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Objective: Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients., Methods: This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function., Results: Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p  = .045 and p  =  0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p  = .025 and p  =  0.036, respectively)., Conclusions: Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.

Objective: Proximal ExTension to Induce COmplete ATtachment (PETTICOAT), which uses downstream bare metal stents for structural support, demonstrates potential, yet its adoption is limited by variable outcomes. This study elucidates the potential of PETTICOAT in aortic dissection, emphasizing the determinants that guide patient selection., Methods: A retrospective analysis of 60 patients who underwent full PETTICOAT for aortic dissections was conducted. A multivariate logistic regression model identified predictors of favorable aortic remodeling. Patients underwent standardized follow-up with computed tomography scans to assess size, volumetric changes, and anatomical conditions. Selection criteria included full PETTICOAT application and a minimum of 3 months of follow-up. Demographics, preoperative conditions, and procedural details were collected and analyzed., Results: The analysis identified predictors of favorable aortic remodeling, including age >60 years, a larger downstream aorta stent graft, a smaller abdominal aorta (<450 mm 2 ), and oral angiotensin II receptor blocker administration. Over a median 47.5 months of follow-up, survival rates in the favorable remodeling (97.3%) and unfavorable groups (100%) were similar. Downstream aortic event-free survival rates did not differ significantly (89.2% vs 73.9%), although the unfavorable group had a relatively higher incidence of distal stent-induced new entries (26.1% vs 8.1%)., Conclusions: The PETTICOAT concept effectively enhances aortic remodeling in complex aortic dissections. Predictors for favorable remodeling, including age, stent graft sizing, aortic diameter, and angiotensin II receptor blocker therapy, offer insights for optimizing patient selection. This approach improves survival outcomes, mitigates risks associated with untreated aortic segments, and provides a minimally invasive solution for aortic dissections. Despite some outcome variations, the technique holds promise for addressing the challenges of aortic dissections, with the potential for further refinement in patient selection and technique application., Competing Interests: Disclosures None., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: As the number of older adults in society increases, their social roles and networks, as well as their physical function, decrease. This study aimed to clarify the association between social networks and physical function among people aged ≥ 60 years in rural Thailand., Patients and Methods: This cross-sectional study was conducted in the Photharam District, Ratchaburi Province, Thailand. Participants were required to be at least 60 years old and be able to walk to the health center. Social networks were surveyed using the Thai version of Lubben Social Network Scores-6. Four physical function measures, namely hand grip strength, five-times-sit-to-stand test, timed up-and-go (TUG) test, and one-leg standing, were considered. Regression analysis was conducted with Lubben Social Network Scores-6 as the dependent variable and the four types of physical function as independent variables., Results: A total of 497 older adults aged 60 years or more were enrolled; 82 were males, and 412 were females. The mean Lubben Social Network Scores-6 was 14.9 ± 5.7. Only the TUG test was associated in a single and multiple regression analysis with the Lubben Social Network Scores-6 as the dependent variable and the four physical function assessments as independent variables., Conclusion: The TUG test assessed the smoothness of normal standing and walking, which are essential physical functions for maintaining a social network and meeting people. This suggests a relationship between physical function and social network., Competing Interests: The authors declare no conflict of interest., (© 2024 Kuniya et al.)

Decreased cough strength in myasthenia gravis (MG) leads to aspiration and increases the risk of MG crisis. The aim of this study was to clarify the reliability and validity of cough peak flow (CPF) measurements in MG. A total of 26 patients with MG who underwent CPF measurements using the peak flow meter by themselves were included. MG symptoms were evaluated by pulmonary function tests and clinical MG assessment scales before and after immune-treatments. The relationship between CPF and pulmonary function tests and MG comprehensive were assessed. The cut-off value of CPF for aspiration risk was determined and the area under the curve (AUC) was calculated. The intraclass correlation coefficient was more than 0.95 for pre-and post-treatment. Positive correlations were found between CPF and almost all spirometric values as well as between the differences of pre-and post-treatment in CPF and quantitative myasthenia gravis score. The CPF for identifying the aspiration risk was used to calculate the CPF cut-off value of 205 L/min with a sensitivity of 0.77, specificity of 0.90, and AUC of 0.85. The CPF, a convenient measure by patients themselves, has a high reliability in patients with MG, and is a useful biomarker reflecting MG symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Arterio-ureteral fistulas (AUFs), which are relatively rare but potentially life-threatening, require prompt diagnosis and treatment. We reported a case of AUFs following robot-assisted laparoscopic radical cystectomy (RARC) with extended pelvic lymph node dissection and ileal conduit urinary diversion for muscle-invasive bladder cancer, which resulted in massive hemorrhage. Urine leaked from the anastomosis between the ureter, and the end of the ileal conduit was infected, which resulted in an AUF between the pseudoaneurysm of the right common iliac artery and the ureter. The AUF was managed successfully by vascular intervention with an arterial stent graft., (© 2024 The Author(s). Asian Journal of Endoscopic Surgery published by Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Background: Nivolumab plus ipilimumab (NIVO + IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). While approximately 40% of patients treated with NIVO + IPI achieve a durable response, 20% develop primary resistance with severe consequences. Therefore, there is a clinical need for criteria to select patients suitable for NIVO + IPI therapy to optimize its therapeutic efficacy. Accordingly, our aim was to evaluate the association between candidate biomarkers measured before treatment initiation and survival., Methods: This was a multi-institutional, retrospective, cohort study of 183 patients with mRCC treated with systematic therapies between August 2015 and July 2023. Of these, 112 received NIVO + IPI as first-line therapy: mean age, 68 years; men, 83.0% (n = 93), and clear cell histology, 80.4% (n = 90). Univariable and multivariable analyses were used to evaluate associations between biomarkers and survival., Results: On univariate analysis, high C-reactive protein and systemic index, a high neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio, and a low lymphocyte-to-monocyte ratio (LMR) were associated with shorter overall survival (OS). On multivariable analysis, a LMR ≤ 3 was retained as an independent factor associated to shorter OS with the highest accuracy (C-index, 0.656; hazard ratio, 7.042; 95% confidence interval, 2.0-25.0; p = 0.002)., Conclusion: A low LMR may identify patients who would be candidate for NIVO + IPI therapy for mRCC., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Purpose: To establish if osteosarcopenia is related to postoperative complications, prognosis, and recurrence of colorectal cancer (CRC) after curative surgery., Methods: The clinical data of 594 patients who underwent curative resection for CRC between January, 2013 and December, 2018 were analyzed retrospectively to examine the relationship between clinicopathological data and osteosarcopenia. The following definitions were used: sarcopenia, low skeletal muscle mass index; osteopenia, low bone mineral density on computed tomography at the level of the 11th thoracic vertebra; and osteosarcopenia, sarcopenia with osteopenia., Results: Osteosarcopenia was identified in 98 patients (16.5%) and found to be a significant risk factor for postoperative complications (odds ratio 2.53; p = 0.011). The 5-year overall survival (OS) and recurrence-free survival (RFS) rates of the patients with osteosarcopenia were significantly lower than those of the patients without osteosarcopenia (OS: 72.5% and 93.9%, respectively, p < 0.0001; RFS: 70.8% and 92.4%, respectively, p < 0.0001). Multivariate analysis identified osteosarcopenia as an independent prognostic factor associated with OS (hazard ratio 3.31; p < 0.0001) and RFS (hazard ratio 3.67; p < 0.0001)., Conclusion: Osteosarcopenia may serve as a predictor of postoperative complications and prognosis after curative surgery for CRC., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Robot-assisted partial nephrectomy (RAPN) has been shown to be a safe and effective method for treatment of small renal tumors, including clinical T1b renal cell carcinoma (RCC); however, the impact of RAPN for cT1b renal tumors on renal function is not well understood. In this retrospective study, 50 patients who underwent RAPN for cT1b renal tumors were evaluated for pre- and post-operative renal function and perioperative clinical factors. Renal function was assessed using the estimated glomerular filtration rate (eGFR) at baseline and on postoperative days (POD) 1, 7, 30, and 180.A significant renal functional decline was defined as ≥ 15% reduction in eGFR at POD180 compared with eGFR at baseline. Logistic regression analyses were used to identify risk factors for renal function decline, including age, sex, RENAL nephrometry score, operative time, and estimated blood loss. The median patient age was 62 years, and the median tumor diameter and RENAL nephrometry score were 44 mm (IQR 43-50) and 8 (IQR 7-9), respectively. Of these patients, 16 (36%) showed a significant renal functional decline at POD 180. In the multivariate analysis, the L component of the RENAL nephrometry score and an estimated blood loss of 200 mL or more were identified as significant risk factors for renal functional decline. These findings suggest that the preoperatively definable L component of the RENAL nephrometry score and intraoperative blood loss, which may be modifiable factors, play significant roles in post-RAPN renal function decline., (© 2024. The Author(s).)

