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Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequ

Although endometriosis is a benign disease, it is associated with cancer-related gene mutations, such as KRAS or PIK3CA. Endometriosis is associated with elevated levels of inflammatory factors that cause severe pain. In a previous study, we demonstrated that KRAS or PIK3CA mutations are associated with the activation of cell proliferation, migration, and invasion in a patient-derived immortalized endometriotic cell line, HMOsisEC10. In this study, we investigated the effects of these mutations on progesterone resistance. Since the HMOsisEC10 had suppressed progesterone receptor (PR) expression, we transduced PR-B to HMOsisEc10 cell lines including KRAS mutant and PIK3CA mutant cell lines. We conducted a migration assay, invasion assay, and MTT assay using dienogest and medroxyprogestrone acetate. All cell lines showed progesterone sensitivity with or without mutations. Regarding inflammatory factors, real-time quantitative RT-PCR revealed that the KRAS mutation cell line exhibited no suppression of Cox-2 and mPGES-1 on progesterone treatment, whereas IL-6, MCP-1, VEGF, and CYP19A1 were significantly suppressed by progesterone in both mutated cell lines. Our results suggest that KRAS mutation and PIK3CA mutation in endometriotic cells may not be associated with progesterone resistance in terms of aggressiveness. However, KRAS mutations may be associated with progesterone resistance in the context of pain.

Background: Percutaneous left atrial appendage closure (LAAC) is an effective therapy to prevent thromboembolic events among patients with atrial fibrillation (AF). However, since the left atrial appendage (LAA) contributes to left atrial volume and serves as a buffer for increasing left atrial pressure, this procedure may impair left atrium (LA) compliance, enlarge LA, and deteriorate diastolic function. In this study, we sought to investigate the change in left atrial volume index (LAVI) following LAAC and its effect on prognosis. Methods and Results: We analyzed 225 patients from the OCEAN-LAAC registry, an ongoing, multicenter Japanese study. Comparing LAVI measurements at baseline and 6 months after LAAC, no significant increase was observed (55.0 [44.0, 70.0] ml/m2 vs. 55.0 [42.0, 75.6] ml/m2; P = 0.31). However, some patients underwent LAVI increase. Particularly, a smaller LAVI (odds ratio [OR]: 0.98 [95 % confidence interval (CI): 0.97–0.996]) and elevated tricuspid regurgitation pressure (TRPG) at baseline (OR: 1.04 [95 % CI: 1.00 – 1.08]) were significantly related to the increase in LAVI at 6-month follow-up. In addition, a 5 ml/m2 increase in LAVI was significantly associated with subsequent heart failure hospitalization (HFH) (hazard ratio: 3.37 [95 % CI: 1.18–9.65]). This association, however, was not observed in patients with lower baseline LAVI (≤55 ml/m2) but was only seen in those with a baseline LAVI over 55 ml/m2. Conclusion: Our study demonstrated an increase in LAVI after LAAC was related to smaller LAVI or elevated TRPG at baseline. The LAVI increase was significantly associated with subsequent HFH.

Abstract Tumor tissues consist of heterogeneous cells that originate from stem cells; however, their cell fate determination program remains incompletely understood. Using patient-derived organoids established from patients with advanced colorectal cancer (CRC), we evaluated the potential of olfactomedin 4 (OLFM4)+ stem cells to produce a bifurcated lineage of progenies with absorptive and secretory properties. In the early phases of organoid reconstruction, OLFM4+ cells preferentially gave rise to secretory cells. Additionally, we found that Paneth-like cells, which do not exist in the normal colon, were induced in response to Notch signaling inhibition. Video recordings of single OLFM4+ cells revealed that organoids containing Paneth-like cells were effectively propagated and that their selective ablation led to organoid collapse. In tumor tissues, Paneth-like cells were identified only in the region where tumor cells lost cell adhesion. These findings indicate that Paneth-like cells are directly produced by OLFM4+ stem cells and that their interaction contributes to tumor formation by providing niche factors. This study reveals the importance of the cell fate specification program for building a complete tumor cellular ecosystem, which might be targeted with novel therapeutics.

