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Abstract Diarrhea is a common enteric disease in piglets that leads to high mortality and economic losses in swine production worldwide. Antibiotics are commonly used to prevent or treat diarrhea in piglets. However, irrational antibiotic use contributes to the development of resistance in bacteria and antibiotic residues in animal products, threatening public health, while causing gut microbiota dysbiosis and antibiotic-resistant bacterial infection in piglets. Therefore, the quest for alternative products (such as probiotics, prebiotics, organic acids, enzymes, essential oils, medium-chain fatty acids, zinc, and plant extracts) has recently been clearly emphasized through the increase in regulations regarding antibiotic use in livestock production. These antibiotic alternatives could lower the risk of antibiotic-resistant bacteria and meet consumer demand for antibiotic-free food. Several antibiotic alternatives have been proposed, including immunomodulatory probiotics, as candidates to reduce the need for antimicrobial therapy. Many studies have revealed that probiotics can avert and cure bacterial diarrhea by regulating the gut function and immune system of piglets. In this review, we focus on the major pathogenic bacteria causing piglet diarrhea, the research status of using probiotics to prevent and treat diarrhea, their possible mechanisms, and the safety issues related to the use of probiotics. Supplementation with probiotics is a possible alternative to antibiotics for the prevention or treatment of bacterial diarrhea in piglets. Furthermore, probiotics exert beneficial effects on feed efficiency and growth performance of piglets. Therefore, appropriate selection and strategies for the use of probiotics may have a positive effect on growth performance and also reduce diarrhea in piglets. This review provides useful information on probiotics for researchers, pig nutritionists, and the additive industry to support their use against bacterial diarrhea in piglets. Graphical Abstract Interaction of probiotics with the gut associated immune system. TLRS, Toll-like receptors; MAPK, Mitogen-activated protein kinases; TRAF, Tumor necrosis factor receptor-associated factor; DC, Dendritic cells; MP, Macrophages; NT, Naïve T cell; IL-10, Interleukin 10 proteins; Tregs, Regulatory T cells; Th1, Type 1 T helper cells; Th2, Type 2 T helper cells; Th17, Type 17 T helper cells; SIgA, Secretory immunoglobulin A; TJs, Tight junctions.

Abstract Background The AmoyDx Pan lung cancer PCR panel (AmoyDx PLC panel) has been approved as a companion diagnostic tool for multiple anticancer agents in patients with non‐small cell lung cancer (NSCLC). However, the suitability of cytology specimens as samples for the AmoyDx PLC panel remains unclear. We evaluated the performance of frozen cell pellets from cytology specimens (FCPs) in the Amoy 9‐in‐1 assay, a preapproval assay of the AmoyDx PLC panel. Methods We retrospectively collected data of NSCLC patients enrolled in LC‐SCRUM‐Asia from the Shizuoka Cancer Center between September 2019 and May 2021. Results A total of 49 cases submitted FCPs for evaluation of oncogenic driver alterations and were assessed using Amoy 9‐in‐1 and next‐generation sequencing (NGS) assays. The success rates of DNA and RNA analyses using the Amoy 9‐in‐1 were both 100%, compared with 86% and 45%, respectively, using NGS assays. Oncogenic driver alterations were detected in 27 (55%) and 23 (47%) patients using Amoy 9‐in‐1 and NGS, respectively. No inconsistent results were observed among 19 cases in which both assays showed successful detection. In the remaining 30 cases, 10 had inconsistent results: nine oncogenic driver alterations (3 MET, 2 ALK, 2 ROS1, and 2 KRAS) were detectable only in Amoy 9‐in‐1, and one epidermal growth factor receptor (EGFR) mutation was detectable only in NGS. Conclusion FCPs can be successfully used in the AmoyDx PLC panel, with higher success rate compared with the NGS assay. The AmoyDx PLC panel may be an option in cases when insufficient tissue sample is available for the NGS assay.

Abstract The efficacy of immune checkpoint inhibitors (ICIs) has been widely recognized in several cancers and is now being used in the perioperative setting for lung cancer. We recently encountered an immune-related adverse event that has not been previously reported: thoracic lymphangitis, which occurred after postoperative ICI treatment for lung cancer. The patient complained of breathlessness and her condition rapidly progressed to hypoxia grade 3. Chest computed tomography revealed significant lymphostasis. With high-dose steroid treatment, the patient showed improvement. Therefore, as the frequency of neoadjuvant, adjuvant, and perioperative ICI use is expected to increase, it is crucial to understand and monitor this adverse event.

Abstract Background Lipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1–27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness. Case presentation A 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels. Conclusion Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.

Abstract Feeding behaviors are determined by two main factors. One is the internal state, such as hunger or previous experiences; the other is external factors, such as sensory stimulation. During starvation, animals must balance food-seeking behavior with energy conservation. The fruit fly, Drosophila melanogaster, serves as a useful model for studying food selectivity and various behaviors related to food intake. However, few studies have directly connected food selectivity with other behaviors, such as locomotor activity and sleep. In this study, we report that flies exhibited a preference for specific positions and spent more time in the proximity of sweet sugars, such as sucrose and sucralose, but not non-sweet and nutritious sugars like xylitol and sorbitol. On the other hand, prolonged exposure to sorbitol increased the staying time of flies in the proximity of sorbitol. Additionally, after starvation, flies immediately exhibited a position preference in the proximity of sorbitol. These findings suggest that flies prefer the proximity of sweet food, and starvation alters their preference for nutritious food, which may be beneficial for their survival.

Abstract The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647–1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648–1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Abstract A total of 739 patients underwent RARP as initial treatment for PCa from November 2011 to October 2018. Data on BCR status, clinical and pathological parameters were collected from the clinical records. After excluding cases with neoadjuvant and/or adjuvant therapies, presence of lymph node or distant metastasis, and positive SM, a total of 537 cases were eligible for the final analysis. The median follow-up of experimental cohort was 28.0 (interquartile: 18.0–43.0) months. We identified the presence of International Society of Urological Pathology grade group (ISUP-GG) ≥ 4 (Hazard ratio (HR) 3.20, 95% Confidence Interval (95% CI) 1.70–6.03, P 20 mm (HR 1.9, 95% CI 1.01–3.70, P = 0.047) as significant factors of BCR in the multivariate analysis. We further developed a risk model according to these factors. Based on this model, 1-year, 3-year, and 5-year BCR-free survival were 100%, 98.9%, 98.9% in the low-risk group; 99.1%, 94.1%, 86.5% in the intermediate-risk group; 93.9%, 84.6%, 58.1% in the high-risk group. Internal validation using the bootstrap method showed a c-index of 0.742 and an optimism-corrected c-index level of 0.731. External validation was also carried out using an integrated database derived from 3 other independent institutions including a total of 387 patients for the final analysis. External validation showed a c-index of 0.655. In conclusion, we identified risk factors of biochemical failure in patients showing negative surgical margin after RARP and further developed a risk model using these risk factors.

