Factors improving the diagnostic performance of targeted biopsies in the diagnosis of significant prostate cancer.

INTRODUCTION: MRI-targeted biopsy improves detection of significant prostate cancer (csPCa) and grade prediction. The aim of this study was to identify factors improving the diagnostic performance of targeted biopsies (TB) in detecting csPCa. METHODS: Retrospective monocenter study of patients who underwent a radical prostatectomy (RP) for prostate cancer (PCa) and diagnosed by transrectal combined biopsies (CB) with elastic MRI/ultrasound fusion. We evaluate the diagnostic performance of standardized (SB), targeted (TB) and CB for csPCa, including sensitivity, specificity, and ROC curve. Univariables and logistic regression analysis were performed to analyze factors improving the diagnostic performance of TB in detecting csPCa on final histopathology. RESULTS: Two hundred four men underwent RP after CB with suspicious lesions (PI-RADS≥3) on MRI were included. csPCa was significantly associated with prostate volume, PSA density, a lesion index in the peripheral zone, with a diameter ≥ 7mm. TB were positives for 174 patients (85.3%). Prostate volume, PSA density, radiological coherence, previous biopsies, and a number of biopsies ≥ 3 were significantly associated with a cancer detection. csPCa on TB, a prostate volume <60ml, an index lesion ≥ 7mm and a peripheral zone location were significant predictive factors for diagnostic of csPCa on final histopathology. Area under the ROC curve values, sensitivities and specificities of CB and TB (adjusted model) were 0.78 [0.72-0.84], 77.3 [70.3-83.4], 78.1 [60-90.7], and 0.85 [0.79-0.90], 83.7 [77.3-88.9] and 75 [56.6-88.5] respectively. CONCLUSION: This study confirms the benefit of CB and suggests that TB for a selected population could be as effective as CB.

Super-relaxed myosins contribute to respiratory muscle hibernation in mechanically ventilated patients.

Patients receiving mechanical ventilation in the intensive care unit (ICU) frequently develop contractile weakness of the diaphragm. Consequently, they may experience difficulty weaning from mechanical ventilation, which increases mortality and poses a high economic burden. Because of a lack of knowledge regarding the molecular changes in the diaphragm, no treatment is currently available to improve diaphragm contractility. We compared diaphragm biopsies from ventilated ICU patients (N = 54) to those of non-ICU patients undergoing thoracic surgery (N = 27). By integrating data from myofiber force measurements, x-ray diffraction experiments, and biochemical assays with clinical data, we found that in myofibers isolated from the diaphragm of ventilated ICU patients, myosin is trapped in an energy-sparing, super-relaxed state, which impairs the binding of myosin to actin during diaphragm contraction. Studies on quadriceps biopsies of ICU patients and on the diaphragm of previously healthy mechanically ventilated rats suggested that the super-relaxed myosins are specific to the diaphragm and not a result of critical illness. Exposing slow- and fast-twitch myofibers isolated from the diaphragm biopsies to small-molecule compounds activating troponin restored contractile force in vitro. These findings support the continued development of drugs that target sarcomere proteins to increase the calcium sensitivity of myofibers for the treatment of ICU-acquired diaphragm weakness.

Human ARMC6 binds in vitro to both cancer genes and telomeric RNA, favoring G-quadruplex structure recognition.