Euglena extract has anti-influenza virus activity, which can be enhanced using quercetin. This zinc ionophore reduces the time needed for zinc to penetrate infected cells and exerts strong anti-influenza virus activity. We investigated this phenomenon by exposing influenza A virus H1N1, cultured in Madin-Darby canine kidney cells, to a Euglena extract and quercetin solution. The viral titer was measured using the focus-forming reduction assay, and zinc levels in the cells were determined using Zinquin ethyl ester. Colby's equation was used to determine whether viral inhibition was due to a synergistic effect. Quercetin synergistically enhanced the anti-influenza virus effect of Euglena extract (inhibition rate: 89.3 % after 24 h) by rapidly inducing cellular zinc production and increasing intracellular zinc content (1.25 times higher than that of the control). This medicinal combination may provide new possibilities for preventing and treating influenza.

Advanced glycation end products (AGEs) accumulate in the plasma of pregnant women with hyperglycemia, potentially inducing oxidative stress and fetal developmental abnormalities. Although intrauterine hyperglycemia has been implicated in excessive fetal growth, the effects of maternal AGEs on fetal development remain unclear. We evaluated the differentiation regulators and cellular signaling in the skeletal muscles of infants born to control mothers (ICM), diabetic mothers (IDM), and diabetic mothers supplemented with either cis-palmitoleic acid (CPA) or trans-palmitoleic acid (TPA). Cell viability, reactive oxygen species levels, and myotube formation were assessed in AGE-exposed C2C12 cells to explore potential mitigation by CPA and TPA. Elevated receptors for AGE expression and decreased Akt and AMPK phosphorylation were evident in rat skeletal muscles in IDM. Maternal palmitoleic acid supplementation alleviated insulin resistance by downregulating RAGE expression and enhancing Akt phosphorylation. The exposure of the C2C12 cells to AGEs reduced cell viability and myotube formation and elevated reactive oxygen species levels, which were attenuated by CPA or TPA supplementation. This suggests that maternal hyperglycemia and plasma AGEs may contribute to skeletal muscle disorders in offspring, which are mitigated by palmitoleic acid supplementation. Hence, the maternal intake of palmitoleic acid during pregnancy may have implications for fetal health.

Circulating microRNAs (miRNAs) were investigated as biomarkers for the diagnosis of early pregnancy in cattle. The levels of prospective miRNA biomarkers and the features of extracellular vesicles (EVs) in the blood were evaluated. In Study 1, plasma samples from cows 21 days after artificial insemination (AI) were examined using RT-qPCR to determine the levels of seven circulating miRNAs. Only the levels of miR-126-3p were significantly lower in the pregnant group than in the non-pregnant group. In Study 2, among individuals not pregnant at the first AI, the miRNA levels were compared between the individuals pregnant at the second AI and those who remained non-pregnant. The miR-25 levels were significantly higher in the pregnant group at the second AI than in the pregnant group at the first AI; miR-19b, miR-27b, and miR-29a levels were also high. In the non-pregnant group, changes were absent in the miRNA levels in the same individual between the first and second AIs. In Study 3, Western blotting and RT-qPCR showed the presence of miRNAs in EVs and their levels were lower than in plasma. Thus, circulating miR-126-3p may serve as a biomarker for the diagnosis of early pregnancy in cattle. In addition, the expression of some miRNAs tended to be higher during pregnancy than during non-pregnancy in the same individual, suggesting their potential as an index to determine pregnancy and non-pregnancy rates using a comparative method.

Background: AT-rich interaction domain 1A (ARID1A) has been proposed as a new biomarker for predicting response to immune checkpoint inhibitors (ICIs). The predictive value of ARID1A for predicting ICI effectiveness has not been reported for endometrial cancer. Therefore, we investigated whether ARID1A negativity predicts ICI effectiveness for endometrial cancer treatment. Methods: We evaluated ARID1A expression, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1/PD-1) by immunostaining endometrial samples from patients with endometrial cancer. Samples in which any of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) were determined to be negative via immunostaining were excluded. In the ARID1A-negative group, microsatellite instability (MSI) status was confirmed via MSI analysis. Results: Of the 102 samples investigated, 25 (24.5%) were ARID1A-negative. CD8 and PD-1 expression did not differ significantly between the ARID1A-negative group and the ARID1A-positive group; however, the ARID1A-negative group showed significantly lower PD-L1 expression. Only three samples (14.2%) in the ARID1A-negative group showed high MSI. Sanger sequencing detected three cases of pathological mutation in the MSH2-binding regions. We also established an ARID1A-knockout human ovarian endometriotic epithelial cell line (HMOsisEC7 ARID1A KO), which remained microsatellite-stable after passage. Conclusion: ARID1A negativity is not suitable as a biomarker for ICI effectiveness in treating endometrial cancer.

