Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.

BACKGROUND: Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. RESULTS: A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels. CONCLUSIONS: Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).

Intraperitoneal administration of carcinoembryonic antigen-directed chimeric antigen receptor T cells is a robust delivery route for effective treatment of peritoneal carcinomatosis from colorectal cancer in pre-clinical study.

BACKGROUND AIMS: Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a highly challenging disease to treat. Systemic chimeric antigen receptor (CAR) T cells have shown impressive efficacy in hematologic malignancies but have been less effective in solid tumors. We explored whether intraperitoneal (i.p.) administration of CAR T cells could provide an effective and robust route of treatment for PC from CRC. METHODS: We generated second-generation carcinoembryonic antigen (CEA)-specific CAR T cells. Various animal models of PC with i.p. and extraperitoneal metastasis were treated by i.p. or intravenous (i.v.) administration of CEA CAR T cells. RESULTS: Intraperitoneally administered CAR T cells exhibited superior anti-tumor activity compared with systemic i.v. cell infusion in an animal model of PC. In addition, i.p. administration conferred a durable effect and protection against tumor recurrence and exerted strong anti-tumor activity in an animal model of PC with metastasis in i.p. or extraperitoneal organs. Moreover, compared with systemic delivery, i.p. transfer of CAR T cells provided increased anti-tumor activity in extraperitoneal tumors without PC. This phenomenon was further confirmed in an animal model of pancreatic carcinoma after i.p. administration of our newly constructed prostate stem cell antigen-directed CAR T cells. CONCLUSIONS: Taken together, our data suggest that i.p. administration of CAR T cells may be a robust delivery route for effective treatment of cancer.

Standardizing In Vitro ß-Lactam Antibiotic Allergy Testing with Synthetic IgE.

The global prevalence of ß-lactam allergy poses a major challenge in administering first-line antibiotics, such as penicillins, to a significant portion of the population. The lack of ß-lactam IgE antibody pools with defined selectivity hampers the standardization and validation of in vitro assays for ß-lactam allergy testing. To address this limitation, this study introduces a synthetic IgE specific to ß-lactam antibiotics as a valuable tool for drug allergy research and diagnostic tests. Using phage display technology, we constructed a library of human single-chain antibody fragments (scFv) to target the primary determinant of amoxicillin, a widely used ß-lactam antibiotic. Subsequently, we produced a complete human synthetic IgE molecule using the highly efficient baculovirus expression vector system. This synthetic IgE molecule served as a standard in an in vitro chemiluminescence immunoassay for ß-lactam antibiotic allergy testing. Our results demonstrated a detection limit of 0.05 IU/mL (0.63 pM), excellent specificity (100%), and a four-fold higher clinical sensitivity (73%) compared to the in vitro reference assay when testing a cohort of 150 serum samples. These findings have significant implications for reliable interlaboratory comparison studies, accurate labeling of allergic patients, and combating the global public health threat of antimicrobial resistance. Furthermore, by serving as a valuable trueness control material, the synthetic IgE facilitates the standardization of diagnostic tests for ß-lactam allergy and demonstrates the potential of utilizing this synthetic strategy as a promising approach for generating reference materials in drug allergy research and diagnostics.

On the Role of N-Heterocyclic Carbene Salts in Alkyl Radical Generation from Alkyl Alcohols: A Computational Study.

Formation of carbon-carbon bonds through cross-coupling reactions using readily available substrates, like alcohols, is crucial for modern organic chemistry. Recently, direct alkyl alcohol functionalization has been achieved by the use of N-Heterocyclic Carbene (NHC) salts via in situ formation of an alcohol-NHC adduct and its activation by a photoredox catalyst to generate carbon-centered alkyl radicals. Experimentally, only electron deficient NHC activators work but the reasons of this behavior remain underexplored. Herein, a DFT computational study of the mechanism of alcohol activation using up to seven NHC salts is performed to shed light into the influence of their electronic properties in the alkyl radical formation. This study demonstrates that four reaction steps are involved in the transformation and characterizes how the electronic properties of the NHC salt affect each step. A fine balance of the NHC electron-richness is proved to be determinant for this transformation.

Evaluating the potential of biodiversity offsets to achieve net gain.

