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In controlled phase II trials, major prognostic factors need to be well balanced between arms. The main procedures used are SPBR (Stratified Permuted Block Randomization) and minimization. First, we provide a systematic review of the treatment allocation procedure used in gastrointestinal oncology controlled phase II trials published in 2019. Second, we performed simulations using data from six phase II studies to measure the impacts of imbalances and bias on the efficacy estimations. From the 40 articles analyzed, all mentioned randomization in both the title and abstract, the median number of patients included was 109, and 77.5% were multicenter. Of the 27 studies that reported at least one stratification variable, 10 included the center as a stratification variable, 10 used minimization, 9 used SBR, and 8 were unspecified. In real data studies, the imbalance increased with the number of centers. The total and marginal imbalances were higher with SBR than with minimization, and the difference increased with the number of centers. The efficiency estimates per arm were close to the original trial estimate in both procedures. Minimization is often used in cases of numerous centers and guarantees better similarity between arms for stratification variables for total and marginal imbalances in phase II trials.

Abstract Background The Response Evaluation Criteria in Solid Tumors (RECIST) are often inadequate for the early assessment of the response to cancer therapy, particularly bevacizumab-based chemotherapy. In a first cohort of patients with colorectal cancer liver metastases (CRLM), we showed that variations of the tumor-to-liver density (TTLD) ratio and modified size-based criteria determined using computed tomography (CT) data at the first restaging were better prognostic criteria than the RECIST. The aims of this study were to confirm the relevance of these radiological biomarkers as early predictors of the long-term clinical outcome and to assess their correlation with contrast-enhanced ultrasound (CEUS) parameters in a new patient cohort. Methods In this post-hoc study of the multicenter STIC-AVASTIN trial, we retrospectively reviewed CT data of patients with CRLM treated with bevacizumab-based regimens. We determined the size, density and TTLD ratio of target liver lesions at baseline and at the first restaging and also performed a morphologic evaluation according to the MD Anderson criteria. We assessed the correlation of these parameters with progression-free survival (PFS) and overall survival (OS) using the log-rank test and a Cox proportional hazard model. We also examined the association between TTLD ratio and quantitative CEUS parameters. Results This analysis concerned 79 of the 137 patients included in the STIC-AVASTIN trial. PFS and OS were significantly longer in patients with tumor size reduction > 15% at first restaging, but were not correlated with TTLD ratio variations. However, PFS was longer in patients with TTLD ratio > 0.6 at baseline and first restaging than in those who did not reach this threshold. In the multivariate analysis, only baseline TTLD ratio > 0.6 was a significant survival predictor. TTLD ratio > 0.6 was associated with improved perfusion parameters. Conclusions Although TTLD ratio variations did not correlate with the long-term clinical outcomes, TTLD absolute values remained a good predictor of survival at baseline and first restaging, and may reflect tumor microvascular features that might influence bevacizumab-based treatment efficiency. Trial registration NCT00489697, registration number of the STIC-AVASTIN trial.

Abstract Background The COVID‐19 pandemic led to a widely documented disruption in cancer care pathway. Since a resurgence of the pandemic was expected after the first lockdown in France, the global impact on the cancer care pathway over the year 2020 was investigated. Aims This study aimed to describe the changes in the oncology care pathway for cancer screening, diagnosis, assessment, diagnosis annoucement procedure and treatment over a one‐year period. Materials & Methods The ONCOCARE‐COV study was a comprehensive, retrospective, descriptive, and cross‐sectional study comparing the years 2019 and 2020. All key indicators along the cancer care pathway assessing the oncological activity over four periods were described. This study was set in a high‐volume, public, single tertiary care center divided in two complementary sites (Reims University Hospital and Godinot Cancer Institute, Reims, France) which was located in a high COVID‐19 incidence area during both peaks of the outbreak. Results A total of 26,566 patient's files were active during the year 2020. Breast screening (−19.5%), announcement dedicated consultations (−9.2%), Intravenous and Hyperthermic Intraoperative Intraperitoneal Chemotherapy (HIPECs) (−25%), and oncogeriatric evaluations (−14.8%) were heavily disrupted in regard to 2020 activity. We identified a clear second outbreak wave impact on medical announcement procedures (October, −14.4%), radiotherapy sessions (October, −16%), number of new health record discussed in multidisciplinary tumor board meeting (November, −14.6%) and HIPECs (November, −100%). Moreover, 2020 cancer care activity stagnated compared to 2019. Discussion The oncological care pathway was heavily disrupted during the first and second peaks of the COVID‐19 outbreak. Between lockdowns, we observed a remarkable but non‐compensatory recovery as well as a lesser impact from the pandemic resurgence. However, in absence of an increase in activity, a backlog persisted. Conclusion Public health efforts are needed to deal with the consequences of the COVID‐19 pandemic on the oncology care pathway.

Celiacomesenteric trunk is a rare variant of celiac artery anatomical variations. Stenosis of celiacomesenteric trunk is a severe usually symptomatic condition which might jeopardize the arterial supply of both supramesocolic organs and the midgut. It was diagnosed in a 79-year-old male during the preoperative workup for a pancreatic adenocarcinoma. Highly developed arterial anastomotic arcades, and mainly Riolan arcade, allowed to bypass this stenosis and to avoid digestive ischemia. Arterial anastomotic arcades are of paramount interest to ensure sufficient supply to the corresponding organs and must be thoroughly evaluated before planned surgery to avoid postoperative ischemia.

Introduction: Preclinical studies have demonstrated the possible role of beta-adrenergic receptors in pancreatic ductal adenocarcinoma (PDAC) tumor invasion and migration. The current study aimed to explore the possible association between survival outcomes and beta-blocker (BB) exposure in patients with advanced PDAC.Methods: This retrospective single-center study included 182 patients with advanced PDAC. Clinical [age, sex, BMI, cardiovascular condition, presence (SBB) or absence (NSBB) of beta-1 selectivity of BB, exposure duration, and multimorbidity], oncological (stage and anticancer treatment regimen), and biological (renal and liver function) data were collected. The endpoints were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for survival outcomes associated with BB exposure were estimated using Cox regression model and propensity score (PS) methods.Results: Forty-one patients (22.5%) were exposed to BB. A total of 104 patients progressed (57.1%) to PDAC and 139 (76.4%) patients died at the end of follow-up (median, 320 days; IQR, 438.75 days). When compared to the non-exposed group, there was no increase in survival outcomes associated with BB use (OS: HR = 1.38, 95% CI = 0.80–2.39, p = 0.25; PFS: adjusted HR = 0.95, 95% CI = 0.48–1.88, p = 0.88). Similar results were obtained using the PS method. Compared to no BB usage, SBB use was associated with a significant decrease in OS (HR = 1.80, 95% CI = 1.16–2.80, p < 10−2).Conclusion: BB exposure was not associated with improved PDAC survival outcomes. Beta-1-selectivity was not independently associated with any differences.

