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The pathomechanisms of autonomic disorders in systemic lupus erythematosus (SLE) remain unclear. We herein report a patient with SLE who developed autonomic disorders presumably caused by autoimmune autonomic ganglionopathy (AAG). A 42-year-old woman with SLE under treatment with corticosteroids and hydroxychloroquine was admitted for recurrence of SLE with thrombocytopenia and nephritis. On admission, she presented with weight loss, orthostatic dizziness, abdominal distension, and difficulty urinating. Marked intestinal dilatation, kidney swelling, bilateral hydronephrosis, and ureteral dilatation were noted on ultrasonography and computed tomography. No evidence of obstruction was observed in the intestines, urinary tracts, or bladder. Transverse myelitis was also ruled out by magnetic resonance imaging. After starting the treatment for the recurrent SLE (intravenous immunoglobulin and methylprednisolone pulse therapy, followed by high-dose oral corticosteroid, mycophenolate mofetil, and tacrolimus), orthostatic dizziness, abdominal distension, and difficulty urinating subsided along with increases in platelet count and decreases in urinary protein. The intestinal dilatation, hydronephrosis, and ureteral dilatation improved. We inferred that her SLE was complicated by AAG based on a positive anti-ganglionic acetylcholine receptor antibody. This case suggested that AAG should be considered as a type of autonomic disorder in SLE.

This study aimed to identify biomarkers to distinguish adult-onset Still’s disease (AOSD) and to predict disease phenotypes. In total, 49 patients diagnosed with AOSD and 200 patients with common diseases (controls) were included in the analysis. The levels of 69 cytokines were analyzed using a multi-suspension cytokine array. Cytokine cluster analysis was performed to identify specific molecular networks. Furthermore, random forest analysis and logistic regression analysis were used to rank cytokines based on their importance and to determine specific biomarkers for identification of AOSD patients and phenotypes. Patients with AOSD demonstrated significantly higher macrophage migration inhibitory factor (MIF) and interleukin (IL)-12(p40) serum levels than controls and patients with rheumatoid arthritis. Serum levels of chemokine (C-C motif) ligand (CCL) 8 and CCL22 were significantly lower in AOSD patients with a polycyclic systemic disease phenotype and could be differentiated with high accuracy from the other phenotypes (cutoff value for CCL8 = 122.7 pg/mL, CCL22 = 593.3 pg/mL, sensitivity 66.7%, specificity 87.1%, area under the curve 0.843). Combined MIF and IL-12(p40) levels may represent a biomarker for differentiating patients with AOSD from those with other diseases. The chemokine profiles of AOSD with a polycyclic systemic disease phenotype may differ from other phenotypes.

Abstract Objectives Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. Methods Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. Results We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. Conclusions We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.

Abstract Background Despite advancements in ultrasonography, locating peripheral veins for catheter placement remains a challenge in patients with altered anatomy owing to multiple surgeries. Herein, we highlight the potential of using the radial vein as an alternative site for ultrasound-guided peripheral venous catheterization. Case presentation We present two cases of patients with extensive surgical histories, including multiple abdominal surgeries, leading to difficult peripheral venous access. Traditional sites for peripheral venous catheterization were unsuitable due to vein narrowing or lack of visibility. In both cases, ultrasonography helped identify the radial vein as the only viable site for catheter placement. The patients underwent successful ultrasonography-guided catheterization of the radial vein without complications, facilitating medical management, including anesthesia induction and intraoperative monitoring. Conclusions The radial vein is a feasible and safe alternative for ultrasound-guided peripheral venous access in patients where traditional venous access sites are compromised.

Abstract Although previous studies have reported that pre-mRNA splicing factors (SFs) are involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), their exact role in promoting HR remains poorly understood. Here, we showed that SART1, an SF upregulated in several types of cancer, promotes DSB end resection, an essential first step of HR. The resection-promoting function of SART1 requires phosphorylation at threonine 430 and 695 by ATM/ATR. SART1 is recruited to DSB sites in a manner dependent on transcription and its RS domain. SART1 is epistatic with BRCA1, a major HR factor, in the promotion of resection, especially transcription-associated resection in the G2 phase. SART1 and BRCA1 accumulate at DSB sites in an interdependent manner, and epistatically counteract the resection blockade posed by 53BP1 and RIF1. Furthermore, chromosome analysis demonstrated that SART1 and BRCA1 epistatically suppressed genomic alterations caused by DSB misrepair in the G2 phase. Collectively, these results indicate that SART1 and BRCA1 cooperatively facilitate resection of DSBs arising in transcriptionally active genomic regions in the G2 phase, thereby promoting faithful repair by HR, and suppressing genome instability.

Abstract Plant growth regulators (PGRs) are involved in multiple aspects of plant life, including plant growth, development, and response to environmental stimuli. They are also vital for the formation of secondary metabolites in various plants. Salvia miltiorrhiza is a famous herbal medicine and has been used commonly for > 2000 years in China, as well as widely used in many other countries. S. miltiorrhiza is extensively used to treat cardiovascular and cerebrovascular diseases in clinical practices and has specific merit against various diseases. Owing to its outstanding medicinal and commercial potential, S. miltiorrhiza has been extensively investigated as an ideal model system for medicinal plant biology. Tanshinones and phenolic acids are primary pharmacological constituents of S. miltiorrhiza. As the growing market for S. miltiorrhiza, the enhancement of its bioactive compounds has become a research hotspot. S. miltiorrhiza exhibits a significant response to various PGRs in the production of phenolic acids and tanshinones. Here, we briefly review the biosynthesis and signal transduction of PGRs in plants. The effects and mechanisms of PGRs on bioactive compound production in S. miltiorrhiza are systematically summarized and future research is discussed. This article provides a scientific basis for further research, cultivation, and metabolic engineering in S. miltiorrhiza.

In recent years, rapid advances in research methods have made single cell analysis possible. Systemic sclerosis (SSc), a disease characterized by the triad of immune abnormalities, fibrosis, and vasculopathy, has also been the subject of various analyses. To summarize the results of single cell analysis in SSc accumulated to date and to deepen our understanding of SSc. Four databases were used to perform a database search on 23rd June 2023. Assessed Grading of Recommendations Assessment, Development and Evaluation certainty of evidence were performed according to PRISMA guidelines. The analysis was completed on July 2023. 17 studies with 358 SSc patients were included. Three studies used PBMCs, six used skin, nine used lung with SSc-interstitial lung diseases (ILDs), and one used lung with SSc-pulmonary arterial hypertension (PAH). The cells studied included immune cells such as T cells, natural killer cells, monocytes, macrophages, and dendritic cells, as well as endothelial cells, fibroblasts, keratinocytes, alveolar type I cells, basal epithelial cells, smooth muscle cells, mesothelial cells, etc. This systematic review revealed the results of single cell analysis, suggesting that PBMCs, skin, SSc-ILD, and SSc-PAH show activation and dysfunction of cells associated with immune-abnormalities, fibrosis, and vasculopathy, respectively.

