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Objective: To analyze the outcomes of transperineal template-guided mapping biopsy (TTMB) in biopsy-naïve men with multiparametric magnetic resonance imaging (mpMRI) results of Prostate Imaging-Reporting and Data System (PI-RADS) 1-2. Patients and methods: We retrospectively reviewed TTMB outcomes in biopsy naïve patients with PI-RADS 1-2 at a single center from August 2018 to May 2023. The patients' clinicopathologic data were reviewed, clinically significant prostate cancer (csPCa) detection rates were identified. We determined significant predictive factors and determined those optimal cutoff point using receiver operating characteristic (ROC) curves. Results: 255 biopsy naïve patients with PI-RADS 1-2 underwent TTMB. 72 (28.2%) were diagnosed with prostate cancer and 30 (11.8%) were diagnosed with csPCa. ROC curves were used to identify predictive factors for diagnosing csPCa. Age (area under ROC curve [AUC]: 0.74, 95% CI: 0.65–0.83, P

Abstract Background Seven-carbon sugars, which rarely exist in nature, are the key constitutional unit of septacidin and hygromycin B in bacteria. These sugars exhibit a potential therapeutic effect for hypoglycaemia and cancer and serve as building blocks for the synthesis of C-glycosides and novel antibiotics. However, chemical and enzymatic approaches for the synthesis of seven-carbon sugars have faced challenges, such as complex reaction steps, low overall yields and high-cost feedstock, limiting their industrial-scale production. Results In this work, we propose a strain engineering approach for synthesising sedoheptulose using glucose as sole feedstock. The gene pfkA encoding 6-phosphofructokinase in Corynebacterium glutamicum was inactivated to direct the carbon flux towards the pentose phosphate pathway in the cellular metabolic network. This genetic modification successfully enabled the synthesis of sedoheptulose from glucose. Additionally, we identified key enzymes responsible for product formation through transcriptome analysis, and their corresponding genes were overexpressed, resulting in a further 20% increase in sedoheptulose production. Conclusion We achieved a sedoheptulose concentration of 24 g/L with a yield of 0.4 g/g glucose in a 1 L fermenter, marking the highest value up to date. The produced sedoheptulose could further function as feedstock for synthesising structural seven-carbon sugars through coupling with enzymatic isomerisation, epimerisation and reduction reactions.

This study aimed to assess the prognostic role of body mass index (BMI) in patients with metastatic renal cell carcinoma (mRCC) treated with first-line immune checkpoint inhibitor (ICI)-based therapy. We searched for relevant studies in the MEDLINE, Embase, and Cochrane Library databases. The initial search yielded 599 records, of which seven articles (2,517 patients) were selected for analysis. Patients with a high BMI had a favorable overall survival (OS) based on hazard ratio (HR) (crude HR 0.69, 95% confidence interval [CI] 0.57–0.83, p

Background: Liver transplantation is the treatment for many end-stage liver diseases and hepatocellular carcinoma but shortage of available organs poses significant challenge. Many centers have used grafts from donors with positive anti-HBc serology but concerns about potential hepatitis B virus reactivation and de novo hepatitis B infection have raised questions about the safety of this approach. This study aimed to evaluate the survival of liver transplant recipients from anti-HBc-positive-donors and assess the risk of hepatitis B reactivation and de novo hepatitis B. Patients and methods: A retrospective single-center cohort study was conducted from 2002 to 2018, comparing who received grafts from anti-HBc-positive-donors to those from anti-HBc-negative-donors. The primary outcome was survival and description cases of hepatitis B reactivation/de novo hepatitis B. Results: We analyzed 1,111 liver transplants, in which 993 (89 %) received grafts from anti-HBc-negative-donors and 118 (11 %) from anti-HBc-positive-donors. Median age of recipients from anti-HBc-positive donors was 56 years and from anti-HBc-negative donors was of 53 years (p = 0.001). Male sex was predominant in both groups. Factors associated with death in multivariate analysis were retransplantation, early allograft dysfunction, high MELD, recipient over 60 years and female donor. The utilization of grafts from anti-HBc-positive-donors did not increase mortality. The majority of HBV reactivation and de novo hepatitis B occurred in anti-HBc positive recipients. The risk of hepatitis B reactivation/de novo hepatitis B was low and manageable. Conclusion: The study supports safety of liver grafts from anti-HBc-positive donors when employing antiviral prophylaxis. These findings contribute to expand donor options and improve patient outcomes

