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Introduction: Even in the era of laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic radical prostatectomy (RALP), we sometimes encounter patients with severe urinary incontinence after surgery. The aim of the present study was to identify predictors of urinary continence recovery among patients with urinary incontinence immediately after surgery (UIIAS). Materials and Methods: We identified 274 patients with clinically localized prostate cancer who underwent LRP and RALP between 2011 and 2018. UIIAS was defined as a urine loss ratio > 0.15 on the first day of urethral catheter removal. Urinary continence recovery was defined as using ≤ 1 pad/day one year after surgery. In the present study, we evaluated factors affecting urinary function recovery one year after surgery among patients with urinary incontinence immediately after LRP and RALP. Results: UIIAS was observed in 191 out of 274 patients (69.7%). A multivariate analysis identified age (< 65 years, p = 0.015) as an independent predictor affecting immediate urinary continence. Among 191 incontinent patients, urinary continence one year after surgery improved in 153 (80.1%). A multivariate analysis identified age (< 65 years, p = 0.003) and estimated blood loss (≥ 100 mL, p = 0.044) as independent predictors affecting urinary continence recovery one year after surgery. Conclusion: The present results suggest that younger patients and patients with higher intraoperative blood loss recover urinary continence one year after surgery even if they are incontinent immediately after surgery.

Since tumors in different human organs may have different tumor microenvironments, we evaluate time-course changes in all tumor locations after pembrolizumab treatment in urothelial carcinoma (UC) to examine the differences in efficacy of pembrolizumab per organ. Further, we uncover the usefulness of inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), CRP, and kinetics of these markers to predict pembrolizumab success and relation to overall survival (OS) in UC.A total of 115 cancerous lesions from 44 UC patients were measurable based on RECIST 1.1 criteria. The serum CRP and NLR levels were measured at baseline prior to pembrolizumab treatment and at least every 3 weeks just prior to pembrolizumab administration.Site-specific success (ie, patients with CR/PR/SD by RESIST 1.1) rates for pembrolizumab treatments were as follows: primary tumors: 67%, lymph node: 70%, lung: 44%, liver: 40%, and peritoneal metastasis: 56%. Focusing on the major metastasis sites, lymph nodes and lungs, we examined the relationships between NLR, CRP, or that kinetics and pembrolizumab success. In lymph nodes, both early NLR kinetics (P = .005) and CRP kinetics (P = .035) was a predictor for pembrolizumab success. On the other hand, none of 4 was not in lung metastases. Regarding to the mortality, the multivariate analysis revealed that early NLR kinetics was a prognostic biomarker for OS among the 4, independent of performance status and liver metastasis.We revealed that site-specific pembrolizumab success in UC. Early NLR kinetics was a predictor for lymph node pembrolizumab success and OS in our cohorts.

Melanoma differentiation–associated gene 5 (MDA5), a member of the retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs), has pivotal roles in innate immune responses against many positive-stranded RNA viruses, including picornavirus and coronavirus. Upon engagement with dsRNA derived from viral infection, MDA5 initiates coordinated signal transduction leading to type I IFN induction to restrict viral replication. In this study, we describe a targeted cleavage events of MDA5 by the 3C protease from Theilovirus. Upon ectopic expression of theilovirus 3C protease from Saffold virus or Theiler’s murine encephalomyelitis virus but not encephalomyocarditis virus, fragments of cleaved MDA5 were observed in a dose-dependent manner. When enzymatically inactive Theilovirus 3C protease was expressed, MDA5 cleavage was completely abrogated. Mass spectrometric analysis identified two cleavage sites at the C terminus of MDA5, cleaving off one of the RNA-binding domains. The same cleavage pattern was observed during Theilovirus infection. The cleavage of MDA5 by Theilovirus protease impaired ATP hydrolysis, RNA binding, and filament assembly on RNA, resulting in dysfunction of MDA5 as an innate immune RNA sensor for IFN induction. Furthermore, the cleavage-resistant MDA5 mutant against the 3C protease showed an enhanced IFN response during Saffold virus infection, indicating that Theilovirus has a strategy to circumvent the antiviral immune response by cleaving MDA5 using 3C protease. In summary, these data suggest MDA5 cleavage by 3C protease as a novel immune evasive strategy of Theilovirus.

Sophisticated functions of biological tissues are supported by small biological units of cells that are localized within a region of 100 μm scale. The cells in these units secrete molecules to form their microenvironment to play a vital role in biological functions. Various microfluidic devices have been developed to analyze the microenvironment but were not designed for cells in a culture dish in a confluent condition, a typical setup for cell and tissue cultivation. This study presents a novel glass capillary-based microfluidic device for studying confluent cells in a culture dish. The multiple capillaries allow the device to confine the local flow in 100 μm or smaller scale to form two adjacent regions with different chemical properties; it can simultaneously perform local cell stimulation and collect secreted molecules from the stimulated cells. Cell removal was achieved upon trypsin stimulation from a limited area (3.8 × 10