Abstract Primary biliary cholangitis (PBC) is frequently associated with autoimmune disease. Although PBC complicated with CREST syndrome (PBC-CREST) has been reported, the long-term outcomes of the affected patients have not been fully investigated. Herein, the long-term outcomes of PBC-CREST were evaluated. Next, the GLOBE and UK-PBC scores were validated and compared between the PBC alone and PBC-CREST groups. A total of 302 patients who were diagnosed with PBC between December 1990 and August 2021 at Fukushima Medical University Hospital were included. The liver transplantation (LT)-free survival rates were compared between patients with PBC alone (n = 245) and those with PBC-CREST (n = 57). Moreover, 173 patients, excluding those with liver-related death/LT within 1 year after ursodeoxycholic acid administration, were divided into two subgroups (PBC alone (n = 147) and PBC-CREST (n = 26)), and the GLOBE and UK-PBC scores were compared between the subgroups. The survival rates without LT (3/5/10 years) were 92/87/80% for the PBC-alone group and 98/96/96% for the PBC-CREST group, with a significantly better prognosis in the PBC-CREST group (log-rank P = 0.0172). Multivariate analysis revealed that the presence of CREST syndrome is an independent protective factor for the presence of cirrhosis. The predicted 5/10/15-year risks of liver-related death or LT based on the UK-PBC score were significantly lower in the PBC-CREST group (2.4/7.6/13.2%) than in the PBC-alone group (4.8/11.8/18.8%) (P

This study aimed to elucidate the clinical features, outcomes and risk factors of flares in patients with systemic lupus erythematosus (SLE). Data were collected from patients with newly diagnosed SLE at the Fukushima Medical University Hospital between 2011 and 2022. Patients who experienced a flare during the study period constituted the flare group, and their clinical features were compared with those of the no-flare group. The cumulative flare-free survival regarding several clinical items was compared between the two groups using Kaplan–Meier’s curves. Among 387 patients with SLE, 83 patients with newly diagnosed SLE were included. Their mean age was 37.9 years, and 29 patients experienced flares during the study period. The general characteristics were similar between the two groups, with the exception of the observation period and anti-SS-A antibody positivity. Regarding therapy, a significantly increased frequency of hydroxychloroquine intake and combination with immunosuppressive agents were observed in the no-flare group. The Kaplan–Meier analysis revealed a significantly higher cumulative flare-free survival in the anti-SS-A negative group and combination immunosuppressive therapy group. In conclusion, anti-SS-A positivity may be a risk factor for SLE flare. In turn, combination immunosuppressive therapy may be beneficial for SLE treatment in daily clinical practice.

Introduction: Acute Leriche syndrome is a rare but potentially life-threatening condition. Pain, pallor, and coldness of the lower extremities serve as clues for suspecting Leriche syndrome. However, the absence of these findings may pose a diagnostic challenge. Case Presentation: An 83-year-old man presented at our emergency department with a complaint of sudden-onset paraparesis. Initially, spinal cord infarction was suspected due to clinical course and neurological findings, but thoracolumbar MRI showed normal findings. On admission, symptoms associated with aortoiliac occlusion were not present, except for muscle atrophy in the thigh. CT angiography revealed aortoiliac occlusion, leading to a diagnosis of Leriche syndrome. Conclusion: Leriche syndrome should be considered as a potential differential diagnosis in patients with acute paraparesis. Muscle atrophy of the lower limbs disproportionate to the clinical course may be the clue for suspecting acute Leriche syndrome with symptoms related to atherosclerotic occlusion which are inconspicuous.

Abstract Background Intra‐abdominal infectious complications (IAICs) following minimally invasive gastrectomy (MIG) for cancer sometimes worsen short‐ and long‐term outcomes. In this study, we focused on the minimum umbilicus–vertebra diameter (MUVD) in preoperative computed tomography (CT) images and robotic surgery to prevent severe IAIC occurrence. Patients and Methods A total of 400 patients with gastric cancer who underwent 204 laparoscopic gastrectomy (LG) and 196 robotic gastrectomy (RG) procedures were enrolled in this study. We retrospectively investigated the significance of the MUVD and robotic surgery for preventing severe IAICs following MIG using multivariate and propensity score matching analysis. Results The MUVD cutoff value was 84 mm by receiver operating characteristic (ROC) curve using severe IAICs as the end point. The MUVD and visceral fat area (VFA) had significantly higher area under the curve (AUC) than BMI (MUVD vs. BMI, p = 0.032; VFA vs. BMI, p

ObjectiveThe purpose of this study was to predict the four cold–heat patterns in patients who have the subjective symptoms of the cold–heat pattern described in the International Classification of Diseases Traditional Medicine Conditions – Module 1 by applying a machine learning algorithm.MethodsSubjects were first-visit Kampo outpatients at six institutions who agreed to participate in this multicenter prospective observational study. The cold pattern model and the heat pattern model were created separately with 148 symptoms, body mass index, blood pressure (systolic and diastolic), age, and sex. Along with a single cold or heat pattern, the tangled heat/cold pattern is defined as being predicted by both cold and heat patterns, while the moderate (heat/cold) pattern is defined as being predicted by neither the cold pattern nor the heat pattern.ResultsWe included 622 participants (mean age ±standard deviation, 54.4 ± 16.9; with female 501). The accuracy, macro-recall, precision, and F1-score of a combination of the two prediction models were 96.7%, 93.2%, 85.6%, and 88.5% respectively. The important items were compatible with the definitions of the cold–heat pattern.ConclusionWe developed a prediction model on cold–heat patterns with data from patients whose subjective cold/heat-related symptoms matched the cold–heat pattern diagnosis by the physician.

Abstract The singlet fission characteristics of aqueous nanoparticles, self‐assembled from ion pairs of tetracene dicarboxylic acid and various amines with or without chirality, are thoroughly investigated. The structure of the ammonium molecule, the counterion, is found to play a decisive role in determining the molecular orientation of the ion pairs and its regularity, spectroscopic properties, the strength of the intermolecular coupling between the tetracene chromophores, and the consequent singlet fission process. Using chiral amines has led to the formation of crystalline nanosheets and efficient singlet fission with a triplet quantum yield as high as 133% ±20% and a rate constant of 6.99 × 109 s−1. The chiral ion pairs also provide a separation channel to free triplets with yields as high as 33% ±10%. In contrast, nanoparticles with achiral counterions do not show singlet fission, which gave low or high fluorescence quantum yields depending on the size of the counterions. The racemic ion pair produces a correlated triplet pair intermediate by singlet fission, but no decorrelation into two free triplets is observed, as triplet‐triplet annihilation dominates. The introduction of chirality enables higher control over orientation and singlet fission in self‐assembled chromophores. It provides new design guidelines for singlet fission materials.

Key Clinical Message A 35‐year‐old male presented with recurrent respiratory papillomatosis. Human papillomavirus type 11 was detected from all sites of tumor tissue DNA by PCR. The pre‐surgery cell‐free DNA (cfDNA) viral load (3.33 × 103 copies/ng DNA) fell below the post‐surgical detection limits on achieving remission, suggesting cfDNA's potential as a biomarker.