Objective. Thermal property (TP) maps of human tissues are useful for tumor treatment and diagnosis. In particular, the blood perfusion rate is significantly different for tumors and healthy tissues. Noninvasive techniques that reconstruct TPs from the temperature measured via magnetic resonance imaging (MRI) by solving an inverse bioheat transfer problem have been developed. A few conventional methods can reconstruct spatially varying TP distributions, but they have several limitations. First, most methods require the numerical Laplacian computation of the temperature, and hence they are sensitive to noise. In addition, some methods require the division of a region of interest (ROI) into sub-regions with homogeneous TPs using prior anatomical information, and they assume an unmeasurable initial temperature distribution. We propose a novel robust reconstruction method without the division of an ROI or the assumption of an initial temperature distribution. Approach. The proposed method estimates blood perfusion rate maps from relative temperature changes. This method avoids the computation of the Laplacian by using integral representations of the Helmholtz decomposition of the heat flux. Main Result. We compare the reconstruction results of the conventional and proposed methods using numerical simulations. The results indicate the robustness of the proposed method. Significance. This study suggests the feasibility of thermal property mapping with MRI using the robust proposed method., (Creative Commons Attribution license.)

Background: Attention is one of the factors involved in selecting input information for the brain. We applied a method for estimating domains with clear boundaries using magnetoencephalography (the domain estimation method) for auditory-evoked responses (N100m) to evaluate the effects of attention in milliseconds. However, because the surface around the auditory cortex is folded in a complicated manner, it is unknown whether the activity in the auditory cortex can be estimated., New Method: The parameter range to express current sources was set to include the auditory cortex. Their search region was expressed as a direct product of the parameter ranges used in the adaptive diagonal curves., Results: Without a limitation of the range, activity was estimated in regions other than the auditory cortex in all cases. However, with the limitation of the range, the activity was estimated in the primary or higher auditory cortex. Further analysis of the limitation of the range showed that the domains activated during attention included the regions activated during no attention for the participants whose amplitudes of N100m were higher during attention., Comparison With Existing Method: We proposed a method for effectively limiting the search region to evaluate the extent of the activated domain in regions with complex folded structures., Conclusion: To evaluate the extent of activated domains in regions with complex folded structures, it is necessary to limit the parameter search range. The area of the activated domains in the auditory cortex may increase by attention on the millisecond timescale., Competing Interests: Declaration of Competing Interest none., (Copyright © 2023 Elsevier B.V. All rights reserved.)

COVID-19 has a range of complications, from no symptoms to severe pneumonia. It can also affect multiple organs including the nervous system. COVID-19 affects the brain, leading to neurological symptoms such as delirium. Delirium, a sudden change in consciousness, can increase the risk of death and prolong the hospital stay. However, research on delirium prediction in patients with COVID-19 is insufficient. This study aimed to identify new risk factors that could predict the onset of delirium in patients with COVID-19 using machine learning (ML) applied to nursing records. This retrospective cohort study used natural language processing and ML to develop a model for classifying the nursing records of patients with delirium. We extracted the features of each word from the model and grouped similar words. To evaluate the usefulness of word groups in predicting the occurrence of delirium in patients with COVID-19, we analyzed the temporal changes in the frequency of occurrence of these word groups before and after the onset of delirium. Moreover, the sensitivity, specificity, and odds ratios were calculated. We identified (1) elimination-related behaviors and conditions and (2) abnormal patient behavior and conditions as risk factors for delirium. Group 1 had the highest sensitivity (0.603), whereas group 2 had the highest specificity and odds ratio (0.938 and 6.903, respectively). These results suggest that these parameters may be useful in predicting delirium in these patients. The risk factors for COVID-19-associated delirium identified in this study were more specific but less sensitive than the ICDSC (Intensive Care Delirium Screening Checklist) and CAM-ICU (Confusion Assessment Method for the Intensive Care Unit). However, they are superior to the ICDSC and CAM-ICU because they can predict delirium without medical staff and at no cost., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Miyazawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Coronavirus disease 2019 (COVID-19) is associated with a marked increase in the inflammatory cytokines, IL-6 and IL-18. Blood purification therapy aimed at controlling cytokines is one treatment option; however, evidence of its effectiveness is needed. Plasma exchange with dialysis (PED) is a blood purification method involving selective plasma exchange with dialysate flowing through the outer hollow fiber of the plasma separator. In this retrospective study, we investigated the efficacy of continuous PED (cPED) over 48 h in five patients with severe COVID-19., Methods: We assessed changes in IL-6 and IL-18, as well as adiponectin (APN)., Results: There were no significant differences in changes in IL-6 and IL-18, but there was a marked improvement in cases with abnormally high IL-6 and IL-18 levels at baseline. APN, which inhibits inflammatory cytokines, was significantly elevated post-cPED., Conclusion: Our results suggest that cPED therapy is an effective treatment for COVID-19., (© 2023 International Society for Apheresis and Japanese Society for Apheresis.)