Armadillo repeat-containing proteins (ARMCs) are a large family found throughout eukaryotes, which play prominent roles in cell adhesion, signaling and cytoskeletal regulation. The ARMC6 protein is highly conserved in primates, including humans, but to date does not have a clear function beyond initial hints of a link to cancer and telomerase activity. We report here in vitro experiments showing ARMC6 binding to DNA promoter sequences from several cancer-related genes (e.g., EGFR, VEGF and c-MYC), and also to the telomeric RNA repeat (TERRA). ARMC6 binding activity appears to recognize G-quadruplex motifs, which are being increasingly implicated as structure-based protein binding sites in chromosome maintenance and repair. In vivo investigation of ARMC6 function revealed that when this protein is overexpressed in human cell lines, there is different expression of genes connected with oncogenic pathways and those implicated in downstream non-canonical telomerase pathways (e.g., VEGF, hTERT, c-MYC, ESM1, MMP3). ARMC6 is already known to interact with human shelterin protein TRF2 and telomerase. The protein binds G-quadruplex structures and does so preferentially to RNA over DNA. As such, this protein may be an example of how a non-canonical nucleic acid structural motif allows mediation between gene regulation and telomeric chromatin rearrangement pathways.

Loss of spontaneous vasomotion precedes impaired cerebrovascular reactivity and microbleeds in a mouse model of cerebral amyloid angiopathy.

Background: Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-ß accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral hemorrhage and an important contributor to age-related cognitive decline. Recent work has suggested that vascular dysfunction may precede symptomatic stages of CAA, and that spontaneous slow oscillations in arteriolar diameter (termed vasomotion), important for amyloid-ß clearance, may be impaired in CAA. Methods: To systematically study the progression of vascular dysfunction in CAA, we used the APP23 mouse model of amyloidosis, which is known to develop spontaneous cerebral microbleeds mimicking human CAA. Using in vivo 2-photon microscopy, we longitudinally imaged unanesthetized APP23 transgenic mice and wildtype littermates from 7 to 14 months of age, tracking amyloid-ß accumulation and vasomotion in individual pial arterioles over time. MRI was used in separate groups of 12-, 18-, and 24-month-old APP23 transgenic mice and wildtype littermates to detect microbleeds and to assess cerebral blood flow and cerebrovascular reactivity with pseudo-continuous arterial spin labeling. Results: We observed a significant decline in vasomotion with age in APP23 mice, while vasomotion remained unchanged in wildtype mice with age. This decline corresponded in timing to initial vascular amyloid-ß deposition (∼8-10 months of age), although was more strongly correlated with age than with vascular amyloid-ß burden in individual arterioles. Declines in vasomotion preceded the development of MRI-visible microbleeds and the loss of smooth muscle actin in arterioles, both of which were observed in APP23 mice by 18 months of age. Additionally, evoked cerebrovascular reactivity was intact in APP23 mice at 12 months of age, but significantly lower in APP23 mice by 24 months of age. Conclusions: Our findings suggest that a decline in spontaneous vasomotion is an early, potentially pre-symptomatic, manifestation of CAA and vascular dysfunction, and a possible future treatment target.

Sludge degradation, nutrient removal and reduction of greenhouse gas emission by a Chironomus-Azolla wastewater treatment cascade.

Wastewater treatment plants (WWTPs) are a point source of nutrients, emit greenhouse gases (GHGs), and produce large volumes of excess sludge. The use of aquatic organisms may be an alternative to the technical post-treatment of WWTP effluent, as they play an important role in nutrient dynamics and carbon balance in natural ecosystems. The aim of this study was therefore to assess the performance of an experimental wastewater-treatment cascade of bioturbating macroinvertebrates and floating plants in terms of sludge degradation, nutrient removal and lowering GHG emission. To this end, a full-factorial experiment was designed, using a recirculating cascade with a WWTP sludge compartment with or without bioturbating Chironomus riparius larvae, and an effluent container with or without the floating plant Azolla filiculoides, resulting in four treatments. To calculate the nitrogen (N), phosphorus (P) and carbon (C) mass balance of this system, the N, P and C concentrations in the effluent, biomass production, and sludge degradation, as well as the N, P and C content of all compartments in the cascade were measured during the 26-day experiment. The presence of Chironomus led to an increased sludge degradation of 44% compared to 25% in the control, a 1.4 times decreased transport of P from the sludge and a 2.4 times increased transport of N out of the sludge, either into Chironomus biomass or into the water column. Furthermore, Chironomus activity decreased methane emissions by 92%. The presence of Azolla resulted in a 15% lower P concentration in the effluent than in the control treatment, and a CO2 uptake of 1.13 kg ha-1 day-1. These additive effects of Chironomus and Azolla resulted in an almost two times higher sludge degradation, and an almost two times lower P concentration in the effluent. This is the first study that shows that a bio-based cascade can strongly reduce GHG and P emissions simultaneously during the combined polishing of wastewater sludge and effluent, benefitting from the additive effects of the presence of both macrophytes and invertebrates. In addition to the microbial based treatment steps already employed on WWTPs, the integration of higher organisms in the treatment process expands the WWTP based ecosystem and allows for the inclusion of macroinvertebrate and macrophyte mediated processes. Applying macroinvertebrate-plant cascades may therefore be a promising tool to tackle the present and future challenges of WWTPs.

