Maf/ham1-like pyrophosphatases of non-canonical nucleotides are host-specific partners of viral RNA-dependent RNA polymerases.

Cassava brown streak disease (CBSD), dubbed the "Ebola of plants", is a serious threat to food security in Africa caused by two viruses of the family Potyviridae: cassava brown streak virus (CBSV) and Ugandan (U)CBSV. Intriguingly, U/CBSV, along with another member of this family and one secoviridae, are the only known RNA viruses encoding a protein of the Maf/ham1-like family, a group of widespread pyrophosphatase of non-canonical nucleotides (ITPase) expressed by all living organisms. Despite the socio-economic impact of CDSD, the relevance and role of this atypical viral factor has not been yet established. Here, using an infectious cDNA clone and reverse genetics, we demonstrate that UCBSV requires the ITPase activity for infectivity in cassava, but not in the model plant Nicotiana benthamiana. HPLC-MS/MS experiments showed that, quite likely, this host-specific constraint is due to an unexpected high concentration of non-canonical nucleotides in cassava. Finally, protein analyses and experimental evolution of mutant viruses indicated that keeping a fraction of the yielded UCBSV ITPase covalently bound to the viral RNA-dependent RNA polymerase (RdRP) optimizes viral fitness, and this seems to be a feature shared by the other members of the Potyviridae family expressing Maf/ham1-like proteins. All in all, our work (i) reveals that the over-accumulation of non-canonical nucleotides in the host might have a key role in antiviral defense, and (ii) provides the first example of an RdRP-ITPase partnership, reinforcing the idea that RNA viruses are incredibly versatile at adaptation to different host setups.

Enhancing patient outcomes: Integrating electronic cardiology consultation in primary care for cancer patients.

BACKGROUND: The prevalence of cancer patients with concomitant cardiovascular (CV) disease is on the rise due to improved cancer prognoses. The aim of this study is to evaluate the long-term outcomes of cancer patients referred to a cardiology department (CD) via primary care using e-consultation. METHODS: We analysed data from cancer patients with prior referrals to a CD between 2010 and 2021 (n = 6889) and compared two care models: traditional in-person consultations and e-consultations. In e-consultation model, cardiologists reviewed electronic health records (e-consultation) to determine whether the demand could be addressed remotely or necessitated an in-person consultation. We used an interrupted time series regression model to assess outcomes during the two periods: (1) time to cardiology consultation, (2) rates of all-cause and CV related hospital admissions and (3) rates of all-cause and CV-related mortality within the first year after the initial consultation or e-consultation at the CD. RESULTS: Introduction of e-consultation for cancer patients referred to cardiology care led to a 51.8% reduction (95%CI: 51.7%-51.9%) in waiting times. Furthermore, we observed decreased 1-year incidence rates, with incidence rate ratios (iRRs) [IC95%] of .75 [.73-.77] for CV-related hospitalizations, .43 [.42-.44] for all-cause hospitalizations, and .87 [.86-.88] for all-cause mortality. CONCLUSIONS: Compared to traditional in-person consultations, an outpatient care program incorporating e-consultation for cancer patients significantly reduced waiting times for cardiology care and demonstrated safety, associated with lower rates of hospital admissions.

Patient's self-reported quality of life as a prognostic factor in metastatic renal cell carcinoma initially treated with TKI: nomogram proposal.

BACKGROUND: Numerous prognostic factors have been described for metastatic renal cell carcinoma (mRCC). There are nomograms to assist in clinical decision-making and inform patients of their disease progression. However, they have a limited capacity and moderate concordance rates. Performance status (PS) is one of the most widely used prognostic factors and most closely related to overall survival (OS), but this is a subjective assessment based solely on the clinician's opinion. Patients must be at the center of care. Patient-reported outcomes (PROs) have shown benefits but are not widespread in daily clinical practice. METHODS: We analyzed 78 consecutive patients diagnosed with mRCC who initiated treatment at our institution between September 2012 and September 2019. We performed a descriptive analysis of the sample's baseline characteristics and the NCCN FKSI 19 questionnaire. We also conducted a survival analysis. RESULTS: The baseline FKSI 19 score demonstrates its prognostic potential, HR of 0.94 (95% CI 0.92-0.97). Our prognostic model would include: FKSI < 58 (HR 3.61 95% CI 1.97-6.61), anemia, thrombocytosis, non-clear cell histology, and metastatic hepatic involvement. AUC 0.86 (95%CI 0.77-0.95). CONCLUSION: Although it would need external validation, the proposed nomogram could be an alternative to other previously described models. The NCCN FKSI 19 baseline score could replace the clinician's subjective determination of PS. CLINICAL TRIAL REGISTRATION: Not applicable.