Abstract The rapid and precise creation of complex molecules while controlling multiple selectivities is the principal objective in synthetic chemistry. Combining data science and organic synthesis to achieve this goal is an emerging trend, but few examples of successful reaction designs are reported. We develop an artificial neural network regression model using bond orbital data to predict chemical reactivities. Actual experimental verification confirms cycloheptatriene-selective [6 + 2]-cycloaddition utilizing nitroso compounds and norcaradiene-selective [4 + 2]-cycloaddition reactions employing benzynes. Additionally, a one-pot asymmetric synthesis is achieved by telescoping the enantioselective dearomatization of non-activated benzenes and cycloadditions. Computational studies provide a rational explanation for the seemingly anomalous occurrence of thermally prohibited suprafacial [6 + 2]-cycloaddition without photoirradiation.

Introduction Patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome have high risks of uterine and cutaneous leiomyomas and renal cell carcinoma (RCC), which are caused by germline mutation of the fumarate hydratase (FH) gene. RCC lesions are mostly high‐grade tumors with a poor prognosis. Case presentation A 37‐year‐old man who had previously undergone treatment for a left RCC was referred to our hospital with a diagnosis of right RCC. Robot‐assisted partial nephrectomy was performed, and the pathological diagnosis revealed fumarate hydratase (FH)‐deficient RCC. The left RCC, which was originally diagnosed as mucinous tubular and spindle cell carcinoma, was reviewed and diagnosed as FH‐deficient RCC. The patient's father and uncle both died of RCC, and the father's tumor was also immunohistochemically proven to be FH‐deficient RCC. Conclusion HLRCC‐related RCC should be considered in a differential diagnosis of young patients with a family history of RCC.

ABSTRACT: Mastitis is one of the most frequent and costly diseases affecting dairy cattle. Natural antibodies (immunoglobulins) and cyclophilin A (CyPA), the most abundant member of the family of peptidyl prolyl cis/trans isomerases, in milk may serve as indicators of mastitis resistance in dairy cattle. However, genetic information for CyPA is not available, and knowledge on the genetic and nongenetic relationships between these immune-related traits and somatic cell score (SCS) and milk yield in dairy cattle is sparse. Therefore, we aimed to comprehensively evaluate whether immune-related traits consisting of 5 Ig classes (IgG, IgG1, IgG2, IgA, and IgM) and CyPA in the test-day milk of Holstein cows can be used as genetic indicators of mastitis resistance by evaluating the genetic and nongenetic relationships with SCS in milk. The nongenetic factors affecting immune-related traits and the effects of these traits on SCS were evaluated. Furthermore, the genetic parameters of immune-related traits according to health status and genetic relationships under different SCS environments were estimated. All immune-related traits were significantly associated with SCS and directly proportional. Additionally, evaluation using a classification tree revealed that IgA, IgG2, and IgG were associated with SCS levels. Genetic factor analyses indicated that heritability estimates were low for CyPA (0.08) but moderate for IgG (0.37), IgA (0.44), and IgM (0.44), with positive genetic correlations among Ig (0.25–0.96). We also evaluated the differences in milk yield and SCS of cows between the low and high groups according to their sires' estimated breeding value for immune-related traits. In the high group, IgA had a significantly lower SCS in milk at 7 to 30 d compared with that in the low group. Furthermore, the Ig in milk had high positive genetic correlations between healthy and infected conditions (0.82–0.99), suggesting that Ig in milk under healthy conditions could interact with those under infected conditions, owing to the genetic ability based on the level of Ig in milk. Thus, Ig in milk are potential indicators for the genetic selection of mastitis resistance. However, because only the relationship between immune-related traits and SCS was investigated in this study, further study on the relationship between clinical mastitis and Ig in milk is needed before Ig can be used as an indicator of mastitis resistance.

Background: Although photodynamic-diagnosed transurethral resection of bladder cancer (PDD-TURBT) and Bacillus Calmette-Guérin (BCG) intravesical instillation are the two representative therapies for non-muscle invasive bladder cancer (NMIBC), no studies directly compare their efficacy. We evaluated the outcome of PDD-TURBT alone compared with white light TURBT with intravesical BCG therapy and analyzed the efficacy of both therapies depending on the characteristics of the tumors. Methods: We retrospectively analyzed intermediate- and high-risk NMIBC patients treated with PDD-TURBT alone (the PDD group) or white light TURBT with BCG therapy (the white light group) using propensity score matched analysis. Results: In the propensity score matched cohort, the 1-, 2-, and 3-year recurrence-free survival rates for the PDD group were 77.6 %, 64.1 %, and 48.1 %, respectively, compared to 84.6 %, 75.1 %, and 75.1 % for the white light group (p = 0.44, 0.27, 0.17, respectively). The difference in recurrence rates between the two groups tended to become more pronounced over time, although there was no significant difference. In the univariate and multivariate analysis, recurrence, multiplicity, and tumor grade were the significant prognostic factors of recurrence in the PDD group (p = 0.010, 0.047, 0.048, respectively). Long-term RFS was similar in the PDD and white light groups when the population was limited to the primary and single tumors, suggesting that PDD-TURBT alone may be sufficient in this spectrum of patients. Conclusions: PDD-TURBT alone is insufficient to control the long-term recurrence of bladder cancer but can be effective in selected cases such as primary and single tumors.

