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The Menez Gwen, Lucky Strike, Rainbow, TAG (Transatlantic Geotraverse) and Snake Pit hydrothermal vent fields on the Mid-Atlantic Ridge were revisited and resampled for geochemical investigation during the BIOBAZ 2013 and BICOSE 2014 research cruises. Geochemical analysis of the major and minor elements of the hydrothermal fluid and concentrations of gases extends and complements the existing dataset. Our results are consistent with values previously reported and fall within the range of the analytical error. This indicates that the hydrothermal vent field system has remained relatively stable over the last few decades. However, some differences were observed and (i) suggested a recent eruption at Menez Gwen, (ii) supported the occurrence of low-temperature serpentinisation in this same site, (iii) supported a change in the reaction zone or axial magma chamber (AMC) depth at Lucky Strike, (iv) an increase of the temperature at depth at Snake Pit and (v) supported the hypothesis of large seawater entrainment through the TAG hydrothermal mound. Besides, it is possible that small temporal and spatial scale processes may control a significant part of the geochemistry, owing to the fact that some variations in the data could not be interpreted. However, our investigation of the organic geochemistry represents a pioneering addition to research for Menez Gwen, Snake Pit and TAG and a much more comprehensive study for Lucky Strike and Rainbow. Concentrations for a wide variety of semi volatile organic compounds (SVOCs) were obtained for the first time at all sites. Our results showed that a great part of the total organic carbon (TOC) could not be allocated by the total SVOCs studied here, suggesting that other processes/sources of organic carbon remain to be identified. The TAG organic geochemistry seemed entirely based on thermogenic processes whereas mixed processes may occur at the other vent field. The presence of n -alkanes suggested the contribution of a low-temperature fluid at all sites. An additional high-temperature organic matter degradation component was likely present at Menez Gwen and Lucky Strike. Our results also indicated that both abiogenic and biogenic processes produced organic compounds. Therefore, we suggest that a portion of the fatty acids at Menez Gwen and polyaromatic hydrocarbons (PAHs) at Rainbow may be derived from abiogenic processes, whereas biogenic processes could be responsible for the presence of n -fatty acids (n -FAs) at Lucky Strike and Rainbow. Moreover, organic geochemistry data appeared to be helpful in understanding some inorganic processes. • geochemistry of 5 hydrothermal vent field in the MAR appear relatively stable over decades • small changes in the geochemistry may need more attention and research as previously thought • a recent eruption may have occured at Menez Gwen • Low-T serpentinisation may occur at Menez Gwen • First report of concentrations of a large set of semi volatile organic coumpounds in hydrothermal fluids from the Atlantic • Organic geochemistry showed a low-T fluid contribution at all sites [ABSTRACT FROM AUTHOR]

The current systems of risk grouping in pediatric acute lymphoblastic leukemia (ALL) fail to predict therapeutic success in 10-35% of patients. To identify better predictive markers of clinical behavior in ALL, we have developed an integrated approach for gene expression profiling that couples suppression subtractive hybridization, concatenated cDNA sequencing, and reverse transcriptase real-time quantitative PCR. Using this approach, a total of 600 differentially expressed genes were identified between t(4;11) ALL and pre-B ALL with no determinant chromosomal translocation. The expression of 67 genes was analyzed in different cytogenetic ALL subgroups and B lymphocytes isolated from healthy donors. Three genes, BACH1, TP53BPL, and H2B/S, were consistently expressed as a significant cluster associated with the low-risk ALL subgroups. A total of 42 genes were differentially expressed in ALL vs normal B lymphocytes, with no specific association with any particular ALL subgroups. The remaining 22 genes were part of a specific expression profile associated with the hyperdiploid, t(12;21), or t(4;11) subgroups. Using an unsupervised hierarchical cluster analysis, the discriminating power of these specific expression profiles allowed the clustering of patients according to their subgroups. These genes could help to understand the difference in treatment response and become therapeutical targets to improve ALL clinical outcomes.Leukemia (2003) 17, 1891-1900. doi:10.1038/sj.leu.2403073 [ABSTRACT FROM AUTHOR]