Herein, we present the successful treatment of a 92-year-old woman who experienced recurrent EC in the vaginal stump and para-aortic lymph nodes. The patient was first treated with paclitaxel and carboplatin for recurrent EC, which was abandoned after two cycles of chemotherapy because of G4 hematologic toxicity. Later, the patient was treated with letrozole for early-stage breast cancer, which was diagnosed simultaneously with EC recurrence. After four months of hormonal therapy, a partial response was observed not only in the lesions in the breast, but also those in the vaginal stump and para-aortic lymph nodes. She had no recurrence of breast cancer or EC, even after six years of treatment with letrozole-based hormonal therapy. Subsequent whole-exome sequencing using the genomic DNA isolated from the surgical specimen in the uterine tumor identified several genetic variants, including actionable mutations, such as CTNNB1 (p.S37F), PIK3R1 (p.M582Is_10), and TP53 c.375 + 5G>T. These data suggest that the efficacy of letrozole is mediated by blocking the mammalian target of the rapamycin pathway. The findings of this study, substantiated via genetic analysis, suggest the possibility of long-term disease-free survival, even in elderly patients with recurrent EC, which was thought to be difficult to cure completely.

Tumor heterogeneity remains an ongoing challenge in the field of cancer therapy. Intratumor heterogeneity significantly complicates the diagnosis of cancer and presents challenging clinical problems due to resistance to drug therapy. This study aimed to elucidate the genetic changes histologically (mucinous cystadenoma (MCA), mucinous borderline tumor (MBT), and mucinous ovarian carcinoma (MOC)) in a portion of mucinous ovarian tumors within the same sample. Seven tumor samples obtained from different patients were used to evaluate the genetic mutations in each component. Intratumor genetic heterogeneity was observed in all patients; among them, BRAF (V600E) and p53 (T118I, P142S, T150I, and T170M) point mutations were observed in the MBT component, while KRAS (G12D and G13D) and PIK3CA (E545K) mutations were found in the MOC component. The current findings suggest that diverse genetic alterations occur in mucinous tumors, according to tumor histology. Tumor heterogeneity and genetic diversity in mucinous ovarian tumors might be the cause of treatment failure. Knowledge of intertumor heterogeneity may lead to an increased understanding of the tumor response to treatment.

ObjectiveReducing dietary salt intake is an essential population strategy for cardiovascular disease (CVD) prevention, but evidence on healthcare costs and outcomes is limited in Japan. We aimed to conduct a pilot economic evaluation under hypothetical scenarios of applying the salt reduction policies of England to Japan.MethodsWe examined salt reduction policies in England: media health promotion campaigns, front-of-pack labeling, and voluntary and mandatory reformulation with best-case and worst-case policy cost scenarios. We assumed that these policies were conducted in Japan for 10 years from 2019. We used published data on epidemiology and healthcare expenditures in Japan and the costs and effects of salt reduction policies in England, and defined the benefits as a decrease in national medical expenditures on CVD. We developed a Markov cohort simulation model of the Japanese population. To estimate the annual net benefits of each policy over 10 years, we subtracted monitoring and policy costs from the benefits. We adopted a health sector perspective and a 2% discount rate.ResultsThe cumulative net benefit over 10 years was largest for mandatory reformulation (best case) at 2,015.1 million USD (with costs of USD 48.3 million and benefits of USD 2063.5 million), followed by voluntary reformulation (net benefit: USD 1,895.1 million, cost: USD 48.1 million, benefit: USD 1,943.2 million), mandatory reformulation (worst case, net benefit: USD 1,447.9 million, cost: USD 1,174.5 million, benefit: USD 2,622.3 million), labeling (net benefit: USD 159.5 million, cost: USD 91.6 million, benefit: USD 251.0 million), and a media campaign (net benefit: USD 140.5 million, cost: USD 110.5 million, benefit: USD 251.0 million). There was no change in the superiority or inferiority of policies when the uncertainty of model parameters was considered.ConclusionMandatory reformulation with the best-case cost scenario might be economically preferable to the other alternatives in Japan. In future research, domestic data on costs and effects of salt reduction policies should be incorporated for model refinement.