IntroductionLevilactobacillus brevis CRL 2013, a plant-derived lactic acid bacterium (LAB) with immunomodulatory properties, has emerged as an efficient producer of γ-aminobutyric acid (GABA). Notably, not all LAB possess the ability to produce GABA, highlighting the importance of specific genetic and environmental conditions for GABA synthesis. This study aimed to elucidate the intriguing GABA-producing machinery of L. brevis CRL 2013 and support its potential for safe application through comprehensive genome analysis.MethodsA comprehensive genome analysis of L. brevis CRL 2013 was performed to identify the presence of antibiotic resistance genes, virulence markers, and genes associated with the glutamate decarboxylase system, which is essential for GABA biosynthesis. Then, an optimized chemically defined culture medium (CDM) was supplemented with monosodium glutamate (MSG) and yeast extract (YE) to analyze their influence on GABA production. Proteomic and transcriptional analyses were conducted to assess changes in protein and gene expression related to GABA production.ResultsThe absence of antibiotic resistance genes and virulence markers in the genome of L. brevis CRL 2013 supports its safety for potential probiotic applications. Genes encoding the glutamate decarboxylase system, including two gad genes (gadA and gadB) and the glutamate antiporter gene (gadC), were identified. The gadB gene is located adjacent to gadC, while gadA resides separately on the chromosome. The transcriptional regulator gadR was found upstream of gadC, with transcriptional analyses demonstrating cotranscription of gadR with gadC. Although MSG supplementation alone did not activate GABA synthesis, the addition of YE significantly enhanced GABA production in the optimized CDM containing glutamate. Proteomic analysis revealed minimal differences between MSG-supplemented and non-supplemented CDM cultures, whereas YE supplementation resulted in significant proteomic changes, including upregulation of GadB. Transcriptional analysis confirmed increased expression of gadB and gadR upon YE supplementation, supporting its role in activating GABA production.ConclusionThese findings provide valuable insights into the influence of nutrient composition on GABA production. Furthermore, they unveil the potential of L. brevis CRL 2013 as a safe, nonpathogenic strain with valuable biotechnological traits which can be further leveraged for its probiotic potential in the food industry.

Crossbreeding in dairy cattle with exotic breeds continues to be an appealing practice to the dairy farmers of Bangladesh. However, there is limited knowledge regarding the impact of crossbreeding on both the physical attributes and milk quality traits of crossbred cattle in Bangladesh. Therefore, the primary objective of this study was to evaluate the impact of crossbreeding Bangladeshi local cattle with the exotic Holstein breed on their body characteristics and milk quality. To achieve the goal, data pertaining to body traits and milk samples were gathered from a total of 981 cows from 19 dairy farms located in the northwestern region of Bangladesh. A trained evaluator measured body condition score (BCS), udder score, locomotion score, and body conformation traits. Milk yield information was acquired from official records, while milk composition details were determined through milk analysis. Notably, crossbred cows (Holstein × Local cattle) exhibited greater values for wither height (141 vs. 135, cm), body length (157 vs. 153, cm), heart girth (211 vs. 204, cm), BCS (3.69 vs. 3.27), and udder score (3.29 vs. 2.08) than their Bangladeshi local counterparts. Furthermore, crossbred cows produced 42.4% and 35.3% more milk (10.89 vs. 7.65, kg/d) and fat-corrected milk (10.35 vs. 7.54, kg/d) than Bangladeshi local cattle. However, milk from crossbred cows displayed lower fat and protein content, although their somatic cell score (SCS) and energy-corrected milk remained similar. Additionally, milk from crossbred cows exhibited a longer coagulation time when compared to that of Bangladeshi local cattle. In conclusion, crossbred cows (Holstein × Local cattle) had improved body characteristics with greater milk yield than Bangladeshi local cattle; however, lower fat and protein contents in milk with longer coagulation time were noted.

Abstract Background Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)‐SCLC, to assess whether conventional NE markers are predictive of ICIs. Methods Patients with untreated ED‐SCLC who received first‐line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first‐line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI‐chemo group) and with chemotherapy alone (chemo group). Results A total of 227 patients were included in the ICI‐chemo and chemo groups, respectively. The progression‐free survival (PFS) tended to be better in patients in the ICI‐chemo group than those treated with chemotherapy alone in patients with NE marker‐positive SCLC. In particular, it was statistically significant in patients with chromogranin A‐positive SCLC (p = 0.036). In patients with NE marker‐negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. Conclusion Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker‐negative SCLC.

Abstract Background and Objective Chronic graft versus host disease (GVHD)‐associated myositis targeting skeletal muscle is a relatively rare but potentially debilitating complication following allogeneic hematopoietic stem cell transplantation (HSCT). We reviewed the clinicopathological features of GVHD‐associated myositis among patients receiving allogeneic HSCT to elucidate the cellular pathogenesis. Methods We retrospectively reviewed clinical data and muscle biopsy results from 17 consecutive patients diagnosed with GVHD‐associated myositis at our institution between 1995 and 2019. Immunostaining findings of GVHD‐associated myositis were compared to those of patients with anti‐tRNA‐synthetase antibody‐associated myopathy (ASM) (n = 13) and dermatomyositis (DM) (n = 12). Results The majority of patients with GVHD‐associated myositis showed subacute or chronic progression of mild to moderate limb weakness together with elevated serum creatine kinase. These patients also exhibited mild C‐reactive protein elevation but were negative for myositis‐related autoantibodies. Programmed death‐1 (PD‐1)‐positive cells were observed in muscle interstitium adjacent to myofibers expressing human leukocyte antigen (HLA)‐DR. The interstitium was also HLA‐DR‐positive, similar to biopsy samples from ASM patients but not DM patients. The proportions of HLA‐DR‐positive muscle fibers and PD‐1‐positive interstitial cells were significantly higher in GVHD and ASM samples than DM samples. The PD‐1‐positive cells were mostly CD‐8‐positive lymphocytes. Discussion GVHD‐associated myositis is characterized by HLA‐DR‐positive myofibers and infiltration of PD‐1‐positive lymphocytes. These features distinguish GVHD‐associated myositis from DM but not from ASM.

Using a 3-D monolithic stacking memory technology of crystalline oxide semiconductor (OS) transistors, we fabricated a test chip having AI accelerator (ACC) memory for weight data of a neural network (NN), backup memory of flip-flops (FF), and CPU memory storing instructions and data. These memories are composed of two-layer OS transistors on Si CMOS, where memories in each layer correspond to a bank. In this structure, bank switching of the ACC memory and the FF backup memory work together, and thus inference of different NNs is switched with low latency and low power so that the power gating standby time can be extended. Consequently, a 92% reduction in power consumption is achieved in inference at a frame rate of 60 fps as compared with a chip using static random access memory (SRAM) as the ACC memory.