Objective In myotonic dystrophy type 1 (DM1), the CTG repeat size in the dystrophia myotonica protein kinase gene has been shown to correlate with disease severity and is a potential predictive marker for respiratory decline. However, genetic testing can be challenging in some clinical situations. We developed a simple formula for estimating the CTG repeat size using a single spirometry test in patients with DM1. Methods In this single-center retrospective study, we reviewed 50 consecutive patients with genetically confirmed DM1 whose follow-up visits were at our hospital. The patients were randomly assigned to training and test analysis subsets. By applying a linear mixed model to the longitudinal spirometry results of the training set, we calculated the fixed effects on the annual respiratory decline. Subsequently, we derived a prediction formula to calculate the repeat size that incorporated %vital capacity (%VC) and the patient's age at the time of the spirometry evaluation; the results were validated by the test set. Results A total of 157 spirometry tests were recorded. The fixed effects on the annual %VC decline wereimg align="middle" src="./Graphics/abst-61_2281_1.jpg"/=-0.90. The derived formula [repeat size=-16.8× (age+%VC/0.90) +2663] had a moderate predictive performance with a mean coefficient of determinationimg align="middle" src="./Graphics/abst-61_2281_2.jpg"/of 0.41. Conclusion The CTG repeat size in patients with DM1 can be potentially predicted using a simple formula based on a single spirometry test conducted at any time over the disease course. It can be useful as a supportive tool for advance care planning when genetic testing is not available.

Background Several preoperative factors have been suggested to be risk factors of disease recurrence after radical cystectomy. There is no study focusing on the impact on prognosis of bladder tumor ureteral invasion in preoperative imaging. Methods The study population consisted of 136 patients, all of whom underwent radical cystectomy during the period between 2007–2019. We excluded patients with concurrent or a history of upper tract urothelial carcinoma and who underwent radical cystectomy for other cancers or nononcologic reasons. The starting point of this study was the timing of neoadjuvant chemotherapy or radical cystectomy and the endpoint was the timing of disease recurrence. To identify the factors influencing recurrence, univariate and multivariate analyses were performed using the Cox proportional hazard model. Recurrence-free survival curves were constructed using the Kaplan-Meier method. Results Ureteral invasion was observed in 20 (14.7%) patients. Disease recurrence was observed in 11 (55.0%) of 20 ureteral invasion positive patients and 35 (30.2%) of 116 ureteral invasion negative patients, respectively. In the ureteral invasion positive group, clinical T and N stage were higher and hydronephrosis were more common than in the ureteral invasion negative group. According to the multivariate analysis, ureteral invasion (hazard ratio: 2.307, p = 0.016) and clinical N stage ≥ 1 (hazard ratio: 2.140, p = 0.028) were independent risk factors for postoperative recurrence. In the ureteral invasion positive group, more local recurrences were observed. Conclusion This study suggested that ureteral invasion in preoperative imaging is a significant risk factor for postoperative recurrence.

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicityin vivo, we prion-challenged conditional knockout mice (male and female) havingHrsdeleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration.SIGNIFICANCE STATEMENTPrion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrPC), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrPC-mediated neurotoxic signaling.

Keloids are benign fibroproliferative skin tumors caused by aberrant wound healing that can negatively impact patient quality of life. The lack of animal models has limited research on pathogenesis or developing effective treatments, and the etiology of keloids remains unknown. Here, we found that the characteristics of stem cells from keloid lesions and the surrounding dermis differ from those of normal skin. Furthermore, the HEDGEHOG (HH) signal and its downstream transcription factor GLI1 were upregulated in keloid patient–derived stem cells. Inhibition of the HH-GLI1 pathway reduced the expression of genes involved in keloids and fibrosis-inducing cytokines, including osteopontin. Moreover, the HH signal inhibitor vismodegib reduced keloid reconstituted tumor size and keloid-related gene expression in nude mice and the collagen bundle and expression of cytokines characteristic for keloids in ex vivo culture of keloid tissues. These results implicate the HH-GLI1 pathway in keloid pathogenesis and suggest therapeutic targets of keloids.

Background: Laparoscopic adrenalectomy is widely performed for a number of hormone-producing tumors and postoperative management depends on the hormones produced. In the present study, we conducted a retrospective analysis to clarify the risk factors for postoperative complications, particularly postoperative fever after laparoscopic adrenalectomy. Methods: We analyzed 406 patients who underwent laparoscopic adrenalectomy at our hospital between 2003 and 2019. Postoperative fever was defined as a fever of 38°C or higher within 72 hours after surgery. We investigated the risk factors for postoperative fever after laparoscopic adrenalectomy. Results: There were 188 males (46%) and 218 females (54%) with a median age of 52 years. Among these patients, tumor pathologies included 188 primary aldosteronism (46%), 75 Cushing syndrome (18%), and 80 pheochromocytoma (20%). Postoperative fever developed in 124 of all patients (31%), 30% of those with primary aldosteronism, 53% of those with pheochromocytoma, and 8% of those with Cushing syndrome. A multivariate logistic regression analysis identified pheochromocytoma and non-Cushing syndrome as independent predictors of postoperative fever. Postoperative fever was observed in 42 out of 80 cases of pheochromocytoma (53%), which was significantly higher than in cases of non-pheochromocytoma (82/326, 25%, pConclusion: Since postoperative fever after laparoscopic adrenalectomy is markedly affected by the hormone produced by pheochromocytoma and Cushing syndrome, it is important to carefully consider the need for treatment.