Laparoscopic but not open surgical skills can be transferred to robot-assisted surgery: A systematic review and meta-analysis.

BACKGROUND: With an increase in robot-assisted surgery across all specialties, adequate training and credentialing strategies need to be identified to ensure patients safety. The meta-analysis assesses the transferability of technical surgical skills between laparoscopic surgery, open surgery, and robot-assisted surgery. DESIGN: A systematic search was conducted in Medline, Cochrane Central Register of Controlled Trials, and Web of Science. Outcomes were categorized into time, process, product, and composite outcome measures and pooled separately using Hedges'g (standardized mean difference [SMD]). Subgroup analyses were performed to assess the effect of study design, virtual reality platforms and task difficulty. RESULTS: Out of 14,120 screened studies, 30 were included in the qualitative synthesis and 26 in the quantitative synthesis. Technical surgical skill transfer was demonstrated from laparoscopic to robot-assisted surgery (composite: SMD 0.40, 95%-confidence interval [CI] [0.19; 0.62], time: SMD 0.62, CI [0.33; 0.91]) and vice versa (composite: SMD 0.66, CI [0.33; 0.99], time [basic skills]: SMD 0.36, CI [0.01; 0.72]). No skill transfer was seen from open to robot-assisted surgery with limited available data. CONCLUSION: Technical surgical skills can be transferred from laparoscopic to robot-assisted surgery and vice versa. Robot-assisted and laparoscopic surgical skills training and credentialing should not be regarded separately, but a reasonable combination could shorten overall training times and increase efficiency. Previous experience in open surgery should not be considered as an imperative prerequisite for training in robot-assisted surgery. Recommendations for studies assessing skill transfer are proposed to increase comparability and significance of future studies. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42018104507.

Addition of iron does not ameliorate sulfide toxicity by sargassum influx to mangroves but dampens methane and nitrous oxide emissions.

Sargassum spp. strandings in the tropical Atlantic harm local ecosystems due to toxic sulfide levels. We conducted a mesocosm experiment to test the efficacy of iron(III) (hydr)oxides in (a) mitigating sulfide toxicity in mangroves resulting from Sargassum and (b) reducing potentially enhanced greenhouse gas emissions. Our results show that iron addition failed to prevent mangrove mortality caused by highly toxic sulfide concentrations, which reached up to 15,000 µmol l-1 in 14 days; timely removal may potentially prevent mangrove death. Sargassum-impacted mesocosms significantly increased methane, nitrous oxide, and carbon dioxide emissions, producing approximately 1 g CO2-equivalents m-2 h-1 during daylight hours, thereby shifting mangroves from sinks to sources of greenhouse gasses. However, iron addition decreased methane emissions by 62 % and nitrous oxide emissions by 57 %. This research reveals that Sargassum strandings have multiple adverse effects related to chemical and ecological dynamics in mangrove ecosystems, including greenhouse gas emissions.

The PAncreatic Surgery Composite Endpoint PACE - Development and Validation of a Clinically Relevant Endpoint Requiring Lower Sample Sizes.