• Shrubs growth rings are relevant indicators of the response of alpine ecosystem to global warming. • At the high-elevation site, our results demonstrate a negative effect of snow cover duration. • At lower elevations, late frost exposure is shown to lead to growth reduction. • Global warming induced a divergence in the growth response of a dominant shrub species to climate. Enhanced shrub growth in a warming alpine climate has potential far-reaching implications, including soil nutrient cycling, carbon storage, or water and surface energy exchanges. Growth ring analysis can yield mid- to long-term, annually resolved records of shrub growth, and thereby offer valuable insights into how growth is driven by interannual climate variability. In the European Alps, dendroecological approaches have shown that dwarf shrub productivity is influenced by interannual variations of growing season temperature but results also point to a negative effect of winter precipitation on radial growth. However, as past work lacked snow cover data, links between snow cover duration, growing season length, energy availability and inter-annual shrub growth remain poorly understood. In this paper, we combined multi-decadal shrub-ring series from 49 individuals sampled at three sites along a 600-m elevational gradient in the Taillefer massif, located in the French Alps to assess growth sensitivity of long-lived and widespread Rhododendron ferrugineum shrubs to both snow cover dynamics and temperature changes. To this end, we computed structural equation models to track the response of shrub radial growth to extending growing season at 1800, 2000 and 2400 m above sea level and for two time periods (i.e. 1959–1988 and 1989–2016). The second period is marked by a significant advance in snow melt-out resulting in a regime shift highlighted at the end of the 1980s by a breakpoint analysis. At the high-elevation site, our results demonstrate a positive effect of increasing growing season length on shrub growth, which is strongly dependent on snowpack depth and snow cover duration. Conversely, at lower elevations, earlier melt-out dates and associated late frost exposure are shown to lead to radial growth reduction. Moreover, the climate signal in ring-width chronologies of R. ferrugineum portrays a weakening since 1988 – similar to a phenomenon observed in series from circumpolar and alpine tree-ring sites and referred to as "divergence". By analyzing long-term records of radial growth along an elevation gradient, our work provides novel insights into the complex responses of shrub growth to climate change in alpine environments. This paper demonstrates that R. ferrugineum , as a dominant alpine shrub species, behave as an ecological indicator of the response of alpine ecosystem to global warming. [ABSTRACT FROM AUTHOR]

The role of the nuclear degrees of freedom in nonlinear two-photon single ionization of H2 molecules interacting with short and intense vacuum ultraviolet pulses is investigated, both experimentally and theoretically, by selecting single resonant vibronic intermediate neutral states. This high selectivity relies on the narrow bandwidth and tunability of the pulses generated at the FERMI free-electron laser. A sustained enhancement of dissociative ionization, which even exceeds nondissociative ionization, is observed and controlled as one selects progressively higher vibronic states. With the help of ab initio calculations for increasing pulse durations, the photoelectron and ion energy spectra obtained with velocity map imaging allow us to identify new photoionization pathways. With pulses of the order of 100 fs, the experiment probes a timescale that lies between that of ultrafast dynamical processes and that of steady state excitations. [ABSTRACT FROM AUTHOR]

We demonstrate that emission of coherent transition radiation by a ∼1 GeV energy-electron beam passing through an Al foil is enhanced in intensity and extended in frequency spectral range, by the energy correlation established along the beam by coherent synchrotron radiation wakefield, in the presence of a proper electron optics in the beam delivery system. Analytical and numerical models, based on experimental electron beam parameters collected at the FERMI free electron laser (FEL), predict transition radiation with two intensity peaks at ∼0.3 THz and ∼1.5 THz, and extending up to 8.5 THz with intensity above 20 dB w.r.t. the main peak. Up to 80-µJ pulse energy integrated over the full bandwidth is expected at the source, and in agreement with experimental pulse energy measurements. By virtue of its implementation in an FEL beam dump line, this work promises dissemination of user-oriented multi-THz beamlines parasitic and self-synchronized to EUV and x-ray FELs. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Organic, Gas, and Element Geochemistry of Hydrothermal Fluids of the Newly Discovered Extensive Hydrothermal Area in the Wallis and Futuna Region (SW Pacific)" in the 2018 issue.

