[Pouchitis showed complete response to ustekinumab].

Pouchitis is the most common long-term complication following ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis. Although several agents, including probiotics, steroids, and immunomodulators, have been used, the treatment of pouchitis remains challenging. Owing to the proven efficacy of biological therapy in inflammatory bowel disease, there is now growing evidence suggesting the potential benefits of biological therapy in refractory pouchitis. Here, we report the case of a 64-year-old woman with pouchitis due to ulcerative colitis who was successfully treated with ustekinumab (UST). The patient developed ulcerative pancolitis at the age of 35. Total colectomy and IPAA with J-pouch anastomosis were performed when the patient was 47 years old. Ileotomy closure was performed 6 months later. Postoperatively, the patient developed steroid-dependent pouchitis. Three years later, she developed steroid-induced diabetes. The patient has been taking 3mg of steroid for 20 years;therefore, her lifetime total steroid dose was 21g. The patient had over 20 episodes of bloody diarrhea a day. The last pouchoscopy in 20XX-9 revealed inflammatory stenosis with deep ulcerations of the afferent limb just before the ileoanal pouch junction. In July 20XX, when we took over her treatment, the policy of treatment was to withdraw her from steroids. Pouchoscopy revealed a widened but still tight afferent limb through which the scope could easily pass, and the ileoanal pouch still showed erosive ileitis without ulcers. Thiopurine administration and steroid tapering were initiated. Steroid tapering increased the erythrocyte sedimentation rate (ESR). As ESR increased, her arthritis exacerbated. Six months after the end of steroid administration, the patient consented to UST treatment. On April 20XX+1, the patient received her first 260-mg UST infusion. At this point, she experienced 14-15 episodes of muddy bloody stools. She had no abdominal pain;however, she experienced shoulder pain. Gradually, UST affected both pouchitis and arthritis. UST treatment was continued at 90mg subcutaneously every 12 weeks without abdominal pain recurrence. Eight months after the first UST infusion, nonsteroidal anti-inflammatory drugs were no longer necessary for shoulder pain. Follow-up pouchoscopy performed 14 months after UST optimization revealed a normal afferent limb without ulcerations in either segment. Pouchitis remission was maintained for over 2 years.

Fibrocyte Phenotype of ENTPD1+CD55+ Cells and Its Association with Pain in Osteoarthritic Synovium.

Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by cartilage erosion, structural changes, and inflammation. Synovial fibroblasts play a crucial role in OA pathophysiology, with abnormal fibroblastic cells contributing significantly to joint pathology. Fibrocytes, expressing markers of both hematopoietic and stromal cells, are implicated in inflammation and fibrosis, yet their marker and role in OA remain unclear. ENTPD1, an ectonucleotidase involved in purinergic signaling and expressed in specific fibroblasts in fibrotic conditions, led us to speculate that ENTPD1 plays a role in OA pathology by being expressed in fibrocytes. This study aimed to investigate the phenotype of ENTPD1+CD55+ and ENTPD1-CD55+ synovial fibroblasts in OA patients. Proteomic analysis revealed a distinct molecular profile in ENTPD1+CD55+ cells, including the upregulation of fibrocyte markers and extracellular matrix-related proteins. Pathway analysis suggested shared mechanisms between OA and rheumatoid arthritis. Correlation analysis revealed an association between ENTPD1+CD55+ fibrocytes and resting pain in OA. These findings highlight the potential involvement of ENTPD1 in OA pain and suggest avenues for targeted therapeutic strategies. Further research is needed to elucidate the underlying molecular mechanisms and validate potential therapeutic targets.

Broadband design of silica-PLC mode-dependent-loss equalizer for 2LP-mode transmission systems.

A new configuration of mode-dependent-loss (MDL) equalizer for two linearly-polarized mode transmission systems using the silica planar lightwave circuit platform is proposed. This device acts as an LP01-mode attenuator (precisely, LP01/LP21 mode converter) to adjust the MDL keeping a high transmission of the LP11 modes. Almost all components constructing the device are based on the adiabatic mode conversion, which brings broadband operation. Especially, a newly proposed E12/E22 mode converter plays a key role in broadband MDL equalization. It is numerically revealed that the flattened spectra with designated transmission can be obtained for the wavelength from 1200 nm to 1650 nm.