AbstractThe complement component C5a contributes to the recruitment of immune cells to inflamed tissues and local inflammation. The proinflammatory cytokine interleukin (IL)-1β is also related to inflammatory disorders through inflammasome activation. However, the association between inflammasome activation and C5a is unclear. Human peripheral blood mononuclear cells (PBMCs) were stimulated with C5a and measured for IL-1β secretion by enzyme-linked immunosorbent assay (ELISA). The pro-IL-1β expression in cell lysates was also examined by Western blot analysis. Similarly, magnetic bead-isolated CD14+ monocyte-depleted and lymphocyte-depleted PBMCs were stimulated with C5a, and immunoblot analysis was performed using an anti-cleaved-IL-1β (p17) antibody. FACS was performed to detect caspase-1-activated cells. C5a-stimulated PBMCs produced IL-1β in C5a concentration-dependent manner. The protein levels of pro-IL-1β in the cell lysates were significantly increased. Furthermore, the cleaved-IL-1β (p17) was faintly detected in the same lysates. Active caspase-1 was demonstrated in C5a-simulated CD14+ monocytes by FACS. Cleaved-IL-1β (p17) was demonstrated in the supernatant of C5a-stimulated PBMCs. Lymphocyte-depleted PBMCs stimulated with C5a but monocyte-depleted PBMCs produced cleaved-IL-1β (p17). C5a induced the production of mature IL-1β in PBMCs. The IL-1β production is mediated mainly by caspase-1 activation in CD14+ monocytes. These results suggest that C5a alone potentiates mature IL-1β production mainly in monocytes.

Abstract Background Robotic-assisted surgery is steadily becoming more prominent. The majority of reports regarding port site hernias (PSHs) have involved laparoscopic procedures. Currently, it is common to suture the fascia at port sites that are 10 mm or larger; however, the closure of 5-mm port sites is not considered mandatory. The da Vinci® surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA) utilizes a distinctive 8-mm port. We report a case of an early-onset PSH at an 8-mm port site after robotic-assisted ileocecal resection. Case presentation A 74-year-old male patient with a body mass index of 19.7 kg/m2 was diagnosed with cecal cancer and underwent robotic-assisted ileocecal resection. A 3-cm midline incision was made at the umbilicus for insufflation. Under laparoscopic visualization, three ports (12 mm, 8 mm, and 8 mm) were inserted in the lower abdomen. An 8-mm port was inserted in the left subcostal region, and a 5-mm port was inserted in the left lateral abdomen. The procedure was performed without significant intraoperative complications. The fascia was closed only at the umbilicus and 12-mm port site; the fascia at the 8-mm port sites was not closed. The patient was initially discharged without complications; however, on postoperative day 11, the patient was urgently hospitalized again because of PSH incarceration. After manual reduction, the fascia was sutured closed under local anesthesia. The hernial defect was small and barely allowed the insertion of a little finger. There was no evidence of compression or significant damage to the fascia. On postoperative day 27, the patient was discharged after experiencing good recovery. Conclusions Robotic-assisted colectomy could contribute to the risk of PSHs because of its surgical characteristics. Although routine closure of the fascia at 8-mm port sites is not mandatory, it may be beneficial in certain cases.

Introduction: Reexposure to anti-EGFR antibodies, such as a reintroduction or rechallenge with anti-EGFR antibodies, has attracted much attention in the field of metastatic colorectal cancer. A reintroduction of anti-EGFR antibodies often shows good therapeutic outcomes, as most patients eligible for such reintroduction discontinued treatment due to adverse events despite a good treatment response during front-line treatment. We herein report a case demonstrating an improvement in exertional dyspnea after the reintroduction of anti-EGFR antibody in a patient with metastatic rectal cancer who developed cancerous lymphangiopathy. Case Presentation: A 68-year-old man who had undergone curative surgery for stage IIIB rectal cancer was diagnosed with multiple lung metastases. During the late-line treatment, respiratory failure developed because of multiple lung metastases and cancerous lymphangiopathy. Two months after the initiation of irinotecan + cetuximab, which had been discontinued due to acneiform eruptions despite a good treatment response as a first-line treatment, his dyspnea and performance status dramatically improved. Conclusion: This case indicates that the reintroduction of anti-EGFR antibody to patients who have discontinued anti-EGFR antibody due to skin toxicity despite a good treatment response is a very useful treatment option for metastatic colorectal cancer.

Abstract Protein arginine methyltransferase 5 (PRMT5) is a well-known epigenetic regulatory enzyme. However, the role of PRMT5-mediated arginine methylation in gene transcription related to cardiac fibrosis is unknown. Here we show that fibroblast-specific deletion of PRMT5 significantly reduces pressure overload-induced cardiac fibrosis and improves cardiac dysfunction in male mice. Both the PRMT5-selective inhibitor EPZ015666 and knockdown of PRMT5 suppress α-smooth muscle actin (α-SMA) expression induced by transforming growth factor-β (TGF-β) in cultured cardiac fibroblasts. TGF-β stimulation promotes the recruitment of the PRMT5/Smad3 complex to the promoter site of α-SMA. It also increases PRMT5-mediated H3R2 symmetric dimethylation, and this increase is inhibited by Smad3 knockdown. TGF-β stimulation increases H3K4 tri-methylation mediated by the WDR5/MLL1 methyltransferase complex, which recognizes H3R2 dimethylation. Finally, treatment with EPZ015666 significantly improves pressure overload-induced cardiac fibrosis and dysfunction. These findings suggest that PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction.

Abstract Purposes Subtotal esophagectomy for esophageal cancer (EC) is associated with high morbidity rates. Tight glycemic control using an artificial pancreas (AP) is one of the promising strategies to reduce postoperative inflammation and morbidities. However, the effects of tight glycemic control using AP in patients with EC are yet to be fully elucidated. Method This study reviewed 96 patients with EC who underwent subtotal esophagectomy. The postoperative inflammation parameters and morbidity rates were compared between patients who used the AP (n = 27) or not (control group, n = 69). AP is a closed-loop system that comprises a continuous glucose monitor and an insulin pump. Results The numbers of white blood cells (WBC) and Neutrophils (Neut) were noted to be lower in the AP group than in the control group, but with no significant difference. The ratio in which the number of WBC, Neut, and CRP on each postoperative day (POD) was divided by those tested preoperatively was used to standardize the results. The ratio of WBC and Neut on 1POD was significantly lower in the AP group than in the control group. The rate of surgical site infection was lower in the AP group than in the control group. Conclusion AP significantly decreased WBC and Neut on 1POD; this suggests the beneficial effects of AP in alleviating postoperative inflammation.