Background/Objectives: To investigate the effect of a fermented soy supplement during 18 months in patients under active surveillance (AS) for low-risk and selected favorable intermediate-risk prostate cancer (PCa), with an emphasis on PSA modulation. Methods: Low-risk patients with ISUP grade 1, clinical stage cT1 or cT2a, PSA < 10 ng/mL and favorable intermediate-risk patients with ISUP grade 2 (<10% pattern 4), clinical stage T2b-c, PSA 10-20 ng/mL. The primary outcome was PSA response defined as maximum PSA rise less than or equal to 0.87 ng/mL after 1 year, based on the weighted average of PSA velocity (PSAV) in previous studies in similar populations. Secondary outcomes were disease progression, adverse histology on repeat biopsy or switch to active therapy. In addition, primary and secondary outcomes with imputed data were also determined as sensitivity analyses, using Mann-Whitney U or Chi-squared tests. Results: Overall, 92 (61.3%) of 150 patients showed a PSA level response. This was more evident in ISUP 1 patients and resulted in fewer follow-up MRIs and fewer control biopsies, as well as a fewer number of positive control biopsies with statistical significance in the imputed dataset. Obtaining a PSA response was numerically associated with less initiated therapy. Conclusions: a fermented soy supplement in patients under AS for low-risk and selected favorable intermediate-risk PCa could be useful in selecting patients who may remain under AS or who may need to switch to active therapy.

Relativistic electron bunches used to produce synchrotron radiation are systematically subjected to spontaneous appearance of microstructures, when a high number of electrons are used. In storage rings, this usually leads to an intense coherent emission in the terahetz range, with powers that are orders of magnitude higher than standard incoherent emission. However this emission generally displays an erratic behavior, which has strongly limited its domain of application so far. In this Letter-inspired by the process of gain switching in lasers-we present a new method for controlling the electron bunch dynamics during this instability. We show that it is possible to trigger the formation of the microstructures in the bunch, and also to considerably enhance the peak power of the coherent terahertz bursts. The experimental demonstration of this scheme-based on the modulation of a rf-cavity signal-is performed at the SOLEIL facility.

Background: Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib., Methods: We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia., Results: Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed., Conclusion: We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Chronic giant diaphragmatic hernia is a severe disease with challenging diagnosis and treatment. Given the risk of loss of domain, the use of botulinum toxin A is an option but has been minimally studied in diaphragmatic hernia surgery., Case Report: We present a case of a giant diaphragmatic hernia in a 66-years-old patient who showed a 12-year history of progressive chronic respiratory insufficiency. There were not notion of traumatic injuries. The CT-scan showed a giant diaphragmatic hernia with herniation of small bowel, right liver, omentum and transverse colon., Method: We assessed the risk of loss of domain using a 3D volumetry based on the Sabbagh score and decided to use Botox injection before laparoscopic reduction of the hernia due to the high risk of complications related to the loss of domain. A computed tomography was performed 24 months after surgery and showed no evidence of recurrence. The patient presented an excellent functional result with a normal physical activity., Conclusion: This report is among the first to highlight the utility of 3D reconstruction in assessing the risk associated with loss of domain and in preparing the abdominal wall with botulinum toxin A for diaphragmatic hernia repair., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nachtergaele, Khalil, Martre, Baste and Roussel.)

Background and Purpose: This study aims to evaluate neutrophil-to-eosinophil ratio (NER) as a prognostic and/or predictive biomarker in metastatic clear cell renal cell carcinoma (m-ccRCC) treated with nivolumab or ipilimumab/nivolumab., Patients/materials and Methods: We performed a retrospective study on m-ccRCC patients treated with nivolumab or ipilimumab/nivolumab (2012-2022). Baseline NER was calculated and correlated with clinical outcomes: response rate (RR), progression free survival (PFS) and overall survival (OS). Corresponding transcriptomic data were analysed., Results: We included 201 m-ccRCC patients, 76 treated with ipilimumab/nivolumab and 125 with nivolumab. Baseline NER was statistically significantly associated with International Metastatic RCC Database Consortium (IMDC) risk groups. Increased NER was associated with shorter PFS and OS in the total patient series and nivolumab-treated patients. In patients treated with ipilimumab/nivolumab, increased NER was only statistically significantly associated with shorter OS. The impact of baseline NER on PFS and OS was independent of IMDC risk stratification. No clear correlation was found between baseline NER and RECIST response or maximal tumour shrinkage. In two additional databases, NER was also associated with PFS and OS in first-line vascular-endothelial-growth-factor-receptor tyrosine-kinase-inhibitors (VEGFR-TKIs), but not to disease-free survival in the post-nephrectomy setting. Lower NER was associated with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors., Interpretation: Lower baseline NER is associated with better PFS and OS, independent of IMDC risk score, in m-ccRCC patients treated with ipilimumab/nivolumab or nivolumab. It correlates with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors. The predictive power of this biomarker is probably limited and insufficient for patient selection.