Evaluating the outcomes and tracking the trajectory of biodiversity offsets is essential to demonstrating their effectiveness as a mechanism to conciliate development and conservation. We reviewed the literature to determine the principles that should underpin biodiversity offset planning and the criteria for offset evaluation at the project level. According to the literature, the core principles of equivalence, additionality, and permanence are used as criteria to evaluate conservation outcomes of offsets. We applied the criteria to evaluate offsets of a large iron ore mining project in the Atlantic Forest in Brazil. We examined equivalence in terms of the amount of area per biodiversity value affected and fauna and flora similarity, additionality in terms of landscape connectivity, and permanence in terms of guarantees to ensure protection and restoration offsets lasting outcomes. We found an offset ratio (amount of affected area:offset area) of 1:1.8 for forests and 1:2 for grasslands. Ecological equivalence (i.e., similarity between affected and offset areas) was found for forested areas, but not for ferruginous rupestrian grasslands or for fauna. Landscape metrics showed that connectivity improved relative to the preproject situation as a result of locating restoration offsets in the largest and best-connected forest patch. Permanence of offsets was addressed by establishing covenants and management measures, but financial guarantees to cover maintenance costs after mine closure were lacking. Offsets should be equivalent in type and size, provide conservation outcomes that would not be obtained without them (additionality), and be lasting (permanence). To monitor and evaluate offsets, it is necessary to determine how well these 3 principles are applied in the planning, implementation, and maintenance of offsets. Achieving measurable conservation outcomes from offsets is a long-term endeavor that requires sustained management support, and is information intensive. Thus, offsets require ongoing monitoring and evaluation as well as adaptive management.

Evaluación del potencial de las compensaciones por biodiversidad para obtener ganancias netas Resumen La evaluación de resultados y el rastreo de la trayectoria de las compensaciones por biodiversidad son esenciales para demostrar su efectividad como mecanismo de conciliación entre el desarrollo y la conservación. Revisamos la literatura para determinar los principios que deberían sustentar los planes de compensación y los criterios para evaluarla a nivel de proyecto. Según la literatura, se usan los principios nucleares de equivalencia, adicionalidad y permanencia como criterio para evaluar los resultados de conservación de las compensaciones. Aplicamos este criterio para evaluar las compensaciones de un gran proyecto minero de mineral de hierro en el Bosque Atlántico de Brasil. Analizamos la equivalencia en términos de cantidad de área por valor de biodiversidad afectado y similitudes entre la flora y fauna; la adicionalidad en términos de conectividad de paisaje; y la permanencia en términos de las garantías que aseguran que las compensaciones tengan resultados longevos de restauración y protección. Descubrimos una proporción en las compensaciones (cantidad del área afectada:área de compensación) de 1:1.8 para los bosques y de 1:2 en los campos naturales. Encontramos equivalencias ecológicas (es decir, la similitud entre las áreas afectadas y las de compensación) para las áreas boscosas, pero no para los campos rupestres ferruginosos ni para la fauna. Las medidas del paisaje mostraron que la conectividad mejoró en relación a la situación previa al proyecto gracias a la ubicación de las compensaciones por restauración en los fragmentos de bosque más grandes y mejor conectados. Establecimos Contractos y medidas de manejo fueron establecidos la permanencia de las compensaciones, pero las garantías económicas para cubrir los costos de mantenimiento después del cierre de la mina no están suficientemente garantizadas. Las compensaciones deberían ser iguales en tipo y tamaño (equivalencia), proporcionar resultados de conservación que no se obtendrían en su ausencia (adicionalidad) y ser duraderas (permanencia). Se necesita determinar cómo se aplican estos tres principios en la planeación, implementación y mantenimiento de las compensaciones para poder monitorearlas. Si se quieren lograr resultados medibles de conservación, se necesita que el manejo cuente con un apoyo mantenido y a largo plazo que contenga con información intensiva. Por lo tanto, las compensaciones requieren un monitoreo y evaluación continua además del manejo adaptativo.

Investigating the Mechanism of Ni-Catalyzed Coupling of Photoredox-Generated Alkyl Radicals and Aryl Bromides: A Computational Study.

Photoredox catalysis has emerged as an alternative to classical cross-coupling reactions, promoting new reactivities. Recently, the use of widely abundant alcohols and aryl bromides as coupling reagents was demonstrated to promote efficient coupling through the Ir/Ni dual photoredox catalytic cycle. However, the mechanism underlying this transformation is still unexplored, and here we report a comprehensive computational study of the catalytic cycle. We have shown that nickel catalysts can promote this reactivity very efficiently through DFT calculations. Two different mechanistic scenarios were explored, suggesting that two catalytic cycles operate simultaneously depending on the concentration of the alkyl radical.