CD39+CD55- Fb Subset Exhibits Myofibroblast-Like Phenotype and Is Associated with Pain in Osteoarthritis of the Knee.

Recent studies utilizing single-cell analysis have unveiled the presence of various fibroblast (Fb) subsets within the synovium under inflammatory conditions in osteoarthritis (OA), distinguishing them from those in rheumatoid arthritis (RA). Moreover, it has been reported that pain in knee OA patients is linked to specific fibroblast subsets. Single-cell expression profiling methods offer an incredibly detailed view of the molecular states of individual cells. However, one limitation of these methods is that they require the destruction of cells during the analysis process, rendering it impossible to directly assess cell function. In our study, we employ flow cytometric analysis, utilizing cell surface markers CD39 and CD55, in an attempt to isolate fibroblast subsets and investigate their relationship with OA pathology. Synovial tissues were obtained from 25 knee OA (KOA) patients. Of these, six samples were analyzed by RNA-seq (n = 3) and LC/MS analysis (n = 3). All 25 samples were analyzed to estimate the proportion of Fb (CD45-CD31-CD90+) subset by flow cytometry. The proportion of Fb subsets (CD39+CD55- and CD39-CD55+) and their association with osteoarthritis pathology were evaluated. CD39+CD55- Fb highly expressed myogenic markers such as CNN1, IGFBP7, MYH11, and TPM1 compared to CD39-CD55+ Fb. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of upregulated differentially expressed genes (DEGs) in CD39+CD55- Fb identified the Apelin pathway and cGMP-PKC-signaling pathway as possibly contributing to pain. LC/MS analysis indicated that proteins encoded by myogenic marker genes, including CNN1, IGFBP7, and MYH11, were also significantly higher than in CD39-CD55+ Fb. CD39-CD55+ Fb highly expressed PRG4 genes and proteins. Upregulated DEGs were enriched for pathways associated with proinflammatory states ('RA', 'TNF signaling pathway', 'IL-17 signaling pathway'). The proportion of CD39+CD55- Fb in synovium significantly correlated with both resting and active pain levels in knee OA (KOA) patients (resting pain, ρ = 0.513, p = 0.009; active pain, ρ = 0.483, p = 0.015). There was no correlation between joint space width (JSW) and the proportion of CD39+CD55- Fb. In contrast, there was no correlation between the proportion of CD39-CD55+ Fb and resting pain, active pain, or JSW. In conclusion, CD39+CD55- cells exhibit a myofibroblast phenotype, and its proportion is associated with KOA pain. Our study sheds light on the potential significance of CD39+CD55- synovial fibroblasts in osteoarthritis, their myofibroblast-like phenotype, and their association with joint pain. These findings provide a foundation for further research into the mechanisms underlying fibrosis, the impact of altered gene expression on osteoarthritic joints, and potential therapeutic strategies.

Enlarged housing space and increased spatial complexity enhance hippocampal neurogenesis but do not increase physical activity in mice.

Introduction: Environmental enrichment (EE) improves various health outcomes, such as hippocampal neurogenesis, in rodents, which is thought to be caused, in part, by increased physical activity. However, the specific effect of each enrichment component, such as enlarged housing spaces and increased spatial complexity with a variety of objects, on physical activity remains unclear because of methodological limitations in measuring physical activity. We aimed to examine whether enlarged housing spaces and increased spatial complexity increase physical activity in mice using a body-implantable actimeter. Methods: Adult male C57BL/6J mice were assigned to either standard housing or EE groups. The housing environment in the EE mice was gradually enriched by enlarging the housing space and the placement of a variety of objects. Physical activity was measured using a body-implanted actimeter. Hippocampal neurogenesis was immunohistochemically examined. Results: Enlarged housing spaces and the placement of a variety of objects did not increase physical activity in mice. In contrast, hippocampal neurogenesis was enhanced in the EE mice, suggesting that environmental interventions successfully provided enriched housing conditions for these mice. Conclusions: These results indicate that enlarged housing spaces and increased spatial complexity do not increase physical activity in mice. Furthermore, we found that EE enhanced hippocampal neurogenesis without increasing activity volume. Besides the current understanding that increasing the amount of physical activity is key to improving hippocampal function, our result suggests that the environment in which physical activity takes place is also a crucial contextual factor in determining the impact of physical activity on hippocampal function.