Background: Minimally invasive surgery has gained momentum for left pancreatic resections. However, debate remains about whether it has any advantage over open surgery for distal pancreatectomy for pancreatic neuroendocrine tumors., Methods: This retrospective review examined pancreatectomies performed for resectable pancreatic neuroendocrine tumors at 21 centers in France between January 2014 and December 2018. Short and long-term outcomes were compared before and after propensity score matching based on tumor size, sex, age, body mass index, center, and method of pancreatic transection., Results: During the period study, 274 patients underwent left pancreatic resection for pancreatic neuroendocrine tumors [109 underwent distal splenopancreatectomy, and 165 underwent spleen-preserving distal pancreatectomy [(splenic vessel preservation (n = 97; 58.7%)/splenic vessel resection (n = 68; 41.3%)]. Before propensity score matching, minimally invasive surgery was associated with a lower rate of major morbidity (P = .004), lower rate of postoperative delayed gastric emptying (P = .04), and higher rate of "textbook" outcomes (P = .04). After propensity score matching, there were 2 groups of 54 patients (n = 30 distal splenopancreatectomy; n = 78 spleen-preserving distal pancreatectomy). Minimally invasive surgery was associated with less blood loss (P = .05), decreased rate of major morbidity (6% vs. 24%; P = .02), less delayed gastric emptying (P = .05) despite similar rates of postoperative fistula, hemorrhage, and reoperation (P > .05). The 5-year overall survival (79% vs. 75%; P = .74) and recurrence-free survival (10% vs 17%; P = .39) were similar., Conclusion: Minimally invasive surgery for left pancreatic resection can be safely proposed for patients with resectable left pancreatic neuroendocrine tumors. Minimally invasive surgery decreases the rate of major complications while providing comparable long-term oncologic outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The impact of cirrhosis on the postoperative outcomes of distal pancreatectomy is yet to be reported. We aimed to evaluate the outcomes of distal pancreatectomy in patients with cirrhosis., Methods: We conducted a retrospective, multicentric study patients with cirrhosis who underwent planned distal pancreatectomy between 2008 and 2020 in French high volume centers. Patients with cirrhosis were matched 1:4 for demographic, surgical, and histologic criteria with patients without cirrhosis. The primary endpoint was severe morbidity (Clavien-Dindo grade ≥III). The secondary endpoints were postoperative complications, specifically related to cirrhosis and pancreatic surgery, and survival for patients with pancreatic adenocarcinoma., Results: Overall, 32 patients with cirrhosis were matched with 128 patients without cirrhosis. Most patients (93.5%) had Child-Pugh A cirrhosis. The severe morbidity rate after distal pancreatectomy was higher in patients with cirrhosis than in those without cirrhosis (28.13% vs 25.75%, P = .11. The operative time was significantly longer in the cirrhotic group compared with controls (P = .01). However, patients with and without cirrhosis had comparable blood loss and conversion rates. Postoperatively, the two groups had similar rates of pancreatic fistula, hemorrhage, reoperation, postoperative mortality, and survival rates at 1, 3, and 5 years., Conclusion: The current study suggests that distal pancreatectomy in high-volume centers is feasible for patients with compensated cirrhosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The venous anatomy of the two-toed sloth ( Choloepus didactylus ) remains poorly understood, particularly in living specimens due to the limitations of traditional cadaveric studies. This study aims to describe the unique venous structures of Choloepus didactylus using computed tomography, enhancing our understanding of this species in a live setting. Three living Choloepus didactylus underwent CT scans as part of routine clinical assessments. The images were reconstructed using 3D Slicer software (version 5.6.2), focusing on the caudal vena cava anatomy. The reconstructions confirmed the presence of a significant intravertebral vein, showing complex venous connections through the ventral sacral foramen and vertebral foramina. These findings highlight notable anatomical variations and challenge existing literature on the species' venous architecture. By employing modern imaging technologies, this research provides new insights into the venous anatomy of Choloepus didactylus , demonstrating the value of non-invasive techniques in studying the anatomical features of live animals, thereby offering a foundation for further comparative and evolutionary studies.