Background: We report a case of diffuse large B-cell lymphoma that progressed rapidly after androgen deprivation therapy for prostate cancer in a patient with a history of IgG4-related disease. Estrogen has been reported to be a possible cause of acute exacerbations of malignant lymphoma only in mouse models. Therefore, its clinical significance has not been clarified., Case Presentation: This case report describes a 75-year-old man with prostate cancer who had IgG4-related disease. Hormone therapy was initiated to treat prostate cancer, but he developed dyspnea and back pain. A diagnosis was made of diffuse large B-cell lymphoma. Immunohistochemistry was positive for estrogen receptor β, which led us to suspect rapid progression of diffuse large B-cell lymphoma due to estrogen suppression by gonadotropin-releasing hormone antagonists. Hormone therapy was discontinued, and the patient received R-CHOP therapy. Subsequently, the lymphoma masses shrunk, and the patient obtained remission., Conclusion: This case is the first report of clinical significance regarding the crucial role of estrogen and estrogen receptor β in malignant lymphoma in a patient with IgG4-related disease. Our report aims to raise awareness of the need to carefully select treatment options for prostate cancer patients with IgG4-related disease or lymphoma., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Although nivolumab plus ipilimumab is the standard treatment for metastatic renal cell carcinoma (RCC), its efficacy and safety in older patients remain unclear. Therefore, this study aimed to assess the clinical outcomes of nivolumab plus ipilimumab for metastatic RCC in patients aged ≥ 75 years., Methods: We enrolled 120 patients with metastatic RCC treated with nivolumab plus ipilimumab from August 2015 to January 2023. Objective response rates (ORRs) were compared between patients aged < 75 and ≥ 75 years. Progression-free survival (PFS), overall survival (OS), and adverse events were compared between the groups. Adverse events were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1., Results: Among the patients, 57 and 63 were classified as intermediate and poor risk, respectively, and one could not be classified. The median follow-up duration after the initiation of treatment was 16 months. The patient characteristics between the groups, except for age, were not significantly different. Intergroup differences in ORR (42% vs. 40%; p = 0.818), PFS (HR: 0.820, 95% CI 0.455-1.479; p = 0.510), and median OS (HR: 1.492, 95% CI 0.737-3.020; p = 0.267) were not significant. The incidence of adverse events (50% vs. 67%; p = 0.111) and nivolumab plus ipilimumab discontinuation due to adverse events was not significantly different between the groups (14% vs. 13%; p = 0.877)., Conclusions: The effectiveness of nivolumab plus ipilimumab was comparable between patients with metastatic RCC aged < 75 and those ≥ 75 years with respect to their ORRs, PFS, OS, and adverse event rates., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The cell membrane of Halobacterium salinarum contains a retinal-binding photoreceptor, sensory rhodopsin II (HsSRII), coupled with its cognate transducer (HsHtrII), allowing repellent phototaxis behavior for shorter wavelength light. Previous studies on SRII from Natronomonas pharaonis (NpSRII) pointed out the importance of the hydrogen bonding interaction between Thr204 NpSRII and Tyr174 NpSRII in signal transfer from SRII to HtrII. Here, we investigated the effect on phototactic function by replacing residues in HsSRII corresponding to Thr204 NpSRII and Tyr174 NpSRII . Whereas replacement of either residue altered the photocycle kinetics, introduction of any mutations at Ser201 HsSRII and Tyr171 HsSRII did not eliminate negative phototaxis function. These observations imply the possibility of the presence of an unidentified molecular mechanism for photophobic signal transduction differing from NpSRII-NpHtrII., (© 2023 Federation of European Biochemical Societies.)

Background: Nivolumab plus ipilimumab (NIVO+IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). Approximately 40% of patients achieve a durable response; however, 20% develop primary resistant disease (PRD) to NIVO+IPI, about which little is known in patients with mRCC. Therefore, this investigation aimed to evaluate the clinical implication of PRD in patients with mRCC to select better candidates in whom NIVO+IPI can be initiated as first-line therapy., Methods: This multi-institutional retrospective cohort study used data collected between August 2015 and January 2023. In total, 120 patients with mRCC treated with NIVO+IPI were eligible. Associations between immune-related adverse events and progression-free survival, overall survival (OS), and objective response rate were analyzed. The relationship between other clinical factors and outcomes was also evaluated., Results: The median observation period was 16 months (interquartile range, 5-27). The median age at NIVO+IPI initiation was 68 years in the male-dominant population (n = 86, 71.7%), and most patients had clear cell histology (n = 104, 86.7%). PRD was recorded in 26 (23.4%) of 111 investigated patients during NIVO+IPI therapy. Patients who experienced PRD showed worse OS (hazard ratio: 4.525, 95% confidence interval [CI]: 2.315-8.850, p < 0.001). Multivariable analysis showed that lymph node metastasis (LNM) (odds ratio: 4.274, 95% CI: 1.075-16.949, p = 0.039) was an independent risk factor for PRD., Conclusions: PRD was strongly correlated with worse survival rates. LNM was independently associated with PRD in patients with mRCC receiving NIVO+IPI as first-line therapy and might indicate that a candidate will not benefit from NIVO+IPI., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: Authors declare no conflict of interests for this article.

Background: Diplonemid flagellates are among the most abundant and species-rich of known marine microeukaryotes, colonizing all habitats, depths, and geographic regions of the world ocean. However, little is known about their genomes, biology, and ecological role., Results: We present the first nuclear genome sequence from a diplonemid, the type species Diplonema papillatum. The ~ 280-Mb genome assembly contains about 32,000 protein-coding genes, likely co-transcribed in groups of up to 100. Gene clusters are separated by long repetitive regions that include numerous transposable elements, which also reside within introns. Analysis of gene-family evolution reveals that the last common diplonemid ancestor underwent considerable metabolic expansion. D. papillatum-specific gains of carbohydrate-degradation capability were apparently acquired via horizontal gene transfer. The predicted breakdown of polysaccharides including pectin and xylan is at odds with reports of peptides being the predominant carbon source of this organism. Secretome analysis together with feeding experiments suggest that D. papillatum is predatory, able to degrade cell walls of live microeukaryotes, macroalgae, and water plants, not only for protoplast feeding but also for metabolizing cell-wall carbohydrates as an energy source. The analysis of environmental barcode samples shows that D. papillatum is confined to temperate coastal waters, presumably acting in bioremediation of eutrophication., Conclusions: Nuclear genome information will allow systematic functional and cell-biology studies in D. papillatum. It will also serve as a reference for the highly diverse diplonemids and provide a point of comparison for studying gene complement evolution in the sister group of Kinetoplastida, including human-pathogenic taxa., (© 2023. The Author(s).)

Background: We investigated the safety and efficacy of physician-modified thoracic endovascular aortic repair using a low-profile device for aortic arch lesions., Methods: A total of 42 consecutive patients (mean age 67.2 ± 12.7 years; 32 men) with aortic arch lesions were treated by physician-modified thoracic endovascular aortic repair using a low-profile device (Zenith Alpha Thoracic Endovascular Graft) with four scallops or 13 fenestrations for the common carotid artery and 38 fenestrations or 30 branches for the left subclavian artery. The aortic repair indications were acute type B aortic dissection (n = 17, 40.5%), degenerative aneurysm (n = 14, 33.3%), chronic dissection aneurysmal degeneration (n = 4, 9.5%), and ulcer-like projection (n = 2, 4.8%). The mean iliac artery diameter was 7.6 ± 1.1 mm., Results: There were no branches covered unintentionally or patients who died and suffered from severe spinal cord ischemia perioperatively. One patient (2.4%) experienced a postoperative minor stroke with full neurological recovery. The mean follow-up time was 18 ± 11 months, with 28 patients (66.7%) having at least 12 months. One access-related complication (2.4%) occurred. Two residual Ia (4.8%) and three residual IIIa (7.1%) endoleaks were treated by reintervention. There were no open repair conversions, ruptures, or other aortic complications., Conclusion: Physician-modified thoracic endovascular aortic repair using the low-profile device may be a safe, feasible, and time-saving method for preserving the cervical artery and has high reproducibility and anatomical reconstruction. However, its durability requires long-term follow-up.