Summary: Nutritional deprivation occurring in most preterm infants postnatally can induce hyperglycemia, a significant and independent risk factor for suppressing physiological retinal vascularization (Phase I retinopathy of prematurity (ROP)), leading to compensatory but pathological neovascularization. Amino acid supplementation reduces retinal neovascularization in mice. Little is known about amino acid contribution to Phase I ROP. In mice modeling hyperglycemia-associated Phase I ROP, we found significant changes in retinal amino acids (including most decreased L-leucine, L-isoleucine, and L-valine). Parenteral L-isoleucine suppressed physiological retinal vascularization. In premature infants, severe ROP was associated with a higher mean intake of parenteral versus enteral amino acids in the first two weeks of life after adjustment for treatment group, gestational age at birth, birth weight, and sex. The number of days with parenteral amino acids support independently predicted severe ROP. Further understanding and modulating amino acids may help improve nutritional intervention and prevent Phase I ROP.

Abstract Pediatric graft-versus-host-disease (GVHD)-related dry eye disease (DED) is often overlooked due to a lack of subjective symptoms and reliable testing, leading to irreversible corneal damage. To study the clinical findings contributing to the accurate detection of pediatric GVHD-related DED, a retrospective study of pediatric patients treated with hematopoietic stem cell transplantation (HSCT) at Keio University Hospital between 2004 and 2017 was conducted. Association and diagnostic values of ophthalmological findings for DED were analyzed. Twenty-six patients who had no ocular complications before HSCT were included in the study. Eleven (42.3%) patients developed new-onset DED. The cotton thread test showed excellent diagnostic accuracy in detecting DED (area under the receiver operating curve, 0.96; sensitivity, 0.95; specificity, 0.85) with a cut-off of 17 mm, which was higher than the conventional threshold of 10 mm. Additionally, the presence of filamentary keratitis (FK) and pseudomembranous conjunctivitis (PC) were significantly associated with the diagnosis of DED (p value, 0.003 and 0.001 for FK and PC, respectively) and displayed good diagnostic performance (sensitivity, 0.46 and 0.54; specificity, 0.97 and 0.97 for FK and PC, respectively). In conclusion, the cotton thread test with a new threshold, the presence of PC and FK, could be helpful for promptly detecting pediatric GVHD-related DED.

This in vivo study aimed to investigate local and systemic immune responses induced by sperm in cows after artificial insemination (AI). Initially, 12 multiparous Japanese Black cows were subjected to intrauterine AI (AI group, n = 6) or saline infusion (control group, n = 6). The uterine body and horn ipsilateral to the ovulatory follicle were mini-flushed with 2 ml of RPMI-1640 medium at different time points (0, 1, 6, 10, 24, 48 h, and 7 days after AI), centrifuged, and the sediments were examined under a light microscope. Vaginal smears were prepared at 0, 1, 6, and 10 h after AI to investigate the sperm backflow. Subsequently, another experiment was conducted by assigning cows to three groups: intrauterine AI (AI group, n = 5), heat-inactivated AI (Heat-AI group, n = 5), or saline infusion (control group, n = 5). Blood samples were collected, and polymorphonuclear neutrophils (PMNs) and peripheral blood mononuclear cells (PBMCs) were separated and analyzed for gene expression using real-time PCR. The results showed that most sperm were rapidly transported either forward into the uterine horn or backward into the vagina within 1 h after AI. The PMNs migrated into the uterine lumen 6 hours after AI. Only active sperm-induced proinflammatory responses in PMNs and PBMCs via upregulation of TNFa, IL8, IL1B, and PGES and downregulation of IL10 at 6 h after AI. These data provide evidence that sperm generate transient proinflammatory responses locally in the uterus and systemically in the peripheral immune cells, which may be prerequisites for uterine clearance, embryo receptivity, and implantation in cows.