Background: Dihydropyrimidine dehydrogenase (DPD) deficiency screening is a pre-therapeutic standard to prevent severe fluoropyrimidine-related toxicity. Although several screening methods exist, the accuracy of their results remains debatable. In France, the uracilemia measurement is considered the standard in DPD deficiency screening. The objective of this study was to describe the hyperuracilemia (⩾16 ng/mL) rate and investigate the influence of hepatic and renal impairment in uracilemia measurements since the guidelines were implemented. Patients and methods: Using a cohort of 1138 patients screened between 18 October 2018 and 18 October 2021, basic demographic characteristics, date of blood sampling, and potential biological confounders including liver function tests [aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin] and estimated glomerular filtration rate (eGFR) were collected. The second same-patient uracilemia analysis was also performed. Temporal change was graphically represented while potential confounders were stratified to show linearity when suspected. Results: Hyperuracilemia was diagnosed in 12.7% ( n = 150) samples with 6.7%, 5.4%, 0.5%, and 0.08% between 16 and 20 ng/mL, 20 and 50 ng/mL, 50 and 150 ng/mL, and >150 ng/mL, respectively. The median uracilemia concentration was 9.4 ng/mL (range: 1.2 and 172.3 ng/mL) and the monthly hyperuracilemia rate decreased steadily from >30% to around 9%. Older age, normalized AST, γGT, ALP results, bilirubin levels, and decreased eGFR were linearly associated with higher plasma uracil concentrations (all p

Background: Several studies have reported the impact of single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor ( VEGF ) pathway genes on the efficacy of bevacizumab in metastatic colorectal cancer (mCRC), but results are still inconsistent. The PRODIGE 9 phase III study compared bevacizumab maintenance versus observation alone after induction chemotherapy with FOLFIRI plus bevacizumab. Objective: We evaluated the impact of SNPs of VEGF-A , VEGF receptors ( VEGFR-1, VEGFR-2 ), and hypoxia inducible factor-1α ( HIF-1α ) on tumor control duration (TCD), overall survival (OS), progression-free survival (PFS), and duration of first chemotherapy free-intervals (CFI). Patients and methods: We included 314/491 patients from PRODIGE 9 with a DNA blood sample available. Nine SNPs were genotyped on germline DNA using real-time Polymerase Chain Reaction TaqMan TM (Thermo Fisher Scientific, Waltham, MA , USA 02451). Results: In the bevacizumab arm, patients with the VEGFR-1 rs9582036 CC genotype ( n = 14) had significantly longer TCD [22.4 months (95% confidence interval (CI): 14.75-not reached)] than patients with the AA or CA genotype [14.4 months (95% CI: 11.7–17.1)] ( p = 0.036), whereas there was no significant difference in the observation arm. In the bevacizumab arm, no significant difference was found between the CC, and AA or CA genotype for OS [28.2 (95% CI: 18.1–42.8) versus 22.5 (95% CI: 18.6–24.6) months, p = 0.5], PFS [9.4 (95% CI: 7.2–11.3) versus 9.2 (95% CI: 8.71–10.1)], and duration of the first CFI [4.6 (95% CI: 1.6–13.3) versus 4.14 (95% CI: 0.5–29.0) months, p = 0.3]. Conclusion: Among mCRC patients treated with bevacizumab maintenance, those with the VEGFR-1 rs9582036 CC genotype experienced longer TCD. The presence of this genotype may thus predict a benefit of bevacizumab maintenance in mCRC.

Circulating tumor DNA (ctDNA) is reported to be promising in localized colorectal cancer (CRC). The present study aimed to retrospectively evaluate the impact of ctDNA in patients with a resected stage II CRC from the PROGIGE 13 trial with available paired tumor and blood samples. A group of recurrent patients were matched one-to-one with nonrecurrent patients according to sex, tumor location, treatment sequence, and blood collection timing. CtDNA was analyzed by digital PCR according to NGS of tumors. Disease-free survival (DFS) and overall survival (OS) were analyzed based on ctDNA, and the risks of recurrence and death were determined. A total of 134 patients were included, with 67 patients in each group. At least one alteration was identified in 115/134 tumors. Postoperative ctDNA was detected in 10/111 (9.0%) informative samples and was detected more frequently in the recurrent group (16.7% versus 1.8%; p = 0.02). The median DFS of ctDNA+ versus ctDNA- patients was 16.8 versus 54 months (p = 0.002), respectively, and the median OS was 51.3 versus 69.5 months (p = 0.03), respectively. CtDNA was associated with recurrence (ORa = 11.13, p = 0.03) and death (HRa = 3.15, p = 0.01). In conclusion, the presence of postoperative ctDNA is associated with both recurrence and survival in stage II CRC.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic neoplasm. Surgery is the factual curative option, but most patients present with advanced disease. In order to increase resectability, results of neoadjuvant chemotherapy (NAC) on metastatic disease were extrapolated to the neoadjuvant setting by many centers. The aim of our study was to retrospectively evaluate the outcome of patients who underwent upfront surgery (US)-PDAC and borderline (BR)-PDAC, and those resected after NAC to determine prognostic factors that might affect the outcome in these resected patients.MethodsOne hundred fifty-one patients between January 2012 and March 2021 in our department were reviewed. Epidemiological characteristics and pre-operative induction treatment were assessed. Pathological reports were analyzed to evaluate the quality of oncological resection (R0/R1). Post-operative mortality and morbidity and survival data were reviewed.ResultsOne hundred thirteen patients were addressed for US, and 38 were considered BR and referred for surgery after induction chemotherapy. The pancreatic resection R0 was 71.5% and R1 28.5%. pT3 rate was significantly higher in the US than BR (58,4% vs 34,2%, p= 0.005). The mean OS and DFS rates were 29.4 months 15.9 months respectively. There was no difference between OS and DFS of US vs BR patients. N0 patients had significantly longer OS and DFS (p=

Abstract Background Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients. Methods Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS)