Background: Current therapeutic agents, including nifurtimox and benznidazole, are not sufficiently effective in the chronic phase of Trypanosoma cruzi infection and are accompanied by various side effects. In this study, 120 kinds of extracts from medicinal herbs used for Kampo formulations and 94 kinds of compounds isolated from medicinal herbs for Kampo formulations were screened for anti-T. cruzi activity in vitro and in vivo., Methods: As an experimental method, a recombinant protozoan cloned strain expressing luciferase, namely Luc2-Tulahuen, was used in the experiments. The in vitro anti-T. cruzi activity on epimastigote, trypomastigote, and amastigote forms was assessed by measuring luminescence intensity after treatment with the Kampo extracts or compounds. In addition, the cytotoxicity of compounds was tested using mouse and human feeder cell lines. The in vivo anti-T. cruzi activity was measured by a murine acute infection model using intraperitoneal injection of trypomastigotes followed by live bioluminescence imaging., Results: As a result, three protoberberine-type alkaloids, namely coptisine chloride, dehydrocorydaline nitrate, and palmatine chloride, showed strong anti-T. cruzi activities with low cytotoxicity. The IC 50 values of these compounds differed depending on the side chain, and the most effective compound, coptisine chloride, showed a significant effect in the acute infection model., Conclusions: For these reasons, coptisine chloride is a hit compound that can be a potential candidate for anti-Chagas disease drugs. In addition, it was expected that there would be room for further improvement by modifying the side chains of the basic skeleton., (© 2023. The Author(s).)

Purpose: We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA)., Methods: This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed., Results: In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs., Conclusions: The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This paper introduces a method for indoor self-localization of a monaural microphone, which is required for various location-based services. By generating two pairs of dipole sound fields, localization is performed on each device, irrespective of the number of devices, based on orthogonal detection of observed signals and some simple operations that are feasible with limited computational resources. A method using multiple source frequencies for enhancing robustness against the effects of reflection and scattering is also proposed. The effectiveness of this method was evaluated by numerical simulations and experiments in an anechoic chamber and indoor environment, and the average errors for the azimuth and zenith angles were 4.8 and 1.9 deg, respectively, in the anechoic chamber and 21 and 11 deg, respectively, in the indoor environment.

Human leukocyte antigen class I (HLA-I) genotypes are suggested to influence the cancer response to checkpoint blockade immunotherapy. This study assessed the impact of germline HLA genotypes on clinical outcomes in patients with chemoresistant advanced urothelial cancer (UC) treated with pembrolizumab. Zygosity, supertypes, evolutionary divergency, and specific alleles of germline HLA-I and -II were evaluated using the Luminex technique in 108 patients with chemoresistant metastatic or locally advanced UC treated with pembrolizumab. Among the 108 patients, 69 died and 83 showed radiographic progression during follow-up. Homozygous for at least one HLA-I locus, absence of the HLA-A03 supertype, and high HLA-I evolutionary divergence were associated with a radiographic response, but were not associated with survival outcomes. Patients with the HLA-DQB1*03:01 allele had significantly lower disease control rates than patients without the allele (17.4% vs. 53.8%, p = 0.002); its presence was also an independent risk factor for progressive disease (hazard ratio 4.35, 95% confidence interval 1.03-18.46). Furthermore, patients with the HLA-DQB1*03:01 allele had significantly worse progression-free survival than patients without the allele (median progression-free survival 3.1 vs. 4.8 months, p = 0.035). There was no significant relationship between any HLA status and the incidence of severe adverse events. Several germline HLA genotypes, especially HLA-DQB1*03:01, may be associated with radiographic progression. However, their impact on treatment response is limited, and germline HLA genotypes was not independently associated with survival outcomes. Further prospective studies are needed to confirm the relationship between germline HLA genotypes and clinical outcomes in patients with chemoresistant advanced UC treated with pembrolizumab., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: A smart glasses system is a computerized communicator with a transparent screen and video camera that can be worn as a pair of glasses. There have been no reports on the use of smart glasses in the prehospital setting., Purpose: To conduct a preliminary investigation on whether smart glasses were smoothly used bidirectionally between the prehospital setting and the receiving hospital., Methods: From March 1, 2022, to March 31, 2022, one smart glasses unit was installed in an ambulance at one branch of the fire department near our hospital. The physician on the computer, who received video and voice transmission from the smart glasses when the ambulance was dispatched, evaluated the transmission status with regard to video reception, voice reception, and voice transmission. In addition, the activity time was compared between cases in which the smart glasses system was used (patient) and not used (control)., Results: During the investigating period, 12 cases were analyzed as patients. The rate of good video reception was 75%, the rate of good voice reception was 50%, and the rate of good voice transmission was 25%. There was no significant change in the activity time between the patient and control groups., Conclusion: We performed a preliminary investigation on the usability of smart glasses in the prehospital setting. Using smart glasses, patient information was shared by video and voice before arrival at the hospital, and did not affect the activity time. However, the instability of the communication status should be recognized., (© 2022 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Background: Although bacillus Calmette-Guerin (BCG) is a standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), a high rate of adverse events with a variety of grades remains a difficulty., Objective: In this randomized, prospective, multicenter study, we examined whether levofloxacin, given after each intravesical instillation of BCG, could improve its tolerance in patients with intermediate- to high-risk urothelial carcinoma of the bladder without compromising its efficacy., Design, Setting, and Participants: Overall, 106 Japanese patients (85 men and 21 women; age: median, 69.5 yr) with primary or recurrent NMIBC were randomized after transurethral resection to induce treatment with intravesical BCG plus levofloxacin (group 1) or BCG alone (group 2)., Intervention: Patients who underwent intravesical instillation of BCG were randomized with or without levofloxacin administration., Outcome Measurements and Statistical Analysis: Adverse events were assessed using the National Cancer Institute-Common Toxicity Criteria version 3.0. Cumulative incidence functions and Kaplan-Meier methods were applied to estimate survival outcomes., Results and Limitations: There was no significant difference in baseline characteristics between the groups. The completion rate of group 1 (85.5%) was not significantly lower than that of group 2 (76.5%; p = 0.321). There was no significant difference in the completion rate of patients with pollakisuria, painful micturition, gross hematuria, fever elevation, and others between the groups. The incidence of adverse events in patients with high-grade pollakisuria (7.3% vs 25.4%, p = 0.041) and fever (0% vs 9.1%, p = 0.034) was significantly lower in group 1. The 5-yr progression-free and cancer-specific survival rates were significantly better in group 1., Conclusions: Prophylactic levofloxacin administration may reduce the severity of adverse events and contribute to better outcomes from BCG intravesical therapy in patients with NMIBC., Patient Summary: Levofloxacin administration seems to be a safe and effective therapy for non-muscle-invasive bladder cancer patients treated with bacillus Calmette-Guerin intravesical therapy., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

CpG methylation of genomic DNA is a well-known repressive epigenetic marker in eukaryotic transcription, and DNA methylation of promoter regions is correlated with gene silencing. In contrast to the promoter regions, the function of DNA methylation during transcription termination remains to be elucidated. A recent study revealed that mouse DNA methyltransferase 3a (Dnmt3a) mainly functions in de novo methylation in the promoter and gene body regions, including transcription termination sites (TTSs), during development. To investigate the relationship between DNA methylation overlapping the TTSs and transcription termination, we performed bioinformatics analysis using six pre-existing Dnmt -/- mouse cell datasets: four types of neurons (three Dnmt3a -/- and one Dnmt1 -/- mutants) and two types of embryonic fibroblasts (MEFs) (Dnmt3a -/- and Dnmt3b -/- mutants). Combined analyses using methylome and transcriptome data revealed that read counts downstream of hypomethylated TTSs were increased in three types of neurons (two Dnmt3a -/- and one Dnmt1 -/- mutants). Among these, an increase in chimeric transcripts downstream of the TTSs was observed in Dnmt3a -/- mature olfactory sensory neurons and Dnmt3a -/- agouti-related peptide (protein)-producing neurons, thereby indicating that read-through occurs in hypomethylated TTSs at specific gene loci in these two mutants. Conversely, in Dnmt3a -/- MEFs, we detected reductions in read counts downstream of hypomethylated TTSs. These results indicate that the hypomethylation of TTSs can both positively and negatively regulate transcription termination, dependent on Dnmt and cell types. This study is the first to identify the aberrant termination of transcription at specific gene loci with DNA hypomethylated TTSs attributable to Dnmt deficiency.