Introdução: A doença fúngica invasiva (DFI) é uma importante causa de morbidade e mortalidade após o transplante de fígado (TF). Os principais agentes associados à DFI precoce são Candida sp. e Aspergillus sp. No entanto, faltam dados na literatura sobre a DFI durante o período peritransplante, as primeiras 24 horas após o transplante. Objetivo: Identificar os fatores de risco para ocorrência de DFI no período peritransplante e fatores de risco de mortalidade em 30 dias após o transplante. Método: Estudo caso-controle retrospectivo unicêntrico de pacientes transplantados de fígado de 2002 a 2017. Resultados: Houve 26 casos de DFI intraoperatória e 78 controles. Na análise multivariada, os dias de internação antes do transplante (OR 1,09, p = 0,01) e anastomose biliodigestiva (OR 5,01, p = 0,02) foram associados à ocorrência de DFI. O uso de antimicrobianos nos 30 dias anteriores ao transplante (HR 5,94, p = 0,009), hemodiálise após TF (HR 6,3, p = 0,004) e disfunção precoce do enxerto (HR 8,94, p = 0,006) foram independentemente associados ao óbito. Conclusão: Pacientes hospitalizados antes do transplante e anastomoses biliodigestivas foram fatores de risco significativos para ocorrência de DFI no período peritransplante, e essas infecções não foram consideradas fator de risco para óbito nos primeiros 30 dias após o transplante.

Abstract The master DNA damage repair histone protein, H2AX, is essential for orchestrating the recruitment of downstream mediator and effector proteins at damaged chromatin. The phosphorylation of H2AX at S139, γH2AX, is well-studied for its DNA repair function. However, the extended C-terminal tail is not characterized. Here, we define the minimal motif on H2AX for the canonical function in activating the MDC1-RNF8-RNF168 phosphorylation-ubiquitination pathway that is important for recruiting repair proteins, such as 53BP1 and BRCA1. Interestingly, H2AX recruits 53BP1 independently from the MDC1-RNF8-RNF168 pathway through its evolved C-terminal linker region with S139 phosphorylation. Mechanistically, 53BP1 recruitment to damaged chromatin is mediated by the interaction between the H2AX C-terminal tail and the 53BP1 Oligomerization-Tudor domains. Moreover, γH2AX-linker mediated 53BP1 recruitment leads to camptothecin resistance in H2AX knockout cells. Overall, our study uncovers an evolved mechanism within the H2AX C-terminal tail for regulating DNA repair proteins at damaged chromatin.

Purpose: This study investigated the efficacy of intravesical gemcitabine as an alternative to bacillus Calmette–Guérin (BCG) therapy. Materials and Methods: Data were retrospectively collected across seven institutions from February 1999 to May 2023. Inclusion criteria included patients with intermediate- or high-risk non-muscle invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumors (TURBT) and received at least four sessions of intravesical gemcitabine or BCG induction therapy. Patient characteristics, complete remission (CR), occurrence, and progression rates were compared. Results: In total, 149 patients were included in this study (gemcitabine, 63; BCG, 86). No differences were apparent between the two groups in baseline characteristics, except for the follow-up period (gemcitabine, 9.2±5.9 months vs. BCG, 43.9±41.4 months, p

Abstract The COHORT trial was conducted to compare the efficacy of androgen deprivation therapy (ADT) alone versus combined with radiation therapy (ADT + RT) for clinically node-positive prostate cancer. We reported adverse events and quality of life between the two treatment groups. Fifty-nine patients were randomized to receive ADT alone or ADT + RT and analyzed as per-protocol. Patients allocated to the ADT alone arm received ADT for at least 2 years. Patients in the ADT + RT arm received additional pelvic RT. Higher rates of grade ≥ 2 acute genitourinary (0% vs. 7.1%) and late gastrointestinal adverse events (0% vs. 14.3%) were reported in the ADT + RT arm compared with the ADT alone. However, grade ≥ 2 late genitourinary toxicity was more common in the ADT alone than the ADT + RT arm (9.7% vs. 3.6%). No grade ≥ 3 adverse events were reported. There was no statistically significant difference in EPIC scores between two treatment arms. However, the urinary and bowel domains tended to decrease and recover in the ADT + RT arm. In conclusion, ADT + RT demonstrated higher rates of adverse events compared to ADT alone. However, the addition of RT did not significantly impact the quality of life.