Abstract Background Several multicenter randomized controlled trials comparing laparoscopy and conventional open surgery for colon cancer have demonstrated that laparoscopic approach achieved the same oncological results while improving significantly early postoperative outcomes. These trials included few elderly patients, with a median age not exceeding 71 years. However, colon cancer is a disease of the elderly. More than 65% of patients operated on for colon cancer belong to this age group, and this proportion may become more pronounced in the coming years. In current practice, laparoscopy is underused in this population. Methods The CELL (Colectomy for cancer in the Elderly by Laparoscopy or Laparotomy) trial is a multicenter, open-label randomized, 2-arm phase III superiority trial. Patients aged 75 years or older with uncomplicated colonic adenocarcinoma or endoscopically unresectable colonic polyp will be randomized to either colectomy by laparoscopy or laparotomy. The primary endpoint of the study is overall postoperative morbidity, defined as any complication classification occurring up to 30 days after surgery. The secondary endpoints are: 30-day and 90-day postoperative mortality, 30-day readmission rate, quality of surgical resection, health-related quality of life and evolution of geriatric assessment. A 35 to 20% overall postoperative morbidity rate reduction is expected for patients operated on by laparoscopy compared with those who underwent surgery by laparotomy. With a two-sided α risk of 5% and a power of 80% (β = 0.20), 276 patients will be required in total. Discussion To date, no dedicated randomized controlled trial has been conducted to evaluate morbidity after colon cancer surgery by laparoscopy or laparotomy in the elderly and the benefits of laparoscopy is still debated in this context. Thus, a prospective multicenter randomized trial evaluating postoperative outcomes specifically in elderly patients operated on for colon cancer by laparoscopy or laparotomy with curative intent is warranted. If significant, such a study might change the current surgical practices and allow a significant improvement in the surgical management of this population, which will be the vast majority of patients treated for colon cancer in the coming years. Trial registration ClinicalTrials.gov NCT03033719 (January 27, 2017).

Oxaliplatin, a pivotal drug in the management of colorectal cancer, causes chemotherapy-induced peripheral neuropathy (CIPN) in a third of cancer survivors. Based on a previous cross-sectional study assessing oxaliplatin-related sensory CIPN in colorectal cancer survivors, a secondary analysis was designed to explore the possibility that different clusters of patients may co-exist among a cohort of patients with oxaliplatin-related CIPN. Other objectives were to characterize these clusters considering CIPN severity, anxiety, depression, health-related quality of life (HRQOL), patients’ characteristics and oxaliplatin treatments. Among the 96 patients analyzed, three clusters were identified (cluster 1: 52, cluster 2: 34, and cluster 3: 10 patients). Clusters were significantly different according to CIPN severity and the proportion of neuropathic pain (cluster 1: low, cluster 2: intermediate, and cluster 3: high). Anxiety, depressive disorders and HRQOL alteration were lower in cluster 1 in comparison to clusters 2 and 3, but not different between clusters 2 and 3. This study underlines that patients with CIPN are not a homogenous group, and that CIPN severity is associated with psychological distress and a decline of HRQOL. Further studies are needed to explore the relation between clusters and CIPN management.

In the FIGHTDIGO study, digestive cancer patients with dynapenia experienced more chemotherapy-induced neurotoxicities. FIGHTDIGOTOX aimed to evaluate the relationship between pre-therapeutic handgrip strength (HGS) and chemotherapy-induced dose-limiting toxicity (DLT) or all-grade toxicity in digestive cancer patients. HGS measurement was performed with a Jamar dynamometer. Dynapenia was defined according to EWGSOP2 criteria (p = 0.007). Low HGS according to our exploratory threshold was associated with more all-grade asthenia (p = 0.014), anemia (p = 0.006), and asthenia with DLT (p = 0.029). Pre-therapeutic dynapenia was not a predictive factor for overall DLT and neurotoxicity in digestive cancer patients but could be a predictive factor of chemotherapy-induced anemia and asthenia. There is a need to better define the threshold of dynapenia in cancer patients.

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with severe fluoropyrimidines-induced toxicity. As of September 2018, French recommendations call for screening for DPD deficiency by plasma uracil quantification prior to all fluoropyrimidine-based chemotherapy. A dose reduction of fluoropyrimidine is recommended when uracil concentration is equal to or greater than 16 ng/mL. This matched retrospective study assessed the impact of DPD screening on the reduction of severe side effects and on the management of DPD-deficient patients. Using a propensity score, we balanced the factors influencing 5-Fluorouracil (5-FU) toxicity. Then, the severity scores (G3 and G4 severity as well as their frequency) of patients who did not benefit from DPD screening were compared with those of patients who benefited from DPD screening for each treatment cycle (from 1 to 4). Among 349 screened patients, 198 treated patients were included. Among them, 31 (15.7%) had DPD deficiency (median uracilemia 19.8 ng/mL (range: 16.1–172.3)). The median toxicity severity score was higher in the unscreened group for each treatment cycle (0 vs. 1, p < 0.001 at each cycle from 1 to 4) as well as the cumulative score during all courses of treatment (p = 0.028). DPD-deficient patients received a significantly lower dose of 5-FU (p < 0.001). This study suggests that pretherapeutic plasmatic uracil assessment, along with 5-FU dosage adjustment, may be beneficial in reducing 5-FU toxicity in real-life patients.

Abstract Background FIGHTDIGO study has shown the feasibility of handgrip strength (HGS) measurements in 201 consecutive digestive cancer patients undergoing chemotherapy. Objective This study focuses on a secondary aim of FIGHTDIGO study: the relationship between muscle mass and HGS. Design Two consecutive bilateral measures of HGS were performed using a Jamar dynamometer before the start of each chemotherapy. The highest value was chosen for final evaluation. Dynapenia (loss of muscle strength) was defined as HGS 25 kg/m2), < 43 cm2/m2 (in men with a BMI