Red Blood Cells Protein Profile Is Modified in Breast Cancer Patients.

Metastasis is the primary cause of death for most breast cancer (BC) patients who succumb to the disease. During the hematogenous dissemination, circulating tumor cells interact with different blood components. Thus, there are microenvironmental and systemic processes contributing to cancer regulation. We have recently published that red blood cells (RBCs) that accompany circulating tumor cells have prognostic value in metastatic BC patients. RBC alterations are related to several diseases. Although the principal known role is gas transport, it has been recently assigned additional functions as regulatory cells on circulation. Hence, to explore their potential contribution to tumor progression, we characterized the proteomic composition of RBCs from 53 BC patients from stages I to III and IV, compared with 33 cancer-free controls. In this work, we observed that RBCs from BC patients showed a different proteomic profile compared to cancer-free controls and between different tumor stages. The differential proteins were mainly related to extracellular components, proteasome, and metabolism. Embryonic hemoglobins, not expected in adults' RBCs, were detected in BC patients. Besides, lysosome-associated membrane glycoprotein 2 emerge as a new RBCs marker with diagnostic and prognostic potential for metastatic BC patients. Seemingly, RBCs are acquiring modifications in their proteomic composition that probably represents the systemic cancer disease, conditioned by the tumor microenvironment.

A New Technique for Arthroscopic Discectomy of the Temporomandibular Joint Disc Perforation: A Technical Note.

Disc perforation represents the result of the degenerative process in joint structures that may lead to pain, joint noise, restricted mouth opening, osteoarthritis, and even dentofacial anomalies. Even though discectomy has proven benefits, with promising outcomes reported, it is mainly described using an open approach. While some arthroscopic techniques have been published, they are limited to managing perforation, edge widening, and inflammation treatment and do not describe complete disc removal. We describe a novel step-by-step arthroscopic discectomy technique utilizing two operative cannulas that completely remove nonfunctional cartilaginous tissue.

Noninvasive detection of microsatellite instability in patients with endometrial cancer.

The analysis of mismatch repair proteins in solid tissue is the standard of care (SoC) for the microsatellite instability (MSI) characterization in endometrial cancer (EC). Uterine aspirates (UAs) or circulating-DNA (cfDNA) samples capture the intratumor heterogeneity and provide a more comprehensive and dynamic molecular diagnosis. Thus, MSI analysis by droplet-digital PCR (ddPCR) in UAs and cfDNA can provide a reliable tool to characterize and follow-up the disease. The UAs, paraffin-embedded tumor tissue (FFPE) and longitudinal plasma samples from a cohort of 90 EC patients were analyzed using ddPCR panel and compared to the SoC. A high concordance (96.67%) was obtained between the analysis of MSI markers in UAs and the SoC. Three discordant cases were validated as unstable by ddPCR on FFPE samples. Besides, a good overall concordance (70.27%) was obtained when comparing the performance of the ddPCR assay on UAs and cfDNA in high-risk tumors. Importantly, our results also evidenced the value of MSI analysis to monitor the disease evolution. MSI evaluation in minimally invasive samples shows great accuracy and sensitivity and provides a valuable tool for the molecular characterization and follow-up of endometrial tumors, opening new opportunities for personalized management of EC.

The Challenge of ab Initio Calculations in Small Neon Clusters.

Weakly bound neon dimer, trimer and tetramers are studied at HF and CCSD(T) levels using Dunning, ANO and SIGMA-s basis sets. Their ground-state binding energies are studied along with some structural properties. SIGMA-s basis sets have been developed explicitly for this issue but in a manner that can be readily applied to other atoms for the study of larger weakly bound systems. The difficulties for attaining accurate results on these systems are assessed by the computation of total, atomization and correlation energies, as well as equilibrium distances, with several basis sets of increasing size, ranging from non-augmented to double-augmented versions. Extrapolations are proposed to predict stabilization energies and the results are compared with previously published data.