Introduction: This study investigated the efficacy and safety of neoadjuvant chemotherapy for locally advance penile squamous cell carcinoma for which current evidence is lacking., Methods: Included patients had locally advanced penile squamous cell carcinoma with clinical lymph node metastasis treated with at least 1 dose of neoadjuvant chemotherapy prior to planned consolidative lymphadenectomy. Objective response rates were assessed using Response Evaluation Criteria in Solid Tumors v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan-Meier method. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events v5.0., Results: A total of 209 patients received neoadjuvant chemotherapy for locally advanced and clinically node-positive penile squamous cell carcinoma. The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 treatment-related adverse events occurred in 35 (17%) patients, and no treatment-related mortality was observed. Of the patients, 201 (97%) completed planned consolidative lymphadenectomy. During follow-up, 106 (52.7%) patients expired, with a median overall survival of 37.0 months (95% confidence interval [CI] = 23.8 to 50.1 months) and median progression-free survival of 26.0 months (95% CI = 11.7 to 40.2 months). Objective response rate was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to neoadjuvant chemotherapy had a longer median overall survival (73.0 vs 17.0 months, P < .01) compared with those who did not. The lymph node pathologic complete response rate was 24.8% in the cohort., Conclusion: Neoadjuvant chemotherapy with lymphadenectomy for locally advanced penile squamous cell carcinoma is well tolerated and active to reduce the disease burden and improve long-term survival outcomes., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A pathology well known by pediatric surgeons, ileal duplication is in rare instances a cause of acute surgical abdomen in adults; that said, its atypical presentation often leads it to be mistaken for other etiologies. Even though it is benign in children, the risk of malignant transformation in adults should be taken into account in surgical procedures., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