Plasmodium parasites cause Malaria disease, which remains a significant threat to global health, affecting 200 million people and causing 400,000 deaths yearly. Plasmodium falciparum and Plasmodium vivax remain the two main malaria species affecting humans. Identifying the malaria disease in blood smears requires years of expertise, even for highly trained specialists. Literature studies have been coping with the automatic identification and classification of malaria. However, several points must be addressed and investigated so these automatic methods can be used clinically in a Computer-aided Diagnosis (CAD) scenario. In this work, we assess the transfer learning approach by using well-known pre-trained deep learning architectures. We considered a database with 6222 Region of Interest (ROI), of which 6002 are from the Broad Bioimage Benchmark Collection (BBBC), and 220 were acquired locally by us at Fundação Oswaldo Cruz (FIOCRUZ) in Porto Velho Velho, Rondônia-Brazil, which is part of the legal Amazon. We exhaustively cross-validated the dataset using 100 distinct partitions with 80% train and 20% test for each considering circular ROIs (rough segmentation). Our experimental results show that DenseNet201 has a potential to identify Plasmodium parasites in ROIs (infected or uninfected) of microscopic images, achieving 99.41% AUC with a fast processing time. We further validated our results, showing that DenseNet201 was significantly better (99% confidence interval) than the other networks considered in the experiment. Our results support claiming that transfer learning with texture features potentially differentiates subjects with malaria, spotting those with Plasmodium even in Leukocytes images, which is a challenge. In Future work, we intend scale our approach by adding more data and developing a friendly user interface for CAD use. We aim at aiding the worldwide population and our local natives living nearby the legal Amazon's rivers.

Abstract To evaluate the recurrence rate and risk factors of recurrence after robot-assisted laparoscopic partial nephrectomy for solitary renal cell carcinoma (RCC). A total of 1265 cases of initial solitary localized RCC were analyzed. The baseline characteristics, complexity (REANL nephrometry score), intra- and peri-operative outcomes, and recurrence were evaluated. Logistic regression was performed to evaluate the factors affecting recurrence after RAPN for solitary localized RCC. Recurrence after robot-assisted partial nephrectomy (RAPN) occurred in 29 patients (2.29%). The median follow-up was 36.0 months. The N domain (nearness to collecting system/sinus) (odd ratio (OR) 3.517, 95% confidence interval (CI) 1.557–7.945, p = 0.002), operation time (OR 1.005, 95% CI 1.001–1.010, p = 0.013), and perioperative transfusion (OR 5.450, 95% CI 1.197–24.816, p = 0.028) affected recurrence. Distant metastasis among patients with recurrence was significantly associated with nearness to the collecting system/sinus (OR 2.982, 95% CI 1.162–7.656, p = 0.023) and distance between the mass and collecting system/sinus (OR 0.758, 95% CI 0.594–0.967, p = 0.026). Nearness to the collecting system/sinus, operation time, and perioperative transfusion affect recurrence after RAPN for solitary localized RCC. Moreover, the proximity to the collecting system/sinus and distance between the mass and collecting system/sinus were significantly related to distant metastasis after RAPN.

