 47 benign, 13 borderline, and 16 malignant phyllodes tumors classified according to the WHO criteria. Various cell cycle-related proteins, including Ki-67, Cyclin A2, Cyclin B1, Cyclin E, phospho-histone H3, and Survivin, were used as proliferation markers. Cutoff values, sensitivity and specificity, and positive predictive value (PPV) were determined using the receiver operator characteristic (ROC) analysis. Results When comparing sensitivity and specificity using cutoff values to differentiate malignant phyllodes tumors from benign and borderline phyllodes tumors separately, only mitotic count alone showed a value exceeding 0.9. Additionally, the mitotic count showed a PPV greater than 0.8 in all three types of differentiation. However, when differentiating between benign and borderline phyllodes tumors, none of the proliferative indices, including mitotic count, exhibited a value greater than 0.9 for both sensitivity and specificity, and the PPV for borderline tumors did not exceed 0.4. Conclusion These findings suggest that mitotic count is the most reliable index for assessing proliferation, for differentiation of malignant from benign or borderline phyllodes tumors. Furthermore, it was revealed that criteria other than the proliferation index play a crucial role in distinguishing between benign and borderline phyllodes tumors.

Purpose In a previous study, protein tyrosine phosphatase non-receptor type (PTPN) 3 was identified as an immune checkpoint molecule in lymphocytes, and its potential as a novel target for cancer immunotherapy was anticipated. However, evaluation of dendritic cell (DC) function as antigen-presenting cells is critical for the development of immunotherapy. In this study, we aimed to analyze the biological effect of PTPN3 on DCs induced from human peripheral blood monocytes obtained from healthy individuals. Methods We used short-interfering RNA to knock down PTP3 in DCs. For DC maturation, we added cancer cell lysate and tumor necrosis factor-α/interferon-α to immature DCs. In the cytotoxic assay, the target cancer cells were SBC5, unmatched with DCs from healthy human leukocyte antigen (HLA)-A24, or Sq-1, matched with DCs. Enzyme-linked immunosorbent assay was used to determine the amount of cytokines. To examine the intracellular signaling system, intracellular staining was used. Results PTPN3 knockdown significantly increased the number of DCs, expression of CD80 and chemokine receptor (CCR)7, and production of interleukin-12p40/p70 in mature DCs. In the HLA-A24-restricted DC and human lung squamous cell carcinoma cell cytotoxic assay, inhibition of PTPN3 expression in mature DCs induced cytotoxic T lymphocytes with increased production of INF-γ and granzyme B, and enhanced toxicity against cancer cells and migration to cancer. Furthermore, inhibition of PTPN3 expression activated the mitogen-activated protein kinase pathway in DCs. Conclusion Based on our findings, inhibition of PTPN3 expression could contribute to the development of novel cancer immunotherapies that activate not only lymphocytes but also DCs.