The role of ferroptosis in cell-to-cell propagation of cell death initiated from focal injury in cardiomyocytes.

AIMS: Ferroptosis has grown in importance as a key factor in ischemia-reperfusion (I/R) injury. This study explores the mechanism underlying fibrotic scarring extending along myofibers in cardiac ischemic injury and demonstrates the integral role of ferroptosis in causing a unique cell death pattern linked to I/R injury. MAIN METHODS: Cadaveric hearts from individuals who had ischemic injury were examined by histological assays. We created a novel model of inducing cell death in H9c2 cells, and used it to demonstrate ferroptotic cell death extending in a cell-to-cell manner. Ex vivo Langendorff-perfused hearts were used alongside the model to replicate cell death extension along myofibers while also demonstrating protective effects of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). KEY FINDINGS: Human hearts from individuals who had I/R injury demonstrated scarring along myofibers that was consistent with mouse models, suggesting that cell death extended from cell-to-cell. Treatment with Ras-selective lethal 3 (RSL3), a ferroptosis inducer, and exposure to excess iron exacerbated cell death propagation in in vitro models, and inhibition of ferroptosis by Fer-1 blunted this effect in both settings. In ex vivo models, Fer-1 was sufficient to reduce cell death along the myofibers caused by external injury. SIGNIFICANCE: The unique I/R injury-induced pattern of cell death along myofibers requires novel injury models that mimic this phenomenon, thus we established new methods to replicate it. Ferroptosis is important in propagating injury between cells and better understanding this mechanism may lead to therapeutic responses that limit I/R injury.

Synthesis of epitope-targeting nanobody based on native protein-protein interactions for FtsZ filamentation suppressor.

Phage display and biopanning are powerful tools for generating binding molecules for a specific target. However, the selection process based only on binding affinity provides no assurance for the antibody's affinity to the target epitope. In this study, we propose a molecular-evolution approach guided by native protein-protein interactions to generate epitope-targeting antibodies. The binding-site sequence in a native protein was grafted into a complementarity-determining region (CDR) in the nanobody, and a nonrelated CDR loop (in the grafted nanobody) was randomized to create a phage display library. In this construction of nanobodies by integrating graft and evolution technology (CAnIGET method), suitable grafting of the functional sequence added functionality to the nanobody, and the molecular-evolution approach enhanced the binding function to inhibit the native protein-protein interactions. To apply for biological tool with growth screening, model nanobodies with an affinity for filamenting temperature-sensitive mutant Z (FtsZ) from Staphylococcus aureus were constructed and completely inhibited the polymerization of FtsZ as a function. Consequently, the expression of these nanobodies drastically decreased the cell division rate. We demonstrate the potential of the CAnIGET method with the use of native protein-protein interactions for steady epitope-specific evolutionary engineering.

Six-week oral prednisolone therapy for immune-related pneumonitis: a single-arm phase II study.