Abstract We compared the progression patterns after radical nephroureterectomy (RNU) and elective distal ureterectomy (DU) in patients with urothelial carcinoma of the distal ureter. Between Jan 2011 and Dec 2020, 127 patients who underwent RNU and 46 who underwent elective DU for distal ureteral cancer were enrolled in this study. The patterns of progression and upper tract recurrence were compared between the two groups. Progression was defined as a local recurrence and/or distant metastasis after surgery. Upper tract recurrence and subsequent treatment in patients with DU were analyzed. Progression occurred in 35 (27.6%) and 10 (21.7%) patients in the RNU and DU groups, respectively. The progression pattern was not significantly different (p = 0.441), and the most common progression site was the lymph nodes in both groups. Multivariate logistic regression analysis revealed that pT2 stage, concomitant lymphovascular invasion, and nodal stage were significant predictors of disease progression. Upper tract recurrence was observed in nine (19.6%) patients with DU, and six (66.7%) patients had a prior history of bladder tumor. All patients with upper tract recurrence after DU were managed with salvage RNU. Elective DU with or without salvage treatment was not a risk factor for disease progression (p = 0.736), overall survival (p = 0.457), cancer-specific survival (p = 0.169), or intravesical recurrence-free survival (p = 0.921). In terms of progression patterns and oncological outcomes, there was no difference between patients who underwent RNU and elective DU with/without salvage treatment. Elective DU should be considered as a therapeutic option for distal ureter tumor.

Abstract The World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading of renal cell carcinoma (RCC) is classified from grade 1–4, regardless of subtype. The National Comprehensive Cancer Network (NCCN) guidelines (2022) state that if there is an adverse pathological feature, such as grade 3 or higher RCC in stage 1 patients, more rigorous follow-up imaging is recommended. However, the RCC guidelines do not provide specific treatment or follow-up policies by tumor grade. Therefore, this study attempted to find out whether tumor grade affects survival rates in patients with metastatic RCC. The Korean Renal Cancer Study Group (KRoCS) database includes 3108 patients diagnosed with metastatic RCC between September 1992 and February 2017, with treatment methods, progression, and survival data collected from 11 tertiary hospitals. To obtain information on survival rates or causes of death, we utilized the Korea National Statistical Office database and institutional medical records. Data were accessed for research purpose on June, 2023. We then reviewed these sources to gather comprehensive and reliable data on the outcomes of our study cohort. This database was retrospectively analyzed, and out of 3108 metastatic RCC patients, 911 had been identified as WHO/ISUP grade. Grades were classified into either a low-grade (WHO/ISUP grade 1–2) or a high-grade group (WHO/ISUP grade 3–4). The patients were then analyzed related to progression and overall survival (OS). In metastatic clear cell RCC patients, the 1-year OS rate was 69.4% and the median OS was 17.0 months (15.5–18.5) followed up to 203.6 months. When comparing the patient groups, 119 low-grade and 873 high-grade cases were identified. No baseline difference was observed between the two groups, except that the high-grade group had a higher ECOG 1 ratio of 50.4% compared with 34.5% for the low-grade group (p = 0.009). There was a significant difference in OS between high-grade and low-grade groups. OS was 16.0 months (14.6–17.4) in the high-grade group and 28.0 months (21.1–34.9) in the low-grade group (p

Purpose: To create a nomogram that can predict the probability of prostate cancer using prostate health index (PHI) and clinical parameters of patients. And the optimal cut-off value of PHI for prostate cancer was also assessed. Materials and Methods: A prospective, multi-center study was conducted. PHI was evaluated prior to biopsy in patients requiring prostate biopsy due to high prostate-specific antigen (PSA). Among screened 1,010 patients, 626 patients with clinically suspected prostate cancer with aged 40 to 85 years, and with PSA levels ranging from 2.5 to 10 ng/mL were analyzed. Results: Among 626 patients, 38.82% (243/626) and 22.52% (141/626) were diagnosed with prostate cancer and clinically significant prostate cancer, respectively. In the PSA 2.5 to 4 ng/mL group, the areas under the curve (AUCs) of the nomograms for overall prostate cancer and clinically significant prostate cancer were 0.796 (0.727–0.866; p

Background The aim of this study was to evaluate the risk factors for prostate-specific antigen (PSA) persistence in pathological stage T3aN0 prostate cancer (PCa) after robot-assisted laparoscopic radical prostatectomy (RALP). Methods A retrospective study was performed on 326 patients with pT3aN0 PCa who underwent RALP between March 2020 and February 2022. PSA persistence was defined as nadir PSA of >0.1 ng/mL after RALP, and the risk factors for PSA persistence were evaluated using logistic regression analysis. Results Among 326 patients, 61 (18.71%) had PSA persistence and 265 (81.29%) had PSA of