Abstract Background Human brown adipose tissue (BAT) activity is associated with lower body fatness and favorable glucose metabolism. Previous studies reported that oral fructose loading induces postprandial fibroblast growth factor 21 (FGF21) secretion. FGF21 is a known inducer of adipose tissue thermogenesis; however, the effects of diet-induced FGF21 secretion on BAT thermogenesis remain to be elucidated. Methods The effects of both single load and daily consumption of fructose on BAT activity were examined using a randomized cross-over trial and a 2-week randomized controlled trial (RCT), respectively. In the cross-over trial, 15 young men consumed a single dose of fructose solution or water and then consumed the other on a subsequent day. The RCT enrolled 22 young men, and the participants were allocated to a group that consumed fructose and a group that consumed water daily for 2 weeks. BAT activity was analyzed using thermography with cold exposure. Plasma FGF21 level was determined by enzyme-linked immunosorbent assay. Results In the cross-over single-load trial, plasma FGF21 levels were significantly increased at 2 h after oral fructose load (p < 0.01); however, there was no significant difference in BAT activity between the fructose load and drinking water. The 2-week RCT revealed that both plasma FGF21 levels and BAT activity were not significantly increased by daily fructose consumption compared to water. Correlation analyses revealed that BAT activity at the baseline and the final measurements were strongly and positively associated with the RCT (r = 0.869, p < 0.001). Changes in BAT activity were significantly and negatively correlated with changes in plasma glucose levels during the 2-week intervention (r = − 0.497, p = 0.022). Conclusions Oral fructose load induces a temporary increase in circulating FGF21 levels; however, this does not activate BAT thermogenesis in healthy young men. Further studies are needed to elucidate the effect of endogenous FGF21 on physiological function. Trial registration This study is registered with the University Hospital Medical Information Network in Japan (number 000051761, registered 1 August 2023, retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000052680 ).

Introduction Condyloma acuminatum usually occurs in the external genitalia and rarely in the bladder mucosa. Here, we report a case of condyloma acuminatum of the bladder that was detected concurrently with urothelial carcinoma. Case presentation A 42‐year‐old man was referred to our urology department with positive urine cytology for urothelial carcinoma. Cystoscopy revealed a broad‐base nonpapillary bladder tumor. The patient underwent a transurethral resection of the bladder tumor. Pathological examination revealed urothelial carcinoma, high‐grade pT1, and concurrent resection of condyloma acuminatum. DNA was extracted from the paraffin‐embedded transurethral resection of the bladder tumor tissue specimens. HPV11 was detected in condylomas by PCR and in situ hybridization, whereas HPV was not detected in urothelial carcinomas. Conclusion We report a rare case of condyloma acuminatum of the bladder that was concurrently diagnosed with urothelial carcinoma from the same site.

Background: In recent years, site-directed therapies (SDTs) targeting progressive lesions in patients with oligometastatic prostate cancer have attracted attention. However, whether they effectively treat oligoprogressive castration-resistant prostate cancer (CRPC) remains unclear. Here, we investigated the efficacy of SDT in patients with oligoprogressive CRPC and identified prognostic factors. Methods: We reviewed 59 patients with oligoprogressive CRPC who underwent SDT targeting prostate or metastatic lesions between April 2014 and March 2022. We evaluated the associations between several pretreatment clinical variables and treatment procedures and a >50% prostate-specific antigen (PSA) response, progression-free survival (PFS), and time to next treatment (TTNT). Results: A PSA response of >50% was observed in 66% of patients. The median PFS and TTNT were 8.3 months and 9.9 months, respectively. Patients with PSA doubling time ≥6 months showed a higher >50% PSA response rate (87% vs. 45%; P 50% PSA response, favorable PFS, and TTNT (P = 0.037, 0.025, and 0.017, respectively). Conclusion: PSA doubling time of ≥6 months may be a key indicator of the favorable efficacy of SDT for oligoprogressive CRPC.

Abstract Background Amrubicin (AMR) regimens have shown efficacy as second‐line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P‐PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P‐PEG as second‐line chemotherapy for SCLC. Methods We retrospectively reviewed patients with SCLC who received AMR as second‐line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P‐PEG in their regimen, patients (n = 60) were divided into P‐PEG (n = 21) and non‐P‐PEG groups, and their clinical outcomes were evaluated. Results Median of AMR treatment cycles was five (range: 1–39 cycles) in P‐PEG group and four (range: 1–15 cycles) in non‐P‐PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P‐PEG group than in the non‐P‐PEG group. The objective response rates were 52.4% and 30.8%, and median progression‐free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P‐PEG and non‐P‐PEG groups, respectively. Conclusions AMR with P‐PEG as second‐line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P‐PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC.

Introduction: Ureteral injuries require surgical intervention as they lead to loss of renal function. The current reconstructive techniques for long ureteral defects are problematic. Consequently, this study aimed to reconstruct the ureter in a rat model using subcutaneously prepared autologous collagen tubes (Biotubes). Methods: The lower ureter of LEW/SsNSlc rats was ligated to dilate the ureter to make anastomosis easier, and reconstruction was performed six days later by anastomosing the dilated ureter and bladder with a Biotube that was prepared subcutaneously in syngeneic rats. Some rats underwent left nephrectomy and ureter reconstruction simultaneously as negative controls to evaluate the effects of urine flow on patency. The other rats were divided into three groups as follows: a group in which the ureter was reconstructed with the Biotube alone, a group in which cardiomyocyte sheets made from the neonatal hearts of syngeneic rats were wrapped around the Biotube, and a group in which an adipose-derived stem cell sheets made from the inguinal fat of adult syngeneic rats were wrapped. Contrast-enhanced computed tomography and pathological evaluations were performed two weeks after reconstruction. Result: In the Biotube alone group, all tubes were occluded and hydronephrosis developed, whereas the urothelium regenerated beyond the anastomosis when the left kidney was not removed, suggesting that urothelial epithelial spread occurred with urinary flow. The patency of the ureteral lumen was obtained in some rats in the cardiomyocyte sheet covered group, whereas stricture or obstruction of the reconstructed ureter was observed in all rats in the other groups. Pathological evaluation revealed a layered urothelial structure in the cardiomyocyte sheet covered group, although only a small amount of cardiomyocyte sheets remained. Conclusion: Urinary flow may support the epithelial spread of the urothelium into the reconstructed ureter. Neonatal rat cardiomyocyte sheets supported the patency of the regenerated ureter with a layered urothelium.