A 65-year-old man was found to have a 1.7 cm right renal mass by follow-up abdominal computed tomography for left total nephrectomy after a traffic accident. The renal mass progressed slowly to 2.2 cm in three years and enhanced magnetic resonance imaging revealed marked T2 weighting hyperintensity of the lesion. Although a radiologist (TK) suggested the diagnosis renal anastomosing hemangioma preoperatively, we could not deny the possibility of renal cell carcinoma completely. Therefore, the patient underwent robot-assisted laparoscopic partial nephrectomy. The tumor was successfully removed without any renal arterial clamping or parenchymal excision. Histopathologically, the lesion was composed of capillary-size blood vessels lined by a single layer of endothelial cells, and was diagnosed as a renal anastomosing hemangioma. There were no signs of postoperative recurrence during the 3 month follow-up.

Single nucleotide polymorphisms (SNPs) reportedly influence the effect of nivolumab in metastatic renal cell carcinoma (mRCC). This study aimed to evaluate the relationship between the clinical outcomes of patients with mRCC and SNPs in programmed cell death protein 1 (PD-1) protein-coding gene ( PDCD1 ) and explore any potential correlation with patient prognosis and incidence of immune-related adverse events (irAEs). In total, 106 patients with mRCC, who were treated with nivolumab alone ( n = 59) or nivolumab and ipilimumab ( n = 47), were enrolled in the study. Three SNPs in the PDCD1 gene, namely PD-1.3 , PD-1.5 , and PD-1.6 , were assessed. Patients harboring the PD-1.6 G allele experienced more severe (odds ratio, 3.390; 95% confidence interval 1.517-7.756; p = 0.003) and multiple (OR, 2.778; 95% CI, 1.020-6.993 p = 0.031) irAEs than those harboring the AA genotype. Thus, the existence of the PDCD1 PD-1.6 polymorphism ( G allele) was associated with the occurrence of severe and multiple irAEs in patients with mRCC. Further evaluation of PDCD1 polymorphisms might help identify patients experiencing irAE by nivolumab treatment.

Introduction: Warm ischemia time (WIT) is a primary concern for robot-assisted laparoscopic partial nephrectomy (RALPN) patients because longer WIT is significantly associated with postoperative deteriorating kidney function. Tumor complexity, determined by the RENAL nephrometry score (RENAL score), can help predict surgical outcomes, but it is unclear what RENAL score and clinical factors affect WIT. This study explored the clinical factors predicting long WIT in experienced surgeon to RALPN., Materials and Methods: In our institute, 174 RALPNs were performed between November 2013 and February 2021, of which 114 were performed by a single surgeon and included in this study. Clinical staging and the total RENAL score were determined based on preoperative CT scans. The cases were divided into three groups based on experience: period 1: 1-38, period 2: 39-76, and period 3: 77-114. The clinical factors associated with longer WIT were analyzed per period., Results: The overall median tumor diameter was 32 mm, and one patient had a positive surgical margin, but there were no cancer-related deaths. In total, there were 18 complications (15.8%). Periods 2 and 3 had larger tumor diameters (p < 0.01) and worse preoperative kidney function (p = 0.029) than period 1. A RENAL L-component score of 3 was associated with longer WIT in period 3 (odds ratio: 3.900; 95% confidence interval: 1.004-15.276; p = 0.044), but the tumor diameter and the total RENAL score were not., Conclusions: A large tumor in the central lesion indicated by the RENAL L-component score was associated with increased WIT in RALPN., (© 2022. The Author(s).)

Magnetic resonance electrical properties tomography (MREPT) noninvasively reconstructs high-resolution electrical property (EP) maps using MRI scanners and is useful for diagnosing cancerous tissues. However, conventional MREPT methods have limitations: sensitivity to noise in the numerical Laplacian operation, difficulty in reconstructing three-dimensional (3D) EPs and convergence not guaranteed in the iterative process. We propose a novel, iterative 3D reconstruction MREPT method without a numerical Laplacian operation. We derive an integral representation of the electric field using its Helmholtz decomposition with Maxwell's equations, under the assumption that the EPs are known on the boundary of the region of interest with the approximation that the unmeasurable magnetic field components are zero. Then, we solve the simultaneous equations composed of the integral representation and Ampere's law using a convex projection algorithm whose convergence is theoretically guaranteed. The efficacy of the proposed method was validated through numerical simulations and a phantom experiment. The results showed that this method is effective in reconstructing 3D EPs and is robust to noise. It was also shown that our proposed method with the unmeasurable component H - enhances the accuracy of the EPs in a background and that with all the components of the magnetic field reduces the artifacts at the center of the slices except when all the components of the electric field are close to zero.

Lard diet (LD) is a risk factor for prostate cancer (PCa) development and progression. Two immunocompetent mouse models fed with isocaloric specific fat diets (LD) enriched in saturated and monounsaturated fatty acid (SMFA), showed significanftly enhanced PCa progression with weight gain compared with a fish oil diet (FOD). High gut microbial divergency resulted from difference in diets, and the abundance of several bacterial species, such as in the orders Clostridiales and Lactobacillales, was markedly altered in the feces of LD- or FOD-fed mice. The proportion of the order Lactobacillales in the gut was negatively involved in SMFA-induced body weight gain and PCa progression. We found the modulation of lipid metabolism and cholesterol biosynthesis pathways with three and seven commonly up- and downregulated genes in PCa tissues, and some of them correlated with the abundance of the order Lactobacillales in mouse gut. The expression of sphingosine 1-phosphate receptor 2, which is associated with the order Lactobacillales and cancer progression in mouse models, was inversely associated with aggressive phenotype and weight gain in patients with PCa using the NCBI Gene Expression Omnibus database. Therefore, SMFA may promote PCa progression with the abundance of specific gut microbial species and overexpression of lipogenic genes in PCa. Therapeutics with alteration of gut microbiota and candidate genes involved in diet-induced PCa progression may be attractive in PCa.

The alignment of spindle-shaped cells in two-dimensional geometries induces singular points called topological defects, at which the alignment angle of the cell cannot be defined. To control defects related to biological roles such as cell apoptosis, calculation methods for predicting the defect positions are required. This study proposes an explicit calculation method for predicting cell alignment and defect positions in non-circular geometries. First, a complex potential is introduced to describe the alignment angles of cells, which is used to derive an explicit formula for cell alignment in a unit disc. Then, the derived formula for the unit disc is extended to the case for non-circular geometries using a numerical conformal mapping. Finally, the complex potential allows a calculation of the Frank elastic energy, which can be minimized with respect to the defect positions to predict their equilibrium state in the geometry. The proposed calculation method is used to demonstrate a numerical prediction of multiple defects in circular and non-circular geometries, which are consistent with previous experimental results., (© 2022 The Authors.)