Background: This study aimed to evaluate the treatment outcomes and define the prostate-specific antigen (PSA) kinetics as potential prognostic factors in patients with intermediate- or high-risk localized prostate cancer (PCa) who underwent moderately hypofractionated radiation therapy. Methods: The study retrospectively reviewed the medical records of 149 patients with intermediate- or high-risk localized PCa who underwent definitive radiation therapy (70 Gy in 28 fractions) without androgen deprivation therapy. Clinical outcomes were analyzed based on risk stratification (favorable-intermediate, unfavorable-intermediate, and high-risk). The biochemical failure rate (BFR) and clinical failure rate (CFR) were stratified based on the PSA nadir and the time to the PSA nadir to identify the prognostic effect of PSA kinetics. Acute and late genitourinary and gastrointestinal adverse events were analyzed. Results: Significant differences were observed in the BFR and CFR according to risk stratification. No recurrence was observed in the favorable intermediate-risk group. The 7-year BFR and CFR for the unfavorable intermediate-risk and high-risk groups were 19.2% and 9.8%, and 31.1% and 25.3%, respectively. Patients with a PSA nadir >0.33 ng/mL or a time to the PSA nadir

Background: We assessed the ability of the combination of multiparametric magnetic resonance imaging (mpMRI) and transperineal template-guided mapping biopsy (TTMB) to determine the eligibility for focal therapy (FT) (hemiablation) in men and compared it with that of histology from radical prostatectomy (RP) specimens. Materials and methods: In this study, 120 men who underwent mpMRI, TTMB, and RP in a single tertiary center from May 2017 to June 2021 were analyzed. The criteria of hemiablation eligibility were unilateral low-to intermediate-risk prostate cancer (limited to a maximum of International Society of Urological Pathology (ISUP) grade group 3 and prostate-specific antigen (PSA)

ObjectiveUsing multi-parametric magnetic resonance imaging (mpMRI) to identify patients with clinical T3a (cT3a) who were overestimated on mpMRI with final pathological T2 (pT2). To suggest that the neurovascular bundle (NVB) can be preserved by evaluating the characteristics of patients according to their pathological grade among cT3a prostate cancer (PCa) patients using mpMRI.Materials and methodsPatients who underwent robot-assisted laparoscopic radical prostatectomy (RALP) were retrospectively analyzed and those patients with clinical T3aN0M0 were enrolled. These enrolled patients were divided into a localized cancer group with pT2 PCa and a locally advanced group with pT3a or higher. Factors affecting the diagnosis of localized PCa after RALP in patients with cT3a PCa were evaluated.ResultsAmong the preoperative parameters of patients with cT3a PCa, the prostate specific antigen density (PSAD) (OR: 3.76, 95% CI: 1.85–7.64, p

Key points The new transperineal ultrasound (TPUS) technique can offer an accessible route in men without an anus. A PI-RADS 5 tumor is a good indication for the new TPUS-guided biopsy technique. The TPUS-guided biopsy is difficult to target a small prostate tumor (