Aims: The addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has shown promising efficacy in advanced squamous cell carcinoma of the anus (SCCA). Preliminary results of Epitopes-HPV01 study showed a high rate of long-lasting complete response to DCF. The prospective, multicenter, Epitopes-HPV02 trial then confirmed the high efficacy of the modified DCF (mDCF) regimen in terms of complete response rate and long-term survival in metastatic or non-resectable locally advanced recurrent SCCA. Here, we present updated results of the Epitopes-HPV01 and Epitopes-HPV02 studies. Patients & methods: Epitopes-HPV01 is a prospective study performed by the regional cancer network of Franche-Comté, France. Epitopes-HPV02 is a phase II study supported by two French collaborative oncological groups, performed in 25 centers. Both studies included patients with metastatic, or with unresectable local recurrent SCCA, treated with DCF regimen. Results: In Epitopes-HPV01, 51 patients were enrolled between September 2012 and January 2019, and 49 patients were included for analysis; while 69 patients were included between September 2014 and December 2016 in Epitopes-HPV02, and 66 patients for analysis. Pooled analysis of 115 patients showed a median progression-free survival of 12.2 months [95% confidence interval (CI) 10.6–16.1] [11.0 months (9.3–16.0) in -HPV02, and 15.6 months (11.2–34.5) in -HPV01, ( p = 0.06)]. The median overall survival was 39.2 months (26.0–109.1) [36.3 in -HPV02 (25.2–NR), and 61.1 months (21.4–120.0) in -HPV01 ( p = 0.62)]. Objective response rate was 87.7% (90.9% in -HPV02 and 83.3% in -HPV01) with 40.3% of complete response (45.5% in -HPV02 and 33.3% in -HPV01). No differences were observed between standard DCF ( n = 54) and mDCF ( n = 58) in terms of OS ( p = 0.57) and PFS ( p = 0.99). 5-years PFS and OS rates were 24.5% and 44.4%, respectively, in the whole population. No treatment-related death was observed. Conclusion: Updated results of Epitopes-HPV01 and 02 studies, as well as the pooled analysis, confirm mDCF as a standard treatment in patients with advanced SCCA.

Efficacy of immune checkpoint inhibitors (ICI) as monotherapy in 2nd line treatment for gastric or gastro-oesophageal junction (GEJ) adenocarcinoma is low, with no evaluation of efficacy and safety of ICI combined with chemotherapy. The DURIGAST PRODIGE 59 study is a randomised, multicentre, phase II study designed to assess the efficacy and safety of the combination of FOLFIRI + Durvalumab +/− Tremelimumab as 2nd line treatment of patients with advanced gastric/GEJ adenocarcinoma. Here, we report data from the safety run-in phase with FOLFIRI Durvalumab (arm A) or FOLFIRI Durvalumab and Tremelimumab (arm B). Among the 11 patients included, 63.6% experienced at least one grade 3–4 adverse events (AEs) related to the treatment, most frequently neutropenia (36.4%). There was only one immune-related AE (grade 2 hyperthyroidism). Ten serious AEs were described among six patients, but only two were related to the treatment, due to the chemotherapy. One seizure epilepsy related to a brain metastasis was observed, but was not related by the investigator to the treatment. However, the Independent Data Monitoring Committee recommended brain imaging at inclusion. This safety run-in phase demonstrates an expected safety profile of FOLFIRI with Durvalumab +/− Tremelimumab combination allowing the randomised phase II.

Abstract Background FIGHTDIGO study showed the feasibility and acceptability of handgrip strength (HGS) measure in routine in 201 consecutive patients with digestive cancer treated with ambulatory chemotherapy. The present study focuses on the second aim of FIGHTDIGO study: the relationships between pre-therapeutic dynapenia and chemotherapy-induced Dose-Limiting Toxicities (DLT). Methods In this ancillary prospective study, DLT were analyzed in a sub-group of 45 chemotherapy-naive patients. Two bilateral consecutive measures of HGS were performed with a Jamar dynamometer before the first cycle of chemotherapy. Dynapenia was defined as HGS

Abstract Background The squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence is markedly increasing. About 15% of patients are diagnosed at metastatic stage, and more than 20% with a localized disease treated by chemoradiotherapy (CRT) will recur. In advanced SCCA, cisplatin and 5-fluorouracil (CF) combination is the standard option but complete response is a rare event and the prognosis remains poor with most disease progression occurring within the first 12 months. We have previously published the potential role of the addition of docetaxel (D). Among 8 consecutive patients with advanced recurrent SCCA after CRT, the DCF regimen induced a complete response in 4 patients, including 3 pathological complete responses. Then, the Epitopes-HPV02 study was designed to confirm the interest of DCF regimen in SCCA patients. Methods This multicentre phase II trial assesses the DCF regimen in advanced SCCA patients. Main eligibility criteria are: histologically proven SCCA, unresectable locally advanced recurrent or metastatic disease, Eastern Cooperative Oncology Group-performance status (ECOG-PS) vs. ≤ 75 years-old) and ECOG-PS (0 vs. 1). The trial was set up based on a Simon’s optimal two-stage design for phase II trials, allowing an early futility interim analysis. The primary endpoint is the observed progression-free survival (PFS) rate at 12 months from the first DCF cycle. A PFS rate below 10% is considered uninteresting, while a PFS rate above 25% is expected. With a unilateral alpha error of 5% and a statistical power of 90%, 66 evaluable patients should be included. Main secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and the correlation of biomarkers with treatment efficacy. Discussion Since the recommended CF regimen is based in a small retrospective analysis and generates a low rate of complete responses, the Epitopes-HPV02 study will establish a new standard in case of a positive result. Associated biomarker studies will contribute to understand the underlying mechanism of resistance and the role of immunity in SCCA. Trial registration NCT02402842 , EudraCT: 2014–001789-81.

Abstract Background Colorectal cancer is a major public health issue worldwide. Interleukin-17 (IL-17) and Th17 (T-helper cell type 17)-related molecules are involved in tumor development and in resistance to bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody used in association with chemotherapy in metastatic colorectal cancer. Some studies have previously shown that IL-17A and IL-17F polymorphisms, respectively rs2275913 and rs763780, are associated with gastric or colorectal cancer risk. Here we aimed at studying the influence of IL-17A-related individual factors on overall survival and progression-free survival in patients with metastatic colorectal cancer treated with a bevacizumab-based chemotherapy. Methods Pre-treatment serum biomarkers were retrospectively evaluated in 122 metastatic colorectal cancer patients treated by bevacizumab in combination with chemotherapy at 2-weeks intervals in a prospective cohort study (NCT00489697). The polymorphisms of IL-17A and IL-17F were analyzed by polymerase chain reaction - restriction fragment length polymorphism. Serum concentrations of Th17-related cytokines were measured by MultiPlex. The impact of individual parameters on overall survival and progression-free survival was assessed using multivariate Cox models. Results High baseline IL-17A serum concentrations were significantly associated with shorter progression-free survival [p = 0.043]. Other baseline serum Th17-related cytokines and polymorphisms of IL-17 were not associated with overall survival or progression-free survival. Conclusions In this ancillary study, baseline serum IL-17A concentration is the only Th17/IL-17 related factor that was significantly associated with the response of patients with metastatic colorectal cancer to bevacizumab. But this main significant result is highly dependent on one case which, if left out, weakens the data. Other clinical studies are required to confirm this association. Trial registration NCT00489697 . June 20, 2007.