Abstract Background Gastric cancer is primarily treated by surgery; however, little is known about the changes in the intraperitoneal immune environment and the prognostic impact of surgery. Surgical stress and cancer-associated inflammation cause immune cells to mobilize into the abdominal cavity via numerous cytokines. One such cytokine, CX3CR1, has various immune-related functions that remain to be fully explained. We characterized the intraperitoneal immune environment by investigating CX3CR1+ cells in intraperitoneal lavage fluid during gastric cancer surgery. Methods Lavage fluid samples were obtained from a total of 41 patients who underwent gastrectomy. The relative expression of various genes was analyzed using quantitative real-time PCR. The association of each gene expression with clinicopathological features and surgical outcomes was examined. The fraction of CX3CR1+ cells was analyzed by flow cytometry. Cytokine profiles in lavage fluid samples were investigated using a cytometric beads array. Results CX3CR1high patients exhibited higher levels of perioperative inflammation in blood tests and more recurrences than CX3CR1low patients. CX3CR1high patients tended to exhibit higher pathological T and N stage than CX3CR1low patients. CX3CR1 was primarily expressed on myeloid-derived suppressor cells and tumor-associated macrophages. In particular, polymorphonuclear myeloid-derived suppressor cells were associated with perioperative inflammation, pathological N, and recurrences. These immunosuppressive cells were associated with a trend toward unfavorable prognosis. Moreover, CX3CR1 expression was correlated with programmed death–1 expression. Conclusions Our results suggest that CX3CR1+ cells are associated with an acute inflammatory response, tumor-promotion, and recurrence. CX3CR1 expression could be taken advantage of as a beneficial therapeutic target for improving immunosuppressive state in the future. In addition, analysis of intra-abdominal CX3CR1+ cells could be useful for characterizing the immune environment after gastric cancer surgery.

Abstract Background The efficacy of robotic gastrectomy (RG) on postoperative complications in patients with gastric cancer (GC) is unclear in terms of the volume of intra‐abdominal fat tissue. Patients and Methods We enrolled 403 patients with GC who had minimally invasive surgery between January 2015 and July 2022. During this time, 197 RG and 206 laparoscopic gastrectomies (LG) were performed on the study participants. According to the computed tomography scan, patients were defined as having or not having visceral obesity based on the visceral fatty area (VFA). In each high and low VFA group, we compared short‐term outcomes between the RG group and LG group. Results After PS matching for patients with high VFA, the two groups were well matched, with 71 cases in both the RG and LG groups. The median surgical time in the RG group was significantly longer (420 vs. 365 min, p

Abstract Objective Managing the risk of epileptic seizures in older adults is increasingly important as the population ages. Leukotriene receptor antagonists (LTRAs) are commonly used to treat asthma or allergic rhinitis. Preclinical studies suggest that LTRAs have antiepileptic effects; however, few population‐based etiological studies on this topic have been available. Our study explored whether LTRAs reduce hospitalization risk associated with epileptic seizures in older individuals with asthma or allergic rhinitis. Methods We conducted a new‐user design analysis using the Shizuoka Kokuho database. We included all individuals aged 60‐89 years who had at least one episode of allergic rhinitis or asthma during the study period. We compared individuals who newly started LTRAs with those who did not take LTRAs. Propensity score matching was used to balance the baseline characteristics of the participants. We compared the hazard ratios for seizure‐related hospitalization between new LTRA users and non‐users and performed subgroup analyses. Results Our matched cohorts consisted of 64 724 new users and non‐users of LTRAs who were aged 60‐89 years and had asthma or allergic rhinitis. During the observation period, 377 (0.58%) and 595 (0.92%) incidents were observed in the LTRA new‐user and non‐user groups, respectively. The hazard ratio for seizure‐related hospitalization was 0.75 (95% confidence interval [CI]: 0.62‐0.92) in the LTRA new‐user group compared with the non‐user group. Subgroup analysis revealed that the hazard ratio was weak in diabetic patients (1.31; 95% CI: 0.72‐2.38). Significance This study indicated that LTRAs reduced seizure‐related hospitalization in older adult patients with allergic rhinitis or asthma. We could not evaluate the severity and related diseases of epileptic seizures during LTRAs. Further studies, including observational studies, detailed multicenter prospective studies, and clinical trials, are needed to validate these findings. Plain Language Summary This study examined if leukotriene receptor antagonists (LTRAs), commonly used for asthma or allergies, could lower seizure risk in older adults. Analyzing health records of 60‐89 year‐olds with asthma or allergies, we found a reduced rate of seizure‐related hospitalizations in those starting LTRAs, though this was not as evident in diabetic patients. Our results suggest potential benefits of LTRAs in preventing seizures in older adults with respiratory issues, but further research is needed to confirm these findings.

AbstractPurpose c-Jun N-terminal kinases (JNKs) comprise a subfamily of mitogen-activated protein kinases (MAPKs). The JNK group is known to be activated by a variety of stimuli. However, the molecular mechanism underlying heat-induced JNK activation is largely unknown. The aim of this study was to clarify how JNK activity is stimulated by heat.Methods and materials The expression levels of various MAPK members in HeLa cells, with or without hyperthermia treatment, were evaluated via western blotting. The kinase activity of MAPK members was assessed through in vitro kinase assays. Cell death was assessed in the absence or presence of siRNAs targeting MAPK-related members.Results Hyperthermia decreased the levels of MAP3Ks, such as ASK1 and MLK3 which are JNK kinase kinase members, but not those of the downstream MAP2K/SEK1 and MAPK/JNK. Despite the reduced or transient phosphorylation of ASK1, MLK3, or SEK1, downstream JNK was phosphorylated in a temperature-dependent manner. In vitro kinase assays demonstrated that heat did not directly stimulate SEK1 or JNK. However, the expression levels of DUSP16, a JNK phosphatase, were decreased upon hyperthermia treatment. DUSP16 knockdown enhanced the heat-induced activation of ASK1–SEK1–JNK pathway and apoptosis.Conclusion JNK was activated in a temperature-dependent manner despite reduced or transient phosphorylation of the upstream MAP3K and MAP2K. Hyperthermia-induced degradation of DUSP16 may induce activation of the ASK1–SEK1–JNK pathway and subsequent apoptosis.

AbstractYKL-40 is implicated in inflammation and tissue repair, but no reports have investigated its involvement in myositis in polymyositis (PM) and dermatomyositis (DM). Therefore, we aimed to investigate the relationship between YKL-40 and PM/DM. We retrospectively enrolled 35 patients diagnosed with PM/DM along with 26 healthy controls (HCs). Both PM and DM were diagnosed according to Bohan and Peter’s criteria. Serum YKL-40 levels were measured, age-corrected to YKL-40 percentile values, and compared to HCs. Patients with myositis without interstitial lung disease were also enrolled and compared to HCs. Immunofluorescence staining was performed to identify YKL-40-positive inflammatory cells in muscle biopsy samples from two patients each with PM and DM. Age-corrected serum YKL-40 levels were significantly higher in patients with PM/DM compared to HCs with and without lung disease; however, these levels decreased significantly after treatment. Immunohistochemical analysis showed infiltration of YKL-40-positive inflammatory cells into the intramuscular sheath and perimuscular membrane. Immunofluorescence staining showed CD68 expression in YKL-40-positive inflammatory cells, suggesting that these cells were macrophages. To the best of our knowledge, this is the first study to demonstrate that YKL-40-positive macrophages are present in PM and DM, indicating that YKL-40 may be involved in PM/DM.

Abstract Background Drug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown. Methods This study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel. Results Of 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%–8.7%) and 7.2% (95% CI 4.0%–11.5%), respectively. There were significant differences according to cancer type (Gray’s test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%–18.0%) at 3 months and 14.2% (95% CI 7.3%–23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%–29.7%) vs 4.3% (95% CI 0.3%–18.2%) at 3 months; and 21.7% (95% CI 7.9%–39.9%) vs 4.3% (95% CI 0.3%–18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64–45.33; Fine–Gray P = .12). Conclusions Patients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.