Bispecific Single-Domain Antibodies as Highly Standardized Synthetic Calibrators for Immunodiagnosis.

Commonly, serological immunoassays and diagnostic kits include reference standard reagents (calibrators) that contain specific antibodies to be measured, which are used for the quantification of unknown antibodies present in the sample. However, in some cases, such as the diagnosis of allergies or autoimmune diseases, it is often difficult to have sufficient quantities of these reference standards, and there are limitations to their lot-to-lot reproducibility and standardization over time. To overcome this difficulty, this study introduces the use of surrogate recombinant calibrators formulated on the basis of two single-domain antibodies (nanobodies) combined through a short peptide linker to produce a recombinant bispecific construct. One of the nanobodies binds to the cognate analyte of the target antibody and the second is specific for the paratope of the secondary detecting antibody. The bispecific nanobody inherits the outstanding properties of stability and low-cost production by bacterial fermentation of the parent nanobodies, and once calibrated against the biological reference standard, it can be reproduced indefinitely from its sequence in a highly standardized manner. As a proof of concept, we present the generation and characterization of two bispecific calibrators with potential application for the diagnosis of allergy against the antibiotics aztreonam and amoxicillin in humans.

Cytoreductive Surgery With or Without HIPEC After Neoadjuvant Chemotherapy in Ovarian Cancer: A Phase 3 Clinical Trial.

BACKGROUND: Cytoreductive surgery (CRS) and administration of hyperthermic intraperitoneal chemotherapy (HIPEC) have shown their efficacy in multiple malignancies and also could offer a prognostic benefit for patients with advanced ovarian cancer. METHODS: A prospective, single-center, parallel-group, randomized phase 3 clinical trial analyzed patients with a diagnosis of carcinomatosis from ovarian cancer treated with neoadjuvant systemic chemotherapy (NACT). In this trial, 71 patients were randomized to receive CRS alone (36 patients) or CRS with HIPEC (35 patients) using cisplatin (75 mg/m2 for 60 min at 42 °C). The primary end point was disease-free survival (DFS). Overall survival (OS), morbidity, and quality of life (QoL) were the secondary end points. RESULTS: During a median follow-up period of 32 months, the median DFS was 12 months in the control group (CRS) and 18 months in the experimental group (CRS and HIPEC). The findings showed HIPEC to be an independent protective factor against the development of recurrence (hazard ratio [HR], 0.12, 95 % confidence interval [CI], 0.02-0.89; p = 0.038). The median OS was 45 months in the control group and 52 months in the experimental group. The respective morbidity rates for any grade (1 to 5) were respectively 58.3 % and 45.7 % (p > 0.05), with a mortality rates of 2.8 % and 2.9 % (p > 0.05). In the dimensions evaluated, CRS with or without HIPEC had no impact on QoL. CONCLUSIONS: For patients who had advanced ovarian cancer treated with NACT, CRS and HIPEC was associated with better DFS and OS, but without a difference in postoperative morbidity, mortality, or in the QoL evaluation.

OVA-LEAK: Prognostic score for colo-rectal anastomotic leakage in patients undergoing ovarian cancer surgery.

OBJECTIVE: The objective of the present study was to define and validate an anastomotic leak prognostic score based on previously described and reported anastomotic leak risk factors (OVA-LEAK: https://n9.cl/ova-leakscore) and to establish if the use of OVA-LEAK score is better than clinical criteria (surgeon's choice) selecting anastomosis to be protected with a diverting ileostomy. MATERIAL & METHODS: This is a retrospective, multicentre cohort study that included patients who underwent cytoreductive surgery for primary advanced or relapsed ovarian cancer with colorectal resection and anastomosis between January 2011 and June 2021. Data from patients already included in the previous predictive model were not considered in the present analysis. To validate the performance of our logistic regression model, we used the OVA-LEAK formula (Annex I: https://n9.cl/ova-leakscore) for estimating leakage probabilities in a new independent cohort. Then, receiver operating characteristic (ROC) analysis was performed and area under the curve (AUC) was used to measure the performance of the model. Additionally, the Brier score was also estimated. 95% confidence intervals (CI) for each of the estimated performance measures were also calculated. RESULTS: 848 out of 1159 recruited patients were finally included in the multivariable logistic regression model validation. The AUC of the new cohort was 0.63 for predicting anastomotic leak. Considering a cut-off point of 22.1% to be 'positive' (to get a leak) this would provide a sensitivity of 0.45, specificity of 0.80, positive predictive value of 0.09 and negative predictive value of 0.97 for anastomotic leak. If we consider this cut-off point to select patients at risk of leak for bowel diversion, up to 22.5% of the sampled patients would undergo a diverting ileostomy and 47% (18/40) of the anastomotic leaks would be 'protected' with the stoma. Nevertheless, if we consider only the 'clinical criteria' for performing or not a diverting ileostomy, only 12.5% (5/40) of the leaks would be 'protected' with a stoma, with a rate of diverting ileostomy of up to 24.3%. CONCLUSIONS: Compared with subjective clinical criteria, the use of a predictive model for anastomotic leak improves the selection of patients who would benefit from a diverting ileostomy without increasing the rate of stoma use.