Inguinal hernia (IH) after radical prostatectomy (RP) is a complication that impairs quality of life; however, the factors contributing to IH after RP remain unclear. Therefore, we herein attempted to identify the factors responsible for the development of IH after RP.We reviewed 622 patients who underwent laparoscopic or robot-assisted laparoscopic RP at our hospital between December 2011 and April 2020. The total fat area and visceral fat area were calculated at the level of the umbilicus using computed tomography, and the subcutaneous fat area (SFA) was calculated by subtracting the visceral fat area from the total fat area. The psoas muscle area was measured at the third lumbar vertebrae level using computed tomography to calculate the psoas muscle mass index, which is used in sarcopenia as an index of muscle mass. We investigated the risk factors for IH after laparoscopic or robot-assisted laparoscopic RP.IH developed in 88 patients (16.7%). Fifty-seven of these patients underwent hernia repair at our hospital, and 56 (98.2%) had indirect hernias. A multivariate analysis identified SFA (odds ratios: 0.383, p 0.001) as an independent predictor for the development of IH. Two-year IH-free survival rates were 77.3% in the small SFA group (SFA 123 cmSubcutaneous fat was associated with the development of IH, particularly indirect IH, after laparoscopic or robot-assisted laparoscopic RP. An indirect IH prevention technique needs to be considered, particularly for patients with less subcutaneous fat.

A new species, Impatiens katjae Nob. Tanaka & J. J. Verm. (Balsaminaceae), from Mandalay Region, central Myanmar, is described and illustrated. This species is similar to I. oblongata Ruchis. & Niet in floral morphology, but differs in having distinctly smaller flowers, 2-flowered axillary inflorescences, much paler pinkish-white flowers, two lateral sepals, and a spurless lower sepal. This new species is assigned to Impatiens L. subg. Impatiens sect. Uniflorae Hook. f. & Thomson.

Purpose To evaluate the high-resolution CT (HRCT) findings of pulmonary infections in patients with hematologic malignancy and compare them between patients with or without hematopoietic stem cell transplantation (HSCT). Materials and methods A total of 128 patients with hematologic malignancy and pulmonary infection were included in this study. The diagnoses of the patients consisted of bacterial pneumonia (37 non-HSCT cases and 14 HSCT cases), pneumocystis pneumonia (PCP) (29 non-HSCT cases and 11 HSCT cases), and fungal infection other than PCP (20 non-HSCT cases and 17 HSCT cases). Two chest radiologists retrospectively evaluated the HRCT criteria and compared them using chi-squared tests and a multiple logistic regression analysis. Results According to the multiple logistic regression analysis, nodules were an indicator in HSCT patients with PCP (p = 0.025; odds ratio, 5.8; 95% confidence interval, 1.2–26.6). The centrilobular distribution of nodules was the most frequent (n = 4, 36%) in HSCT patients with PCP. A mosaic pattern was an indicator of PCP in both HSCT and non-HSCT patients. There were no significant differences in other infections. Conclusion The mosaic pattern could be an indicator of PCP in both HSCT and non-HSCT patients. Nodules with centrilobular distribution might be relatively frequent HRCT findings of PCP in HSCT patients.

Introduction: The aim of this retrospective study was to elucidate predictors of survival in metastatic renal cell carcinoma (mRCC) patients in an International Metastatic Renal Cell Carcinoma Database Consortium favorable risk group treated with frontline therapy without immune checkpoint inhibitors. Methods: A total of 238 patients with mRCC were reviewed. Among them, 55 patients in favorable risk group treated with single-agent systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 46.2 months after first-line treatment initiation, the median progression-free survival (PFS) was 29.3 months, and the median OS has not been reached. The estimated percentage of patients who were alive at 12 and 24 months were 96.1 and 94.1%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.972, 95% confidence interval [CI]: 0.944–0.997, p = 0.0299) and the metastases limited to lung (HR: 3.852, 95% CI: 1.080–24.502, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusion: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.

PDF file - 33K, Correlation of clinicopathological parameters and MVD or Vasohibin-1 expression in the 175 study patients: Patients with high grade tumors and �pT2 had significantly higher levels of VASH1 density

PDF file - 169K, Supplementary Figure 1A. Kaplan-Meier recurrence-free survival of the 171 patients after surgery for UTUC stratified according to the cut-off level of MVD 70/mm2: High level of MVD was not an independent predictor of tumor recurrence (P = 0.216). Supplementary Figure 1B. Kaplan-Meier cancer-specific survival of the 171 patients after surgery for UTUC stratified according to the cut-off level of MVD 70/mm2: High level of MVD was not an independent predictor of cancer-specific survival (P = 0.473). Supplementary Figure 1C. Kaplan-Meier recurrence-free survival of the 171 patients after surgery for UTUC stratified according to the cut-off level of MVD 80/mm2: High level of MVD was not an independent predictor of tumor recurrence (P = 0.092). Supplementary Figure 1D. Kaplan-Meier cancer-specific survival of the 171 patients after surgery for UTUC stratified according to the cut-off level of MVD 80/mm2: High level of MVD was not an independent predictor of cancer-specific survival (P = 0.345). Supplementary Figure 1E. Kaplan-Meier recurrence-free survival of the 171 patients after surgery for UTUC stratified according to the cut-off level of VASH1 density 40/mm2: High level of VASH1 density was an independent predictor of tumor recurrence (P = 0.017). Supplementary Figure 1F. Kaplan-Meier cancer-specific survival of the 171 patients after surgery for UTUC stratified according to the cut-off level of VASH1 density 40/mm2: High level of VASH1 density was an independent predictor of cancer-specific survival (P = 0.042). Supplementary Figure 1G. Kaplan-Meier recurrence-free survival of the 171 patients after surgery for UTUC stratified according to the cut-off level of VASH1 density 50/mm2: High level of VASH1 density was an independent predictor of tumor recurrence (P = 0.005). Supplementary Figure 1H. Kaplan-Meier cancer-specific survival of the 171 patients after surgery for UTUC stratified according to the cut-off level of VASH1 density 50/mm2. High level of VASH1 density was an independent predictor of cancer-specific survival (P = 0.027).