Inter-observer variability in male pelvic-floor MRI measurements that might predict post-prostatectomy incontinence.

INTRODUCTION: Current studies are focusing on the relationship between anatomical variables in preoperative prostate MRI and the development of post-prostatectomy incontinence (PPI). Nevertheless, there is little evidence regarding the reliability of these measurements. The objective of this study was to analyze the concordance between urologists and radiologists for anatomical measurements that might be PPI predictors. MATERIAL AND METHODS: Pelvic floor measurements with 3T-MRI were performed by two radiologists and two urologists independently and blindly. Interobserver agreement was determined using the intraclass correlation coefficient (ICC) and the Bland-Altman plot. RESULTS: The concordance was good-acceptable for most measurements, except for the levator ani and puborectalis muscle thickness (some ICC values < 0.20/p value > 0.05). The anatomical parameters with the highest degree of agreement were intravesical prostatic protrusion (IPP) and prostate volume (most of the ICC values > 0.60). The membranous urethral length (MUL) and the angle of the membranous urethra-prostate axis (aLUMP) presented ICC > 0.40. The obturator internus muscle thickness (OIT), urethral width and intraprostatic urethral length presented a fair-moderate degree of agreement (ICC > 0.20). Regarding the agreement between different specialists, the highest degree was obtained for the two radiologists and for urologist 1-radiologist 2 (moderate median agreement), while urologist 2 with each of the radiologists had a regular median agreement. CONCLUSIONS: MUL, IPP, prostate volume, aLUMP, OIT, urethral width and prostatic length show acceptable inter-observer concordance and they would be reliable as possible predictors of PPI. Levator ani and puborectalis muscle thickness show bad agreement. Interobserver agreement might not be greatly influenced by previous professional experience.

Percutaneous radiofrequency ablation is an effective treatment option for small renal masses, comparable to partial nephrectomy.

OBJECTIVES: The standard therapy for small renal masses (SRMs) remains partial nephrectomy (PN), which is associated with relatively high morbidity and complication rate. Therefore, percutaneous radiofrequency ablation (PRFA) emerges as an alternative therapy. This study aimed to compare the efficacy, safety, and oncological outcomes of PRFA versus PN. METHODS: A multicenter non-inferiority study with retrospective analysis of 291 patients with SRMs (N0M0), who underwent PN or PRFA (2:1), recruited prospectively from two hospitals in the Andalusian Public Health System, Spain, between 2014 and 2021. Comparisons of treatment features were evaluated using the t test, Wilcoxon-Mann-Whitney U test, chi-square test, Fisher test, and Cochran-Armitage trend test. Kaplan-Meier curves depicted overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS) rates in the overall study population. RESULTS: A total of 291 consecutive patients were identified; 111 and 180 patients underwent PRFA and PN, respectively. Median follow-up time was 38 and 48 months, and mean hospitalization days were 1.04 and 3.57 days, respectively. The variables underpinned with high surgical risk were significantly increased in PRFA compared to those in PN (mean age was 64.56 and 57.47 years, the solitary kidney presence was 12.6% and 5.6%, ASA score ≥ 3 was 36% and 14.5%, respectively). The rest of oncological outcomes were comparable amongst PRFA and PN. Patients undergoing PRFA did not improve OS, LRFS, and MFS compared to those undergoing PN. Limitations comprise retrospective design and limited statistical power. CONCLUSION: PRFA for SMRs in high-risk patients is non-inferior in terms of oncological outcomes and safety compared to PN. CLINICAL RELEVANCE STATEMENT: Our study has a direct clinical application as it proves that radiofrequency ablation is an effective and uncomplicated therapeutic option for patients with small renal masses. KEY POINTS: •There are non-inferiority results in overall survival, local recurrence-free survival, and metastasis-free survival between PRFA and PN. •Our two-center study showed that PRFA is non-inferior to PN in oncological outcomes. •Contrast-enhanced power ultrasound-guided PRFA provides an effective therapy for T1 renal tumors.