Abstract Complete mesocolic excision (CME) with central vascular ligation (CVL) in laparoscopic surgery for right-sided colon cancer (RSCC) requires a precise understanding of the vascular anatomy. The efficacy of intraoperative ultrasound (IUS) in the identification of blood vessels for RSCC surgery was not evaluated. The aim of this study was to compare the intraoperative and short-term outcomes of CME with CVL with or without IUS by laparoscopic surgery for RSCC. We performed IUS on 26 patients of RSCC and compared with a total of 124 patients who underwent the surgery for RSCC at our institution. Propensity score matching (PSM) was performed to reduce the confounding effects to imbalances in the use of IUS. The IUS identified the main feeding artery and the accompanying vein in all 26 cases. After PSM, the amount of intraoperative blood loss in the IUS group was significantly lower than that in the conventional group (5 ml vs. 30 ml, p = 0.035) and no significant difference of the postoperative complications was observed. The IUS reduced the risk of bleeding in the surgery for RSCC. The IUS is a safe and feasible technique that help the surgeons for anatomical understandings under real-time condition in the laparoscopic surgery of RSCC.

Abstract The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

Abstract We aimed to compare the effects of cardiovascular disease risk in Japanese patients with type 2 diabetes on sodium–glucose cotransporter 2 inhibitors (SGLT2Is) or metformin. This retrospective, real‐world cohort study was carried out using a claims database and propensity score matching; 58,402 eligible patients (29,201 per group) were included. The outcomes included nonfatal myocardial infarction, angina pectoris, nonfatal stroke, hospitalization for heart failure and composite end‐points. The hazard ratio (HR) for the composite end‐point was 0.79, which was lower for SGLT2Is than for metformin. For male patients (HR 0.76), patients aged

Medical care for domestic dogs is now respected worldwide as being at a similar level to that of humans. We previously established a test method to determine whole mitochondrial DNA (mtDNA) using oral mucosal DNA that may be useful for medical care and welfare. However, the sample types tested in dogs are not limited to those obtained from the oral mucosa. Therefore, in the present study, we attempted to establish a test method to determine whole mtDNA sequences using feces, which represents the least invasive specimen. Two Japanese domestic dogs were used in the present study. DNA was extracted from approximately 100 mg of fresh feces from each dog, and PCRs were performed using four primer pairs that can amplify whole mtDNA. Following PCR, amplicons were pooled to create a DNA library using an experimental robot with an original program. Data were then acquired via NGS and data analysis was performed. The results showed that the whole mtDNA sequence of the two dogs was determined with high accuracy. Our results suggest that feces can be adapted for mitochondrial disease and individual identification testing and could serve as a useful testing method for the future medical care and welfare of domestic dogs.

Abstract We report a case of ruptured cystic artery pseudoaneurysm after self‐expandable metal stent placement for malignant biliary obstruction. A 78‐year‐old woman on palliative care after chemotherapy for unresectable pancreatic head cancer presented with obstructive jaundice. Imaging revealed a dilated common bile duct and an enlarged gallbladder with cystic wall thickening. Endoscopic retrograde cholangiopancreatography was performed and a fully‐covered self‐expandable metal stent was placed in the bile duct, leading to resolution of jaundice. She presented with hematochezia 7 days later. Contrast‐enhanced computed tomography revealed a cystic artery pseudoaneurysm with extravasation of contrast into a blood‐filled gallbladder. Hemostasis was achieved after emergent transcatheter arterial embolization. Rupture of cystic artery pseudoaneurysm should be raised as a differential diagnosis for hemobilia after self‐expandable metal stent placement, particularly in cases accompanied by inflamed gallbladders.

BackgroundAutoinflammation with cytokine dysregulation may be implicated in the pathophysiology of adult-onset Still’s disease (AOSD); however, the relationship between galectins and cytokines in patients with active AOSD remains unknown. We aimed to examine the relationship between circulating cytokines/chemokines and galectin-3 (Gal-3) or its ligand, Mac-2 binding protein glycosylation isomer (M2BPGi), in Japanese patients with AOSD.MethodsWe recruited 44 consecutive patients diagnosed with AOSD according to the Yamaguchi criteria, 50 patients with rheumatoid arthritis (RA) as disease controls, and 27 healthy participants. Serum M2BPGi levels were directly measured using a HISCL M2BPGi reagent kit and an automatic immunoanalyzer (HISCL-5000). Serum Gal-3 concentrations were measured by enzyme-linked immunosorbent assay. The serum levels of 69 cytokines were analyzed in patients with AOSD using a multi-suspension cytokine array. We performed a cluster analysis of each cytokine expressed in patients with AOSD to identify specific molecular networks.ResultsSignificant increases in the serum concentrations of Gal-3 and M2BPGi were found in the serum of patients with AOSD compared with patients with RA and healthy participants (both p

Abstract Fluorescence imaging, a key technique in biological research, frequently utilizes fluorogenic probes for precise imaging in living systems. Tetrazine is an effective emission quencher in fluorogenic probe designs, which can be selectively damaged upon bioorthogonal click reactions, leading to considerable emission enhancement. Despite significant efforts to increase the emission enhancement ratio (IAC/IBC) of tetrazine‐functionalized fluorogenic probes, the influence of molecular aggregation on the emission properties has been largely overlooked in these probe designs. In this study, we reveal that an ultrahigh IAC/IBC can be realized in the aggregate system when tetrazine is paired with aggregation‐induced emission (AIE) luminogens. Tetrazine amplifies its quenching efficiency upon aggregation and drastically reduce background emissions. Subsequent click reactions damage tetrazine and trigger significant AIE, leading to considerably enhanced IAC/IBC. We further showcase the capability of these ultra‐fluorogenic systems in selective imaging of multiple organelles in living cells. We term this unique fluorogenicity of AIE luminogen‐quencher complexes with amplified dark‐bright states as “Matthew effect” in aggregate emission, potentially providing a universal approach to attain ultrahigh IAC/IBC in diverse fluorogenic systems.

Summary: Background: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignant epithelial tumor endemic to Southern China and Southeast Asia. While previous studies have revealed a low frequency of gene mutations in NPC, its epigenomic aberrations are not fully elucidated apart from DNA hypermethylation. Epigenomic rewiring and enhancer dysregulation, such as enhancer hijacking due to genomic structural changes or extrachromosomal DNA, drive cancer progression. Methods: We conducted Hi-C, 4C-seq, ChIP-seq, and RNA-seq analyses to comprehensively elucidate the epigenome and interactome of NPC using C666-1 EBV(+)-NPC cell lines, NP69T immortalized nasopharyngeal epithelial cells, clinical NPC biopsy samples, and in vitro EBV infection in HK1 and NPC-TW01 EBV(−) cell lines. Findings: In C666-1, the EBV genome significantly interacted with inactive B compartments of host cells; the significant association of EBV-interacting regions (EBVIRs) with B compartment was confirmed using clinical NPC and in vitro EBV infection model. EBVIRs in C666-1 showed significantly higher levels of active histone modifications compared with NP69T. Aberrant activation of EBVIRs after EBV infection was validated using in vitro EBV infection models. Within the EBVIR-overlapping topologically associating domains, 14 H3K4me3(+) genes were significantly upregulated in C666-1. Target genes of EBVIRs including PLA2G4A, PTGS2 and CITED2, interacted with the enhancers activated in EBVIRs and were highly expressed in NPC, and their knockdown significantly reduced cell proliferation. Interpretation: The EBV genome contributes to NPC tumorigenesis through “enhancer infestation” by interacting with the inactive B compartments of the host genome and aberrantly activating enhancers. Funding: The funds are listed in the Acknowledgements section.