Purpose: Vasohibin-1 (VASH1) is a novel angiogenic molecule that is specifically expressed in activated vascular endothelial cells, and the status of VASH1 expression has been documented in cancer angiogenesis. The aim of this study was to address the prognostic value of VASH1 expression in upper urinary tract urothelial carcinomas (UTUC).Experimental Design: We retrospectively analyzed the clinical records of 171 patients with locally advanced UTUC (Ta-3N0M0). The median follow-up period was 3.8 years. We immunohistochemically examined the accomplished microvessels with anti-CD34 as microvessel density (MVD) and the microvessels with activated endothelial cells as VASH1 density. Then, we analyzed the association between immunohistochemical expression and clinical outcomes.Results: Forty-two patients experienced tumor recurrence and of these 34 died of the disease during follow-up. VASH1 density was significantly associated with tumor grade, pathologic T stage, and MVD. The 5-year recurrence-free and cancer-specific survival rates were 66.1% and 72.8% in patients with VASH1 density (≥ 40/mm2) and 81.0% and 86.5% in their counterparts, respectively (P < 0.05). MVD was not an independent predictor of tumor recurrence or cancer-specific survival. Multivariate analyses revealed that high VASH1 density was an independent prognostic indicator of both tumor recurrence (P = 0.024, HR = 2.10) and cancer-specific survival (P = 0.031, HR = 2.23) as well as other standard prognostic factors including high tumor grade and lymphovascular invasion.Conclusions: VASH1 density represents a clinically relevant predictor of patient prognosis in UTUC. The results suggest that VASH1 density could become a new biomarker and provide additional prognostic information in patients with UTUC. Clin Cancer Res; 18(15); 4145–53. ©2012 AACR.

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PDF file - 13K, Univariate and multivariate analysis for recurrence-free survival and cancer-specific survival of 175 UTUC patients: Multivariate analysis showed that high tumor grade, presence of LVI, positive pN and high VASH1 density were independent predictors of recurrence and cancer-specific survival

PDF file - 31K, Univariate and multivariate analysis for recurrence-free survival and cancer-specific survival in 171 UTUC patients: We used the cutoff value of MVD � 80/mm2 and VASH1 density � 50/mm2 according to the mean values. The levels of VASH1 density were independent predictors for a decrease in recurrence-free (HR = 2.08) and cancer-specific survival (HR = 2.06)

PDF file - 2.9MB, Supplementary Figure 2A. Immunostaining for CD34 in the case of pTa, low grade, and LVI negative UTUC with low VASH1 density: CD34 staining was observed in endothelial cells of microvascular vessels in the tumor lesion. Supplementary Figure 2B. Immunostaining for VASH1: the same case with 2A. VASH1 staining of vascular endothelial cells was negative or negligible. We observed low VASH1 density. Supplementary Figure 2C. Negative control slide: the same case with 2A-2B. The appropriate negative control slide was prepared. Supplementary Figure 2D. Immunostaining for CD34 in the case of pTa, low grade, and LVI negative UTUC with high VASH1 density: CD34 staining was observed in endothelial cells of microvascular vessels in the tumor lesion. Supplementary Figure 2E. Immunostaining for VASH1: the same case with 2D. VASH1 staining of vascular endothelial cells was strong. We observed high VASH1 density. Supplementary Figure 2F. Negative control slide: the same case with 2D-2E. The appropriate negative control slide was prepared. Supplementary Figure 2G. Immunostaining for CD34 in the case of pT3b, high grade, and LVI positive UTUC with low VASH1 density: CD34 staining was observed in endothelial cells of microvascular vessels in the tumor lesion. Supplementary Figure 2H. Immunostaining for VASH1: the same case with 2G. VASH1 staining of vascular endothelial cells was negative or negligible. We observed low VASH1 density. Supplementary Figure 2I. Negative control slide: the same case with 2G-2H. The appropriate negative control slide was prepared. Supplementary Figure 2J. Immunostaining for CD34 in the case of pT3b, high grade, and LVI positive UTUC with high VASH1 density: CD34 staining was observed in endothelial cells of microvascular vessels in the tumor lesion. Supplementary Figure 2K. Immunostaining for VASH1: the same case with 2J. VASH1 staining of vascular endothelial cells was strong. We observed high VASH1 density. Supplementary Figure 2L. Negative control slide: the same case with 2J-2K.