Objectives: We retrospectively investigated if robot-assisted laparoscopic partial nephrectomy (RAPN) contributes to a decrease in resected parenchymal volume (RPV), an increase in postoperative parenchymal volume (PPV), and an improvement of postoperative renal function when compared with conventional laparoscopic partial nephrectomy (LPN) using a three-dimensional image analysis system., Methods: Patients who underwent LPN (n = 37) and RAPN (n = 66) from November 2013 to November 2018 were included in this study. All patients had a tumor diameter of 4 cm or less. Patients with an anatomical or functional single kidney were excluded. RPV and PPV were measured using SYNAPSE VINCENT®. The surgical outcomes were compared between the two groups., Results: Warm ischemic time in the RAPN group was significantly shorter than that in the LPN group (p < 0.001). The ratio of RPV to tumor volume (RPV/TV) in the RAPN group was significantly lower than that in the LPN group (p = 0.016). PPV in the RAPN group was significantly higher than that in the LPN group (p = 0.049). The decreased estimated glomerular filtration rate in the RAPN group was significantly lower than that in the LPN group on days 1, 7, 30, 90, and 180 after surgery., Conclusions: Postoperative renal function in the RAPN group was significantly better than that in the LPN group in both the short and long term. In addition to a short warm ischemia time, the decreased RPV/TV and increased PPV may have contributed to the improvement of postoperative renal function., (© 2021 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

The increase in antibiotic resistance and the emergence of new bacterial infections have intensified the research for natural products from plants with associated therapy. This study aimed to verify the antibacterial and antioxidant activity of crude extracts of the genus Plectranthus species, being the first report on the modulation of aminoglycosides antibiotic activity by Plectranthus amboinicus extracts. The chemical composition was obtained by chemical prospecting and High-Performance Liquid Chromatography with diode arrangement detector (HPLC/DAD). The antibacterial activities of the extracts alone or in association with aminoglycosides were analyzed using the microdilution test. The antioxidant activity was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging. The phytochemical prospection allowed the flavonoids, saponins, tannins and triterpenoids to be identified. Quercetin, rutin, gallic acid, chlorogenic acid, caffeic acid, catechin, kaempferol, glycosylated kaempferol, quercitrin, and isoquercitrin were identified and quantified. The principal component analysis (PCA) observed the influence of flavonoids and phenolic acids from Plectranthus species on studied activities. Phytochemical tests with the extracts indicated, especially, the presence of flavonoids, confirmed by quantitative analysis by HPLC. The results revealed antibacterial activities, and synergistic effects combined with aminoglycosides, as well as antioxidant potential, especially for P. ornatus species, with IC 50 of 32.21 µg/mL. Multivariate analyzes show that the inclusion of data from the antioxidant and antibacterial activity suggests that the antioxidant effect of these species presents a significant contribution to the synergistic effect of phytoconstituents, especially based on the flavonoid contents. The results of this study suggest the antibacterial activity of Plectranthus extracts, as well as their potential in modifying the resistance of the analyzed aminoglycosides.

Background: The efficacy assessment of human anti-IgE monoclonal antibodies (mAbs) in animal models before clinical trials is hampered due to the lack of cross-reactivity of anti-IgE mAbs between species., Objective: We developed CRE-DR (an anti-dog IgE monoclonal antibody), an anti-IgE mouse mAb that recognizes canine and human IgE, and then examined its IgE specificity and cross-reactivity between three animal and human species., Methods: After mouse immunization with a synthetic peptide derived from canine IgE ( 282 NTNDWIEGETYYC 294 ), we generated a hybridoma producing CRE-DR. The CRE-DR purified from the ascites of hybridoma-inoculated mice was used for ELISA and Western blot analysis to examine reactivity to dog, human, and rodent IgEs as well as recombinant bovine serum albumin (BSA)-conjugated to canine, human, and rodent IgE amino acid peptides corresponding to the immunizing sequence. We then performed enzyme-linked immunosorbent assays (ELISAs) for dog IgE using sera from dogs with atopic dermatitis (AD) after inhibition with canine IgE and IgG. The amino acid sequence recognized by CRE-DR was identified by ELISA using synthetic peptides., Results: CRE-DR is a monoclonal mouse IgG1κ specific for dog IgE, and the ELISA values in atopic dog sera were inhibited by dog IgE, but not dog IgG. The binding of CRE-DR to human IgE was relatively maintained, but not to rodent IgEs, which results were confirmed with the BSA-conjugated IgE peptides of the various species. The CRE-DR reactivity was supported by the comparison of amino acid sequence of CRE-DR epitope, DWIEGETYYC, in dog IgE; one, two, and three amino acids were substituted in the human, rat, and mouse IgE epitopes, respectively., Conclusions and Clinical Relevance: CRE-DR is a mAb cross-reactive to dog and human IgEs, which can allow the use of a dog model of allergy to test the efficacy of a CRE-DR-derived anti-IgE therapeutic mAb before human clinical trials., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

In this article, a structured acoustic holography technique in the self-positioning method of a single microphone from the monaurally recorded signals is proposed. A series of three-dimensional ultrasonic holograms, designed for positioning in a workspace, are sequentially projected. As a result, the microphone receives a position-dependent sequence of amplitude signals encoded with information on the observation position. Subsequently, the microphone position is determined by obtaining the peak position of the cross-correlation function between the received signal and the reference signal. Experiments were conducted using a custom-made phased array of 40-kHz ultrasound transducers to evaluate the positioning accuracy. It is demonstrated that when applied to a 100×100×50 mm 3 workspace, the measurement error was less than 1 mm at all observation points in the numerical experiment, which was maintained for more than 96% of the points in the real-environment experiments. The proposed method is advantageous in that it does not use the phase information of the recorded signals, thus requiring no multiple synchronized recordings as the microphone-array-based methods. In addition, this scheme does not directly use the absolute value of the received amplitude as a positioning clue, which means that no amplitude-to-voltage calibration is required.

A 46-year-old woman was referred to our hospital with a left-sided renal tumor pointed out by ultrasonography at the time of a medical checkup．Computed tomography revealed a mass measuring 88×77×68 mm on the upper pole of the left kidney. She was diagnosed with cT2aN0M0 clear cell renal cell carcinoma. Laparoscopic left nephrectomy was performed uneventfully. Histopathological diagnosis was clear cell renal cell carcinoma, G2, v1, pT2. Four months after surgery, lung metastases appeared, and systemic therapy was given sequentially as follows ; sunitinib for 2 months, nivolumab for 8 months, axitinib for 17 months, and pazopanib for 2 months．However, metastases progressed, and a re-administration of nivolumab was planned. The nivolumab re-treatment resulted in a marked reduction in multiple lung metastases despite the previous failure by nivolumab treatment. There are few reports on the therapeutic effect of re-administration of nivolumab. We report a case of successful treatment by re-administration of nivolumab.