An important challenge in the real-world management of patients with advanced clear-cell renal cell carcinoma (aRCC) is determining who might benefit from immune checkpoint blockade (ICB). Here we performed a comprehensive multiomics mapping of aRCC in the context of ICB treatment, involving discovery analyses in a real-world data cohort followed by validation in independent cohorts. We cross-connected bulk-tumor transcriptomes across >1,000 patients with validations at single-cell and spatial resolutions, revealing a patient-specific crosstalk between proinflammatory tumor-associated macrophages and (pre-)exhausted CD8 + T cells that was distinguished by a human leukocyte antigen repertoire with higher preference for tumoral neoantigens. A cross-omics machine learning pipeline helped derive a new tumor transcriptomic footprint of neoantigen-favoring human leukocyte antigen alleles. This machine learning signature correlated with positive outcome following ICB treatment in both real-world data and independent clinical cohorts. In experiments using the RENCA-tumor mouse model, CD40 agonism combined with PD1 blockade potentiated both proinflammatory tumor-associated macrophages and CD8 + T cells, thereby achieving maximal antitumor efficacy relative to other tested regimens. Thus, we present a new multiomics and spatial map of the immune-community architecture that drives ICB response in patients with aRCC., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To investigate the effect of a dietary supplement containing fermented soy on PSA, IPSS, changes in prostate volume and prostate cancer (PCa) development after a 6-month challenge in men at increased risk of PCa and negative previous biopsies. MATERIALS AND METHODS: Patients with an elevated risk of PCa, defined by either 1 of the following criteria: PSA >3 ng/mL, suspect lesion at digital rectal examination (DRE), suspect lesion at transrectal ultrasound (TRUS)/magnetic resonance imaging (MRI) and previous negative prostate biopsies (at least 8 cores) within 12 months before inclusion. Statistical analysis was carried out using a non-parametric 1-sided paired Wilcoxon rank sum test, chi-square test, and Fisher's exact test., Results: In this trial, 94 patients were eligible for analysis. A PSA response was detected in 81% of the cases. In 25.8% (24/93) of patients, a decrease of at least 3 points on the IPSS was observed. The median prostate volume did not statistically change after 6 months (P = .908). Patients with PSA modulation required fewer investigations and had fewer positive biopsies (P <.001) and significantly fewer ISUP ≥3 lesions (P = .02)., Conclusion: We observed a significantly lower PSA level after a 6-month challenge with a fermented soy-containing supplement, and an effect on IPSS in a subset of patients. Prescribing a fermented soy supplement in patients with an increased PCa risk could lead to a better selection of patients at real increased risk of having occult PCa., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The KEYNOTE-564 randomised controlled trial showed a disease-free survival benefit of adjuvant pembrolizumab (aPZB) in comparison to placebo for patients with clear cell renal cell carcinoma (ccRCC) at high risk of recurrence. Despite its recommendation by the European Association of Urology guidelines, the ultimate value of aPZB has recently been questioned. Arguably, patients who might benefit the most from aPZB are those whose probability of RCC recurrence outweighs their probability of dying from other causes over a reasonable timeframe after surgery. To assess the potential impact of this hypothesis on "eligibility" for aPZB, we queried our prospectively collected multi-institutional database for consecutive patients undergoing surgery for nonmetastatic renal masses (cT1-4 N0-1 M0) between 2015 and 2021 to identify ccRCC cases meeting the KEYNOTE-564 criteria. We stratified the patients using the risk-adapted model proposed by Stewart-Merrill et al (whereby stopping follow-up is warranted when the estimated risk of other-cause mortality [OCM] outweighs the estimated risk of RCC recurrence). Then we explored the proportion of patients whose follow-up could theoretically be stopped at 2, 5, 10, or 20 yr, for whom "eligibility" for aPZB might be more controversial. Overall, 1745 patients with ccRCC were included, of whom 419 (24%) met the KEYNOTE-564 criteria. The proportion of patients "not eligible" for aPZB because of higher probability of OCM than of RCC recurrence would have been 81%, 66%, 43%, and 29% at "recommended" follow-up of ≤2.0, ≤5, ≤10, and ≤20 yr, respectively. To the best of our knowledge, this is the first study providing insights to support shared decision-making regarding eligibility for aPZB for patients with nonmetastatic ccRCC with a focus on patient-related factors beyond tumour-driven prognostic scores. PATIENT SUMMARY: An immunotherapy drug call pembrolizumab given after surgery for nonmetastatic kidney cancer may benefit some patients who have a high risk of disease recurrence, but it can have immune-related side effects. We found that comparing the risk of death from other causes and the risk of cancer recurrence could help in reducing overtreatment of patients who might not benefit from this drug., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Aim: The role of histomorphological subtyping is an issue of debate in papillary renal cell carcinoma (papRCC). This multi-institutional study investigated the prognostic role of histomorphological subtyping in patients undergoing curative surgery for nonmetastatic papRCC., Patients and Methods: A total of 1,086 patients undergoing curative surgery were included from a retrospectively collected multi-institutional nonmetastatic papRCC database. The patients were divided into 2 groups based on histomorphological subtyping (type 1, n = 669 and type 2, n = 417). Furthermore, a propensity score-matching (PSM) cohort in 1:1 ratio (n = 317 for each subtype) was created to reduce the effect of potential confounding variables. The primary outcome of the study, the predictive role of histomorphological subtyping on the prognosis (recurrence free survival [RFS], cancer specific survival [CSS] and overall survival [OS]) in nonmetastatic papRCC after curative surgery, was investigated in both overall and PSM cohorts., Results: In overall cohort, type 2 group were older (66 vs. 63 years, P = 0.015) and more frequently underwent radical nephrectomy (37.4% vs. 25.6%, P < 0.001) and lymphadenectomy (22.3% vs. 15.1%, P = 0.003). Tumor size (4.5 vs. 3.8 cm, P < 0.001) was greater, and nuclear grade (P < 0.001), pT stage (P < 0.001), pN stage (P < 0.001), VENUSS score (P < 0.001) and VENUSS high risk (P < 0.001) were significantly higher in type 2 group. 5-year RFS (89.6% vs. 74.2%, P < 0.001), CSS (93.9% vs. 84.2%, P < 0.001) and OS (88.5% vs. 78.5%, P < 0.001) were significantly lower in type 2 group. On multivariable analyses, type 2 was a significant predictor for RFS (HR:1.86 [95%CI:1.33-2.61], P < 0.001) and CSS (HR:1.91 [95%CI:1.20-3.04], P = 0.006), but not for OS (HR:1.27 [95%CI:0.92-1.76], P = 0.150). In PSM cohort balanced with age, gender, symptoms at diagnosis, pT and pN stages, tumor grade, surgical margin status, sarcomatoid features, rhabdoid features, and presence of necrosis, type 2 increased recurrence risk (HR:1.75 [95%CI: 1.16-2.65]; P = 0.008), but not cancer specific mortality (HR: 1.57 [95%CI: 0.91-2.68]; P = 0.102) and overall mortality (HR: 1.01 [95%CI: 0.68-1.48]; P = 0.981) CONCLUSIONS: This multiinstitutional study suggested that type 2 was associated with adverse histopathologic outcomes, and predictor of RFS and CSS after surgical treatment of nonmetastatic papRCC, in overall cohort. In propensity score-matching cohort, type 2 remained the predictor of RFS. Eventhough 5th WHO classification for renal tumors eliminated histomorphological subtyping, these findings suggest that subtyping is relevant from the point of prognostic view., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The mechanisms underpinning the replication of genomic DNA have recently been challenged in Archaea . Indeed, the lack of origin of replication has no deleterious effect on growth, suggesting that replication initiation relies on homologous recombination. Recombination-dependent replication (RDR) appears to be based on the recombinase RadA, which is of absolute requirement when no initiation origins are detected. The origin of this flexibility in the initiation of replication and the extent to which it is used in nature are yet to be understood. Here, we followed the process of DNA replication throughout the growth stages of Thermococcus barophilus . We combined deep sequencing and genetics to elucidate the dynamics of oriC utilization according to growth phases. We discovered that in T. barophilus , the use of oriC diminishes from the lag to the middle of the log phase, and subsequently increases gradually upon entering the stationary phase. Although oriC demonstrates no indispensability, RadA does exhibit essentiality. Notably, a knockdown mutant strain provides confirmation of the pivotal role of RadA in RDR for the first time. Thus, we demonstrate the existence of a tight combination between oriC utilization and homologous recombination to initiate DNA replication along the growth phases. Overall, this study demonstrates how diverse physiological states can influence the initiation of DNA replication, offering insights into how environmental sensing might impact this fundamental mechanism of life., Importance: Replication of DNA is highly important in all organisms. It initiates at a specific locus called ori , which serves as the binding site for scaffold proteins-either Cdc6 or DnaA-depending on the domain of life. However, recent studies have shown that the Archaea , Haloferax volcanii and Thermococcus kodakarensis could subsist without ori . Recombination-dependent replication (RDR), via the recombinase RadA, is the mechanism that uses homologous recombination to initiate DNA replication. The extent to which ori 's use is necessary in natural growth remains to be characterized. In this study, using Thermococcus barophilus , we demonstrated that DNA replication initiation relies on both oriC and RDR throughout its physiological growth, each to varying degrees depending on the phase. Notably, a knockdown RadA mutant confirmed the prominent use of RDR during the log phase. Moreover, the study of ploidy in oriC and radA mutant strains showed that the number of chromosomes per cell is a critical proxy for ensuring proper growth and cell survival., Competing Interests: The authors declare no conflict of interest.