The laser-induced grain structure of pure tungsten was evaluated using a nanosecond Q-switched Nd:YAG laser. The grain structure, crystal orientation, and grain boundary angular distribution were analyzed through electron backscatter diffraction analysis, both before and after laser processing. The mechanical properties of pure tungsten after laser processing were also measured. The results obtained indicate that laser processing-induced recrystallization can offer micro-nano surface treatment of materials without compromising the mechanical properties.

Background. Intragraft microthrombi prevent complete organ perfusion, thereby compromising the viability maintained by preservation solutions or machine perfusion. Herein, we developed and evaluated a hypobaric perfusion method for flushing microthrombi from kidney grafts with prolonged circulatory arrest in a porcine model. Methods. Porcine renal grafts with 1-h warm ischemia were flushed with heparin-containing perfusate in a normobaric environment (control group) or a hypobaric environment of −20 to −30 mm Hg (hypobaric perfusion group) for 10 min using a gravity drip from a 1-m height. Perfusion parameters, histological findings in ex vivo blood perfusion experiments (2 control and 4 hypobaric perfusion kidneys), and safety in allogeneic porcine transplantation experiments (1 donor to 2 recipients) were evaluated. Results. The −20 mm Hg hypobaric perfusion group exhibited greater maximal flow than the control group (20.4 versus 6.9 mL/min; P = 0.028). Histological evaluation following 3 h of static cold storage and 10 min ex vivo porcine whole-blood perfusion revealed statistically significant reductions in congestion and edema (1.5 versus 3, and 0.5 versus 4 on a 5-point scale, from 0 to 4; P = 0.014 and 0.006, respectively) in the medulla along with improved ischemia–reperfusion injury scores (4.0 versus 4.7 on a 6-point scale, from 0 to 5; P = 0.004) in the −20 mm Hg hypobaric perfusion group. Kidney grafts perfused under −30 mm Hg hypobaric environment followed by 3 h of static cold storage could be used for porcine allogeneic transplantation without any macroscopic damage to the graft, effect on intraoperative handling, or perioperative adverse events. Thus, the hypobaric perfusion method was considered safe. Conclusions. Perfusion in a hypobaric environment may prevent graft congestion, edema, and further reperfusion injury by flushing out erythrocytes occluding the medullary capillaries, improving marginal renal graft quality, and reducing the number of discarded grafts.

We demonstrate high-definition, direct-printing of micron-scale metallic dots, comprised of close-packed gold nanoparticles, by utilizing the optical vortex laser-induced forward transfer technique. We observe that the spin angular momentum of the optical vortex, associated with circular polarization, assists in the close-packing of the gold nanoparticles within the printed dots. The printed dots exhibit excellent electrical conductivity without any additional sintering processes. This technique of applying optical vortex laser-induced forward transfer to metallic dots is an innovative approach to metal printing, which does not require additional sintering. It also serves to highlight new insights into light–matter interactions.

Background While concomitant medications can affect the efficacy of immune checkpoint inhibitors (ICIs), few studies have assessed associations of concomitant medications with the occurrence and profile of immune-related adverse events (irAEs).Methods This study assessed associations of concomitant medication (antibiotics/proton pump inhibitors (PPIs)/corticosteroids)-based risk model termed the “drug score” with survival and the occurrence and profile of irAEs in 851 patients with advanced cancer treated with ICIs (with or without other agents). The study also assessed the survival impact of the occurrence of irAEs, using a landmark analysis to minimize immortal time bias. Multivariable Cox proportional hazard analyses were conducted for progression-free survival (PFS) and overall survival (OS).Results The drug score classified patients into three risk groups, with significantly different PFS and OS. Notably, the score’s predictive capability was better in patients treated with ICIs only than in those treated with ICIs plus other agents. The landmark analysis showed that patients who developed irAEs had significantly longer PFS and OS than those without irAEs. Generally, concomitant medications were negatively associated with the occurrence of irAEs, especially endocrine irAEs, whereas PPI use was positively associated with gastrointestinal irAEs, as an exception.Conclusions Using a large pan-cancer cohort, the prognostic ability of the drug score was validated, as well as that of the occurrence of irAEs. The negative association between concomitant medications and irAE occurrence could be an indirect measure of the detrimental effect on the immune system induced by one or more concomitant drugs.

Abstract Most of previous photocatalysts contain metal species, thus exploring a metal-free photocatalyst is still challenging. A metal-free photocatalyst has an advantage for the development of economical and non-toxic artificial photosynthesis system and/or environmental purification applications. In this study, rhombohedral boron monosulfide (r-BS) was synthesized by a high-pressure solid-state reaction, and its photocatalytic properties were investigated. r-BS absorbed visible light, and its photocurrent action spectrum also exhibited visible light responsivity. The r-BS evolved hydrogen (H2) from water under ultraviolet (UV) as well as under visible light irradiation, and its internal quantum efficiency reached 1.8% under UV light irradiation. In addition to the H2 evolution reaction, the r-BS photocatalyst drove carbon dioxide (CO2) reduction and dye oxidation reactions under UV irradiation. Although bare r-BS was not so stable under strong light irradiation in water, cocatalyst modification improved its stability. These results indicate that r-BS is a new class of non-metal photocatalyst applicable for H2 production, CO2 reduction, and environmental purification reactions.

Abstract Although hormone therapy is effective for the treatment of prostate cancer (Pca), many patients develop a lethal type of Pca called castration-resistant prostate cancer (CRPC). Dysregulation of DNA damage response (DDR)-related genes leads to Pca progression. Here, we explored DDR-related signals upregulated in CRPC tissues. We analyzed the gene expression profiles in our RNA-sequence (RNA-seq) dataset containing benign prostate, primary Pca, and CRPC samples. We identified six DDR-related genes (Ribonuclease H2 Subunit A (RNASEH2A), replication factor C subunit 2 (RFC2), RFC4, DNA Ligase 1 (LIG1), DNA polymerase D1 (POLD1), and DNA polymerase E4 (POLE4)) that were upregulated in CRPC compared with Pca tissues. By analyzing public databases and validation studies, we focused on RFC2 as a new biomarker. Functional analysis demonstrated that silencing of RFC2 expression inhibited cell proliferation and induced the expression of DNA damage and apoptosis markers in CRPC model cells. Furthermore, immunohistochemical (IHC) analysis revealed that high expression of RFC2 protein correlated with poor prognosis in patients with Pca and increased expression in CRPC tissues compared with localized Pca. Thus, our study suggests that six DDR-related genes would be important for Pca progression. RFC2 could be a useful biomarker associated with poor outcomes of patients with Pca.