Effect of capmatinib on the pharmacokinetics of substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with MET-dysregulated solid tumours.

BACKGROUND: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. METHODS: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator. RESULTS: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (Cmax ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUClast ), respectively, with no change in Cmax . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. CONCLUSION: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure.

Distal Endarterectomy Combined With Endovascular Proximal Treatment: The Hybrid DEEP Retrograde Technique for High-Complexity Infrainguinal Disease.

Purpose: We present a hybrid technique for the treatment of chronic limb-threatening ischemia (CLTI) due to complex, multilevel infrainguinal disease. It consists of an open distal endarterectomy combined with endovascular proximal treatment (the DEEP technique). Materials and Methods: This was a prospective cohort study. Thirty-three limbs (30 patients) were treated. Main inclusion criteria were absence of significant disease in femoral bifurcation associated with a complex infrainguinal pattern. This approach was specially considered in absence of suitable vein for bypass, obesity, hostile groin, and overall high surgical risk. Results: Mean age was 72.8 ± 10 years (ranging 50-93). Most cases presented with severe limb threatening onset (90.9% Rutherford >4 and 81.8% WIfi >3) due to high-complexity infrainguinal disease pattern (Global Limb Anatomic Staging System [GLASS] stage III) in 31/33 (93.9%), chronic total occlusions (CTOs) in 24/33 (72.7%), and severe calcification (Peripheral Arterial Calcium Scoring System [PACSS] grade 4) in 22/33 (66.6%). Mean lesion length was 228.2 mm ± 83 (ranging 40-340 mm). In all procedures, a covered-stent (25 cm length Viabahn) was implanted in a retrograde fashion as the endovascular component. Effective revascularization was achieved in all cases, showing significant clinical and hemodynamic improvement (median pre- and postprocedure ankle-brachial index [ABI]: 0.3 and 0.9, respectively). Results at 12 months follow-up were as follows: 93.9% limb salvage ratio, 75.7% primary patency, 84.6% assisted primary patency, and 90.9% secondary patency. Major adverse limb events (MALE) and cardiovascular events (MACE) occurred in 8/33 (24.2%) and 2/33 (6%), respectively. Mean length of postoperative stay was 7.5 ± 6.92 days (3-27). Conclusion: This less invasive hybrid technique has promising short-term results for limb salvage and it is worth to be included in vascular armamentarium for CLTI revascularization in selected patients.

Darolutamide in Spanish patients with nonmetastatic castration-resistant prostate cancer: ARAMIS subgroup analysis.

Aim: Darolutamide significantly prolonged metastasis-free survival (MFS) versus placebo in the Phase III ARAMIS study. We analyzed outcomes in Spanish participants in ARAMIS. Patients & methods: Patients with high-risk nonmetastatic castration-resistant prostate cancer were randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus androgen-deprivation therapy. The primary end point was MFS. Descriptive statistics are reported for this post hoc analysis. Results: In Spanish participants, darolutamide (n = 75) prolonged MFS versus placebo (n = 42): hazard ratio 0.345, 95% confidence interval 0.175-0.681. The incidence and type of treatment-emergent adverse events were comparable between treatment arms. Conclusion: For Spanish participants in ARAMIS, efficacy outcomes favored darolutamide versus placebo, with a similar safety profile, consistent with the overall ARAMIS population. Clinical Trials Registration: NCT02200614 (ClinicalTrials.gov).

Darolutamide is an oral treatment for a type of prostate cancer that has stopped responding to other treatments and is at risk of spreading to other parts of the body (termed "nonmetastatic castration-resistant prostate cancer" or "nmCRPC"). In the international ARAMIS study, patients treated with darolutamide lived longer without their cancer spreading than patients who were given placebo (sugar) pills. We wanted to know whether Spanish patients in ARAMIS had similar characteristics and treatment outcomes to other patients in the study. We found that the 75 Spanish patients who were treated with darolutamide had a significantly lower risk of their cancer spreading than the 42 Spanish patients who received placebo. The two groups of Spanish patients had similar side effects.

Post-Intensive Care Unit Multidisciplinary Approach in Patients with Severe Bilateral SARS-CoV-2 Pneumonia.