Acute renal disease in patients with ovarian peritoneal carcinomatosis treated with cytoreduction and HIPEC: the influence of surgery and the cytostatic agent used.

BACKGROUND: The main objective of this study was to evaluate the differences between cisplatin and paclitaxel in the development of postoperative renal toxicity, using as a reference the RIFLE (Risk, Injury, Insufficiency, Loss, and End-stage renal function) and AKIN (Acute Kidney Injury Network) criteria in patients with primary or recurrent ovarian cancer with peritoneal dissemination treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: One hundred fifty-two patients who were treated between December 2007 and June 2017 were analyzed. RESULTS: Patients who received previous platinum-based chemotherapy had higher baseline creatinine levels than those who had not (p = 0.05). A total of 11 (7.2%) and 4 (2.6%) patients developed an acute renal dysfunction (ARD) during the postoperative period of cytoreduction and HIPEC according to the RIFLE and AKI criteria respectively. RIFLE detects a higher rate of ARD due to different parameters such as GFR (7.2% versus 2.6%, p = 0.016). Performing ostomy (p = 0.007; OR: 39.320; 95% CI = 2.74-56.13) and using of cisplatin during HIPEC treatment (p = 0.017; OR = 13.619; 95% IC = 1.600-25.95) were factors independently related to a higher rate of ARD. CONCLUSION: ARD has a multifactorial origin. Cisplatin was associated with the development of a higher rate of ARD than paclitaxel. Diagnosis of ARD did not correlate with worse survival figures.

Effects of three biochars on copper immobilization and soil microbial communities in a metal-contaminated soil using a metallophyte and two agricultural plants.

Biochar (BC) is a porous, carbonaceous material produced by slow pyrolysis of biomass under oxygen-limited conditions. BC production has been attracting research interest because it modifies soil physicochemical characteristics and improves the growth of plants in problem soils. These benefits may be best actualized for soils contaminated by metals, where remediation is hampered by metal toxicity to both plants and soil microbial communities. The objectives of this study were to evaluate the impact of the addition of chicken manure biochar (CMB), oat hull biochar (OHB), or pine bark biochar (PBB) on copper (Cu) bioavailability in a Cu-contaminated soil, the effectiveness of these BCs promoting plant growth, and its effects on soil microbial communities supporting these plants. A sandy soil (338 mg Cu kg-1) was amended with CMB, OHB, and PBB, and the metallophyte Oenothera picensis or the agricultural species Solanum lycopersicum and Lolium perenne were grown for 3 months. The BCs produced an increase in soil pH, reduced the exchangeable Cu, and increased Cu bound to organic matter and residual fractions. All BCs enhanced the quality of contaminated soil and increased the plant biomass production, notably for S. lycopersicum, which grew until 12 times more than plants in non-amended soil. While BC addition reduced the concentration of Cu in soil pore water, the amendment did not reduce the concentrations of Cu in shoot tissues. BC additions also stimulated soil microorganisms, increasing basal respiration and DHA activity and modifying microbial communities, especially in soils supporting L. perenne. These results indicate that BCs represent an effective tool to remediate Cu-contaminated sandy soils.

Virtual Reality Exposure Treatment in Phobias: a Systematic Review.