Introduction Disseminated carcinomatosis of the bone marrow in prostate cancer is rare and has a poor prognosis. Although strong evidence suggests that novel hormonal agents improve the prognosis of metastatic prostate cancer, their effectiveness in cases of disseminated carcinomatosis of the bone marrow remains unclear. Case presentation We encountered two cases of prostate cancer with disseminated carcinomatosis of the bone marrow at the time of initial diagnosis. One patient was treated with enzalutamide, abiraterone, docetaxel, cabazitaxel, denosumab, and radium‐223 and died 38 months after the initial diagnosis. The other patient was treated with apalutamide and denosumab, and had progression‐free survival for 17 months after the initial diagnosis. Conclusion These results suggest that novel hormonal agents may improve the prognosis of prostate cancer even in patients with disseminated carcinomatosis of the bone marrow.

Introduction Intravesical Bacillus Calmette–Guérin immunotherapy is an effective treatment for non‐muscle‐invasive bladder cancer, which is occasionally associated with side effects and complications. The incidence of significant renal complications after intravesical Bacillus Calmette–Guérin immunotherapy is less than 2%. We report a case of renal granuloma after intravesical Bacillus Calmette–Guérin immunotherapy for bladder cancer, which radiologically resembled a papillary renal cell carcinoma. Case presentation A 65‐year‐old man, who had a medical history of urothelial carcinoma and received intravesical Bacillus Calmette–Guérin therapy, was referred to our Urology Department with a right renal tumor. Imaging findings suggested papillary renal cell carcinoma. Robot‐assisted partial nephrectomy was performed, and the histopathological examination revealed epithelioid cell granuloma, which were considered to be Bacillus Calmette–Guérin‐related renal granuloma. Conclusion Bacillus Calmette–Guérin‐related renal granuloma mimicking papillary renal cell carcinoma have been reported. We should consider the possibility of renal granulomas when encountering image abnormalities for patients treated with intravesical Bacillus Calmette–Guérin therapy.

Introduction Subcutaneous emphysema is a relatively common complication in laparoscopic surgery. However, airway obstruction secondary to subcutaneous emphysema is rare. Case presentation A 63‐year‐old woman with a 56‐mm left renal tumor underwent a robot‐assisted partial nephrectomy. The operative time was 155 min, the insufflation time was 108 min, and the estimated blood loss was 70 mL. The pneumoperitoneum pressure was maintained at 12 mmHg, except at 15 mmHg for 19 min during tumor resection. The end‐tidal CO2 was

Abstract Hereditary transthyretin (ATTRv) amyloidosis is a rare and autosomal dominant disorder associated with mutations in the transthyretin gene. Patients present with diverse symptoms related to sensory, motor, and autonomic neuropathy, as well as gastrointestinal, ocular, cardiac, renal and orthopedic symptoms, resulting from the deposition of transthyretin amyloid fibrils in multiple organs. The progressive nature of ATTRv amyloidosis necessitates pre- and post-onset monitoring of the disease. This review article is primarily based on a collation of discussions from a medical advisory board meeting in August 2021. In this article, we summarize the best practices in amyloidosis centers in three major endemic countries for ATTRv amyloidosis (Japan, Brazil, and Portugal), where most patients carry the Val30Met mutation in the transthyretin gene and the patients’ genetic background was proven to be the same. The discussions highlighted the similarities and differences in the management of asymptomatic gene mutation carriers among the three countries in terms of the use of noninvasive tests and tissue biopsies and timing of starting the investigations. In addition, this article discusses a set of practical tests and examinations for monitoring disease progression applicable to neurologists working in diverse medical settings and generalizable in non-endemic countries and areas. This set of assessments consists of periodic (every 6 to 12 months) evaluations of patients’ nutritional status and autonomic, renal, cardiac, ophthalmologic, and neurological functions. Physical examinations and patient-reported outcome assessments should be also scheduled every 6 to 12 months. Programs for monitoring gene mutation carriers and robust referral networks can aid in appropriate patient management in pre- to post-onset stages. For pre- and post-symptom onset testing for ATTRv amyloidosis, various noninvasive techniques are available; however, their applicability differs depending on the medical setting in each country and region, and the optimal option should be selected in view of the clinical settings, medical environment, and available healthcare resources in each region.

Background: Hunner-type interstitial cystitis (HIC) is an immunological, chronic inflammatory disease. The efficacy of corticosteroid as a treatment for HIC is unclear. Objective: To assess the efficacy and safety of low-dose oral prednisolone (PSL) treatment for patients with refractory HIC. Design, setting, and participants: This retrospective observational study reviewed the clinical outcomes of 31 patients with refractory HIC who received oral PSL daily (initial dose, 5.0 or 7.5 mg) for at least 12 mo between 2016 and 2023. The dose was tapered to the minimum that maintained symptom relief during follow-up. Outcome measurements and statistical analysis: Treatment outcomes were evaluated using a seven-graded global response assessment (scores ≥+2, moderately or markedly improved, were defined as treatment response), O’Leary and Sant symptom and problem indices (OSSI/OSPI), overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, a quality of life (QOL) score, and frequency-volume chart variables. Related complications were also documented. Results and limitations: The mean follow-up period was 20.1 ± 14.6 mo. The overall response rates at 1, 3, 6, 9, and 12 mo at doses of 6.7, 6.7, 5.2, 4.0, and 3.0 mg were 38.7%, 48.4%, 54.8%, 61.3%, and 64.5%, respectively. Compared with baseline, OSSI/OSPI and pain intensity improved significantly from 1 mo after PSL induction. The OABSS, QOL score, urinary frequency, and voided volume improved significantly from 9 mo after PSL induction. No patients discontinued treatment due to adverse events, although hypertension and glucose intolerance occurred in two patients, but these were resolved by temporal medications. Conclusions: This study showed that low-dose oral PSL significantly improves bladder pain, urinary symptoms, and QOL in patients with HIC, without serious adverse events. Further prospective evaluation is warranted to verify the potential efficacy and safety of low-dose PSL for HIC. Patient summary: This retrospective observational study reviewed the clinical outcomes of 31 patients suffering from refractory Hunner-type interstitial cystitis treated with low-dose oral prednisolone. Low-dose prednisolone improved bladder pain, urinary symptoms, and quality of life significantly, without serious adverse events. The response rate of 64.5% at 12 mo was comparable with the rates reported in previous studies that used higher doses of prednisolone. This study provides a rationale for further prospective evaluation of low-dose prednisolone for this intractable disease.