Background: Short and long-term sequelae after admission to the intensive care unit (ICU) for coronavirus disease 2019 (COVID-19) are to be expected, which makes multidisciplinary care key in the support of physical and cognitive recovery. Objective: To describe, from a multidisciplinary perspective, the sequelae one month after hospital discharge among patients who required ICU admission for severe COVID-19 pneumonia. Design: Prospective cohort study. Environment: Multidisciplinary outpatient clinic. Population: Patients with severe COVID-19 pneumonia, post- ICU admission. Methods: A total of 104 patients completed the study in the multidisciplinary outpatient clinic. The tests performed included spirometry, measurement of respiratory muscle pressure, loss of body cell mass (BCM) and BCM index (BCMI), general joint and muscular mobility, the short physical performance battery (SPPB or Guralnik test), grip strength with hand dynamometer, the six-minute walk test (6-MWT), the functional assessment of chronic illness therapy-fatigue scale (FACIT-F), the European quality of life-5 dimensions (EQ-5D), the Barthel index and the Montreal cognitive assessment test (MoCA). While rehabilitation was not necessary for 23 patients, 38 patients attended group rehabilitation sessions and other 43 patients received home rehabilitation. Endpoints: The main sequelae detected in patients were fatigue (75.96%), dyspnoea (64.42%) and oxygen therapy on discharge (37.5%). The MoCA showed a mean score compatible with mild cognitive decline. The main impairment of joint mobility was limited shoulder (11.54%) and shoulder girdle (2.88%) mobility; whereas for muscle mobility, lower limb limitations (16.35%) were the main dysfunction. Distal neuropathy was present in 23.08% of patients, most frequently located in lower limbs (15.38%). Finally, 50% of patients reported moderate limitation in the EQ-5D, with a mean score of 60.62 points (SD 20.15) in perceived quality of life. Conclusions: Our findings support the need for a multidisciplinary and comprehensive evaluation of patients after ICU admission for COVID-19 because of the wide range of sequelae, which also mean that these patients need a long-term follow-up. Impact on clinical rehabilitation: This study provides data supporting the key role of rehabilitation during the follow-up of severe patients, thus facilitating their reintegration in society and a suitable adaptation to daily living.

First report of Culicoides caucoliberensis in Spain: Exploring molecular phylogeny, host-feeding behaviour and avian haemosporidian parasites.

Culicoides biting midges (Diptera: Ceratopogonidae) are vectors of pathogens that affect wildlife and livestock. Understanding the composition and distribution of vector species is crucial for implementing control strategies and preventing the spread of infectious diseases. This study provides a morphological and molecular characterisation of Culicoides caucoliberensis, which represents the first record for Spain, increasing the number of Culicoides species in the country to 85. A total of 213 specimens were collected using Onderstepoort-ultraviolet down-draught light traps on a rocky coastline in the Balearic Islands during two sampling periods in 2022. Phylogenetic analysis showed that C. caucoliberensis forms a monophyletic cluster within the Maritimus group. Host preferences were determined for the first time and showed propensity to feed on the European shag (Phalacrocorax aristotelis). The vector role of C. caucoliberensis for haemosporidian transmission remains unclear since molecular detection of Haemosporidians (Haemoproteus and Plasmodium) was negative for all the pools of parous and engorged females analysed. This study emphasises the importance of conducting entomofauna studies in lesser-known Mediterranean islet landscapes and highlights the need for research on vectors within the One Health framework.

Quantitative proteomics in medication-related osteonecrosis of the jaw: A proof-of-concept study.