Objective The hallmarks of the chronic inflammatory disease polymyalgia rheumatica (PMR) include pain, and morning stiffness in areas of the neck, shoulder and pelvic girdle. The human leucocyte antigen (HLA) gene was reported to be an important risk factor for PMR, but it has not been analysed precisely, especially in populations other than Europeans.Methods Genotyping of DRB1 and DQB1 was performed in Japanese PMR patients (n=270) and controls (n=413). Associations between allele carrier and genotype frequencies were determined for PMR.Results DRB1*04:05 was associated with a predisposition to PMR (p=0.0006, Pc=0.0193, OR 1.85, 95% CI 1.31 to 2.62). DRB1*09:01 was associated with protection against PMR (p=1.46×10−5, Pc=0.0004, OR 0.40, 95% CI 0.26 to 0.61). A shared epitope (SE) associated with PMR (p=3.07×10−6, OR 2.11, 95% CI 1.54 to 2.88). DQB1*03:03 (p=0.0010, Pc=0.0140, OR 0.52, 95% CI 0.35 to 0.77) was associated with protection against PMR and DQB1*04:01 (p=0.0009, Pc=0.0140, OR 1.82, 95% CI 1.28 to 2.58) was associated with predisposition to PMR. A gene dosage effect was observed for DRB1*09:01 and DQB1*03:03, but not for DRB1*04:05, SE or DQB1*04:01. Haplotype and logistic regression analyses suggested a protective effect for DRB1*09:01.Conclusion This study is the first to demonstrate predisposing associations of DRB1*04:05, SE, and DQB1*04:01, and protective associations of DRB1*09:01 and DQB1*03:03 with PMR in Japanese patients. Our data indicate HLA has predisposing and protective effects on the pathogenesis of PMR.

Abstract Background Immune checkpoint inhibitors (ICIs), including nivolumab, have been approved to treat esophageal cancer. However, these remedies are not fit for all patients with esophageal cancer; therefore, a predictive surrogate marker is needed to assess their effectiveness. CD103+CD8+ tumor-infiltrating lymphocytes, defined as tissue-resident memory T cells (TRM), are promising indicators of response to ICIs, but it remains to be elucidated. This study investigated the association between the efficacy of ICIs and TRM. Methods The relationships between TRM infiltrating esophageal cancer, clinicopathological features, and prognosis after nivolumab initiation were examined using immunostaining. Tissue samples were obtained from surgically resected specimens of 37 patients with esophageal cancer who received nivolumab as a secondary or subsequent therapy. In addition, TRM infiltration was compared with programmed death-ligand 1 (PD-L1) expression and blood count parameters as predictors of nivolumab effectiveness. Results TRM-rich patients had a significant survival benefit after nivolumab initiation (12-months overall survival 70.8% vs 37.2%, p = 0.0485; 12-months progression-free survival 31.2% vs 0%, p = 0.0153) and experienced immune-related adverse events more frequently than TRM-poor patients (6 vs 2 patients). TRM infiltration was weakly correlated with PD-L1 positivity (r = 0.374, p = 0.022), but TRM may indicate more sensitive response to ICIs than PD-L1 expression in this study. Some blood test parameters also weakly correlated with TRM but did not impact prognosis. Conclusions TRM-rich patients have a favorable prognosis after nivolumab initiation. Our results suggest that TRM are vital for antitumor immunity and are a promising predictor of ICIs effectiveness.

Abstract Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.

Abstract Background Thoracic duct cysts are extremely rare mediastinal tumors. We report a case of a thoracic duct cyst extending from the caudal aspect of the left main bronchus to the left renal artery that was safely and completely resected via bilateral thoracoscopic surgery in the prone position. Case presentation A 77-year-old male was referred to our hospital for follow-up computed tomography (CT) of prostate cancer, which revealed a mediastinal tumor and fatty low-density along the posterior mediastinum of the para-aortic artery with a slightly high-density component. Magnetic resonance imaging revealed a T2-weighted image with high intensity. The preoperative radiological diagnosis was lipoma or well-differentiated liposarcoma. CT in the prone position suggested that the tumor could be resected from the thoracic cavity to the caudal side, and bilateral thoracoscopic surgery was performed in the prone position. Based on the surgical findings, the tumor was diagnosed as a thoracic duct cyst rather than a lipoma. Dissection around the thoracic duct cyst was performed using a vessel-sealing system to prevent leakage of the chyle, and reliable clipping was performed to resect the cisterna chyli. Histopathological examination revealed smooth muscle structures around the cyst, suggestive of a thoracic duct cyst. The diagnosis of a thoracic duct cyst was made based on a high triglyceride level of 1310 mg/dL on examination of the milky-white cyst fluid. The patient's postoperative course was uneventful, and he was discharged 4 days postoperatively. A CT scan performed 13 months after surgery showed no recurrence. Conclusions A rare thoracic duct cyst extending from the mediastinum to the cisterna chyli was safely and completely resected using bilateral thoracoscopic surgery, with the patient in the prone position.

Abstract Background Ultrasound-guided central venous catheterization has become a standard procedure. However, mechanical complications are still reported. Case presentation An 85-year-old woman presented with coagulopathic bladder tamponade. Ultrasound-guided right internal jugular venous catheterization was planned because of difficult peripheral venous access. A guidewire was advanced through a needle inserted at the midpoint of the right carotid triangle. The guidewire was identified in the short axis, but not in the long-axis ultrasound view, leading to inadvertent insertion of the catheter into the right subclavian artery through the internal jugular vein. Stent graft insertion was performed for perforation closure. The patient exhibited no symptoms of cerebral ischemia following stent graft insertion. Discussion This case demonstrated that the needle-sticking site should not be placed close to the clavicle for ultrasound-guided internal jugular venous catheterization, as it may not confirm the position of guidewire in the long-axis ultrasound view.

Abstract Background Insulinoma in women during pregnancy and postpartum is very rare; approximately 65% of cases are diagnosed early in pregnancy and ~ 35% immediately after delivery, few being found in middle or late pregnancy, likely due to increased insulin resistance seen after early-stage pregnancy. We successfully treated a case of insulinoma in which severe hypoglycemic coma immediately after delivery occasioned detailed investigation and diagnosis. Case presentation Our patient experienced hypoglycemic coma in the 3rd month of pregnancy (initially considered due to her hyperemesis gravidarum) that improved spontaneously during the gestational period. No abnormalities of plasma glucose or body weight were found in regular checkups during her pregnancy; however, recurrence of hypoglycemic coma after delivery led us to suspect insulinoma. While contrast enhanced computer tomography and endoscopic ultrasonography (EUS) initially failed to detect a tumor in the pancreas, selective arterial calcium stimulation test revealed an insulin-secreting tumor localized in the pancreatic body. She then underwent spleen-preserving distal pancreatectomy; a 10-mm tumor positive for chromogranin A, synaptophysin and insulin was identified. Conclusions Although pregnancy can mask insulinoma-associated symptoms and make diagnosis challenging, hypoglycemic episodes during early pregnancy, which were observed in this case, are suggestive of insulinoma. Importantly, in this case, accurate preoperative localization of the tumor enabled prompt curative surgery after delivery. Thus, clinical vigilance for the occurrence of insulinoma and its localization is appropriate for pregnant women suffering severe hypoglycemia.