OBJECTIVE: To provide a composite endpoint in pancreatic surgery. SUMMARY BACKGROUND DATA: Single endpoints in prospective and randomized studies have become impractical due to their low frequency and the marginal benefit of new interventions. METHODS: Data from prospective studies were used to develop (n=1273) and validate (n=544) a composite endpoint based on postoperative pancreatic fistula, post-pancreatectomy hemorrhage as well as reoperation and reinterventions. All patients had pancreatectomies of different extents. The association of the developed PAncreatic surgery Composite Endpoint (PACE) with prolonged length of hospital stay (LOS) >75th percentile and mortality was assessed. A single-institution database was used for external validation (n = 2666). Sample size calculations were made for single outcomes and the composite endpoint. RESULTS: In the internal validation cohort, the PACE demonstrated an AUC of 78.0%, a sensitivity of 90.4% and a specificity of 67.6% in predicting a prolonged LOS. In the external cohort, the AUC was 76.9%, the sensitivity 73.8% and the specificity 80.1%. The 90-day mortality rate was significantly different for patients with a positive versus a negative PACE both in the development and internal validation cohort (5.1% vs 0.9%; P< 0.001), as well as in the external validation cohort (8.5% vs 1.2%, P< 0.001). The PACE enabled sample size reductions of up to 80.5% compared to single outcomes. CONCLUSION: The PACE performed well in predicting prolonged hospital stays and can be used as a standardized and clinically relevant endpoint for future prospective trials enabling lower sample sizes and therefore improved feasibility compared to single outcome parameters.

Polishing wastewater effluent using plants: floating plants perform better than submerged plants in both nutrient removal and reduction of greenhouse gas emission.

While research on aquatic plants used in treatment wetlands is abundant, little is known about the use of plants in hydroponic ecological wastewater treatment, and its simultaneous effect on greenhouse gas (GHG) emissions. Here, we assess the effectiveness of floating and submerged plants in removing nutrients and preventing GHG emissions from wastewater effluent. We grew two species of floating plants, Azolla filiculoides and Lemna minor, and two species of submerged plants, Ceratophyllum demersum and Callitriche platycarpa, on a batch of domestic wastewater effluent without any solid substrate. In these systems, we monitored nitrogen and phosphorus removal and fluxes of CO2, CH4 and N2O, for 2 weeks. In general, floating plants produced the most biomass, whereas submerged plants were rapidly overgrown by filamentous algae. Floating plants removed nutrients most efficiently; both floating species removed 100% of the phosphate while Lemna also removed 97-100% of the inorganic nitrogen, as opposed to a removal of 81-88% in submerged plants with algae treatments. Moreover, aquaria covered by floating plants had roughly three times higher GHG uptake than the treatments with submerged plants or controls without plants. Thus, effluent polishing by floating plants can be a promising avenue for climate-smart wastewater polishing.

[Quality of healthcare in oncological patients from health personnel's perspective]. / Calidad de la atención en pacientes oncológicos desde la perspectiva del personal de salud.

INTRODUCTION: The quality of care in health institutions is a constant challenge, mainly in oncology. The literature shows it has partially evaluated in contrast to it proposed by Donabedian; in addition, health personnel's perspective, who has direct contact with the patient, knows and executes the care process, has not been considered. The objective of the present study was to establish a framework to evaluate the quality of healthcare provided to patients with colorectal or ovarian cancer from health personnel's perspective. MATERIAL AND METHODS: Cross-sectional study that included health personnel belonging to nine services of a cancer hospital. A questionnaire was applied to evaluate the quality of healthcare through amenities, the interpersonal and scientific-technical dimension (Donabedian's model). The variables were standardized, compliance with them among services was compared using non-parametric tests (Kruskal-Wallis test and Mann-Whitney U test), and 40 indicators were evaluated. RESULTS: Health personnel's 181 members participated, the evaluated oncology hospital presented regular compliance to the quality of healthcare (bad ≤82, regular 83-109, good ≥110). When comparing this in the nine services, differences were detected between surgery and radiotherapy (higher compliance scores, 132 and 126 respectively) versus the other services P<.05. Both services had more than 25 indicators with compliance ≥80%. CONCLUSIONS: It is shown that the established framework is useful for evaluating the quality of healthcare from health personnel's perspective (an approach not used so far for this type of evaluation), by detecting differences in its compliance, specific problems and its causes by service.