BACKGROUND:Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. EPIdemiology GIST, is an observational multicenter longitudinal follow-up cohort study reporting the prescribing patterns of imatinib in patients with GIST and the impact of the treatment in a real-world (standard clinical) setting. METHODS:Eligible patients had a confirmed diagnosis of unresectable or metastatic KIT-positive GIST and started treatment with imatinib for the first time between May 24, 2002, and June 30, 2010. During routine visits, annual collection of clinical characteristics was requested, i.e., age, GIST stage at diagnosis, history, imatinib treatment duration and dosage, adherence, and concomitant medications. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analyzed using descriptive statistics. RESULTS:Of 151 patients enrolled, imatinib was initiated for 126 patients before enrollment and for 25 patients on the day of enrollment or soon after. The patient characteristics were similar to those in published prospective trials. The estimated 1-, 2-, 3-, and 4-year overall survival rates were 90.4% (95% confidence interval [CI; 84.8%-94.0%]), 84.7% (95% CI [78.1%-89.4%]), 73.0% (95% CI [65.0%-79.4%]), and 60.7% (95% CI [51.4%-68.8%]), respectively. The most common adverse events (AEs) were diarrhea (39%), asthenia (39%), eyelid or periorbital edema (32%), abdominal pain (23%), and anemia (21%). Eight of 126 serious AEs were possibly related to the treatment as assessed by investigators. CONCLUSIONS:Study results showed that patients in real-life populations are generally treated in accordance with national and international clinical recommendations and have outcomes comparable to those of patients in clinical trials.

The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch®) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p = 0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p < 0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.

Malignant hemorrhagic ascites may complicate the terminal evolution of digestive cancers with peritoneal carcinomatosis. It has a bad influence on prognosis and may severely impair patients’ quality of life. Palliative laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) has been proposed to treat debilitating malignant ascites. Two cases of peritoneal carcinomatosis causing hemorrhagic ascites and severe anemia that needed iterative blood transfusions are reported. These patients were treated by laparoscopic HIPEC (mitomycin C and cisplatin with an inflow temperature of 43°C), resulting in cessation of peritoneal bleeding. No postoperative complication or relapse of ascites occurred during the following months. No more blood transfusion was needed. Laparoscopic HIPEC might be an effective and safe therapeutic option to consider in patients with malignant hemorrhagic ascites.

Abstract Since the 5th Assessment Report of the Intergovernmental Panel on Climate Change (AR5) an extended concept of the energetic analysis of climate change including forcings, feedbacks and adjustment processes has become widely adopted. Adjustments are defined as processes that occur in response to the introduction of a climate forcing agent, but that are independent of global‐mean surface temperature changes. Most considered are the adjustments that impact the Earth energy budget and strengthen or weaken the instantaneous radiative forcing due to the forcing agent. Some adjustment mechanisms also impact other aspects of climate not related to the Earth radiation budget. Since AR5 and a following description by Sherwood et al. (2015, https://doi.org/10.1175/bams‐d‐13‐00167.1), much research on adjustments has been performed and is reviewed here. We classify the adjustment mechanisms into six main categories, and discuss methods of quantifying these adjustments in terms of their potentials, shortcomings and practicality. We furthermore describe aspects of adjustments that act beyond the energetic framework, and we propose new ideas to observe adjustments or to make use of observations to constrain their representation in models. Altogether, the problem of adjustments is now on a robust scientific footing, and better quantification and observational constraint is possible. This allows for improvements in understanding and quantifying climate change.

Background Pulmonary arterial hypertension (PAH) ultimately leads to right ventricular failure and premature death. The identification of circulating biomarkers with prognostic utility is considered a priority. As chronic inflammation is recognized as key pathogenic driver, we sought to identify inflammation‐related circulating proteins that add incremental value to current risk stratification models for long‐term survival in patients with PAH. Methods and Results Plasma levels of 384 inflammatory proteins were measured with the proximity extension assay technology in patients with PAH (n=60) and controls with normal hemodynamics (n=28). Among these, 51 analytes were significantly overexpressed in the plasma of patients with PAH compared with controls. Cox proportional hazard analyses and C‐statistics were performed to assess the prognostic value and the incremental prognostic value of differentially expressed proteins. A panel of 6 proteins (CRIM1 [cysteine rich transmembrane bone morphogenetic protein regulator 1], HGF [hepatocyte growth factor], FSTL3 [follistatin‐like 3], PLAUR [plasminogen activator, urokinase receptor], CLSTN2 [calsyntenin 2], SPON1 [spondin 1]) were independently associated with death/lung transplantation at the time of PAH diagnosis after adjustment for the 2015 European Society of Cardiology/European Respiratory Society guidelines, the REVEAL (Registry to Evaluate Early and Long‐Term PAH Disease Management) 2.0 risk scores, and the refined 4‐strata risk assessment. CRIM1, PLAUR, FSTL3, and SPON1 showed incremental prognostic value on top of the predictive models. As determined by Western blot, FSTL3 and SPON1 were significantly upregulated in the right ventricle of patients with PAH and animal models (monocrotaline‐injected and pulmonary artery banding‐subjected rats). Conclusions In addition to revealing new actors likely involved in cardiopulmonary remodeling in PAH, our screening identified promising circulating biomarkers to improve risk prediction in PAH, which should be externally confirmed.

Abstract Estimation of the perturbation to the Earth's energy budget by contrail outbreaks is required for estimating the climate impact of aviation and verifying the climate benefits of proposed contrail avoidance strategies such as aircraft rerouting. Here we identified two successive large‐scale contrail outbreaks developing in clear‐sky conditions in geostationary and polar‐orbiting satellite infrared images of Western Europe lasting from 22–23 June 2020. Their hourly cloud radiative effect, obtained using geostationary satellite cloud retrievals and radiative transfer calculations, is negative or weakly positive during daytime and positive during nighttime. The cumulative energy forcing of the two outbreaks is 7 PJ and −8.5 PJ, with uncertainties of 3 PJ, stemming each from approximately 15–20 flights over periods of 19 and 7 hr, respectively. This study suggests that an automated quantification of contrail outbreak radiative effect is possible, at least for contrails forming in clear sky conditions.

The insula is often considered the fifth lobe of the brain and is increasingly recognized as one of the most connected regions in the brain, with widespread connections to cortical and subcortical structures. As a follow-up to our previous tractography work, we investigated the resting-state functional connectivity (rsFC) profiles of insular subregions and assessed their concordance with structural connectivity. We used the CONN toolbox to analyze the rsFC of the same 19 insular regions of interest (ROIs) we used in our prior tractography work and regrouped them into six subregions based on their connectivity pattern similarity. Our analysis of 50 healthy participants confirms the known broad connectivity of the insula and shows novel and specific whole-brain and intra-connectivity patterns of insular subregions. By examining such subregions, our findings provide a more detailed pattern of connectivity than prior studies that may prove useful for comparison between patients.