Background and Objective: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has been called into question on the basis of clinical trial data from the tyrosine kinase inhibitor (TKI) era. Comparative analyses of CN for patients treated with immuno-oncology (IO) versus TKI agents are sparse. Our objective was to compare CN timing and outcomes among patients who received TKI versus IO therapy., Methods: This was a multicenter retrospective analysis of patients who underwent CN using data from the REMARCC (Registry of Metastatic RCC) database. The cohort was divided into TKI versus IO first-line therapy groups. The primary outcome was all-cause mortality (ACM). Secondary outcomes included cancer-specific mortality (CSM). Multivariable analysis was used to identify factors predictive for ACM and CSM. The Kaplan-Meier method was used to analyze 5-yr overall survival (OS) and cancer-specific survival (CSS) with stratification by primary systemic therapy and timing in relation to CN., Key Findings and Limitations: We analyzed data for 189 patients (148 TKI + CN, 41 IO +CN; median follow-up 23.2 mo). Multivariable analysis revealed that a greater number of metastases (hazard ratio [HR] 1.06; p = 0.015), greater primary tumor size (HR 1.10; p  = 0.043), TKI receipt (HR 2.36; p  = 0.015), and initiation of systemic therapy after CN (HR 1.49; p  = 0.039) were associated with worse ACM. A greater number of metastases at diagnosis (HR 1.07; p  = 0.011), greater primary tumor size (HR 1.12; p  = 0.018), TKI receipt (HR 5.43; p  = 0.004), and initiation of systemic therapy after CN (HR 2.04; p  < 0.001) were associated with worse CSM. Kaplan-Meier analyses revealed greater 5-yr rates for OS (51% vs 27%; p  < 0.001) and CSS (83% vs 30%; p  < 0.001) for IO +CN versus TKI + CN. This difference persisted in a subgroup analysis for patients with intermediate or poor risk, with 5-yr OS rates of 50% for IO + CN versus 30% for TKI + CN ( p  < 0.001). A subanalysis stratified by CN timing revealed better 5-yr rates for OS (50% vs 30%; p  = 0.042) and CSS (90% vs 30%, p  = 0.019) for delayed CN after IO therapy, but not after TKI therapy., Conclusions and Clinical Implications: For patients who underwent CN, systemic therapy before CN was associated with better outcomes. In addition, IO therapy was associated with better survival outcomes in comparison to TKI therapy. Our findings question the applicability of clinical trial data from the TKI era to CN in the IO era for mRCC., Patient Summary: For patients with metastatic kidney cancer treated with surgery, better survival outcomes were observed for those who also received immunotherapy in comparison to therapy targeting specific proteins in the body (tyrosine kinase inhibitors, TKIs). Immunotherapy or TKI treatment resulted in better outcomes if it was received before rather than after surgery., (© 2024 Published by Elsevier B.V. on behalf of European Association of Urology.)