Reduced excitatory neuron activity and interneuron-type-specific deficits in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive decline. These impairments correlate with early alterations in neuronal network activity in AD patients. Disruptions in the activity of individual neurons have been reported in mouse models of amyloidosis. However, the impact of amyloid pathology on the spontaneous activity of distinct neuronal types remains unexplored in vivo. Here we use in vivo calcium imaging with multiphoton microscopy to monitor and compare the activity of excitatory and two types of inhibitory interneurons in the cortices of APP/PS1 and control mice under isoflurane anesthesia. We also determine the relationship between amyloid accumulation and the deficits in spontaneous activity in APP/PS1 mice. We show that somatostatin-expressing (SOM) interneurons are hyperactive, while parvalbumin-expressing interneurons are hypoactive in APP/PS1 mice. Only SOM interneuron hyperactivity correlated with proximity to amyloid plaque. These inhibitory deficits were accompanied by decreased excitatory neuron activity in APP/PS1 mice. Our study identifies cell-specific neuronal firing deficits in APP/PS1 mice driven by amyloid pathology. These findings highlight the importance of addressing the complexity of neuron-specific deficits to ameliorate circuit dysfunction in Alzheimer's disease.

French AFU Cancer Committee Guidelines - Update 2022-2024: Non-muscle-invasive bladder cancer (NMIBC).

OBJECTIVE: To update the ccAFU recommendations for the management of bladder tumours that do not infiltrate the bladder muscle (NBMIC). METHODS: A systematic review (Medline) of the literature from 2020 to 2022 was performed, taking account of the diagnosis, treatment options and surveillance of NMIBC, while evaluating the references with their levels of evidence. RESULTS: The diagnosis of NMIBC (Ta, T1, CIS) is made after complete full-thickness tumour resection. The use of bladder fluorescence and the indication of a second look (4-6 weeks) help to improve the initial diagnosis. The EORTC score is used to assess the risk of recurrence and/or tumour progression. Through the stratification of patients in low, intermediate and high-risk categories, adjuvant treatment can be proposed: intravesical chemotherapy (immediate postoperative, initiation regimen) or BCG (initiation and maintenance regimen) instillations, or even the indication of cystectomy for BCG-resistant patients. CONCLUSION: Updating the ccAFU recommendations should contribute to improving patient management, as well as the diagnosis and treatment of NMIBC.

French AFU Cancer Committee Guidelines - Update 2022-2024: Muscle-Invasive Bladder Cancer (MIBC).

OBJECTIVE: To update the CCAFU recommendations for the management of muscle invasive bladder carcinoma (MIBC). METHODS: A systematic review (Medline) of the literature from 2020 to 2022 was performed taking account of the diagnosis, treatment options and surveillance of NMIBC and MIBC, while evaluating the references with their levels of evidence. RESULTS: MIBC is diagnosed after the most complete tumour resection possible. MIBC grading is based on CTU along with chest CT. Multiparametric pelvic MRI could be an alternative. Cystectomy with extensive lymphadenectomy is the gold standard treatment for non-metastatic MIBC. It should be preceded by platinum-based neoadjuvant chemotherapy in patients in good general health with satisfactory renal function. Enterocystoplasty is proposed in men and women in the absence of contraindications and when the urethral resection is negative on extemporaneous examination. Otherwise, transileal cutaneous ureterostomy is the recommended method of urinary diversion. Inclusion of all patients in an ERAS (Enhanced Recovery After Surgery) protocol is recommended. For metastatic MIBC, first line treatment with platinum-based chemotherapy (GC or MVAC) is recommended, if general health (PS>1) and renal function (clearance>60mL/min) so allow (only 50% of the cases). Pembrolizumab immunotherapy has demonstrated an overall survival benefit in second-line treatment. CONCLUSION: Updating the ccAFU recommendations should contribute to improving patient management, as well as the diagnosis and decision-making concerning MIBC treatment.