Introdução: Enterococcus spp. resistentes à vancomicina (VRE) são microrganismos multidroga resistentes (MDRO) comumente isolados em pacientes submetidos a transplante de fígado (TF), e estão potencialmente associados a piores desfechos clínicos. Existem poucos dados sobre os fatores de risco para a colonização e infecção por VRE nessa população. Nosso objetivo é identificar os fatores de risco associados à colonização e infecção por VRE após TF. Métodos: Esse é um estudo de coorte retrospectivo que incluiu todos os adultos submetidos a TF entre 2010 e 2019 em um hospital de alta complexidade. O período de acompanhamento foi de 180 dias após TF. A análise estatística incluiu variáveis relacionadas às características dos pacientes, procedimentos e complicações pós transplante. Utilizamos o modelo de regressão de Cox para análises univariadas e multivariadas. Resultados: Foram incluídos 855 pacientes, a mediana de idade foi 54 anos (IQR 41 - 61) e escore de MELD no TF de 21 (IQR 13 - 29). 107 (13%) adquiriram VRE antes do TF. A colonização após o TF ocorreu em 144 pacientes (19%), sendo que 80 (9%) desenvolveram infecção por VRE. As infecções mais comuns foram infecção do sítio cirúrgico (36-45%) e infecção da corrente sanguínea relacionada ao cateter (22-28%), o tempo médio entre o TF e a infecção por VRE foi de 15 dias. Os fatores de risco para colonização por VRE identificados na análise multivariada foram CLIF-SOFA elevado no pré-TF (p < 0.001), ascite refratária no pré-TF (p = 0.03), tempo prolongado de internação no pré-TF (p = 0.005) e reoperação pós-TF (p < 0.001). A presença de doença hepática por HCV foi identificada como fator protetor (p = 0.03). Para infecção por VRE, as variáveis preditoras no modelo final foram colonização por VRE pré-TF (p < 0.001), colonização por VRE pós-TF (p < 0.001), hepatite fulminante (p = 002), reoperação (p < 0.001), retransplante (p < 0.001), sangramento intraoperatório (p = 0.04) e transplante combinado (p = 0.04). A mortalidade em 180 dias após o TF foi de 20%, 27% e 53% para pacientes não colonizados por VRE, pacientes colonizados por VRE, mas não infectados, e pacientes infectados por VRE, respectivamente. A infecção e colonização por VRE foram associadas à mortalidade em 180 dias após o TF. Conclusões: A colonização por VRE antes e após o TF é um dos principais fatores de risco para a ocorrência de infecção por VRE. A infecção por VRE diminui substancialmente a sobrevida dos receptores de TF.

A esporotricose é uma micose subcutânea negligenciada, geralmente adquirida por inoculação traumática de material contaminado, podendo também ser transmitida por arranhões ou mordidas de gatos infectados. Nas últimas décadas, a transmissão zoonótica do Sporothrix brasiliensis tornou-se a principal forma de infecção no Brasil e está associada a apresentações incomuns da doença. Embora a maioria dos casos de esporotricose afete a pele e o tecido subcutâneo, formas disseminadas e extracutâneas são descritas em imunodeprimidos. Raros casos foram descritos em receptores de transplante de órgãos sólidos, a maioria de rim. O presente trabalho relata um caso de esporotricose em um receptor de transplante de fígado. Paciente, sexo feminino, 57 anos com antecedente de transplante de fígado em 2017 por cirrose alcoólica, em uso de everolimo (nível sérico 5,2 ng/mL) e e tacrolimo (nível sérico 3,2 ng/mL), busca serviço por queixa de lesões eritematosas dolorosas difusas com evolução de duas semanas. Paciente morava em uma fazenda no interior de São Paulo com sua família e animais de estimação, incluindo gatos saudáveis, quando evoluiu com placas eritematosas infiltradas, com centro descamativo, em locais não contíguos, especialmente em membros inferiores e dorso. Em investigação, foi realizada biópsia de pele que identificou infiltrado histiocitário difuso com leveduras na coloração Grocott, com posterior crescimento em cultura de Sporothrix brasiliensis, identificado por PCR. Foi iniciado itraconazol oral, porém paciente apresentou resposta insatisfatória após um mês de tratamento, com disseminação das lesões para face. Foi internada para receber anfotericina B lipossomal 3 mg/kg/dia e após 4 semanas foi de alta com isavuconazol oral. Poucos dias após, paciente necessitou de reinternação, tendo sido mantida com anfotericina B lipossomal pela indisponibilidade de isavuconazol para internados. Paciente apresentou recorrência das lesões, optada pela associação de terbinafina, com evolução satisfatória após. Na alta, a paciente permaneceu com terapia combinada de isavuconazol e terbinafina, com melhora clínica e sem toxicidade nos 6 meses posteriores. No contexto de pacientes imunodeprimidos, a esporotricose é uma condição rara associada a formas mais graves de apresentação e desafios diagnósticos e terapêuticos. Relatamos o caso de uma esporotricose cutânea disseminada em receptor de transplante hepático tardio, com resposta insatisfatória à monoterapia com itraconazol.