Regulation of mRNA translation is a crucial step in controlling gene expression in stressed cells, impacting many pathologies, including heart ischemia. In recent years, ribosome heterogeneity has emerged as a key control mechanism driving the translation of subsets of mRNAs. In this study, we investigated variations in ribosome composition in human cardiomyocytes subjected to endoplasmic reticulum stress induced by tunicamycin treatment. Our findings demonstrate that this stress inhibits global translation in cardiomyocytes while activating internal ribosome entry site (IRES)-dependent translation. Analysis of translating ribosome composition in stressed and unstressed cardiomyocytes was conducted using mass spectrometry. We observed no significant changes in ribosomal protein composition, but several mitochondrial ribosomal proteins (MRPs) were identified in cytosolic polysomes, showing drastic variations between stressed and unstressed cells. The most notable increase in polysomes of stressed cells was observed in MRPS15. Its interaction with ribosomal proteins was confirmed by proximity ligation assay (PLA) and immunoprecipitation, suggesting its intrinsic role as a ribosomal component during stress. Knock-down or overexpression experiments of MRPS15 revealed its role as an activator of IRES-dependent translation. Furthermore, polysome profiling after immunoprecipitation with anti-MRPS15 antibody revealed that the "MRPS15 ribosome" is specialized in translating mRNAs involved in the unfolded protein response.

Background and Objective: Renal tumour biopsy (RTB) can help in risk stratification of renal tumours with implications for management, but its utilisation varies. Our objective was to report current practice patterns, experiences, and perceptions of RTB and research gaps regarding RTB for small renal masses (SRMs)., Methods: Two web-based surveys, one for health care providers (HCPs) and one for patients, were distributed via the European Association of Urology Young Academic Urologist Renal Cancer Working Group and the European Society of Residents in Urology in January 2023., Key Findings and Limitations: The HCP survey received 210 responses (response rate 51%) and the patient survey 54 responses (response rate 59%). A minority of HCPs offer RTB to >50% of patients (14%), while 48% offer it in <10% of cases. Most HCPs reported that RTB influences (61.5%) or sometimes influences (37.1%) management decisions. Patients were more likely to favour active treatment if RTB showed high-grade cancer and less likely to favour active treatment for benign histology. HCPs identified situations in which they would not favour RTB, such as cystic tumours and challenging anatomic locations. RTB availability (67%) and concerns about delays to treatment (43%) were barriers to offering RTB. Priority research gaps include a trial demonstrating that RTB leads to better clinical outcomes, and better evidence that benign/indolent tumours do not require active treatment., Conclusions and Clinical Implications: Utilisation of RTB for SRMs in Europe is low, even though both HCPs and patients reported that RTB results can affect disease management. Improving timely access to RTB and generating evidence on outcomes associated with RTB use are priorities for the kidney cancer community., Patient Summary: A biopsy of a kidney mass can help patients and doctors make decisions on treatment, but our survey found that many patients in Europe are not offered this option. Better access to biopsy services is needed, as well as more research on what happens to patients after biopsy., (© 2024 The Author(s).)

The widespread use of computed tomography (CT) for diagnosing and screening abdominal conditions often reveals rare, asymptomatic anomalies. There is a wide range of documented congenital variations in the anatomy of the inferior vena cava (IVC) and hepatic veins. In this report, we detail an exceptionally unusual variant of the IVC that follows a frontward and intraliver course, terminating at the anterior section of the right atrium. To gain a deeper insight into this anomaly, we employed 3D reconstruction techniques using the software Slicer and Blender., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Long non-coding (lnc) RNAs, once considered as junk and useless, are now broadly recognized to have major functions in the cell. LncRNAs are defined as non-coding RNAs of more than 200 nucleotides, regulate all steps of gene expression. Their origin is diverse, they can arise from intronic, intergenic or overlapping region, in sense or antisense direction. LncRNAs are mainly described for their action on transcription, while their action at the translational level is more rarely cited. However, the bibliography in the field is more and more abundant. The present synopsis of lncRNAs involved in the control of translation reveals a wide field of regulation of gene expression, with at least nine distinct molecular mechanisms. Furthermore, it appears that all these lncRNAs are involved in various pathologies including cancer, cardiovascular and neurodegenerative diseases., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)