BACKGROUND: There has been no prospective trial for treatment of immune-related pneumonitis (irP) occurred after immune checkpoint inhibitors (ICIs). METHODS: In this single-arm phase II study, patients with cancer with grade ≥2 irP received oral prednisolone (1 mg/kg/day), tapered over 6 weeks. The primary endpoint was a pneumonitis control rate at 6 weeks from the start of the study treatment, defined as complete disappearance or partial improvement of irP in high-resolution CT of the chest. RESULTS: Among 57 patients enrolled, 56 were included in the final analysis. The most frequent cause of irP was single ICI therapy (51.8%), followed by combination with chemotherapy plus ICI (39.3%). Thirty-five (62.5%) patients had grade 2 irP and 21 (37.5%) had grade ≥3. Fifty-one (91.1%) patients completed the study treatment while 5 discontinued the study treatment because of relapse of irP (n=1), death from cancer (n=1), occurrence of immune-related hepatitis (n=1), extension of the treatment duration more than 6 weeks (n=1), and attending physician's decision (n=1). Six weeks after the start of the study treatment, 16 (28.5%) patients demonstrated complete recovery from irP, 35 (62.5%) had a partial improvement in irP, 1 (1.8%) had a relapse of irP, and 4 (7.1%) were not evaluable. The pneumonitis control rate at 6 weeks was 91.1% (95% CI, 80.7% to 96.1%). Twelve weeks after the start of the study treatment, 5 (8.9%), 27 (48.2%), and 15 (26.8%) patients demonstrated complete recovery, partial improvement, and relapse, respectively, and 9 (16.1%) were not evaluable. The pneumonitis control rate at 12 weeks was 57.1% (95% CI, 44.1% to 69.2%). During the observation period, 18 (32.1%) patients experienced a relapse of irP, and of those, 17 received re-treatment with corticosteroids. Grade ≥3 adverse events occurred in 10 (17.9%) patients, in which hyperglycemia was most frequent (n=6). There was no treatment-related death. CONCLUSIONS: In this first prospective study for irP, prednisolone at 1 mg/kg/day, tapered over 6 weeks, demonstrated a promising clinical benefit and manageable toxicity, suggesting a potential treatment option for irP. TRIAL REGISTRATION NUMBER: jRCT: 1041190029.

Design of silica-PLC LP11 mode rotator based on adiabatic mode conversion.

A silica-based LP11 mode rotator, which is one of the basic and indispensable optical components for space division multiplexing, with multiple tapered trenches is proposed. Compared with the conventional interference-based LP11 mode rotator with a simple L-shape waveguide, the proposed LP11 mode rotator has many advantages in a mode conversion efficiency, an insertion loss, and a fabrication tolerance because the operation principle is based on the adiabatic mode conversion. By using an approach of the shortcut to adiabaticity, the proposed device is effectively miniaturized rather than the standard tapered structures. Among the LP11 mode rotators in the silica-based mode multi/demultiplexers, the proposed type will be a considerably promising candidate.

Cytokine profiling identifies circulating IL-6 and IL-15 as prognostic stratifiers in patients with non-small cell lung cancer receiving anti-PD-1/PD-L1 blockade therapy.

Whether circulating levels of specific cytokines at baseline link with treatment efficacy of immune checkpoint blockade (ICB) therapy in patients with non-small cell lung cancer remains unknown. In this study, serum samples were collected in two independent, prospective, multicenter cohorts before the initiation of ICB. Twenty cytokines were quantified, and cutoff values were determined by receiver operating characteristic analyses to predict non-durable benefit. The associations of each dichotomized cytokine status with survival outcomes were assessed. In the discovery cohort (atezolizumab cohort; N = 81), there were significant differences in progression-free survival (PFS) in accordance with the levels of IL-6 (log-rank test, P = 0.0014), IL-15 (P = 0.00011), MCP-1 (P = 0.013), MIP-1ß (P = 0.0035), and PDGF-AB/BB (P = 0.016). Of these, levels of IL-6 and IL-15 were also significantly prognostic in the validation cohort (nivolumab cohort, N = 139) for PFS (log-rank test, P = 0.011 for IL-6 and P = 0.00065 for IL-15) and overall survival (OS; P = 3.3E-6 for IL-6 and P = 0.0022 for IL-15). In the merged cohort, IL-6high and IL-15high were identified as independent unfavorable prognostic factors for PFS and OS. The combined IL-6 and IL-15 status stratified patient survival outcomes into three distinct groups for both PFS and OS. In conclusion, combined assessment of circulating IL-6 and IL-15 levels at baseline provides valuable information to stratify the clinical outcome of patients with non-small cell lung cancer treated with ICB. Further studies are required to decipher the mechanistic basis of this finding.

Thermal stress, hydration, and salivary and respiratory stress markers in curling players performing a match in the cold.