Tumor suppressor p53 plays a central role in the DNA damage response. DNA-damaging agents modulate nuclear actin dynamics, influencing cell behaviors; however, it remains unclear whether p53 affects the structure of nuclear actin filaments. Here, we show that actin filament formation in the nucleus induced by the DNA-damaging agent doxorubicin (DOXO) treatment is suppressed by p53 via caspase-1 expression. In DOXO-treated cells, the nuclear actin filament formation was promoted by p53 depletion. Whilst the DOXO treatment caused an increase in caspase-1 expression, which was largely attenuated by p53 depletion, overexpression of caspase-1 reduced DOXO-induced formation of nuclear actin filaments in p53-depleted cells. By contrast, caspase-1 inhibition, together with DOXO treatment, induced nuclear actin filament formation even in cells bearing wild-type p53. These results suggest that p53-mediated expression of caspase-1 suppresses nuclear actin filament formation. In addition, we found that expression of nLifeact-GFP, which contains the filamentous actin (F-actin)-binding peptide and nuclear localization signal (NLS), promoted the bundling of nuclear actin filaments and strongly altered the chromatin structure in DOXO-treated, p53-depleted cells. Given that the loss of p53 is associated with cancer progression, the results of this study raised the possibility that artificial reinforcement of nuclear actin filaments by nLifeact-GFP may enhance the cytotoxicity effect of DNA-damaging agents in aggressive cancer cells.

Impatiens yinyinkyii M.M.Latt, B.B.Park & Nob.Tanaka and I. horizontalis M.M.Latt, B.B.Park & Nob.Tanaka (Balsaminaceae) are described and illustrated. Those new species were discovered in Htamanthi Wildlife Sanctuary, northwestern Myanmar. Description, photographic data as well as the comparative characters with their similar species are provided. Impatiens yinyinkyii is similar to I. masonii Hook.f., but differs in having three dark purple blotches in center of flower, specifically at base of dorsal and upper petals of united petals. Impatiens horizontalis resembles I. stenantha Hook.f., I. prostrata Hook. f., I. repens Moon, I. procumbens Franch and I. reptans Hook. f. in having larger, glabrous and elliptic to lanceolate leaves, serrate margin with antrorse bristles, deeply bucciniform lower sepal, twisted spur with abruptly capitate tip, linear ovary, spheroid seed and finally uncommon conspicuous stout stem which is horizontally creeping.

Purpose: Laparoscopic adrenalectomy is widely performed for a number of hormone-producing tumors and postoperative management depends on the hormones produced. In the present study, we conducted a retrospective analysis to clarify the risk factors for postoperative complications, particularly postoperative fever after laparoscopic adrenalectomy. Methods: We analyzed 406 patients who underwent laparoscopic adrenalectomy at our hospital between 2003 and 2019. Postoperative fever was defined as a fever of 38°C or higher within 72 hours after surgery. We investigated the risk factors for postoperative fever after laparoscopic adrenalectomy. Results: There were 188 males (46%) and 218 females (54%) with a median age of 52 years. Among these patients, tumor pathologies included 188 primary aldosteronism (46%), 75 Cushing syndrome (18%), and 80 pheochromocytoma (20%). Postoperative fever developed in 124 of all patients (31%), 30% of those with primary aldosteronism, 53% of those with pheochromocytoma, and 8% of those with Cushing syndrome. A multivariate logistic regression analysis identified pheochromocytoma and non-Cushing syndrome as independent predictors of postoperative fever. Postoperative fever was observed in 42 out of 80 cases of pheochromocytoma (53%), which was significantly higher than in cases of non-pheochromocytoma (82/326, 25%, pConclusion: Since postoperative fever after laparoscopic adrenalectomy is markedly affected by the hormone produced by pheochromocytoma and Cushing syndrome, it is important to carefully consider the need for treatment.

Volatile organic compounds (VOCs), CO2, temperature, and humidity in a private room in a care facility for the elderly were measured and the behavior of a resident and staff were recorded in order to clarify the effects of the resident’s behavior, especially defecation, on indoor air quality. Average indoor concentrations of total VOCs (in μg m-3) in summer, autumn, and winter were 40.9, 16.7, and 18.8, respectively. Average indoor concentrations of CO2 in summer, autumn, and winter were 813, 761, and 1144 ppm, respectively, revealing a tendency for the concentrations of CO2 to be higher in winter, in contrast to the VOC concentration. The concentrations of VOCs and CO2 were 1.1 to 1.5 times higher when the resident was present in the room than when the resident was absent. This result suggests that one of the main sources of VOC and CO2 emissions in indoor air was the resident. Acetic acid, 1-butanol, propanoic acid, hexanoic acid, and phenol, which are contained in human sweat, exhaled air, and excrement, were the predominant VOCs in the air of the room regardless of the season, and these five components accounted for more than 90% of the total VOCs. The concentrations of these components were higher when the resident was present in the room, suggesting that the resident was the main source of these components. Based on the changes in the VOC and CO2 concentrations over time and the records of the resident and the staff, it was noted that VOC concentrations decreased, in some cases, before and after diaper changes. Our research suggests that certain aspects of the behavior of residents can be inferred by monitoring changes in indoor air quality.

Several clinical studies have been conducted into the practicality and safety of regenerative therapy using hESC/iPSC-retinal pigment epithelium (RPE) as a treatment for the diseases including age-related macular degeneration. These studies used either suspensions of RPE cells or an RPE cell sheet. The cells can be injected using a minimally invasive procedure but the delivery of an intended number of cells at an exact target location is difficult; cell sheets take a longer time to prepare, and the surgical procedure is invasive but can be placed at the target area. In the research reported here, we combined the advantages of the two approaches by producing a quickly formed hiPSC-RPE strip in as short as 2 days. The strip readily expanded into a monolayer sheet on the plate, and after transplantation in nude rats, it showed a potency to partly expand with the correct apical/basal polarity in vivo, although limited in expansion area in the presence of healthy host RPE. The strip could be injected into a target area in animal eyes using a 24G canula tip.