Abstract Carbon dioxide removal is essential for achieving the Paris Agreement targets. Here we compare bioenergy with carbon capture and storage (BECCS) and afforestation and reforestation in terms of their carbon removal potentials and impacts on carbon cycle and surface climate under an overshoot pathway using Earth System Model simulations. Althought initially BECCS can remove more carbon in allocated areas, carbon dioxide emissions from land use change regionally offset the benefits of BECCS compared to afforestation, depending on the carbon capture and storage efficiency and timescales required to achieve mitigation targets. Furthermore, BECCS may cause local cooling in high- and mid-latitude subregions of the Northern Hemisphere dominated by albedo effects, while afforestation causes local cooling in subtropical and tropical subregions through non-radiative mechanisms. The decision to allocate land to bioenergy crops or forests should account for their respective carbon removal potentials, modulated by carbon-concentration and carbon-climate feedbacks, and the effects on climate.

Abstract With the urgent need to implement the EU countries pledges and to monitor the effectiveness of Green Deal plan, Monitoring Reporting and Verification tools are needed to track how emissions are changing for all the sectors. Current official inventories only provide annual estimates of national CO2 emissions with a lag of 1+ year which do not capture the variations of emissions due to recent shocks including COVID lockdowns and economic rebounds, war in Ukraine. Here we present a near-real-time country-level dataset of daily fossil fuel and cement emissions from January 2019 through December 2021 for 27 EU countries and UK, which called Carbon Monitor Europe. The data are calculated separately for six sectors: power, industry, ground transportation, domestic aviation, international aviation and residential. Daily CO2 emissions are estimated from a large set of activity data compiled from different sources. The goal of this dataset is to improve the timeliness and temporal resolution of emissions for European countries, to inform the public and decision makers about current emissions changes in Europe.

Abstract Background Viral nervous necrosis (VNN) is a major disease that affects European sea bass, and understanding the biological mechanisms that underlie VNN resistance is important for the welfare of farmed fish and sustainability of production systems. The aim of this study was to identify genomic regions and genes that are associated with VNN resistance in sea bass. Results We generated a dataset of 838,451 single nucleotide polymorphisms (SNPs) identified from whole-genome sequencing (WGS) in the parental generation of two commercial populations (A: 2371 individuals and B: 3428 individuals) of European sea bass with phenotypic records for binary survival in a VNN challenge. For each population, three cohorts were submitted to a red-spotted grouper nervous necrosis virus (RGNNV) challenge by immersion and genotyped on a 57K SNP chip. After imputation of WGS SNPs from their parents, quantitative trait loci (QTL) were mapped using a Bayesian sparse linear mixed model (BSLMM). We found several QTL regions that were specific to one of the populations on different linkage groups (LG), and one 127-kb QTL region on LG12 that was shared by both populations and included the genes ZDHHC14, which encodes a palmitoyltransferase, and IFI6/IFI27-like, which encodes an interferon-alpha induced protein. The most significant SNP in this QTL region was only 1.9 kb downstream of the coding sequence of the IFI6/IFI27-like gene. An unrelated population of four large families was used to validate the effect of the QTL. Survival rates of susceptible genotypes were 40.6% and 45.4% in populations A and B, respectively, while that of the resistant genotype was 66.2% in population B and 78% in population A. Conclusions We have identified a genomic region that carries a major QTL for resistance to VNN and includes the ZDHHC14 and IFI6/IFI27-like genes. The potential involvement of the interferon pathway, a well-known anti-viral defense mechanism in several organisms (chicken, human, or fish), in survival to VNN infection is of particular interest. Our results can lead to major improvements for sea bass breeding programs through marker-assisted genomic selection to obtain more resistant fish.

Abstract Background Around 50% of gastric cancers are diagnosed at an advanced stage. Several chemotherapy regimens are now internationally validated. Few data are available on the routine daily management of advanced gastric or gastroesophageal junction cancers. We aimed to describe chemotherapy practices, tolerance, and efficacy overall survival (OS) and Progression free survival (PFS) in a prospective French cohort. Methods Patients starting palliative chemotherapy were prospectively enrolled in 49 French centres. The primary objective was to report and describe patients' characteristics and treatment strategies. Secondary objectives were OS, PFS, objective response rate, adverse events rate, performance status deterioration during the chemotherapy. Results A total of 182 patients were included; 179 were analysed. Most patients received platinium‐based chemotherapy as the first treatment and FOLFIRI as second; 62.0% of patients received a second line, and 32.4% a third line. More than two thirds of Her2‐positive patients were first treated with trastuzumab. The FOLFIRI regimen was the most frequently used second‐line therapy. Median OS was 13.3 months, similar whatever the chemotherapy or combinations used in the first line. One‐ and 2‐year OS increased with the number of chemotherapy lines received, from respectively 24.7% and 5.7% (1 line), to 46.9% and 12.4% (2 lines) and 88.1% and 29.9% (3 or more lines) (p

Transitioning to a hydrogen economy has the potential to mitigate carbon dioxide emissions. The hydrogen leakage rate and the production pathways appear, based on simulations with a global model, as key leverages to reach a clear climate benefit from a large-scale transition to a hydrogen economy.

Measurement(s) carbon dioxide emissions Technology Type(s) fossil fuel consumption

Abstract The Radiative Forcing Model Intercomparison Project (RFMIP) allows estimates of effective radiative forcing (ERF) in the Coupled Model Intercomparison Project phase six (CMIP6). We analyze the RFMIP output, including the new experiments from models that use the same parameterization for anthropogenic aerosols (RFMIP‐SpAer), to characterize and better understand model differences in aerosol ERF. We find little changes in the aerosol ERF for 1970–2014 in the CMIP6 multi‐model mean, which implies greenhouse gases primarily explain the positive trend in the total anthropogenic ERF. Cloud‐mediated effects dominate the present‐day aerosol ERF in most models. The results highlight a regional increase in marine cloudiness due to aerosols, despite suppressed cloud lifetime effects in that RFMIP‐SpAer experiment. Negative cloud‐mediated effects mask positive direct effects in many models, which arise from strong anthropogenic aerosol absorption. The findings suggest opportunities to better constrain simulated ERF by revisiting the optical properties and long‐range transport of aerosols.