Summary: The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.

Abstract Background Early intervention to reduce the impact of adverse events (AEs) may improve patients’ quality of life and enable optimal treatment duration. Methods This nationwide, multicenter, prospective, longitudinal, 1-year observational study investigated patients’ self-management of AEs associated with targeted therapy for advanced renal cell carcinoma (RCC) and explored corresponding outcomes, including treatment duration and patient-reported outcomes (PROs). Results We enrolled 77 advanced RCC patients (mean age 62 years) treated with a first targeted therapy. 210 cases of seven AEs of interest (fatigue, hand-foot syndrome, oral mucosal inflammation, diarrhea, gastrointestinal symptoms, hypertension, and anorexia) were observed. Most AEs were mild to moderate. Overall, 63.4% of patients were identified as managing their AEs well, reporting numerically longer treatment duration and significantly higher PRO scores than patients identified as poor managers. Conclusions Longer treatment duration and improved PROs were observed when advanced RCC patients managed targeted therapy-associated AEs well. Repeated education for consolidating AE self-management could be considered to enhance overall treatment outcomes.

177Lu-EDTMP (Ethylenediamine tetramethylene phosphonic acid) is the most used radioactive agent for pain palliation in bone cancer patients. The present study aims to study the impact of relaxin-2 on the 177Lu-EDTMP associated cell toxicity and death in osteosarcoma cells. MG63 and Saos-2 cells were cultured with 177Lu-EDTMP (37 MBq) for 24 h with and without pretreatment of recombinant relaxin 2 (RLXH2) for 12 and 24 h. 177Lu-EDTMP associated cellular deterioration and death was determined by LDH, MTT, and trypan blue dye assays. ELISA-based kit was used to determine apoptotic DNA fragmentation. Western blotting was used to determine expression levels of apoptotic-related signalling pathway proteins like bcl2, poly(ADP-ribose) polymerase (PARP), and MAPK (mitogen-activated protein kinase). Our results found that RLXH2 counters 177Lu-EDTMP associated cellular toxicity. Similarly, RLXH2 was able to counter 177Lu-EDTMP induced cell death in a concentration and time--dependent manner. Furthermore, it was found that RLXH2 treatment prevents apoptosis in 177Lu-EDTMP challenged cells through activation of the notch-1 pathway in a concentration- and time-dependent manner. We reported that RLXH2 significantly declined cellular toxicity and apoptosis associated with 177Lu-EDTMP in MG63 and Saos-2 cells through the notch-1 pathway.

Androgen deprivation therapy (ADT) is a primary treatment for advanced prostate cancer (PCa), but resistance often leads to castration-resistant PCa (CRPC). CRPC remains androgen receptor (AR)-dependent, and AR overexpression causes vulnerability to high doses of androgen in CRPC. Bipolar androgen therapy (BAT) refers to the periodic administration of testosterone, resulting in oscillation between supraphysiologic and near-castrate serum testosterone levels. In this study, we evaluated the efficacy of BAT against CRPC in a preclinical setting. To emulate CRPC characteristics, PCa cell lines (LNCaP, VCaP, and 22Rv1) were cultured in phenol red-free RPMI-1640 medium supplemented with 10% dextran-coated charcoal treated FBS (A− cell line). Cell viability, AR, and AR-V7 expression were evaluated using the Cell Counting Kit-8 and Western blotting. In vivo studies involved 12 castrated NOG mice injected with LNCaP/A− cells, treated with testosterone pellets or controls in 2-week cycles. Tumor sizes were measured post a 6-week treatment cycle. Bicalutamide inhibited PCa cell viability but not in the adapted cell lines. Supraphysiologic androgen levels suppressed AR-expressing PCa cell growth in vitro. In vivo, high AR-expressing LNCaP cells proliferated under castrate conditions, while BAT-treated xenografts exhibited significant growth inhibition with low Ki-67 and mitotic indexes and a high cell death index. This study provides preliminary evidence that BAT is effective for the treatment of CRPC through rapid cycling between supraphysiologic and near-castrate serum testosterone levels, inducing an anti-tumor effect.