French AFU Cancer Committee Guidelines - Update 2022-2024: Upper urinary tract urothelial cancer (UTUC).

INTRODUCTION: The aim was to propose an update of the French Urology Association Cancer Committee (ccAFU) Recommendations on the management of upper urinary tract urothelial carcinomas (UUT-UC). METHODS: A systematic Medline search was performed between 2020 and 2022, taking account of the diagnosis, treatment options and follow-up of UUT-UC, while evaluating the references with their levels of evidence. RESULTS: The diagnosis of this rare pathology is based on CTU acquisition during excretion and flexible ureterorenoscopy with histological biopsies. Radical nephroureterectomy (RNU) remains the gold standard for surgical treatment. Nevertheless conservative treatment can be discussed for low risk lesions: tumour of low-grade, with no infiltration on imaging, unifocal<2cm, eligible for full treatment therefore requiring close endoscopic surveillance by flexible ureteroscopy in compliant patients. After RNU, postoperative instillation of chemotherapy is recommended to reduce the risk of recurrence in the bladder. Adjuvant chemotherapy has shown clinical benefits compared to surveillance after RNU for tumours (pT2-T4 N0-3 M0). CONCLUSION: These updated recommendations should contribute to improving not only patients' level of care, but also the diagnosis and decision-making concerning treatment for UUT-UC.

Temperature response of aquatic greenhouse gas emissions differs between dominant plant types.

Greenhouse gas (GHG) emissions from small inland waters are disproportionately large. Climate warming is expected to favor dominance of algae and free-floating plants at the expense of submerged plants. Through different routes these functional plant types may have far-reaching impacts on freshwater GHG emissions in future warmer waters, which are yet unknown. We conducted a 1,000 L mesocosm experiment testing the effects of plant type and warming on GHG emissions from temperate inland waters dominated by either algae, free-floating or submerged plants in controls and warmed (+4 °C) treatments for one year each. Our results show that the effect of experimental warming on GHG fluxes differs between dominance of different functional plant types, mainly by modulating methane ebullition, an often-dominant GHG emission pathway. Specifically, we demonstrate that the response to experimental warming was strongest for free-floating and lowest for submerged plant-dominated systems. Importantly, our results suggest that anticipated shifts in plant type from submerged plants to a dominance of algae or free-floating plants with warming may increase total GHG emissions from shallow waters. This, together with a warming-induced emission response, represents a so far overlooked positive climate feedback. Management strategies aimed at favouring submerged plant dominance may thus substantially mitigate GHG emissions.

Predicted COVID-19 molecular effects on endometrium reveal key dysregulated genes and functions.

COVID-19 exerts systemic effects that can compromise various organs and systems. Although retrospective and in silico studies and prospective preliminary analysis have assessed the possibility of direct infection of the endometrium, there is a lack of in-depth and prospective studies on the impact of systemic disease on key endometrial genes and functions across the menstrual cycle and window of implantation. Gene expression data have been obtained from (i) healthy secretory endometrium collected from 42 women without endometrial pathologies and (ii) nasopharyngeal swabs from 231 women with COVID-19 and 30 negative controls. To predict how COVID-19-related gene expression changes impact key endometrial genes and functions, an in silico model was developed by integrating the endometrial and COVID-19 datasets in an affected mid-secretory endometrium gene co-expression network. An endometrial validation set comprising 16 women (8 confirmed to have COVID-19 and 8 negative test controls) was prospectively collected to validate the expression of key genes. We predicted that five genes important for embryo implantation were affected by COVID-19 (downregulation of COBL, GPX3 and SOCS3, and upregulation of DOCK2 and SLC2A3). We experimentally validated these genes in COVID-19 patients using endometrial biopsies during the secretory phase of the menstrual cycle. The results generally support the in silico model predictions, suggesting that the transcriptomic landscape changes mediated by COVID-19 affect endometrial receptivity genes and key processes necessary for fertility, such as immune system function, protection against oxidative damage and development vital for embryo implantation and early development.