Summary: Historical genomes can provide important insights into recent genomic changes in horses, especially the development of modern breeds. In this study, we characterized 8.7 million genomic variants from a panel of 430 horses from 73 breeds, including newly sequenced genomes from 20 Clydesdales and 10 Shire horses. We used this modern genomic variation to impute the genomes of four historically important horses, consisting of publicly available genomes from 2 Przewalski’s horses, 1 Thoroughbred, and a newly sequenced Clydesdale. Using these historical genomes, we identified modern horses with higher genetic similarity to those in the past and unveiled increased inbreeding in recent times. We genotyped variants associated with appearance and behavior to uncover previously unknown characteristics of these important historical horses. Overall, we provide insights into the history of Thoroughbred and Clydesdale breeds and highlight genomic changes in the endangered Przewalski’s horse following a century of captive breeding.

Summary: Background: Omega-3 fatty acids are critical for neuropsychological functioning. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. The potential benefit on adolescent neurodevelopment of consuming walnuts, a source of omega-3 alpha-linolenic acid (ALA), remains unclear. Methods: We conducted a 6-month multi-school-based randomised controlled nutrition intervention trial to assess whether walnut consumption has beneficial effects on the neuropsychological and behavioural development of adolescents. The study took place between 04/01/2016 and 06/30/2017 in twelve different high schools in Barcelona, Spain (ClinicalTrials.gov Identifier: NCT02590848). A total of 771 healthy teenagers aged 11–16 years were randomised into two equal groups (intervention or control). The intervention group received 30 g/day of raw walnut kernels to be incorporated into their diet for 6 months. Multiple primary endpoints concerning neuropsychological (working memory, attention, fluid intelligence, and executive function) and behavioural (socio-emotional and attention deficit hyperactivity disorder [ADHD] symptoms) development were assessed at baseline and after intervention. Red blood cell (RBC) ALA status was determined at baseline and 6 months as a measure of compliance. Main analyses were based on intention-to-treat using a linear mixed-effects model. A per-protocol effect of the intervention was analysed using inverse-probability weighting to account for post-randomisation prognostic factors (including adherence) using generalised estimating equations. Findings: In intention-to-treat analyses, at 6 months there were no statistically significant changes between the intervention and control groups for all primary endpoints. RBC ALA (%) significantly increased only in the intervention group, coefficient = 0.04 (95% Confidence Interval (CI) = 0.03, 0.06; p

ABSTRACT Enterococcus cecorum is an emerging pathogen responsible for osteomyelitis, spondylitis, and femoral head necrosis causing animal suffering and mortality and requiring antimicrobial use in poultry. Paradoxically, E. cecorum is a common inhabitant of the intestinal microbiota of adult chickens. Despite evidence suggesting the existence of clones with pathogenic potential, the genetic and phenotypic relatedness of disease-associated isolates remains little investigated. Here, we sequenced and analyzed the genomes and characterized the phenotypes of more than 100 isolates, the majority of which were collected over the last 10 years from 16 French broiler farms. Comparative genomics, genome-wide association studies, and the measured susceptibility to serum, biofilm-forming capacity, and adhesion to chicken type II collagen were used to identify features associated with clinical isolates. We found that none of the tested phenotypes could discriminate the origin of the isolates or the phylogenetic group. Instead, we found that most clinical isolates are grouped phylogenetically, and our analyses selected six genes that discriminate 94% of isolates associated with disease from those that are not. Analysis of the resistome and the mobilome revealed that multidrug-resistant clones of E. cecorum cluster into a few clades and that integrative conjugative elements and genomic islands are the main carriers of antimicrobial resistance. This comprehensive genomic analysis shows that disease-associated clones of E. cecorum belong mainly to one phylogenetic clade. IMPORTANCE Enterococcus cecorum is an important pathogen of poultry worldwide. It causes a number of locomotor disorders and septicemia, particularly in fast-growing broilers. Animal suffering, antimicrobial use, and associated economic losses require a better understanding of disease-associated E. cecorum isolates. To address this need, we performed whole-genome sequencing and analysis of a large collection of isolates responsible for outbreaks in France. By providing the first data set on the genetic diversity and resistome of E. cecorum strains circulating in France, we pinpoint an epidemic lineage that is probably also circulating elsewhere that should be targeted preferentially by preventive strategies in order to reduce the burden of E. cecorum-related diseases.

Measurement(s) Climate response Technology Type(s) Climate models Sample Characteristic - Environment The climate system

There is an increasing recognition of the crucial role of the right ventricle (RV) in determining the functional status and prognosis in multiple conditions. In the past decade, the epigenetic regulation (DNA methylation, histone modification, and non-coding RNAs) of gene expression has been raised as a critical determinant of RV development, RV physiological function, and RV pathological dysfunction. We thus aimed to perform an up-to-date review of the literature, gathering knowledge on the epigenetic modifications associated with RV function/dysfunction. Therefore, we conducted a systematic review of studies assessing the contribution of epigenetic modifications to RV development and/or the progression of RV dysfunction regardless of the causal pathology. English literature published on PubMed, between the inception of the study and 1 January 2023, was evaluated. Two authors independently evaluated whether studies met eligibility criteria before study results were extracted. Amongst the 817 studies screened, 109 studies were included in this review, including 69 that used human samples (e.g., RV myocardium, blood). While 37 proposed an epigenetic-based therapeutic intervention to improve RV function, none involved a clinical trial and 70 are descriptive. Surprisingly, we observed a substantial discrepancy between studies investigating the expression (up or down) and/or the contribution of the same epigenetic modifications on RV function or development. This exhaustive review of the literature summarizes the relevant epigenetic studies focusing on RV in human or preclinical setting.

Bioenergy crops has been proposed as a climate mitigation measure, but how the biophysical effects of large-scale cultivation would influence the climate is not well known. Here, the authors use models to show that large-scale cultivation could cool the global land by 0.03 to 0.08 °C.

New climate models show a stronger warming with greenhouse gas emissions than is suggested by observations. Here, the authors argue that internal variability of the Atlantic Ocean may have dampened some of the recent warming, which could explain part of the disagreement between the newer models and observations.