Curling is a target-based team sport played in a cold environment. The type of stress curling players face during a curling match remains to be determined. In the present study, 16 Japanese curling players performed a practice curling match (six ends lasting 90 min), wherein the following variables were documented: core and skin temperatures, heart rate, thermal sensation and comfort, urine-specific gravity, body fluid loss, salivary cortisol, α-amylase activity, salivary secretory immunoglobulin A (SIgA), and fractionated exhaled nitric oxide (FeNO, a respiratory stress marker). Pre-match resting core temperature was 37.24 ± 0.31°C, which increased up to 37.73 ± 0.41°C during the match (p < 0.001). Facial skin temperatures decreased after the match (all p ≤ 0.015), whereas finger skin temperatures remained unchanged (p ≥ 0.375). Thermal discomfort increased following the match but thermal sensation remained unchanged. Following the match, players lost 0.29 ± 0.15 L body fluid (sweat, respiratory evaporation, and urine), which was nearly compensated by fluid ingestion of 0.22 ± 0.13 L (p = 0.119). Nevertheless, urine-specific gravity increased from 1.021 ± 0.010 to 1.024 ± 0.008 after the match (p = 0.012), with 31% and 50% players being dehydrated at pre- and post-match, respectively. Salivary cortisol decreased (p < 0.001) after the match without changes in salivary SIgA, α-amylase activity, and FeNO (all p ≥ 0.113). Therefore, during a curling match, the core temperature and thermal discomfort increase, whereas the face skin temperature decreases. Additionally, players may undergo dehydration before the match, which could be exacerbated after the match.

Serum immune modulators associated with immune-related toxicities and efficacy of atezolizumab in patients with non-small cell lung cancer.

PURPOSE: Identifying patients at high risk of immune-related adverse events (irAEs) that impede the achievement of durable efficacy of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy is important in improving their management. Identification of a novel predictive factor of therapeutic benefit is also important in improving patient selection for treatment with PD-1/PD-L1 inhibitors. Further determinants driving response and linking with irAEs are urgently required. METHODS: To address these unmet needs in the field, we explored whether 27 soluble checkpoint proteins and immunomodulatory proteins in serum at the therapy baseline and after week 3 were associated with irAE onset and therapeutic efficacy using MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel assays in a prospective, multicenter cohort of 81 patients with non-small cell lung cancer (NSCLC) receiving atezolizumab monotherapy. RESULTS: By competing-risks regression analysis, we identified that high levels of B cell-activating factor (BAFF) at baseline were a significant and strong risk factor of irAEs (hazard ratio, 5.61; 95% confidence interval, 2.43-12.96; P < 0.0001). We also identified that increased inducible T cell co-stimulator (ICOS) during the first therapeutic cycle was an independent factor associated with prolonged progression-free survival and overall survival. CONCLUSION: These findings are in keeping with the reported mechanistic basis of these molecules and may provide potential guidance for clinical decision-making to improve patient care. Further validation studies are warranted. Trial registration UMIN000035616 (January 28, 2019).

Intramuscular Adipose Tissue Content as a Predictor of Incisional Hernia after Hepatic Resection.

BACKGROUND: Incisional hernia (IH) is a common surgical complication, with an incidence of 6-31% following major abdominal surgery. This study aimed to investigate the impact of intramuscular adipose tissue content (IMAC) on the incidence of IH in patients who underwent hepatic resection. METHODS: Data of 205 patients who underwent open hepatic resection between 2007 and 2019 at Ehime University Hospital were retrospectively analyzed. Patient characteristics, perioperative findings, and body composition were compared between patients with IH and those without IH. The quantity and quality of skeletal muscle, calculated as skeletal muscle index and IMAC, were evaluated using preoperative computerized tomography images. RESULTS: Forty (19.5%) patients were diagnosed with IH. The cumulative incidence rates were 15.6% at 1 year and 19.6% at 3 years. On univariate analysis, body mass index, areas of subcutaneous and visceral fat, and IMAC were significantly higher in the IH group than in the non-IH group (p = 0.0023, 0.0070, 0.0047, and 0.0080, respectively). No significant difference in skeletal muscle index was found between the groups (p = 0.3548). The incidence of diabetes mellitus, intraoperative transfusion, and postoperative wound infection was significantly higher in the IH group than in the non-IH group (p = 0.0361, 0.0078, and 0.0299, respectively). On multivariate analysis, a high IMAC and wound infection were independent risk factors for IH (adjusted odds ratio, 2.83 and 4.52, respectively; p = 0.0152 and 0.0164, respectively). CONCLUSION: IMAC can predict the incidence of IH in patients undergoing hepatic resection.