Background Previous clinical trials have demonstrated the potential efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) in patients with cancer involving homologous recombination repair (HRR) gene-mutation. Moreover, HRR gene-mutated cancers are effectively treated with immune checkpoint inhibitors (ICIs) with the increase in tumor mutation burden. We have proposed to conduct a multicenter, single-arm phase II trial (IMAGENE trial) for evaluating the efficacy and safety of niraparib (PARPi) plus programmed cell death-1 inhibitor combination therapy in patients with HRR gene-mutated cancers who are refractory to ICIs therapy using a next generation sequencing-based circulating tumor DNA (ctDNA) and tumor tissue analysis. Methods Key eligibility criteria for this trial includes HRR gene-mutated tumor determined by any cancer gene tests; progression after previous ICI treatment; and Eastern Cooperative Oncology Group Performance Status ≤ 1. The primary endpoint is the confirmed objective response rate (ORR) in all patients. The secondary endpoints include the confirmed ORR in patients with HRR gene-mutation of ctDNA using the Caris Assure (CARIS, USA). The target sample size of the IMAGENE trial is 57 patients. Biomarker analyses will be performed in parallel using the Caris Assure, proteome analysis, and T cell repertoire analysis to reveal tumor immunosurveillance in peripheral blood. Expected outcome Our trial aims to confirm the clinical benefit of PARPi plus ICI combination therapy in ICI-resistant patients. Furthermore, through translational research, our trial will shed light on which patients would benefit from the targeted combination therapy for patients with HRR gene-mutated tumor even after the failure of ICIs. Trial registration The IMAGENE trial: jRCT, Clinical trial no.: jRCT2051210120, Registered date: November 9, 2021.

IL‐2 is a pleiotropic cytokine that regulates immune cell homeostasis. Its immunomodulatory function has been used clinically as an active immunotherapy agent for metastatic cancers. However, severe adverse effects, including the vascular leak syndrome and the preferential stimulation of anti‐immunogenic Treg rather than effector T cells, have been obstacles. We newly designed a mutein IL‐2, Mutakine‐6 (MK‐6), with reduced IL‐2Rα–binding capability. MK‐6 induced comparable cell growth potential toward IL‐2Rβγ–positive T cells but was far less efficient in in vitro Treg proliferation and STAT5 activation. Unlike IL‐2, in vivo administration of MK‐6 produced minimal adverse effects. Using CT26 and B16F10‐syngeneic tumor models, we found MK‐6 was highly efficacious on tumor regression. Serum albumin conjugation to MK‐6 prolonged in vivo half‐life and accumulated in CT26 tumors, showing enhanced antitumor effect. Tumor‐infiltrating leukocytes analysis revealed that albumin‐fused MK‐6 increased the ratio of effector CD8+ T cells to CD4+ Treg cells. These results demonstrated that MK‐6 is an efficient immunomodulator potentially used for improved immunotherapy with decreased adverse effects and attenuated Treg stimulation., Albumin‐conjugated IL‐2 mutein, MK‐6, exerts a potent antitumor effect in the CT26 tumor model.

Real-time onsite monitoring of indoor airborne microbes in a residential property in central Tokyo was carried out in 2020 and 2021, following the onset of the COVID-19 pandemic. A microbial sensor utilizing fluorescence emitted by microorganisms was used to measure bioaerosol concentrations in the living room and children’s bedroom as well as on the balcony. Indoor PM2.5 was also monitored simultaneously at certain time points using a PM2.5 sensor. The behavior of the residents was also recorded during some monitoring periods. The average number concentration of microbes as fungi in the living room was 15,100, 58,800, and 10,600 counts m-3 in spring, summer, and winter, respectively, increasing in summer when the outside temperature was high. Microbial number concentrations were closely related to human behavior, increasing rapidly during periods of physical activity, but decreasing again within 20-30 min of the activity ending. There was no clear correlation between indoor microbial number concentrations and PM2.5 concentrations, suggesting that indoor microorganisms are concentrated in coarse particles, such as dust, which are quickly removed via gravitational settling. The concentration of indoor airborne microorganisms decreased significantly after ventilation, and although an occasional increase was observed immediately after ventilation, concentrations decreased again rapidly within 10-20 min. These results suggest that even a short period of ventilation can significantly reduce the indoor bioaerosol © 2021 by Asian Association for Atmospheric Environment

In this study, a corrosion-stable silica membrane was developed to be used in H2 purification during the hydrogen iodide decomposition (2HI → H2 + I2), which is a new application of the silica membranes. From a practical perspective, the membrane separation length was enlarged up to 400 mm and one end of the membrane tubes was closed to avoid any thermal variation along the membrane length and sealing issues. The silica membranes consisted of a three-layer structure comprising a porous α-Al2O3 ceramic support, an intermediate layer, and a top silica layer. The intermediate layer was composed of γ-Al2O3 or silica, and the top silica layer that is H2 selective was prepared via counter-diffusion chemical vapor deposition of a hexyltrimethoxysilane. To the best of our knowledge, this is the first report of 400-mm-long closed-end silica membranes supported on Si-formed α-Al2O3 tubes produced via chemical vapor deposition method. A 400-mm-long closed-end membrane using a Si-formed α-Al2O3 tube exhibited a higher H2/SF6 selectivity of 1240 but lower H2 permeance of 1.4 × 10−7 mol Pa−1 m−2 s−1 with compared with the membrane using a γ-Al2O3-formed α-Al2O3 tube (907 and 5.6 × 10−7 mol Pa−1 m−2 s−1, respectively). The membrane using the Si-formed α-Al2O3 tube was more stable in corrosive HI gas than a membrane with a γ-Al2O3-formed α-Al2O3 tube after 300 h of stability tests. In conclusion, the developed silica membranes using the Si-formed α-Al2O3 tubes seem suitable for membrane reactors that produce H2 on large scale using HI decomposition in the thermochemical iodine–sulfur process.