Background: We investigated the necessity of multiple core biopsies when performing transperineal template-guided mapping biopsy (TTMB) for patients with large prostates and no suspicious lesions on multiparametric magnetic resonance imaging (mpMRI). Materials and methods: We retrospectively analyzed 304 patients on active surveillance (AS), 212 patients with previously negative transrectal ultrasound-guided biopsy (TRUS-Bx) and 67 biopsy naïve patients who underwent TTMB between May 2017 and December 2020. The number of core biopsies and acute urinary retention (AUR) rates were analyzed in relation to the prostate volume (PV). Cancer detection rate according to the prostate volume and Prostate Imaging-Reporting and Data System (PI-RADS) scores were compared using the Pearson Chi-square test. Results: AUR occurred more frequently in patients with PV over 39 cc (5.5% vs. 24.4%, P

Purpose: To assess the safety and efficacy of gemcitabine and cisplatin as neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive bladder cancer (MIBC). Materials and Methods: Patients with clinical T2-T4aN0M0 MIBC eligible for radical cystectomy and cisplatin-based chemotherapy were treated with gemcitabine 1,000 mg/m2 on days 1, 8 and 15, and cisplatin 70 mg/m2 on day 1 every 28 days for 3 cycles. After clinical re-staging with computed tomography scans and cystoscopy, patients with clinical complete response (CR) were eligible to proceed without cystectomy and receive bladder preservation chemoradiotherapy involving weekly cisplatin 10 mg/m2 and up to 70.2 Gy of radiation. The primary endpoint of the present prospective phase II study was metastasis-free survival (MFS). Results: Between Oct 2017 and Nov 2019, a total of 138 MIBC patients were enrolled and treated with neoadjuvant gemcitabine/cisplatin. Neoadjuvant chemotherapy was well-tolerated, with fatigue, nausea, and pruritus being the most commonly observed adverse events. After completion of planned neoadjuvant chemotherapy, 54 patients with a clinical CR and 10 patients who did not have CR but refused surgery received bladder preservation chemoradiotherapy. With a median follow-up duration of 34 months (95% confidence interval [CI], 32%–36%), the 3-year MFS rate in 64 chemoradiotherapy patients was calculated to be 70% (95% CI, 58%–82%). Conclusions: Neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy based on the clinical CR was feasible and efficacious in the treatment of MIBC.

AbstractPseudouridine (Psi) is one of the most frequent post-transcriptional modification of RNA. Enzymatic Psi modification occurs on rRNA, snRNA, snoRNA, tRNA, and non-coding RNA and has recently been discovered on mRNA. Transcriptome-wide detection of Psi (Psi-seq) has yet to be performed for the widely studied model organism Drosophila melanogasterRluA-2w1118

Microplastics (MPs) in natural environments undergo complex aging processes, changing their interactions with coexisting antibiotics, and posing unpredictable ecological risks. However, the joint toxicity of aged MPs (aMPs) and antibiotics to bacteria, especially at the molecular level, is unclear. In this study, non-thermal plasma technology was used to simultaneously simulate various radical oxidation and physical reactions that occur naturally in the environment, breaking the limitation of simple aging process in laboratory aging technologies. After aging, we investigated the altered properties of aMPs, their interactions with ciprofloxacin (CIP), and the molecular responses of E. coli exposed to pristine MPs (13.5 mg/L), aMPs (13.5 mg/L), and CIP (2 μg/L) individually or simultaneously. aMPs bound far more CIP to their surfaces than pristine MPs, especially in freshwater ecosystems. Notably, the growth of E. coli exposed to aMPs alone was inhibited, whereas pristine MPs exposure didn’t affect the growth of E. coli. Moreover, the most differentially expressed genes in E. coli were induced by the coexposure of aMPs and CIP. Although E. coli depended on chemotaxis to improve its flagellar rotation and escaped the stress of pollutants, the coexposure of aMPs and CIP still caused cell membrane damage, oxidative stress, obstruction of DNA replication, and osmotic imbalance in E. coli. This study filled the knowledge gap between the toxicity of aMPs and pristine MPs coexisting with antibiotics at the transcription level, helping in the accurate assessment of the potential risks of MPs to the environment.