Assessment of inconsistencies in the solvent-accessible surfaces of proteins between crystal structures and solution structures observed by LC-MS.

Structural proteomics techniques are useful for identifying the binding sites of proteins. The surface of a target protein with and without a bound binding partner is artificially labeled using a hydroxy radical, deuterium, or a low-molecular-weight chemical, and the difference in the label strength with and without the bound partner is determined. Label strength maps are then prepared on the Protein Data Bank (PDB) structure to identify the binding surface. However, the surface-accessible sites determined using such structural proteomics methods are frequently inconsistent with those calculated based on PDB structures, speculating that the measurement determines chemical accessibility rather than solvent accessibility. In this study, the solvent-accessible surface of human serum albumin was analyzed using covalent protein labeling with varying concentrations of CH2O and then compared to surfaces derived from 27 PDB structures. The results indicated that inconsistencies in solvent-accessible surface area values calculated from PDB structures are not caused by the limited capabilities of liquid chromatography-mass spectrometry coupled with covalent protein painting but instead are due to the lack of PDB data representing the structures in solution.

Prevalence and risk factors of poor subjective sleep quality in elite judo athletes.

This study aimed to determine the prevalence and risk factors of poor subjective sleep quality in elite judo athletes. A subjective cross-sectional questionnaire survey was conducted with 106 elite judo athletes who participated in the training camp of the Japanese national team. Eighty-six respondents (men: 52.3%; average age: 22.9 ± 3.1 years) with complete responses were included in the analysis (valid response rate: 81.1%). Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). The prevalence of poor sleep quality (PSQI score ≥ 5.5), the mean PSQI score, and subscale scores were investigated. Relationships between poor sleep quality and attributes, lifestyle habits, competition-based activities, and psychological distress were explored using Fisher's exact tests and multivariate logistic regression analysis. Thirty-five respondents (40.7%) reported poor sleep quality. The percentage and subscale scores of the respondents for sleep latency, sleep duration, and daytime dysfunction were higher than those of the population of Japanese national-level athletes. The mean PSQI score of the respondents was similar to that of some elite athlete populations but higher than those of others. Multivariate logistic regression analysis revealed that psychological distress was associated with poor sleep quality. In conclusion, the prevalence of poor subjective sleep quality in elite judo athletes was suggested to be similar or higher among elite athlete population. Sleep latency, sleep duration, and daytime dysfunction status were worse in elite judo athletes than in Japanese national-level athletes. Psychological distress was a risk factor for poor subjective sleep quality in elite judo athletes. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-023-00444-6.

Association between the Preoperative C-Reactive Protein-to-Albumin Ratio and the Risk for Postoperative Pancreatic Fistula following Distal Pancreatectomy for Pancreatic Cancer.

Postoperative pancreatic fistula (POPF) are major postoperative complications (POCs) following distal pancreatectomy (DP). Notably, POPF may worsen the prognosis of patients with pancreatic cancer. Previously reported risks for POCs include body mass index, pancreatic texture, and albumin levels. Moreover, the C-reactive protein-to-albumin ratio (CAR) is a valuable parameter for prognostication. On the other hand, POCs sometimes lead to a worse prognosis in several cancer types. Thus, we assumed that CAR could be a risk factor for POPFs. This study investigated whether CAR can predict POPF risk in patients with pancreatic cancer following DP. This retrospective study included 72 patients who underwent DP for pancreatic cancer at Ehime University between January 2009 and August 2022. All patients underwent preoperative CAR screening. Risk factors for POPF were analyzed. POPF were observed in 17 of 72 (23.6%) patients. POPF were significantly associated with a higher CAR (p = 0.001). The receiver operating characteristic curve analysis determined the cutoff value for CAR to be 0.05 (sensitivity: 76.5%, specificity: 88.9%, likelihood ratio: 6.88), indicating an increased POPF risk. Univariate and multivariate analysis revealed that CAR ≥ 0.05 was a statistically independent factor for POPF (p < 0.001, p = 0.013). Therefore, CAR has the potential to predict POPF following DP.