The thermochemical water-splitting iodine–sulfur process facilitates hydrogen production. This study proposes a new loop operation by subdividing the process configuration into four sections before transferring the continuous operation. The loop operation should define the section affecting the fluctuations to easily stabilize the system. The proposed loop operation was validated by analyzing the material and heat balances using a process simulator. The calculated results showed that the material balances of the respective loop sections were closed without component discharge to outside sections. The loop operation would transfer to the continuous operation by connecting all sections. Considering the switching of operation modes, the material and heat balance showed no or little difference, indicating that two operation modes can only be changed by switching the pipelines. Thus, the loop sections can be operated individually to stabilize the IS process system, and the loop operation can be transferred smoothly to the continuous operation.

OBJECTIVE Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. DESIGN AND PATIENTS Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39-) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39- T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.

Indoor air quality (IAQ) in houses is often deteriorated by chemical substances emitted from heating, building materials, or other household goods. Since it is difficult for occupants to recognize air pollution, they rarely understand the actual conditions of the IAQ. An investigation into the actual condition of IAQ in houses was therefore conducted in this study. Carbon dioxide (CO2) concentrations in 24 occupied houses was measured, and the results from our analysis showed that the use of combustion heaters increased the concentration of CO2 and led to indoor air pollution. Results indicate that as outdoor temperature decreased, the frequency of ventilation decreased simultaneously, and CO2 concentration increased. Results of the questionnaire survey revealed that the actual IAQ in each house did not match the level of awareness its occupants had regarding ventilation. Along with this difficulty in perceiving air pollution, the lack of knowledge about ventilation systems and the effects of combustion heating may be additional barriers to IAQ awareness.

The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC). A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed. Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9 months, 95% confidence interval, CI 4.1–19.8, p = 0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p = 0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14–0.99, p = 0.047). The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

Clarifying the influences of paleoclimate changes on the disjunct distribution formation of plants allows a historical and mechanical understanding of current vegetation and biodiversity. This study investigated the influences of paleoclimate changes on the present disjunct distribution formation of Pinus koraiensis (Korean pine) using species distribution modeling. A species distribution model (SDM) was built using maximum entropy principle algorithms (MaxEnt), data from 152 occurrences of the species, and four bioclimatic variables at 2.5 arcminute (approximately 5 km) spatial resolution. The simulation revealed the excellent fit of the MaxEnt model performance, with an area under the curve (AUC) value of 0.922 and continuous Boyce index (BCI) value of 0.925 with fivefold cross-validation. The most important climatic factor was the minimum temperature of the coldest month. Suitable habitats for the species ranged between − 30.1 and − 4.1 °C. Projected suitable habitats under the Last Glacial Maximum (approximately 22,000 years ago [ka BP]: LGM) period showed wide distributions in eastern China, the southern part of the Korean Peninsula, and the Japanese Archipelago. After the mid-Holocene (approximately 6 ka BP), the suitable habitats expanded northwards in continental regions and retreated from both north and southwest of Japan. This eventually formed disjunct suitable habitats in central Japan. An increase in temperature after the LGM period caused the migration of P. koraiensis toward new, suitable habitats in continental Northeast Asia, while species in the Japanese Archipelago retreated, forming the present disjunct distributions.

To evaluate the association between a sign and visceral pleural invasion (VPI) of peripheral non–small-cell lung cancer (NSCLC) that does not appear touching the pleural surface. A total of 221 consecutive patients with NSCLC that did not appear touching the pleural surface, ≤ 3 cm in solid tumor diameter, and was surgically resected between January 2009 and December 2015 were included. We focused on the flat distortion of the tumor caused by an arch-shaped linear tag between the tumor and the pleura on CT and named it a bridge tag sign. We evaluated the associations between the clinicopathological features of the tumor, including the bridge tag sign, and VPI. We also evaluated the associations between histopathological findings and the bridge tag sign. The utility of the bridge tag sign in the diagnosis of VPI was statistically assessed. The bridge tag sign was observed in 48 (20.8%) patients. VPI was positive in 9 (4.1%) patients; among these, the bridge tag sign was positive in 8 patients. In multivariate analysis, a bridge tag sign was significantly associated with VPI. The bridge tag sign was associated with longer contact length of the pleura with the tumor and trapezoid type pleural retraction. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the bridge tag sign in the diagnosis of VPI were 88.9%, 83.5%, 83.7%, 18.6%, and 99.4%, respectively. A bridge tag sign on CT might improve the accuracy of the prediction of VPI. • We present the bridge tag sign which is defined as a flat distortion of an NSCLC tumor by an arch-shaped linear tag between the tumor and chest wall or interlobar fissure. • The bridge tag sign was an independent predictive factor for visceral pleural invasion. • The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the bridge tag sign in the diagnosis of visceral pleural invasion were 88.9%, 83.5%, 83.7%, 18.6%, and 99.4%, respectively.