We compare the relative efficacy of virtual reality therapy exposure (VRET) versus in vivo therapy exposure among individuals suffering from phobias. A systematic search was completed up to 03 April 2020, using the following databases: ACM Digital Library, ResearchGate, IEEE, Science Direct, MIT PressJournals, Center for Direct Scientific Communication (CCSD) and Mary Ann Liebert Publishers. Five authors searched the databases using the following terms: Virtual Reality, Phobia, Mental health, Computing, Therapy, HMD, CAVE, Virtual ambient, in virtuo, Avoidance, Exposure, VRET, in vivo, Anxiety, Agoraphobia, Social Phobia, Stimuli, Cognitive-behaviour. All studies that evaluate the effect of in virtuo exposure towards phobia rehabilitation were selected. By reviewing the article, each author then applied the inclusion and exclusion criteria, and 30 articles were selected. Data extracted included the number of samples, amount of sessions, study variables that may affect the final outcome, therapy technology. The data provided was synthesized using a meta-analysis based on the results. The results demonstrated a positive outcome of Virtual Reality Exposure Treatment in the treatment of most phobias. In contrast, some of these treatments did not work for a few specific phobias in which the standard procedures were more effective. The findings suggest that for some specific phobias treatment, Virtual Reality Exposure Treatment does not reach the in vivo exposure level of immersion and presence. Further research is needed to perform studies with higher-dimension samples, since many papers report a low sample size and that is probably why many of them have inconclusive results.

Controlled donation after circulatory death up to 80 years for liver transplantation: Pushing the limit again.

Our main objective was to compare liver transplant (LT) results between donation after circulatory death (DCD) and donation after brainstem death (DBD) in our hospital and to analyze, within the DCD group, the influence of age on the results obtained with DCD donors aged >70 years and up to 80 years. All DCD-LTs performed were analyzed prospectively. The results of the DCD group were compared with those of a control group who received a DBD-LT immediately after each DCD-LT. Later, the results obtained within the DCD group were analyzed according to the age of the donors, considering 2 subgroups with a cut-off point at 70 years. Survival results for LT with DCD and super rapid recovery were not inferior to those obtained in a similar group of patients transplanted with DBD livers. However, the cost of DCD was a higher rate of biliary complications, including ischemic cholangiopathy. Donor age was not a negative factor.

Defense mechanisms to increasing back pressure for hepatic oxygen transport and venous return in porcine fecal peritonitis.

High central venous pressure (CVP) acutely decreases venous return. How this affects hepatic oxygen transport in sepsis remains unclear. The aim of this study was to evaluate the effects of repeated increases in CVP via standard nursing procedures (NPs) on hepato-splanchnic and renal oxygen transport in a prolonged porcine sepsis model. Twenty anesthetized and mechanically ventilated pigs with regional hemodynamics monitored were randomized to fecal peritonitis or controls (n = 10 pigs/group). Resuscitation was started after 8 h of observation and continued for 3 days. NPs were performed at baseline and 8 h, 32 h, 56 h, and 72 h after resuscitation started. NPs increased CVP by 4-7 mmHg in both groups. In controls, this was associated with less decrease in hepatic arterial (Qha; 62 ± 70 mL/min) than portal venous flow (Qpv; 364 ± 151 mL/min). Portal venous oxygen content and hepatic O2 delivery (Do2) and consumption (V̇o2) decreased by 11 ± 6 mL/dL and 0.9 ± 0.3 and 0.4 ± 0.3 mL·min-1·kg-1, respectively. In septic animals, hepatic Do2 decreased more in response to increasing CVP (1.5 ± 0.9 mL·min-1·kg-1), which was attributable to a larger fall in both Qha (88 ± 66 ml/min) and portal O2 content (14 ± 10 mL/dL, all P < 0.05). This resulted in numerically lower hepatic V̇o2 since O2 extraction did not increase significantly. In control conditions, a smaller decrease in Qha compared with Qpv helped to limit the reduction in hepatic V̇o2 in response to acute CVP increase. In sepsis, the contribution of Qha to maintain hepatic Do2 was reduced, which jeopardized hepatic V̇o2 further. Renal arterial flow was similarly affected by CVP increase as Qha.NEW & NOTEWORTHY Sepsis impairs intrinsic mechanisms to attenuate effects of increasing back pressure on hepatic oxygen transport.

Multiparametric Highly Sensitive Chemiluminescence Immunoassay for Quantification of ß-Lactam-Specific Immunoglobulin E.