Abstract Introduction Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non‐squamous, non‐small cell lung cancer (NSCLC). Data regarding the addition of bevacizumab, especially in maintenance treatment, are insufficient. Methods Eligibility criteria included: no prior chemotherapy; advanced, non‐squamous, NSCLC; performance status ≤1; and epidermal growth factor receptor mutation‐negative. Patients (N = 108) received induction chemotherapy with cisplatin, pemetrexed, and bevacizumab every 3 weeks for four cycles, and tumor response was needed to confirm four‐week response duration. Patients with at least stable disease were randomized to pemetrexed/bevacizumab or pemetrexed alone. The primary endpoint was progression‐free survival (PFS) after induction chemotherapy. Myeloid‐derived suppressor cell (MDSC) counts of peripheral blood samples were also analyzed. Results Thirty‐five patients each were randomized to the pemetrexed/bevacizumab group and the pemetrexed alone group. PFS was significantly better in the pemetrexed/bevacizumab group than in the pemetrexed alone group (7.0 vs. 5.4 months, hazard ratio: 0.56 [0.34–0.93], log‐rank p = 0.023). In patients with partial response to induction therapy, median overall survival was 23.3 months in the pemetrexed alone group and 29.6 months in the pemetrexed/bevacizumab group (log‐rank p = 0.077). Pretreatment monocytic (M)‐MDSC counts tended to be greater in the pemetrexed/bevacizumab group with poor PFS than in those with good PFS (p = 0.0724). Conclusions Addition of bevacizumab to pemetrexed as maintenance therapy prolonged PFS in patients with untreated, advanced, non‐squamous NSCLC. Furthermore, an early response to induction therapy and pretreatment M‐MDSC counts may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin and pemetrexed.

Abstract Background The powered circular stapler, which was developed with the aim of providing reliable and reproducible anastomosis, provides complete anastomosis, resulting in a reduced risk of anastomotic leakage. The aim of this study was to compare the incidence of anastomotic leakage between a conventional manual circular stapler (MCS) and the ECHELON CIRCULAR™ Powered Stapler (ECPS) in patients with left-sided colorectal cancer who underwent anastomosis with the double stapling technique. Methods A total of 187 patients with left-sided colorectal cancer who underwent anastomosis with the double stapling technique with a conventional MCS or the ECPS during surgery at Osaka City University Hospital between January 2016 and July 2022 were enrolled in this study. Results The incidence of anastomotic leakage in the ECPS group was significantly lower than that in the MCS group (4.4% versus 14.3%, p = 0.048). Furthermore, even after propensity score matching, an association was found between the use of the ECPS and a reduced incidence of anastomotic leakage. Conclusion The ECPS has the potential to help reduce the rate of anastomotic leakage in left-sided colorectal surgery.

Abstract Fertilization controls various aspects of cereal growth such as tiller number, leaf size, and panicle size. However, despite such benefits, global chemical fertilizer use must be reduced to achieve sustainable agriculture. Here, based on field transcriptome data from leaf samples collected during rice cultivation, we identify fertilizer responsive genes and focus on Os1900, a gene orthologous to Arabidopsis thaliana MAX1, which is involved in strigolactone biosynthesis. Elaborate genetic and biochemical analyses using CRISPR/Cas9 mutants reveal that Os1900 together with another MAX1-like gene, Os5100, play a critical role in controlling the conversion of carlactone into carlactonoic acid during strigolactone biosynthesis and tillering in rice. Detailed analyses of a series of Os1900 promoter deletion mutations suggest that fertilization controls tiller number in rice through transcriptional regulation of Os1900, and that a few promoter mutations alone can increase tiller numbers and grain yields even under minor-fertilizer conditions, whereas a single defective os1900 mutation does not increase tillers under normal fertilizer condition. Such Os1900 promoter mutations have potential uses in breeding programs for sustainable rice production.

Abstract Background To prevent anastomotic leakage in patients with left-sided colorectal cancer who underwent double-stapling technique (DST) anastomosis, we investigated a new method: DST anastomosis with a polyglycolic acid (PGA) sheet. This procedure has been shown to have the potential to decrease the rate of anastomotic leakage. However, due to the small number of cases enrolled in our previous study, it was not possible to compare the outcomes of the new and conventional procedures. The aim of this study was to evaluate the effect of the PGA sheet on preventing anastomotic leakage in patients with left-sided colorectal cancer who underwent DST anastomosis by retrospectively comparing the anastomotic leakage rate between the PGA sheet and conventional groups. Methods A total of 356 patients with left-sided colorectal cancer who underwent DST anastomosis during surgery at Osaka City University Hospital between January 2016 and April 2022 were enrolled in this study. Propensity score matching was performed to reduce the confounding effects secondary to imbalances in the use of PGA sheets. Results The PGA sheet was used in 43 cases (PGA sheet group) and it was not used in 313 cases (conventional group). After propensity score matching, the incidence of anastomotic leakage in the PGA sheet group was significantly lower than that in the conventional group. Conclusion DST anastomosis with PGA sheet, which is easy to perform, contributes to the reduction of anastomotic leakage rate by increasing the strength of the anastomotic site.

BackgroundCaspase-1 is a crucial component in the inflammasome activation cascade. This study evaluated the potential of serum caspase-1 level as an inflammatory biomarker in patients with adult-onset Still's disease (AOSD).MethodsThe study included 51 consecutive patients diagnosed with AOSD based on the Yamaguchi criteria, 66 patients with rheumatoid arthritis (RA) as disease control, and 36 healthy controls (HCs). Serum caspase-1 concentrations were measured using enzyme-linked immunosorbent assay. The serum 69 cytokine levels were analyzed using a multisuspension cytokine array in patients with AOSD, and a cluster analysis of each cytokine was performed to determine specific molecular networks.ResultsPatients with AOSD had significantly increased serum caspase-1 levels versus patients with RA (p < 0.001) and HCs (p < 0.001). Additionally, serum caspase-1 demonstrated significant positive correlations with AOSD disease activity score (Pouchot score, r = 0.59, p < 0.001) and serum ferritin (r = 0.54, p < 0.001). Furthermore, among patients with AOSD, significant correlations existed between serum caspase-1 and inflammatory cytokines, including interleukin-18. Immunoblot analysis detected the cleaved form of caspase-1 (p20) in the serum of untreated patients with AOSD, not in those from patients with inactive AOSD receiving immunosuppressive treatments.ConclusionsCaspase-1 is a useful biomarker for AOSD diagnosis and monitoring. Caspase-1 activation could be correlated with the inflammatory component of AOSD, specifically through proinflammatory cytokine induction via inflammasome activation cascades.