Background: Since malignant struma ovarii is a very rare disease, its carcinogenic mechanism has not been elucidated. Here, we sought to identify the genetic lesions that may have led to the carcinogenesis of a rare case of malignant struma ovarii (follicular carcinoma) with peritoneal dissemination. Methods: DNA was extracted from the paraffin-embedded sections of normal uterine tissues and malignant struma ovarii for genetic analysis. Whole-exome sequencing and DNA methylation analysis were then performed. Results: Germline variants of RECQL4, CNTNAP2, and PRDM2, which are tumor-suppressor genes, were detected by whole-exome sequencing. Somatic uniparental disomy (UPD) was also observed in these three genes. Additionally, the methylation of FRMD6-AS2, SESN3, CYTL1, MIR4429, HIF3A, and ATP1B2, which are associated with tumor growth suppression, was detected by DNA methylation analysis. Conclusions: Somatic UPD and DNA methylation in tumor suppressor genes may be associated with the pathogenesis of malignant struma ovarii. To our knowledge, this is the first report of whole-exome sequencing and DNA methylation analysis in malignant struma ovarii. Genetic and DNA methylation analysis may help elucidate the mechanism of carcinogenesis in rare diseases and guide treatment decisions.

Recognizing Textual Entailment (RTE) is among the most fundamental tasks in natural language processing applications, such as question answering and machine translation. One of the main challenges in logic-based approaches to this task is the lack of background knowledge. This study proposes a logical inference system with phrasal knowledge by comparing their visual representations based on the intuition that visual representations enable people to judge entailment relations. First, we obtain candidate phrase pairs for phrasal knowledge from logical inference. Second, using a vision-and-language model, we acquire the visual representations of these phrases in the form of images or embedding vectors. Finally, we compare these obtained visual representations to determine whether to inject the knowledge corresponding to the candidate. In addition to simple similarity between phrases, we also consider asymmetric relations when comparing visual representations. Our logical inference system improved accuracy on the SICK dataset compared with a previous logical inference system, SPSA (Selector of Predicates with Shared Arguments). Moreover, our asymmetric evaluation functions using vision-and-language models are effective at capturing the entailment relations of word pairs in HyperLex.

(1) Background: In patients with heart failure (HF) and impaired nutritional status or decreased muscle mass, sodium-glucose cotransporter-2 inhibitors (SGLT2is) may worsen these conditions and result in poor prognosis, especially worsening of frailty. We aimed to investigate the relationship between SGLT2is and clinical outcomes, including frailty-related events, in patients with HF and malnutrition, frailty, sarcopenia, or cachexia. (2) Methods: In this retrospective observational cohort study, a global federated health research network provided data on patients with HF and malnutrition, frailty, sarcopenia, or cachexia from January 2016 to December 2021. We investigated the incidence of the composite endpoint of death or frailty-related events within one year. (3) Results: Among 214,778 patients included in the analysis, 4715 were treated with SGLT2is. After propensity score matching, 4697 patients in the SGLT2is group were matched with 4697 patients in the non-SGLT2is groups. The incidence of the composite endpoint, mortality, and frailty-related events was lower in the SGLT2is group than in the non-SGLT2is group (composite endpoint, 65.6% versus 77.6%, p < 0.001; mortality, 17.4% vs. 35.5%, p < 0.001; frailty-related events, 59.4% vs. 64.3%, p < 0.001). (4) Conclusions: Patients with HF and malnutrition, frailty, sarcopenia, or cachexia had a high incidence of death and frailty-related events. SGLT2is were associated with a lower incidence of these events.