In the activation of cell-mediated adaptive immune responses that play major roles in the elimination of virus-infected or tumor cells, it is important that dendritic cells present antigen peptides on major histocompatibility complex (MHC) class I molecules and activate pathogen-specific cytotoxic T lymphocytes (CTL). As exogenous peptide antigens are generally presented on MHC class II but not class I, the development of a method for exogenous antigen delivery that facilitates MHC class I presentation is necessary for a potentially effective vaccine that is expected to provoke cell-mediated adaptive immune responses. Here, we developed extracellular vesicles that incorporate antigenic proteins by utilizing endosomal sorting complexes required for transport (ESCRT)-mediated vesicle formation pathway. Furthermore, we proved that these vesicles could deliver their contents to the cytoplasm of dendritic cells and activate antigen-specific CTLs. These technologies could be applied to the development of novel CTL-inducing peptide vaccines.

Background Quantitative analyses of computed tomography (CT) images using computer-aided detection (CAD) are correlated with visual assessments and pulmonary function test findings and might be useful for predicting the prognosis of patients with idiopathic pulmonary fibrosis (IPF). Purpose To evaluate the association between the quantitative analysis of long-term follow-up CT of IPF and the progression and prognosis. Material and Methods A total of 48 patients with IPF who received over one year of follow-up CT were included in this study. The results of quantitative analyses (emphysema, ground-glass attenuation [GGA], consolidation, reticulation, and honeycombing) using a CAD software program of initial and follow-up CT findings were evaluated, and the association with the progression of the total lesion of IPF and prognosis using Spearman's rank correlation and Cox regression analyses was considered. Results Results of quantitative analyses of consolidation, reticulation, honeycombing, and the total lesion on initial CT were correlated with progressive changes in the total lesion of IPF per year (r = 0.4375, 0.4128, 0.4649, and 0.4095, respectively). The results of quantitative analyses of honeycombing (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.03−1.89, P = 0.0314) and GGA (HR = 0.85, 95% CI = 0.72−0.99, P = 0.0384) at initial CT were prognostic factors according to a multivariate Cox regression analysis. Conclusion The quantitative analysis of honeycombing using a CAD software program of CT findings may be useful for predicting the progression and prognosis of patients with IPF.

We characterize here the airborne lipids (β/ω-hydroxy fatty acids: FAs) specific to soil microbes and plant waxes over suburban Tokyo in simultaneously collected aerosols and rainwater from spring ...

The salvage treatments for biochemical recurrence (BCR) include local external beam radiation therapy (RT) and systemic androgen-deprivation therapy (ADT). We reviewed patients who underwent radical prostatectomy (RP) and developed BCR at three institutions. After excluding patients whose nadir prostate-specific antigen (PSA) was higher than 0.2 ng/mL, those who received neoadjuvant/adjuvant therapy, and those whose BCR was not treated until their PSA exceeded 4.0 ng/mL, the remaining 335 patients comprised the cohort of this study. Salvage RT and ADT were performed for 154 and 181 patients, respectively. After the failure of salvage RT, all patients received subsequent ADT. The starting point of this study was the timing of BCR and the endpoint was the development of castration-resistant prostate cancer (CRPC). During the mean follow-up period of 8.5 years after BCR, CRPC was observed in 13 patients administered RT and 24 patients administered ADT. Kaplan–Meier curves demonstrated no significant difference in CRPC-free survival between the RT and ADT groups (10-year CRPC-free survival 89.9 vs. 86.3%, p = 0.199). On the other hand, we found a significant difference in CRPC-free survival between the RT and ADT groups in 50 high-risk patients with two risk factors of Grade Group ≥ 4 and PSA-doubling time

To differentiate between infectious and non-infectious diseases occurring in immunocompromised patients without acquired immunodeficiency syndrome (AIDS) using high-resolution computed tomography (HRCT).HRCT images of 555 patients with chest complications were reviewed retrospectively. Infectious diseases (n=341) included bacterial pneumonia (n=123), fungal infection (n=80), septic emboli (n=11), tuberculosis (n=15), pneumocystis pneumonia (n=101), and cytomegalovirus pneumonia (n=11), while non-infectious diseases (n=214) included drug toxicity (n=84), infiltration of underlying diseases (n=83), idiopathic pneumonia syndrome (n=34), diffuse alveolar haemorrhage (n=8), and pulmonary oedema (n=5). Lung parenchymal abnormalities were compared between the two groups using the χThe χ2 test results showed significant differences in many HRCT findings between the two groups. Multiple logistic regression analysis results indicated the presence of nodules with a halo and the absence of interlobular septal (ILS) thickening were the significant indicators that could differentiate infectious from non-infectious diseases. ILS thickening was generally less frequent among most infectious diseases and more frequent among most non-infectious diseases, with a good odds ratio (7.887, p0.001). The sensitivity and accuracy for infectious diseases in the absence of ILS thickening were better (70% and 73%, respectively) than those of nodules with a halo (19% and 48%, respectively), while the specificity in the nodules with a halo was better (93%) than that of ILS thickening (78%).The presence of nodules with a halo or the absence of ILS thickening tends to suggest infectious disease. Specifically, ILS thickening seems to be a more reliable indicator.