ß-lactams (BLCs) are the most widely used antibiotics and consequently the most common cause of drug allergy in the world. The diagnosis of drug allergy is complex and represents a serious challenge that includes a wide variety of methods. In vitro tests are based on the immunological determination of allergen-specific IgE, but the tests in the market lack the required sensitivity and specificity. In addition, the large sample volume, long incubation times, and single-plex configuration have brought their use into question to complement the clinical information. Here, we report a chemiluminescence immunoassay (CLIA) for multiparametric quantification of specific IgE to penicillin G, penicillin V, amoxicillin, and piperacillin, using histone H1 as a carrier. The developed CLIA allowed the determination of BLC-specific IgE below 0.1 IU/mL, thus allowing identification of allergic patients with better sensitivity, using only 25 µL of a sample (serum). The immunoassay was successfully applied in a cohort of 140 human serum samples, showing good sensitivity (64.6%) as well as specificity (100%), which significantly improve the predictive character of existing BLC-allergy in vitro tests.

Exogenous strigolactones impact metabolic profiles and phosphate starvation signalling in roots.

Strigolactones (SLs) are important ex-planta signalling molecules in the rhizosphere, promoting the association with beneficial microorganisms, but also affecting plant interactions with harmful organisms. They are also plant hormones in-planta, acting as modulators of plant responses under nutrient-deficient conditions, mainly phosphate (Pi) starvation. In the present work, we investigate the potential role of SLs as regulators of early Pi starvation signalling in plants. A short-term pulse of the synthetic SL analogue 2'-epi-GR24 promoted SL accumulation and the expression of Pi starvation markers in tomato and wheat under Pi deprivation. 2'-epi-GR24 application also increased SL production and the expression of Pi starvation markers under normal Pi conditions, being its effect dependent on the endogenous SL levels. Remarkably, 2'-epi-GR24 also impacted the root metabolic profile under these conditions, promoting the levels of metabolites associated to plant responses to Pi limitation, thus partially mimicking the pattern observed under Pi deprivation. The results suggest an endogenous role for SLs as Pi starvation signals. In agreement with this idea, SL-deficient plants were less sensitive to this stress. Based on the results, we propose that SLs may act as early modulators of plant responses to P starvation.

Secondary surgical cytoreduction needs to be assessed taking into account surgical technique, completeness of cytoreduction, and extent of disease.

Recent evidence suggested that secondary surgical cytoreduction followed by chemotherapy does not result in longer overall survival in patients with platinum-sensitive recurrent ovarian cancer.This statement is based on a phase III multicenter, randomized clinical trial that lacks a description of the surgical protocol, the surgical technique, and the surgical variables. In a study that evaluates surgical cytoreduction, it is mandatory to assess the grade of cytoreductive surgery achieved (Sugarbaker PH, Langenbeck's Arch Surg 384:576-87, 1999), the extent of disease using PCI (Peritoneal Cancer Index), the technique itself, and the existence of a multidisciplinary approach with extensive upper abdominal procedures in experienced centers (Ren et al, BMC Cancer 15:1-12, 2015). There is evidence proving that the quality of cytoreduction (Al Rawahi et al, Cochrane Database Syst Rev 2013, 2013), the measurement of the amount of disease by PCI (Elzarkaa et al, J Gynecol Oncol 29, 2018), and a multidisciplinary approach with supramesocolic procedures (Ren et al, BMC Cancer 15:1-12, 2015) impact overall survival.This study fails to compare chemotherapy with secondary cytoreductive surgery since, due to the lack of variables, we can assess neither the performed surgery nor its criteria. This study should not be taken into account to recommend chemotherapy alone over a surgical approach in this group of patients.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Gastric Cancer with Peritoneal Carcinomatosis: Multicenter Study of Spanish Group of Peritoneal Oncologic Surgery (GECOP).