SMAD4 Loss Induces c-MYC-Mediated NLE1 Upregulation to Support Protein Biosynthesis, Colorectal Cancer Growth, and Metastasis.

Growth and metastasis of colorectal cancer is closely connected to the biosynthetic capacity of tumor cells, and colorectal cancer stem cells that reside at the top of the intratumoral hierarchy are especially dependent on this feature. By performing disease modeling on patient-derived tumor organoids, we found that elevated expression of the ribosome biogenesis factor NLE1 occurs upon SMAD4 loss in TGFß1-exposed colorectal cancer organoids. TGFß signaling-mediated downregulation of NLE1 was prevented by ectopic expression of c-MYC, which occupied an E-box-containing region within the NLE1 promoter. Elevated levels of NLE1 were found in colorectal cancer cohorts compared with normal tissues and in colorectal cancer subtypes characterized by Wnt/MYC and intestinal stem cell gene expression. In colorectal cancer cells and organoids, NLE1 was limiting for de novo protein biosynthesis. Upon NLE1 ablation, colorectal cancer cell lines activated p38/MAPK signaling, accumulated p62- and LC3-positive structures indicative of impaired autophagy, and displayed more reactive oxygen species. Phenotypically, knockout of NLE1 inhibit.ed proliferation, migration and invasion, clonogenicity, and anchorage-independent growth. NLE1 loss also increased the fraction of apoptotic tumor cells, and deletion of TP53 further sensitized NLE1-deficient colorectal cancer cells to apoptosis. In an endoscopy-guided orthotopic mouse transplantation model, ablation of NLE1 impaired tumor growth in the colon and reduced primary tumor-derived liver metastasis. In patients with colorectal cancer, NLE1 mRNA levels predicted overall and relapse-free survival. Taken together, these data reveal a critical role of NLE1 in colorectal cancer growth and progression and suggest that NLE1 represents a potential therapeutic target in colorectal cancer patients. SIGNIFICANCE: NLE1 limits de novo protein biosynthesis and the tumorigenic potential of advanced colorectal cancer cells, suggesting NLE1 could be targeted to improve the treatment of metastatic colorectal cancer.

Reaction of Thiosulfate Dehydrogenase with a Substrate Mimic Induces Dissociation of the Cysteine Heme Ligand Giving Insights into the Mechanism of Oxidative Catalysis.

Thiosulfate dehydrogenases are bacterial cytochromes that contribute to the oxidation of inorganic sulfur. The active sites of these enzymes contain low-spin c-type heme with Cys-/His axial ligation. However, the reduction potentials of these hemes are several hundred mV more negative than that of the thiosulfate/tetrathionate couple (Em, +198 mV), making it difficult to rationalize the thiosulfate oxidizing capability. Here, we describe the reaction of Campylobacter jejuni thiosulfate dehydrogenase (TsdA) with sulfite, an analogue of thiosulfate. The reaction leads to stoichiometric conversion of the active site Cys to cysteinyl sulfonate (Cα-CH2-S-SO3-) such that the protein exists in a form closely resembling a proposed intermediate in the pathway for thiosulfate oxidation that carries a cysteinyl thiosulfate (Cα-CH2-S-SSO3-). The active site heme in the stable sulfonated protein displays an Em approximately 200 mV more positive than the Cys-/His-ligated state. This can explain the thiosulfate oxidizing activity of the enzyme and allows us to propose a catalytic mechanism for thiosulfate oxidation. Substrate-driven release of the Cys heme ligand allows that side chain to provide the site of substrate binding and redox transformation; the neighboring heme then simply provides a site for electron relay to an appropriate partner. This chemistry is distinct from that displayed by the Cys-ligated hemes found in gas-sensing hemoproteins and in enzymes such as the cytochromes P450. Thus, a further class of thiolate-ligated hemes is proposed, as exemplified by the TsdA centers that have evolved to catalyze the controlled redox transformations of inorganic oxo anions of sulfur.