The metabolic reprogramming of phospholipids may affect intracellular signal transduction pathways. A high-fat diet (HFD) is attributed to prostate cancer (PCa) progression, but the expression pattern and role of phospholipids in HFD-mediated PCa progression remains unclear. In this study, HFD enhanced LNCaP xenograft tumor growth by upregulating the phosphatidylinositol (PI) 3-kinase (PI3K)/AKT signaling pathway. A lipidomic analysis using xenograft tumors showed that phosphoinositides, especially PI (3,4,5)-trisphosphate (PIP 3 ), including several species containing C38:4, C38:3, and C40:4 fatty acids, increased in the HFD group compared to control. Fatty acid synthase (FASN) was significantly upregulated in xenograft tumors under HFD in both gene and protein levels. PCa cell growth was significantly inhibited through the decreased AKT signaling pathway by treatment with cerulenin, a chemical FASN inhibitor, which also downregulated PIP, PIP 2 , and PIP 3 but not PI. Thus, dietary fat influences PCa progression and alters phosphoinositides, especially PIP 3 , a critical player in the PI3K/AKT pathway. These results may offer appropriate targets, such as FASN, for dietary intervention and/or chemoprevention to reduce PCa incidence and progression., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Extracellular vesicles (EV) heterogeneity is a crucial issue in biology and medicine. In addition, tumor-associated macrophages are key components in cancer microenvironment and immunology. We developed a combination method of size exclusion chromatography and concentration filters (SEC-CF) and aimed to characterize different EV types by their size, cargo types, and functions. A human monocytic leukemia cell line THP-1 was differentiated to CD14-positive macrophage-like cells by stimulation with PMA (phorbol 12-myristate 13-acetate) but not M1 or M2 types. Using the SEC-CF method, the following five EV types were fractionated from the culture supernatant of macrophage-like cells: (i) rare large EVs (500-3000 nm) reminiscent of apoptosomes, (ii) EVs (100-500 nm) reminiscent of microvesicles (or microparticles), (iii) EVs (80-300 nm) containing CD9-positive large exosomes (EXO-L), (iv) EVs (20-200 nm) containing unidentified vesicles/particles, and (v) EVs (10-70 nm) containing CD63/HSP90-positive small exosomes (EXO-S) and particles. For a molecular transfer assay, we developed a THP-1-based stable cell line producinga GFP-fused palmitoylation signal (palmGFP) associated with the membrane. The THP1/palmGFP cells were differentiated into macrophages producing palmGFP-contained EVs. The macrophage/palmGFP-secreted EXO-S and EXO-L efficiently transferred the palmGFP to receiver human oral carcinoma cells (HSC-3/palmTomato), as compared to other EV types. In addition, the macrophage-secreted EXO-S and EXO-L significantly reduced the cell viability (ATP content) in oral carcinoma cells. Taken together, the SEC-CF method is useful for the purification of large and small exosomes with higher molecular transfer activities, enabling efficient molecular delivery to target cells.

Background: Recent studies have indicated that a high-fat diet (HFD) and/or HFD-induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. This study aimed to delineate the molecular mechanisms of PCa progression under HFD milieus and define the stromal microenvironment focusing on macrophage inhibitory cytokine-1 (MIC-1) activation., Methods: We investigated the effects of HFD on PCa stromal microenvironment and MIC-1 signaling activation using PC-3M-luc-C6 PCa model mice fed with HFD or control diet. Further, we explored the effect of periprostatic adipocytes derived from primary PCa patients on activation and cytokine secretion of prostate stromal fibroblasts. Expression patterns and roles of MIC-1 signaling on human PCa stroma activation and progression were also investigated., Results: HFD stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequently increased the secretion of interleukin (IL)-8 and IL-6 from prostate stromal fibroblasts in PC-3M-luc-C6 PCa mouse model. In addition, periprostatic adipocytes directly stimulated MIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through the upregulation of adipose lipolysis and free fatty acid release. The increased serum MIC-1 was significantly correlated with human PCa stroma activation, high serum IL-8, IL-6, and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial-derived neurotrophic factor receptor α-like (GFRAL), a specific receptor of MIC-1, was highly expressed in both cytoplasm and membrane of PCa cells and surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy., Conclusion: HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity-induced PCa progression., (© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Background: Zinc-finger E-box-binding homeobox 1 (ZEB1) is an important regulator of epithelial-mesenchymal transition (EMT) and is involved in the maintenance of cancer stem cells (CSCs) via miR-200c and BMI1 pathway. Recent studies revealed that ZEB1 contributes to the EMT-mediated acquired resistance to gefitinib in EGFR-mutant non-small cell lung cancer (NSCLC). However, the precise role of ZEB1 in the maintenance of lung CSCs that lead to acquired resistance to gefitinib remains unclear., Methods: PC9 and HCC827 NSCLC cell lines were treated with high concentrations of gefitinib, and surviving cells were referred to as "gefitinib-resistant persisters" (GRPs). ZEB1 knockdown or overexpression was performed to determine the biological significance of ZEB1 in the CSC features of GRPs, and animal models were studied for in vivo validation. Expression of ZEB1, BMI1, and ALDH1A1 was analyzed by immunohistochemistry in tumor specimens from NSCLC patients with acquired resistance to gefitinib., Results: GRPs had characteristic features of mesenchymal and CSC phenotypes with high expression of ZEB1 and BMI1, and decreased miR-200c, in vitro and in vivo. ZEB1 silencing attenuated the suppression of miR-200c, resulting in the reduction in BMI1 and reversed the mesenchymal and CSC features of GRPs. Furthermore, ZEB1 overexpression induced EMT and increased the levels of CD133- and BMI1-positive GRPs in vitro and gefitinib resistance in vivo. Finally, ZEB1, BMI1, and ALDH1A1 were highly expressed in tumor specimens from EGFR-mutant NSCLC patients with gefitinib resistance., Conclusions: ZEB1 plays an important role in gefitinib-resistant lung CSCs with EMT features via regulation of miR-200c and BMI1., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

A 35-year-old male patient with end-stage renal disease due to vesicoureteral reflux preemptively received a renal graft from his father. The patient had a history of allergy to contrast-enhancing media. He received oral tacrolimus (TAC) and mycophenolate mofetil without any problems for 2 days before kidney transplantation. During the induction period of the surgery, his systolic blood pressure (sBP) decreased to 60 mmHg approximately 1 hour after initiating intravenous tacrolimus (TAC-IV) and intravenous piperacillin (PIPC), and the anesthesiologist suspected drug-induced anaphylaxis and stopped administration of the medications. Because TAC had been administered preoperatively without any adverse events, PIPC was suspected as the causative agent of the anaphylaxis. After the patient's hemodynamics returned to baseline, TAC-IV was restarted. However, his sBP rapidly decreased to 40 mmHg and the patient developed wheezing. He was diagnosed with drug-induced anaphylaxis due to castor oil derivatives in the TAC-IV formulation. The patient's sBP was restored with the administration of some vasopressors, and kidney transplantation was then performed without difficulty. Two days after kidney transplantation, oral TAC was administered without anaphylaxis. Clinicians should consider that not only the drug itself but also its additives or metabolites could induce anaphylaxis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi). It was originally a Latin American endemic health problem, but now is expanding worldwide as a result of increasing migration. The currently available drugs for Chagas disease, benznidazole and nifurtimox, provoke severe adverse effects, and thus the development of new drugs is urgently required. Ubiquinone (UQ) is essential for respiratory chain and redox balance in trypanosomatid protozoans, therefore we aimed to provide evidence that inhibitors of the UQ biosynthesis have trypanocidal activities. In this study, inhibitors of the human COQ7, a key enzyme of the UQ synthesis, were tested for their trypanocidal activities because they were expected to cross-react and inhibit trypanosomal COQ7 due to their genetic homology. We show the trypanocidal activity of a newly found human COQ7 inhibitor, an oxazinoquinoline derivative. The structurally similar compounds were selected from the commercially available compounds by 2D and 3D ligand-based similarity searches. Among 38 compounds selected, 12 compounds with the oxazinoquinoline structure inhibited significantly the growth of epimastigotes of T. cruzi. The most effective 3 compounds also showed the significant antitrypanosomal activity against the mammalian stage of T. cruzi at lower concentrations than benznidazole, a commonly used drug today. We found that epimastigotes treated with the inhibitor contained reduced levels of UQ9. Further, the growth of epimastigotes treated with the inhibitors was partially rescued by UQ10 supplementation to the culture medium. These results suggest that the antitrypanosomal mechanism of the oxazinoquinoline derivatives results from inhibition of the trypanosomal UQ synthesis leading to a shortage of the UQ pool. Our data indicate that the UQ synthesis pathway of T. cruzi is a promising drug target for Chagas disease., Competing Interests: The authors have declared that no competing interests exist.