Background: This study aimed to compare the oncologic and surgical outcomes of patients treated with robot-assisted modified radical hysterectomy (RAMRH) and total laparoscopic modified radical hysterectomy (TLMRH) for endometrial cancer (EC) with those of patients treated with abdominal modified radical hysterectomy (AMRH). Methods: We performed a retrospective analysis of 133 patients with early-stage EC who underwent different surgical approaches (RAMRH, n = 14; TLMRH, n = 94; AMRH, n = 25) between 2018 and 2021 at Shimane University Hospital. The data on clinical outcomes, including estimated blood loss, duration of surgery, duration of hospital stay, and number of dissected lymph nodes were collected from the patients’ electronic medical records. Kaplan–Meier curves were used to plot survival data, and log-rank tests were used to determine the statistical significance of differences in survival rates. Results: RAMRH showed the lowest bleeding volume (RAMRH: 95 ± 123.21 mL; TLMRH: 140.74 ± 172.60 mL; AMRH: 482.6 ± 429 mL) and shortest hospital stay (RAMRH: 6.43 ± 1.09 days; TLMRH: 7.30 ± 3.39 days; AMRH: 9.88 ± 2.65 days) among the three groups. The number of dissected lymph nodes tended to be higher in the RAMRH group than that in the TLMRH or AMRH group. The different surgical approaches did not correlate with progression-free survival and overall survival. Conclusions: Both RAMRH and TLMRH are safe, feasible, innovative, and minimally invasive surgical alternatives to AMRH for patients with EC.

Antimicrobial resistance to currently available antibiotics requires innovation of antibiotics. Here, the authors identify a critical inhibitory site in an energy-producing enzyme, which can lead to rational design of antibiotics.

Abstract Background Electronic cigarettes (e-cigarettes) are used worldwide as a substitute for conventional cigarettes. Although they are primarily intended to support smoking cessation, e-cigarettes have been identified as a gateway to smoking habits for young people. Multiple recent reports have described the health effects of inhaling e-cigarettes. E-cigarette liquid (e-liquid) is mainly composed of propylene glycol (PG) and glycerol (Gly), and the aerosol generated by these devices primarily contains these two components. Thus, this study aimed to evaluate the effects of PG and Gly on human small airway epithelial cells (SAECs). Methods SAECs were exposed to PG or Gly, and cell proliferation, cell viability, lactate dehydrogenase (LDH) release, DNA damage, cell cycle, and apoptosis were evaluated. Additionally, SAECs derived from chronic obstructive pulmonary disease (COPD) patients (COPD-SAECs) were investigated. Results Exposure of SAECs to PG significantly inhibited proliferation (1%, PG, p = 0.021; 2–4% PG, p

Few studies have reported hormonal agent use in the treatment of low-grade serous ovarian carcinomas (LGSOCs), which are chemoresistant. Considering the need for novel effective therapies, we investigated the hormone receptor expression and hormonal inhibition efficacy in LGSOCs. Using immunohistochemistry, we assessed the estrogen receptor (ER) expression status in 33 cases of histologically confirmed serous ovarian tumors, including 10, 11, and 12 cases of LGSOCs, serous borderline tumors (SBTs), and serous cystadenomas (SCAs), respectively. The genetic background reported in our previous study was used in the current study. MPSC1 cells, which were established from LGSOCs, were used in cell proliferation assays. We observed a higher ER expression in LGSOCs and SBTs than in SCAs (70%, 81%, and 50%, respectively). Thus, LGSOCs and SBTs exhibit higher ER expression than SCAs. Moreover, the PIK3CA mutation positively correlated with ER expression in LGSOCs (p = 0.0113). MPSC1 cells showed low ER expression on Western blotting. MPSC1 cell proliferation was significantly inhibited by fulvestrant (a selective ER downregulator). The activation of ER and PI3K/AKT signaling pathways may play an important role in LGSOC carcinogenesis. ER downregulation with fulvestrant or combination therapy with PI3K inhibitors is a possible novel treatment for patients with LGSOCs.

Ovarian seromucinous tumors (SMBTs) are relatively rare, and their carcinogenesis is largely unknown. In this study, the molecular features of SMBTs in Japan are assessed. DNA was extracted from microdissected paraffin-embedded sections from 23 SMBT cases. Genetic mutations (KRAS, BRAF, PIK3CA, and ERBB2) were evaluated using Sanger sequencing. Immunohistochemistry for p53, ARID1A, and PTEN was also performed as a surrogate for the loss of functional mutations in these tumor suppressor genes. The prevalence of KRAS, BRAF, PIK3CA, and ERBB2 mutations was 4.3% (1/23), 8.6% (2/23), 8.6% (2/23), and 17.3% (4/23), respectively. Overexpression or loss of p53 expression occurred in 26% (6/23), loss of ARID1A expression in 4.3% (1/23), and none of the cases showed expression of PTEN loss. These findings suggest that KRAS/BRAF/PIK3CA and PTEN mutations are rare carcinogenic events in SMBTs. The high frequency of positive p53 staining and a low frequency of loss of ARID1A staining suggests that SMBT carcinogenesis may be related to the alteration of p53 rather than that of ARID1A. ERBB2 oncogenic mutations may play an important role in the tumorigenesis of Japanese SMBTs.