Antimicrobial use and its association with the presence of methicillin-resistant staphylococci (MRS) and extended-spectrum beta-lactamases (ESBL)-producing coliforms in mastitic milk on dairy farms in the Chiba Prefecture, Japan.

Food-producing animals, including dairy cattle, are potential reservoirs of antimicrobial resistance. However, there is limited data on antimicrobial use and the selection of resistant bacteria. Therefore, we investigated the association between antimicrobial use and resistance to mastitis pathogens using 2016 data from milk samples collected from cows with mastitis in 134 dairy farms in Chiba Prefecture, one of the principal dairy production prefectures in Japan. We recorded the antimicrobial use and isolation of methicillin-resistant staphylococci (MRS) and extended-spectrum beta-lactamase (ESBL)-producing coliforms (E. coli and Klebsiella spp.), and used the antimicrobial treatment incidence (ATI; the theoretical number of animals per 1000 animal-days subjected to antimicrobial treatment) to indicate antimicrobial use on each farm. The farms in which MRS or ESBL-producing coliforms were isolated from at least one mastitic milk sample were classified as antimicrobial resistance (AMR)-positive, and those in which neither MRS nor ESBL-producing coliforms were isolated were classified as AMR-negative. The AMR-positive farms showed a significantly higher ATI (median 45.17) than AMR-negative farms (median 38.40). The results indicate that high antimicrobial usage is associated with AMR in staphylococci and coliforms isolated from mastitic milk on dairy farms in Chiba Prefecture.

[A Case of Unresectable Hepatocellular Carcinoma Treated using Lenvatinib and Conversion Surgery].

A 57-year-old man was treated with lenvatinib for unresectable hepatocellular carcinoma(HCC). Thereafter, the tumor marker levels decreased, and the tumor became resectable. The patient underwent portal vein embolization followed by laparoscopic extended left lobectomy. The patient's postoperative course was uneventful, and the tumor marker levels remained within the normal range. No recurrence was observed 3 months after surgery. In recent years, the use of systemic chemotherapy with drugs, such as lenvatinib, followed by conversion surgery has been reported in some cases of unresectable HCC. The present case reports successful conversion surgery following lenvatinib treatment.

A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation.

N-glycan-mediated activation of the thrombopoietin receptor (MPL) under pathological conditions has been implicated in myeloproliferative neoplasms induced by mutant calreticulin, which forms an endogenous receptor-agonist complex that traffics to the cell surface and constitutively activates the receptor. However, the molecular basis for this mechanism is elusive because oncogenic activation occurs only in the cell-intrinsic complex and is thus cannot be replicated with external agonists. Here, we describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. In-depth characterization of lectin-induced activation showed that, similar to oncogenic activation, sugar chain-mediated activation persists due to limited receptor internalization. The strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. Overall, the existence of sugar-mediated MPL activation, in which the mode of activation is different from the original ligand, suggests that receptor activation is unpredictably diverse in living organisms.

Ferroptosis in heart failure.

With its complicated pathobiology and pathophysiology, heart failure (HF) remains an increasingly prevalent epidemic that threatens global human health. Ferroptosis is a form of regulated cell death characterized by the iron-dependent lethal accumulation of lipid peroxides in the membrane system and is different from other types of cell death such as apoptosis and necrosis. Mounting evidence supports the claim that ferroptosis is mainly regulated by several biological pathways including iron handling, redox homeostasis, and lipid metabolism. Recently, ferroptosis has been identified to play an important role in HF induced by different stimuli such as myocardial infarction, myocardial ischemia reperfusion, chemotherapy, and others. Thus, it is of great significance to deeply explore the role of ferroptosis in HF, which might be a prerequisite to precise drug targets and novel therapeutic strategies based on ferroptosis-related medicine. Here, we review current knowledge on the link between ferroptosis and HF, followed by critical perspectives on the development and progression of ferroptotic signals and cardiac remodeling in HF.