BACKGROUND: Gastric cancer (GC) with peritoneal carcinomatosis (PC) is traditionally considered a terminal stage of the disease. The use of a multimodal treatment, including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), can benefit these patients. Our goal was to evaluate the morbidity and survival outcomes of these patients. METHODS: This is a retrospective, multicenter study from a prospective national database of patients diagnosed with PC secondary to GC treated with CRS and HIPEC from June 2006 to October 2017. RESULTS: Eighty-eight patients from seven specialized Spanish institutions were treated with CRS and HIPEC, with median age of 53 years; 51% were women. Median Peritoneal Cancer Index (PCI) was 6, and complete cytoreduction was achieved in 80 patients (90.9%). HIPEC was administered in 85 cases with 4 different regimens (Cisplatin + Doxorubicin, Mitomycin-C + Cisplatin, Mitomycin-C and Oxaliplatin). Twenty-seven cases (31%) had severe morbidity (grade III-IV) and 3 patients died in the postoperative period (3.4%). Median follow-up was 32 months. Median overall survival (OS) was 21.2 months, with 1-year OS of 79.9% and 3-year OS of 30.9%. Median disease-free survival (DFS) was 11.6 months, with 1-year DFS of 46.1% and 3-year DFS of 21.7%. After multivariate analysis, the extent of peritoneal disease (PCI ≥ 7) was identified as the only independent factor that influenced OS (hazard ratio [HR] 2.37, 95% confidence interval [CI] 1.26-4.46, p = 0.007). CONCLUSIONS: The multimodal treatment, including CRS and HIPEC, for GC with PC can improve the survival results in selected patients (PCI < 7) and in referral centers.

Phosphate acquisition efficiency in wheat is related to root:shoot ratio, strigolactone levels, and PHO2 regulation.

Inorganic phosphorus (Pi) fertilizers are expected to become scarce in the near future; so, breeding for improved Pi acquisition-related root traits would decrease the need for fertilizer application. This work aimed to decipher the physiological and molecular mechanisms underlying the differences between two commercial wheat cultivars (Crac and Tukan) with contrasting Pi acquisition efficiencies (PAE). For that, four independent experiments with different growth conditions were conducted. When grown under non-limiting Pi conditions, both cultivars performed similarly. Crac was less affected by Pi starvation than Tukan, presenting higher biomass production, and an enhanced root development, root:shoot ratio, and root efficiency for Pi uptake under this condition. Higher PAE in Crac correlated with enhanced expression of the Pi transporter genes TaPht1;2 and TaPht1;10. Crac also presented a faster and higher modulation of the IPS1-miR399-PHO2 pathway upon Pi starvation. Interestingly, Crac showed increased levels of strigolactones, suggesting a direct relationship between this phytohormone and plant P responses. Based on these findings, we propose that higher PAE of the cultivar Crac is associated with an improved P signalling through a fine-tuning modulation of PHO2 activity, which seems to be regulated by strigolactones. This knowledge will help to develop new strategies for improved plant performance under P stress conditions.

Mutations of RAS/RAF Proto-oncogenes Impair Survival After Cytoreductive Surgery and HIPEC for Peritoneal Metastasis of Colorectal Origin.

BACKGROUND: Adequate selection of patients with peritoneal metastasis (PM) for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains critical for successful long-term outcomes. Factors reflecting tumor biology are currently poorly represented in the selection process. The prognostic relevance of RAS/RAF mutations in patients with PM remains unclear. METHODS: Survival data of patients with colorectal PM operated in 6 European tertiary centers were retrospectively collected and predictive factors for survival identified by Cox regression analyses. A simple point-based risk score was developed to allow patient selection and outcome prediction. RESULTS: Data of 524 patients with a median age of 59 years and a median peritoneal cancer index of 7 (interquartile range: 3-12) were collected. A complete resection was possible in 505 patients; overall morbidity and 90-day mortality were 50.9% and 2.1%, respectively. PCI [hazard ratio (HR): 1.08], N1 stage (HR: 2.15), N2 stage (HR: 2.57), G3 stage (HR: 1.80) as well as KRAS (HR: 1.46) and BRAF (HR: 3.97) mutations were found to significantly impair survival after CRS/HIPEC on multivariate analyses. Mutations of RAS/RAF impaired survival independently of targeted treatment against EGFR. Consequently, a simple point-based risk score termed BIOSCOPE (BIOlogical Score of COlorectal PEritoneal metastasis) based on PCI, N-, G-, and RAS/RAF status was developed, which showed good discrimination [development area under the curve (AUC) = 0.72, validation AUC = 0.70], calibration (P = 0.401) and allowed categorization of patients into 4 groups with strongly divergent survival outcomes. CONCLUSION: RAS/RAF mutations impair survival after CRS/HIPEC. The novel BIOSCOPE score reflects tumor biology, adequately stratifies long-term outcomes, and improves patient assessment and selection.