BackgroundJanus kinase (JAK) inhibitors (JAKis) are effective therapeutic agents against rheumatoid arthritis (RA). However, patients having RA with particular risk factors may have a higher incidence of adverse effects (AEs), including major cardiovascular events (MACE) and infections. In this multicenter cohort study, we aimed to clarify the risk factors affecting the drug retention of JAKis in patients with RA.MethodsWe retrospectively evaluated patients with RA who received their first JAKi (tofacitinib, baricitinib, upadacitinib, or filgotinib) at our institute. The clinical outcomes, including AEs, were recorded, particularly MACE and serious infections. The drug retention rates were analyzed using the Kaplan-Meier method, and risk factors affecting drug retention rates were determined using a multivariable Cox regression hazards model.ResultsOverall 184 patients with RA receiving their first use of baricitinib (57.6%), tofacitinib (23.9%), upadacitinib (12.0%), or filgotinib (6.5%) were included in this study. Fifty-six (30.4%) patients discontinued JAKi treatment owing to ineffectiveness (9.2%) or AEs, including infections (21.2%). The overall drug retention rates were significantly lower in patients treated with pan-JAKi than in those treated with JAK1 inhibitors (p = 0.03). In the Cox regression model, the presence of baseline high RA disease activity, use of glucocorticoid and treatments with pan-JAKis were associated with reduced drug retention rates of JAKis (p < 0.001, p = 0.01 and 0.04, respectively). Pan-JAKi treated patients with high disease activity had significantly lower drug retention rates (p < 0.001).ConclusionsIn a real-world setting, the drug retention rates of JAKis were reduced mainly by treatment discontinuation owing to AEs. Treatment with pan-JAKis and high baseline RA disease activity were identified as predictive factors for the discontinuation of JAKis. Lower drug retention rates were found in patients receiving pan-JAKis with high disease activity than in those without high disease activity.

Aim. The aim of this study was to investigate whether cytokines associated with tumour necrosis factor- (TNF-) α and interleukin- (IL-) 6 signalling could predict rheumatoid arthritis (RA) clinical remission (CR) with Janus kinase inhibitor (JAKinib) treatment using the Simplified Disease Activity Index (SDAI). Methods. Eighty-nine patients with RA treated with JAKinibs were enrolled, and their clinical data were collected retrospectively. CR was defined as an SDAI≤3.3 after 6 months of treatment with JAKinib. The serum samples of 89 patients were analysed for IL-6, soluble IL-6 receptor (sIL-6R), soluble gp130 (spg130), and soluble TNF receptor- (sTNFR-) I and sTNFR-II titres. Results. There were no significant differences in the baseline clinical parameters between the CR and non-CR groups. Serum levels of IL-6, sIL-6R, and sgp130 were not significantly different; whereas, the serum sTNFR-I and sTNFR-II levels were significantly lower in the CR group. Univariate and multivariate logistic regression analysis showed that the baseline log sTNFR II values (OR: 0.002; p=0.034) were predictors of CR. Conclusions. Patients with RA can be stratified prior to JAKinib administration using serum sTNFR-I and sTNFR-II levels but not serum IL-6 axis cytokine levels (IL-6, sIL-6R, and sgp130).

BackgroundSubtotal esophagectomy with lymph node dissection followed by neoadjuvant chemotherapy (NAC) is the standard treatment for stage II-III esophageal cancer. Esophagectomy is still associated with high morbidity rates, and reducing these rates remains challenging. Among several complications, postoperative pneumonia (PP) is sometimes fatal, which has been reportedly caused by sarcopenia. Thus, nutritional support and rehabilitation may be promising for preventing skeletal muscle mass loss and reduce the incidence of PP.MethodsThis single-center, randomized, open-label, pilot trial will randomize a total of 40 patients with esophageal cancer in a 1:1 ratio either to ISOCAL Clear + rehabilitation arm or only rehabilitation arm. Although all patients will be educated about rehabilitation by a specialized physician and will be asked to undergo the prespecified rehabilitation program, patients treated with ISOCAL Clear + rehabilitation arm will be supplemented by 400 mL of ISOCAL Clear (Nestlé Japan Ltd, Tokyo, Japan) per day during two courses of NAC with docetaxel, cisplatin, and fluorouracil. Body composition will be assessed using Inbody (Inbody Co., Ltd., Tokyo, Japan) just before starting NAC and surgery. The primary endpoint is the change of skeletal muscle index (SMI) during NAC. Secondary endpoints include (i) body weight, total skeletal muscle mass, appendicular skeletal muscle mass, and lean body mass index changes; (ii) the percentage of ISOCAL Clear continuation; (iii) appetite evaluation; (iv) the percentage of targeted calorie achievement; (v) adverse events of NAC; (vi) postoperative complication rates; and (vii) postoperative hospital stay.DiscussionThis prospective trial assesses the efficacy of nutritional support in addition to rehabilitation during NAC for patients with esophageal cancer. The results will be utilized in assessing whether the effects of nutritional support by ISOCAL Clear are promising or not and in planning future larger clinical trials.

BackgroundMaintaining good communication and engagement between people with dementia and their caregivers is a major challenge in dementia care. Cognitive stimulation is a psychosocial intervention that supports communication and engagement, and several digital applications for cognitive stimulation have been developed. Personalization is an important factor for obtaining sustainable benefits, but the time and effort required to personalize and optimize applications often makes them difficult for routine use by nonspecialist caregivers and families. Although artificial intelligence (AI) has great potential to support automation of the personalization process, its use is largely unexplored because of the lack of suitable data from which to develop and train machine learning models. ObjectiveThis pilot study aims to evaluate a digital application called Aikomi in Japanese care homes for its potential to (1) create and deliver personalized cognitive stimulation programs to promote communication and engagement between people with dementia and usual care staff and (2) capture meaningful personalized data suitable for the development of AI systems. MethodsA modular technology platform was developed and used to create personalized programs for 15 people with dementia living in 4 residential care facilities in Japan with the cooperation of a family member or care staff. A single intervention with the program was conducted with the person with dementia together with a care staff member, and for some participants, smell stimulation was provided using selected smell sticks in conjunction with the digital program. All sessions were recorded using a video camera, and the combined personalized data obtained by the platform were analyzed. ResultsMost people with dementia (10/15, 67%) showed high levels of engagement (>40 on Engagement of a Person with Dementia Scale), and there were no incidences of negative reactions toward the programs. Care staff reported that some participants showed extended concentration and spontaneous communication while using Aikomi, which was not their usual behavior. Smell stimulation promoted engagement for some participants even when they were unable to identify the smell. No changes in well-being were observed following the intervention according to the Mental Function Impairment Scale. The level of response to each type of content in the stimulation program varied greatly according to the person with dementia, and personalized data captured by the Aikomi platform enabled understanding of correlations between stimulation content and responses for each participant. ConclusionsThis study suggests that the Aikomi digital application is acceptable for use by persons with dementia and care staff and may have the potential to promote communication and engagement. The platform captures personalized data, which can provide suitable input for machine learning. Further investigation of Aikomi will be conducted to develop AI systems and create personalized digital cognitive stimulation applications that can be easily used by nonspecialist caregivers.