Abstract Radical cystectomy is a gold-standard treatment for muscle-invasive bladder cancer. We recently introduced robot-assisted radical cystectomy (RARC) with perioperative enhanced recovery after surgery (ERAS). The medical records of patients with bladder cancer who underwent open radical cystectomy (ORC) or RARC/ERAS at NTT Medical Center Tokyo were retrospectively reviewed to compare the surgical outcomes, hospital stay, and medical costs between groups. Multidisciplinary full ERAS items were provided for the RARC/ERAS group. The median estimated blood losses in the ORC and RARC/ERAS groups were 650 and 100 mL, and the median operative times were 312 and 445 min, respectively. In addition, the median times to liquid food intake in these groups were 6 and 0 days, the median times to first flatus and first defecation were 2 and 1 day, and 3 and 1.5 days, respectively. The rates of postoperative ileus in the ORC and RARC/ERAS groups were 27.5% and 4.5%, and the median postoperative hospital stays was 26.5 and 12 days, respectively. Medical costs excluding surgery were significantly lower in the RARC/ERAS group. In conclusion, RARC/ERAS represents a safe treatment option for muscle-invasive bladder cancer with decreased perioperative complications and lower medical costs.

In previous studies, it was demonstrated that Corynebacterium pseudodiphtheriticum 090104, isolated from the human nasopharynx, modulates respiratory immunity, improving protection against infections. Here, the antagonistic effect of the 090104 strain on respiratory pathogens, including Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, was explored. In a series of in vitro studies, the capacity of C. pseudodiphtheriticum 090104, its bacterium-like particles, and its culture supernatants to coaggregate, inhibit the growth, and change the virulent phenotype of pathogenic bacteria was evaluated. The results showed that the 090104 strain was able to exert a bacteriostatic effect on K. pneumoniae and S. pneumoniae growth. In addition, C. pseudodiphtheriticum 090104 coaggregated, inhibited biofilm formation, and induced phenotypic changes in all the respiratory pathogens evaluated. In conclusion, this work demonstrated that, in addition to its beneficial effects exerted by host–microbe interactions, C. pseudodiphtheriticum 090104 can enhance protection against respiratory pathogens through its microbe–microbe interactions. The mechanisms involved in such interactions should be evaluated in future research.

3-(4-Hydroxy-3-methoxyphenyl)propionic acid (HMPA), also known as dihydroferulic acid, is a hydroxycinnamic acid derivative that can be derived from the microbial transformation of dietary polyphenols or naturally obtained from fermented foods. Although numerous studies have documented its antioxidant and anti-obesity effects, the effect of HMPA on muscle function remains unknown. This study investigated the effects of HMPA on muscle strength and exercise endurance capacity. Mice were orally administered low and high doses of HMPA for 14 days and subjected to grip force and treadmill exhaustion tests to evaluate muscle function. Our results showed that HMPA-administered groups significantly enhanced absolute grip strength (p = 0.0256) and relative grip strength (p = 0.0209), and low-dose HMPA decreased the plasma level of blood urea nitrogen after exercise (p = 0.0183), but HMPA did not affect endurance performance. Low-dose HMPA administration increased Myf5 expression in sedentary mice (p = 0.0106), suggesting that low-dose HMPA may promote muscle development. Additionally, HMPA improved hepatic glucose and lipid metabolism, and inhibited muscular lipid metabolism and protein catabolism, as indicated by changes in mRNA expression levels of related genes. These findings suggest that HMPA may be a promising dietary supplement for muscle health and performance.

Lacticaseibacillus rhamnosus CRL1505 possesses immunomodulatory activities in the gastrointestinal and respiratory tracts when administered orally. Its adhesion to the intestinal mucosa does not condition its beneficial effects. The intranasal administration of L. rhamnosus CRL1505 is more effective than the oral route at modulating immunity in the respiratory tract. Nonetheless, it has not yet been established whether the adherence of the CRL1505 strain to the respiratory mucosa is needed to provide the immune benefits to the host. In this study, we evaluated the role of adhesion to the respiratory mucosa of the mucus-binding factor (mbf) knock-out L. rhamnosus CRL1505 mutant (Δmbf CRL1505) in the context of a Toll-like receptor 3 (TLR3)-triggered innate immunity response. In vitro adhesion studies in porcine bronchial epitheliocytes (PBE cells) indicated that L. rhamnosus Δmbf CRL1505 adhered weakly compared to the wild-type strain. However, in vivo studies in mice demonstrated that the Δmbf CRL1505 also reduced lung damage and modulated cytokine production in the respiratory tract after the activation of TLR3 to a similar extent as the wild-type strain. In addition, the mutant and the wild-type strains modulated the production of cytokines and antiviral factors by alveolar macrophages in the same way. These results suggest that the Mbf protein is partially involved in the ability of L. rhamnosus CRL1505 to adhere to the respiratory epithelium, but the protein is not necessary for the CRL1505 strain to exert its immunomodulatory beneficial effects. These findings are a step forward in the understanding of molecular interactions that mediate the beneficial effects of nasally administered probiotics.

ABSTRACT Purpose: This study aimed to compare the degree of maturation and development of fetal pig segmental intestinal tissue with that of spheroids created by in-vitro reaggregation of dissociated fetal intestinal cells after transplantation into immunodeficient mice. Methods: Fetal pig small intestines were transplanted as segmental grafts into the omentum and subrenal capsules of immunodeficient mice or enzymatically treated to generate single cells. Spheroids made by in-vitro reaggregation of these cells were transplanted into the subrenal capsules of immunodeficient mice. The segmental grafts and spheroids were harvested four and eight weeks after transplantation, and the structural maturity and in-vivo development of these specimens were histologically evaluated. Results: The spheroids were engrafted and supplied blood vessels from the host mice, but an intestinal layered structure was not clearly observed, and there was almost no change in size. On the other hand, the segmental grafts formed deep crypts in the mucus membrane, the inner circular layer, and outer longitudinal muscles. The crypts of the transplanted grafts harvested at eight weeks were much deeper, and the smooth muscle layer and the enteric nervous system were more mature than those of grafts harvested at the fourth week, although the intestinal peristaltic wave was not observed. Conclusions: Spheroids created from fetal small intestinal cells could not form layered structures or mature sufficiently. Conversely, segmental tissues structurally matured and developed after in-vivo transplantation and are therefore potential grafts for transplantation.