Phenotypic plasticity is a key component of the ability of organisms to respond to changing environmental conditions. In this study, we aimed to study the establishment of DNA methylation marks in response to an environmental stress in rainbow trout and to assess whether these marks depend on the genetic background. The environmental stress chosen here was temperature, a known induction factor of epigenetic marks in fish. To disentangle the role of epigenetic mechanisms such as DNA methylation in generating phenotypic variations, nine rainbow trout isogenic lines with no genetic variability within a line were used. For each line, half of the eggs were incubated at standard temperature (11°C) and the other half at high temperature (16°C), from eyed-stage to hatching. In order to gain a first insight into the establishment of DNA methylation marks in response to an early temperature regime (control 11°C vs. heated 16°C), we have studied the expression of 8 dnmt3 (DNA methyltransferase) genes, potentially involved in de novo methylation, and analysed global DNA methylation in the different rainbow trout isogenic lines using LUMA (LUminometric Methylation Assay). Finally, finer investigation of genome-wide methylation patterns was performed using EpiRADseq, a reduced-representation library approach based on the ddRADseq (Double Digest Restriction Associated DNA) protocol, for six rainbow trout isogenic lines. We have demonstrated that thermal history during embryonic development alters patterns of DNA methylation, but to a greater or lesser extent depending on the genetic background.

Multi-annual to decadal changes in climate are accompanied by changes in extreme events that cause major impacts on society and severe challenges for adaptation. Early warnings of such changes are now potentially possible through operational decadal predictions. However, improved understanding of the causes of regional changes in climate on these timescales is needed both to attribute recent events and to gain further confidence in forecasts. Here we document the Large Ensemble Single Forcing Model Intercomparison Project that will address this need through coordinated model experiments enabling the impacts of different external drivers to be isolated. We highlight the need to account for model errors and propose an attribution approach that exploits differences between models to diagnose the real-world situation and overcomes potential errors in atmospheric circulation changes. The experiments and analysis proposed here will provide substantial improvements to our ability to understand near-term changes in climate and will support the World Climate Research Program Lighthouse Activity on Explaining and Predicting Earth System Change.

Vanilla planifolia, the species cultivated to produce one of the world’s most popular flavors, is highly prone to partial genome endoreplication, which leads to highly unbalanced DNA content in cells. We report here the first molecular evidence of partial endoreplication at the chromosome scale by the assembly and annotation of an accurate haplotype-phased genome of V. planifolia. Cytogenetic data demonstrated that the diploid genome size is 4.09 Gb, with 16 chromosome pairs, although aneuploid cells are frequently observed. Using PacBio HiFi and optical mapping, we assembled and phased a diploid genome of 3.4 Gb with a scaffold N50 of 1.2 Mb and 59 128 predicted protein-coding genes. The atypical k-mer frequencies and the uneven sequencing depth observed agreed with our expectation of unbalanced genome representation. Sixty-seven percent of the genes were scattered over only 30% of the genome, putatively linking gene-rich regions and the endoreplication phenomenon. By contrast, low-coverage regions (non-endoreplicated) were rich in repeated elements but also contained 33% of the annotated genes. Furthermore, this assembly showed distinct haplotype-specific sequencing depth variation patterns, suggesting complex molecular regulation of endoreplication along the chromosomes. This high-quality, anchored assembly represents 83% of the estimated V. planifolia genome. It provides a significant step toward the elucidation of this complex genome. To support post-genomics efforts, we developed the Vanilla Genome Hub, a user-friendly integrated web portal that enables centralized access to high-throughput genomic and other omics data and interoperable use of bioinformatics tools.

Airlines optimize flight trajectories in order to minimize their operational costs, of which fuel consumption is a large contributor. It is known that flight trajectories are not fuel-optimal because of airspace congestion and restrictions, safety regulations, bad weather and other operational constraints. However, the extent to which trajectories are not fuel-optimal (and therefore CO2-optimal) is not well known. In this study, we present two methods for optimizing the flight cruising time by taking best advantage of the wind pattern at a given flight level and for constant airspeed. We test these methods against actual flight trajectories recorded under the In-service Aircraft for a Global Observing System (IAGOS) programme. One method is more robust than the other (computationally faster) method, but when successful, the two methods agree very well with each other, with optima generally within the order of 0.1%. The IAGOS actual cruising trajectories are on average 1% longer than the computed optimal for the transatlantic route, which leaves little room for improvement given that by construction the actual trajectory cannot be better than our optimum. The average degree of non-optimality is larger for some other routes and can be up to 10%. On some routes, there are also outlier flights that are not well optimized; however, the reason for this is not known.

The evolutionary and domestication history of apricots is poorly understood. Here, the authors provide four apricot high-quality genome assemblies, the genomes of 578 accessions from natural and cultivated populations, and show that Chinese and European apricots constitute two different gene pools, resulting from independent domestication events.

China has pledged to achieve carbon neutrality in 2060. Here the authors find a promising option to abate 1.0 Gt CO2-eq yr− 1 of carbon emissions at a marginal cost of $69 (t CO2-eq)−1 by retrofitting 222 GW of coal power plants to co-fire with biomass and upgrading to CCS operation across 2836 counties in China.

Abstract Background The impact of individual genetic and genomic variations on immune responses is an emerging lever investigated in vaccination strategies. In our study, we used genetic and pre-vaccination blood transcriptomic data to study vaccine effectiveness in pigs. Results A cohort of 182 Large White pigs was vaccinated against Mycoplasma hyopneumoniae (M. hyo) at weaning (28 days of age), with a booster 21 days later. Vaccine response was assessed by measuring seric M. hyo antibodies (Ab) at 0 (vaccination day), 21 (booster day), 28, 35, and 118 days post-vaccination (dpv). Inter-individual variability of M. hyo Ab levels was observed at all time points and the corresponding heritabilities ranged from 0.46 to 0.57. Ab persistence was higher in females than in males. Genome-wide association studies with a 658 K SNP panel revealed two genomic regions associated with variations of M. hyo Ab levels at 21 dpv at positions where immunity-related genes have been mapped, DAB2IP on chromosome 1, and ASAP1, CYRIB and GSDMC on chromosome 4. We studied covariations of Ab responses with the pre-vaccination blood transcriptome obtained by RNA-Seq for a subset of 82 pigs. Weighted gene correlation network and differential expression analyses between pigs that differed in Ab responses highlighted biological functions that were enriched in heme biosynthesis and platelet activation for low response at 21 dpv, innate antiviral immunity and dendritic cells for high response at 28 and 35 dpv, and cell adhesion and extracellular matrix for high response at 118 dpv. Sparse partial least squares discriminant analysis identified 101 genes that efficiently predicted divergent responders at all time points. We found weak negative correlations of M. hyo Ab levels with body weight traits, which revealed a trade-off that needs to be further explored. Conclusions We confirmed the influence of the host genetics on vaccine effectiveness to M. hyo and provided evidence that the pre-vaccination blood transcriptome co-varies with the Ab response. Our results highlight that both genetic markers and blood biomarkers could be used as potential predictors of vaccine response levels and more studies are required to assess whether they can be exploited in breeding programs.