Introduction. Chronic obstructive pulmonary disease (COPD) is the third leading cause of death, and COPD exacerbation worsens the prognosis. Eosinophilic airway inflammation is a COPD phenotype that causes COPD exacerbation and is correlated with peripheral blood eosinophil count. We analyzed real-world data of COPD patients to assess the risk factors of COPD exacerbation focusing on blood eosinophils. Materials and Methods. Patients with COPD who visited our hospital between January 1, 2018, and December 31, 2018, were recruited, and their background information, spirometry data, laboratory test results, and moderate-to-severe exacerbation events during the one-year follow-up period were collected from the electronic medical records and analyzed. The COPD exacerbation risk factors were assessed using univariate and multivariate logistic regression analyses. Results. Twenty-two of 271 (8.1%) patients experienced moderate-to-severe exacerbation. Patients with exacerbation showed worse pulmonary function, and we found that a high blood eosinophil count (≥350 cells/μL; p=0.014), low % FEV1 (

BackgroundAlthough lung ultrasound has been reported to be a portable, cost-effective, and accurate method to detect pneumonia, it has not been widely used because of the difficulty in its interpretation. Here, we aimed to investigate the effectiveness of a novel artificial intelligence-based automated pneumonia detection method using point-of-care lung ultrasound (AI-POCUS) for the coronavirus disease 2019 (COVID-19).MethodsWe enrolled consecutive patients admitted with COVID-19 who underwent computed tomography (CT) in August and September 2021. A 12-zone AI-POCUS was performed by a novice observer using a pocket-size device within 24 h of the CT scan. Fifteen control subjects were also scanned. Additionally, the accuracy of the simplified 8-zone scan excluding the dorsal chest, was assessed. More than three B-lines detected in one lung zone were considered zone-level positive, and the presence of positive AI-POCUS in any lung zone was considered patient-level positive. The sample size calculation was not performed given the retrospective all-comer nature of the study.ResultsA total of 577 lung zones from 56 subjects (59.4 ± 14.8 years, 23% female) were evaluated using AI-POCUS. The mean number of days from disease onset was 9, and 14% of patients were under mechanical ventilation. The CT-validated pneumonia was seen in 71.4% of patients at total 577 lung zones (53.3%). The 12-zone AI-POCUS for detecting CT-validated pneumonia in the patient-level showed the accuracy of 94.5% (85.1%- 98.1%), sensitivity of 92.3% (79.7%- 97.3%), specificity of 100% (80.6%- 100%), positive predictive value of 95.0% (89.6% - 97.7%), and Kappa of 0.33 (0.27-0.40). When simplified with 8-zone scan, the accuracy, sensitivity, and sensitivity were 83.9% (72.2%- 91.3%), 77.5% (62.5%- 87.7%), and 100% (80.6%- 100%), respectively. The zone-level accuracy, sensitivity, and specificity of AI-POCUS were 65.3% (61.4%- 69.1%), 37.2% (32.0%- 42.7%), and 97.8% (95.2%- 99.0%), respectively.InterpretationAI-POCUS using the novel pocket-size ultrasound system showed excellent agreement with CT-validated COVID-19 pneumonia, even when used by a novice observer.

Ryo Negishi et al. utilize a size-dependent recovery method with gel-based cell manipulation to isolate single circulating tumor cells (CTCs) for transcriptomic analysis. They demonstrate the utility of this approach by analyzing the transcriptomic profile of CTCs from human gastric cancer patients.