The recent discovery of “ultrahot” ( P < 1 day) Neptunes has come as a surprise: some of these planets have managed to retain gaseous envelopes despite being close enough to their host stars to trigger strong photoevaporation and/or Roche lobe overflow. Here, we investigate atmospheric escape in LTT 9779b, an ultrahot Neptune with a volatile-rich envelope. We observed two transits of this planet using the newly commissioned WINERED spectrograph ( R ∼ 68,000) on the 6.5 m Clay/Magellan II Telescope, aiming to detect an extended upper atmosphere in the He 10830 Å triplet. We found no detectable planetary absorption: in a 0.75 Å passband centered on the triplet, we set a 2 σ upper limit of 0.12% ( δ R _p / H < 14) and a 3 σ upper limit of 0.20% ( δ R _p / H < 22). Using a H/He isothermal Parker wind model, we found corresponding 95% and 99.7% upper limits on the planetary mass-loss rate of $\dot{M}\lt {10}^{10.03}$ g s ^−1 and $\dot{M}\lt {10}^{11.11}$ g s ^−1 , respectively, smaller than predicted by outflow models even considering the weak stellar X-ray and ultraviolet emission. The low evaporation rate is plausibly explained by a metal-rich envelope, which would decrease the atmospheric scale height and increase the cooling rate of the outflow. This hypothesis is imminently testable: if metals commonly weaken planetary outflows, then we expect that JWST will find high atmospheric metallicities for small planets that have evaded detection in He 10830 Å.

The emergence and spread of antibiotic resistance threat forced to explore alternative strategies for improving the resistance to pathogens in livestock production. Probiotic lactic acid bacteria represent an alternative for this objective. In this study, seven Lactiplantibacillus plantarum strains from porcine colostrum and milk were isolated, identified and characterized in terms of their abilities to modulate immunity in porcine intestinal epithelial (PIE) cells. Then, two potential immunoregulatory strains were studied in terms of their ability to utilize and grow in wakame (Undaria pinnafida). Isolates were identified by 16S rRNA gene and evaluated by studying their interaction with PIE cells. The expressions of peptidoglycan recognition proteins (PGRPs), nucleotide-binding oligomerization domain (NODs), host defense peptides (pBD), and type I interferons (IFNs) were evaluated by RT-qPCR. The strain 4M4417 showed a remarkable capacity to differentially regulate the expression of PGRP1, PGRP3, NOD1, NOD2, and pBD1 in PIE cells. On the other hand, the strain 4M4326 was the most efficient to improve the expression of IFN-α and IFN-β in PIE cells challenged with poly (I:C). Both L. plantarum 4M4326 and 4M4417 were characterized in terms of their ability to utilize wakame. Results demonstrated that both strains efficiently grew in wakame-based broth. Our results suggest that L. planatrum 4M4326 and 4M4417 are interesting candidates to develop immunomodulatory feeds based on wakame utilization. These new immunosynbiotic feeds could help to reduce severity of intestinal infections and improve immune health status in pigs.

Early child maltreatment, such as child abuse and neglect, is well known to affect the development of social skills. However, the mechanisms by which such an adverse environment interrupts the development of social skills remain unelucidated. Identifying the period and brain regions that are susceptible to adverse environments can lead to appropriate developmental care later in life. We recently reported an excitatory/inhibitory imbalance and low activity during social behavior in the medial prefrontal cortex (mPFC) of the maternal separation (MS) animal model of early life neglect after maturation. Based on these results, in the present study, we investigated how MS disturbs factors related to excitatory and inhibitory neurons in the mPFC until the critical period of mPFC development. Additionally, we evaluated whether the effects of MS could be recovered in an enriched environment after MS exposure. Rat pups were separated from their dams on postnatal days (PDs) 2–20 (twice daily, 3 h each) and compared with the mother-reared control (MRC) group. Gene expression analysis revealed that various factors related to excitatory and inhibitory neurons were transiently disturbed in the mPFC during MS. A similar tendency was found in the sensory cortex; however, decreased parvalbumin (PV) expression persisted until PD 35 only in the mPFC. Moreover, the number of PV+ interneurons decreased in the ventromedial prefrontal cortex (vmPFC) on PD 35 in the MS group. Additionally, perineural net formation surrounding PV+ interneurons, which is an indicator of maturity and critical period closure, was unchanged, indicating that the decreased PV+ interneurons were not simply attributable to developmental delay. This reduction of PV+ interneurons improved to the level observed in the MRC group by the enriched environment from PD 21 after the MS period. These results suggest that an early adverse environment disturbs the development of the mPFC but that these abnormalities allow room for recovery depending on the subsequent environment. Considering that PV+ interneurons in the mPFC play an important role in social skills such as empathy, an early rearing environment is likely a very important factor in the subsequent acquisition of social skills.

Abstract Introduction Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. Methods The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. Results At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10–10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10–7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10–7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10–15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10–15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. Conclusion Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment. Trial Registration Number ClinicalTrials.gov: NCT03759379.

Abstract Molecular targeted therapy using poly (ADP-ribose) polymerase inhibitors has improved survival in patients with castration-resistant prostate cancer (CRPC). However, this approach is only effective in patients with specific genetic mutations, and additional drug discovery targeting epigenetic modulators is required. Here, we evaluated the involvement of the transcriptional coregulator ESS2 in prostate cancer. ESS2-knockdown PC3 cells dramatically inhibited proliferation in tumor xenografts in nude mice. Microarray analysis revealed that ESS2 regulated mRNA levels of chromodomain helicase DNA binding protein 1 (CHD1)-related genes and other cancer-related genes, such as PPAR-γ, WNT5A, and TGF-β, in prostate cancer. ESS2 knockdown reduced nuclear factor (NF)-κB/CHD1 recruitment and histone H3K36me3 levels on the promoters of target genes (TNF and CCL2). In addition, we found that the transcriptional activities of NF-κB, NFAT and SMAD2/3 were enhanced by ESS2. Tamoxifen-inducible Ess2-knockout mice showed delayed prostate development with hypoplasia and disruption of luminal cells in the ventral prostate. Overall, these findings identified ESS2 acts as a transcriptional coregulator in prostate cancer and ESS2 can be novel epigenetic therapeutic target for CRPC.