[Guidelines from the cancer committee of the French Association of Urology (CC-AFU) for adequate intravesical instillations of Mitomycin C, Epirubicin, and BCG for non-muscle invasive bladder cancer]. / Recommandations du Comité de cancérologie de l'Association Française d'Urologie (CC-AFU) pour la bonne pratique des instillations intravésicales de mitomycine C, d'épirubicine et de BCG pour le traitement des tumeurs de la vessie n'infiltrant pas le muscle (TVNIM).

INTRODUCTION: Intravesical instillations of mitomycin C, epirubicin and BCG are considered as the standard treatment for most patients diagnosed with non-muscle invasive bladder cancer. These guidelines aim to optimize the adjuvant intravesical treatment in order to increase the efficacy and lower the morbidity associated with its administration. METHODS: We conducted a daily practice survey, an online search of available national regulation recommendations and of published guidelines. A bibliography search in French and English using Medline® and Embase® with the keywords "BCG"; "mitomycin C"; "epirubicin"; "bladder"; "complication"; "toxicity"; "adverse reaction"; "prevention" and "treatment" was performed November 2021. RESULTS: Patient information should be given by the attending physician before the first intravesical instillation. A medical exam to look for specific contraindications is also mandatory to select adequate candidates. Intravesical instillations should be delivered in health-care centers where urologic endoscopic procedures are routinely performed. Attending urologist or specialized nurse should check for negative pretreatment urine test. Intravesical instillation can only be delivered after bladder catheter has been inserted in the bladder without any injury of the lower urinary tract. The pharmaceutical agent should be kept in the bladder for two hours. Finally, voiding within the 6hours following intravesical instillations should be done in the sitting position and the patient should drink at least 2 liters of water per day for 2 days. CONCLUSION: The delivery of intravesical instillations of mitomycin C, epirubicin and BCG should follow a standardized procedure for better efficacy and lower morbidity.

[Guidelines from the cancer (CC-AFU) and infection disease (CI-AFU) committees of the French Association of Urology for the management of adverse events and complications of BCG]. / Recommandations des Comités de cancérologie (CC-AFU) et d'infectiologie (CI-AFU) de l'Association française d'urologie pour la prise en charge effets indésirables et complications du BCG.

INTRODUCTION: Intravesical instillations of BCG are recommended for the treatment of high-risk non-muscle-invasive bladder cancer. However, their prolonged use remains limited by the associated potentially serious adverse effects or complications. The purpose of this article was to provide updated recommendations for the diagnosis and management of adverse events (AEs) or complications of intravesical BCG instillations. MATERIALS AND METHODS: Review of the literature in Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using the following MeSH keywords or a combination of these keywords: "bladder," "BCG," "complication," "toxicity," "adverse events," "prevention," and "treatment". RESULTS: AEs or complications of BCG included genitourinary and systemic symptoms. The most common complications (cystitis, moderate fever) should be treated symptomatically and may require adjustment to allow patients to have the most complete BCG treatment possible. Serious complications are rare but must be identified promptly because of the life-threatening nature of the disease. Their management is based on the combination of anti-tuberculosis treatments, anti-inflammatory drugs and the definitive discontinuation of BCG. CONCLUSION: The management of BCG AEs requires early identification, rational and effective treatment if necessary, and discussion of the continuation of treatment for each situation.