Background: Local tissue eosinophilia and Th2 cytokines are characteristic features of seasonal allergic rhinitis. Airway remodelling is a feature of asthma whereas evidence for remodelling in allergic rhinitis (AR) is conflicting., Objective: By use of a novel human repetitive nasal allergen challenge (RAC) model, we evaluated the relationship between allergic inflammation and features of remodelling in AR., Methods: Twelve patients with moderate-severe AR underwent 5 alternate day challenges with diluent which after 4 weeks were followed by 5 alternate day challenges with grass pollen extract. Nasal symptoms, Th1/Th2 cytokines in nasal secretion and serum were evaluated. Nasal biopsies were taken 24 hours after the 1st and 5th challenges with diluent and with allergen. Sixteen healthy controls underwent a single challenge with diluent and with allergen. Using immunohistochemistry, epithelial and submucosal inflammatory cells and remodelling markers were evaluated by computed image analysis., Results: There was an increase in early and late-phase symptoms after every allergen challenge compared to diluent (both P < .05) with evidence of both clinical and immunological priming. Nasal tissue eosinophils and IL-5 in nasal secretion increased significantly after RAC compared to corresponding diluent challenges (P < .01, P = .01, respectively). There was a correlation between submucosal mast cells and the early-phase clinical response (r = 0.79, P = .007) and an association between epithelial eosinophils and IL-5 concentrations in nasal secretion (r = 0.69, P = .06) in allergic rhinitis. No differences were observed after RAC with regard to epithelial integrity, reticular basement membrane thickness, glandular area, expression of markers of activation of airway remodelling including α-SMA, HSP-47, extracellular matrix (MMP7, 9 and TIMP-1), angiogenesis and lymphangiogenesis for AR compared with healthy controls., Conclusion: Novel repetitive nasal allergen challenge in participants with severe persistent seasonal allergic rhinitis resulted in tissue eosinophilia and increases in IL-5 but no structural changes. Our data support no link between robust Th2-inflammation and development of airway remodelling in AR., (© 2020 John Wiley & Sons Ltd.)

The collective orientation relaxation (COR) of water molecules in aqueous solutions is faster or slower with an increase in the concentration of the solutions than that in pure water; for example, acceleration (deceleration) of the COR is observed in a solution of sodium chloride (tetramethylammonium chloride) with increasing concentration. However, the molecular mechanism of the solution and concentration dependence of the relaxation time of the COR has not yet been clarified. We theoretically investigate the concentration dependence of the COR of water molecules in solutions of tetramethylammonium chloride (TMACl), guanidinium chloride (GdmCl), and sodium chloride (NaCl). Based on the Mori-Zwanzig equation, we identify two opposing factors that determine the COR of water molecules in any aqueous solution: the correlation of dipole moments and the single-molecule orientation relaxation. We reveal the molecular mechanism of the concentration dependence of the relaxation time of the COR in the TMACl, GdmCl, and NaCl solutions in terms of these two factors.

Innate immune reactions are believed to be associated with ischemia/reperfusion injury (IRI), and IRI might be treatable by expanding regulatory T cells (Tregs), which can suppress the excessive responses of the immune system. Organ IRI is known to be closely involved in the expression of costimulatory molecules. The present study aimed to assess whether Tregs endogenously expanded by the administration of trichostatin A (TsA), a histone deacetylase inhibitor, could reduce renal IRI and to clarify their association with the expression of costimulatory molecules in a murine model. In this study, the wild-type mice used for an IRI model were randomly divided into the following four treatment groups: TsA group, DMSO group (control), DMSO+PC61 group, and TsA + PC61 group. Renal injury in the early phase after IRI was ameliorated in the TsA group (increased Tregs) when compared with the other groups. After renal IRI, both the mRNA and the protein levels of anti-inflammatory cytokines, IL-10 and TGF-β in the kidney and spleen were significantly higher in the TsA group than in the other groups, whereas the IL-6 levels were significantly lower in the TsA group than in the other groups. These results were offset by the administration of PC61, supporting that the renoprotective effect of TsA in this study is Treg dependent. mRNA expression levels of CD80, CD86, and ICAM-1 were lower in the TsA group, consistent with Treg control of injury through costimulatory molecules. Our findings suggest that endogenously expanded Tregs coordinate postischemic immune responses and decrease the expression of costimulatory molecules after renal IRI, and thus, they might ameliorate renal IRI. TsA administration for expanding Tregs is a promising therapeutic strategy for renal IRI., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This case-control study aimed to assess oxidative stress alterations in autism spectrum disorder (ASD). We used the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously, in combination with conventional oxidative stress markers to investigate the ability of this MULTIS approach as a non-behavioural diagnostic tool for children with ASD. Serum samples of 39 children with ASD and 58 age-matched children with typical development were analysed. The ASD group showed decreased hydroxyl radical ( · OH) and singlet oxygen scavenging activity with increased serum coenzyme Q10 oxidation rate, indicating a prooxidative tendency in ASD. By contrast, scavenging activities against superoxide (O 2 ·- ) and alkoxyl radical (RO · ) were increased in the ASD group suggesting antioxidative shifts. In the subgroup analysis of 6-year-olds or younger, the combination of · OH, O 2 ·- , and RO · scavenging activities predicted ASD with high odds ratio (50.4), positive likelihood (12.6), and percentage of correct classification (87.0%). Our results indicate that oxidative stress in children with ASD is not simply elevated but rather shows a compensatory shift. MULTIS measurements may serve as a very powerful non-behavioural tool for the diagnosis of ASD in children.

Axitinib, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, will be used in combination first-line therapies against metastatic renal cell carcinoma (mRCC), but its effects as a first-line monotherapy are unclear. Thus, we aimed to elucidate pretreatment clinical factors that predict the prognosis of patients with mRCC receiving first-line axitinib therapy. We enrolled 63 patients with mRCC treated with axitinib as first-line therapy between Nov. 2003 and Jul. 2018. Progression-free survival (PFS) and overall survival (OS) were assessed using the Wald χ 2 statistic in Cox proportional hazards regression. Median patient age was 67 (range: 25-85) years. Seven (11.1%) patients were classified as being at favorable risk, 33 (52.4%) at intermediate risk, and 23 (36.5%) at poor risk according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk classification system. Median follow-up duration after axitinib initiation was 14 (range: 1-72) months. Median PFS and OS were 18 months and 65 months, respectively. Cox regression analyses of clinical predictors revealed that high C-reactive protein (CRP) levels were significantly correlated with shorter PFS [hazard ratio (HR), 1.63; 95% confidence interval (CI) 1.7-4.0)], whereas spindle cells and poor IMDC risk scores were related to worse OS (HR, 2.87 and 2.88, respectively; 95% CI 1.4-11.0 and 1.1-8.5, respectively). Thus, patients with mRCC and spindle histology or poor IMDC risk scores had worse OS, and those with high CRP levels had shorter PFS in first-line axitinib treatment. Other therapies might be more suitable for initial management of such patients.