We previously reported that glycation induces insulin resistance in the hearts of newborn pups from a gestational diabetes mellitus (GDM) rat model. Administration of n-3 unsaturated fatty acids suppressed glycation and improved signaling in GDM rat pups. In this study, we investigated their effects on cranial neurons using the GDM rat model and PC12 cells derived from rat adrenal pheochromocytomas. Additionally, we examined whether n-3 and n-7 unsaturated fatty acids (cis-palmitoleic acid [CPA] and trans-palmitoleic acid [TPA]) ameliorate the detrimental effects of high glucose exposure on rats. In the neonatal cerebrum of GDM rats, increased levels of advanced glycation end products (AGEs) inhibited Akt phosphorylation; however, CPA and TPA intake during pregnancy ameliorated these abnormalities. Furthermore, exposure to high-glucose-induced apoptosis in PC12 cells compared to the cells cultured in control glucose. PC12 cells exposed to high-glucose with fatty acids exhibited reduced AGE production and apoptosis induction compared to the high-glucose group. These findings suggest that a hyperglycemic environment during pregnancy promotes AGE formation in brain neuronal proteins and induces apoptosis. Both TPA and CPA mitigated these abnormalities; however, CPA is cytotoxic, highlighting its safety in pregnant women.

Background: Recurrent angioedema (RecAE) has a substantial impact on patients’ daily lives. However, there have been no disease-specific patient-reported outcomes (PROs) available in Japan to measure disease activity and health-related QoL impairment in such patients. Methods: Japanese versions of the Angioedema Activity Score (AAS) and the Angioedema Quality of Life Questionnaire (AE-QoL) were examined for their validity and reliability. By using these questionnaires, the relationship between disease activity and QoL impairment among the Japanese population of RecAE were analyzed in real-world setting. Results: The Japanese AAS and AE-QoL domains showed good internal consistency of 0.967 and > 0.835. For known group validity, AAS28 and AE-QoL total scores were higher in more severe patients than those with milder disease and QoL impairment, respectively. AAS28 showed strong correlation with indexes of disease activity, while the AE-QoL total score correlated with Dermatology Life Quality Index (DLQI). Sufficient reproductivity of the AAS and AE-QoL was shown by their intraclass correlation coefficients of 0.890 and 0.700. The Japanese population is characterized by the total score of AAS28, 34.3 ± 38.8 (mean ± SD); and AE-QoL, 38.7 ± 25.2. Each domain score of AE-QoL was 32.4 ± 29.7 in “Functioning”, 35.0 ± 27.8 in “Fatigue/mood”, 50.7 ± 30.6 in “Fears/shame”, or 24.7 ± 29.8 in “Food”. Changes in AAS28 and AE-QoL positively correlated to Patient global assessment of disease activity and DLQI, respectively. Conclusions: The Japanese AAS and AE-QoL are valid and reliable instruments for Japanese patients with RecAE, and active disease affecting QoL. They help assess disease activity and QoL of RecAE in routine patient care and clinical trials.

Abstract Previous studies have largely failed to clarify the relationship between p16INK4A status and cervical adenocarcinoma prognosis. The current study aimed to examine the clinical and pathological significance of p16INK4A expression in several cervical adenocarcinoma subtypes. Eighty-two samples collected from patients with cervical adenocarcinoma were formalin fixed and paraffin embedded. Next, p16INK4A levels were analyzed with immunohistochemistry. Additionally, the relationship between p16INK4A expression and clinicopathological factors as well as prognosis was evaluated. The expression of p16INK4A was mostly detected in all usual cervical adenocarcinoma subtypes. In the gastric type, only a few cases were positive for p16INK4A expression. Results of the Kaplan–Meier analysis indicated that the positive p16INK4A expression in tumor cells was significantly associated with favorable progression-free survival and overall survival in patients with cervical adenocarcinoma (p = 0.018 and p = 0.047, respectively, log-rank test). Our findings suggest that the status of p16INK4A expression may influence prognosis. Thus, p16INK4A expression could be used as a biomarker for improving the prognosis of patients with cervical adenocarcinoma.

Summary: Senescent cells accumulation is associated with aging and age-related diseases, and recent findings suggest that autophagy, the activity of the intracellular degradation system, decreases during senescence. In this protocol, we detail steps to induce cellular senescence in response to DNA damage, evaluate the senescent state using SA-β-gal staining and western blot for p21, LAMP1, and Lamin B1, and detect autophagy via LC3 western blotting. This protocol can be used in most cell lines and for various types of senescent cells.For complete details on the use and execution of this protocol, please refer to Yamamoto-Imoto et al. (2022). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.