OBJECTIVE: Medication-related osteonecrosis of the jaw (MRONJ) is a paradoxical effect associated with bone-modifying agents (BMAs) and other drugs. Currently, no valuable diagnostic or prognosis biomarkers exist. The goal of this research was to study MRONJ-related salivary proteome. MATERIALS AND METHODS: This case-control aimed to study salivary proteome in MRONJ versus control groups (i) formed from BMAs consumers and (ii) healthy individuals to unravel biomarkers. Thirty-eight samples of unstimulated whole saliva (18 MRONJ patients, 10 BMA consumers, and 10 healthy controls) were collected. Proteomic analysis by SWATH-MS coupled with bioinformatics analysis was executed. RESULTS: A total of 586 proteins were identified, 175 proteins showed significant differences among MRONJ versus controls. SWATH-MS revealed differentially expressed proteins among three groups, which have never been isolated. These proteins had distinct roles including cell envelope organization, positive regulation of vesicle fusion, positive regulation of receptor binding, or regulation of low-density lipoprotein particle clearance. Integrative analysis prioritized 3 proteins (MMP9, AACT, and HBD). Under receiver-operating characteristic analysis, this panel discriminated MRONJ with a sensitivity of 90% and a specificity of 78.9%. CONCLUSION: These findings may inform a novel biomarker panel for MRONJ prediction or diagnosis. Nonetheless, further research is needed to validate this panel.

Monitoring mosquito richness in an understudied area: can environmental DNA metabarcoding be a complementary approach to adult trapping?

Mosquito surveillance programmes are essential to assess the risks of local vector-borne disease outbreaks as well as for early detection of mosquito invasion events. Surveys are usually performed with traditional sampling tools (i.e., ovitraps and dipping method for immature stages or light or decoy traps for adults). Over the past decade, numerous studies have highlighted that environmental DNA (eDNA) sampling can enhance invertebrate species detection and provide community composition metrics. However, the usefulness of eDNA for detection of mosquito species has, to date, been largely neglected. Here, we sampled water from potential larval breeding sites along a gradient of anthropogenic perturbations, from the core of an oil palm plantation to the rainforest on São Tomé Island (Gulf of Guinea, Africa). We showed that (i) species of mosquitoes could be detected via metabarcoding mostly when larvae were visible, (ii) larvae species richness was greater using eDNA than visual identification and (iii) new mosquito species were also detected by the eDNA approach. We provide a critical discussion of the pros and cons of eDNA metabarcoding for monitoring mosquito species diversity and recommendations for future research directions that could facilitate the adoption of eDNA as a tool for assessing insect vector communities.

Parp Inhibitors and Radiotherapy: A New Combination for Prostate Cancer (Systematic Review).

PARPi, in combination with ionizing radiation, has demonstrated the ability to enhance cellular radiosensitivity in different tumors. The rationale is that the exposure to radiation leads to both physical and biochemical damage to DNA, prompting cells to initiate three primary mechanisms for DNA repair. Two double-stranded DNA breaks (DSB) repair pathways: (1) non-homologous end-joining (NHEJ) and (2) homologous recombination (HR); and (3) a single-stranded DNA break (SSB) repair pathway (base excision repair, BER). In this scenario, PARPi can serve as radiosensitizers by leveraging the BER pathway. This mechanism heightens the likelihood of replication forks collapsing, consequently leading to the formation of persistent DSBs. Together, the combination of PARPi and radiotherapy is a potent oncological strategy. This combination has proven its efficacy in different tumors. However, in prostate cancer, there are only preclinical studies to support it and, recently, an ongoing clinical trial. The objective of this paper is to perform a review of the current evidence regarding the use of PARPi and radiotherapy (RT) in PCa and to give future insight on this topic.

Ascites-Derived Organoids to Depict Platinum Resistance in Gynaecological Serous Carcinomas.

Gynaecological serous carcinomas (GSCs) constitute a distinctive entity among female tumours characterised by a very poor prognosis. In addition to late-stage diagnosis and a high rate of recurrent disease associated with massive peritoneal carcinomatosis, the systematic acquisition of resistance to first-line chemotherapy based on platinum determines the unfavourable outcome of GSC patients. To explore the molecular mechanisms associated with platinum resistance, we generated patient-derived organoids (PDOs) from liquid biopsies of GSC patients. PDOs are emerging as a relevant preclinical model system to assist in clinical decision making, mainly from tumoural tissue and particularly for personalised therapeutic options. To approach platinum resistance in a GSC context, proficient PDOs were generated from the ascitic fluid of ovarian, primary peritoneal and uterine serous carcinoma patients in platinum-sensitive and platinum-resistant clinical settings from the uterine aspirate of a uterine serous carcinoma patient, and we also induced platinum resistance in vitro in a representative platinum-sensitive PDO. Histological and immunofluorescent characterisation of these ascites-derived organoids showed resemblance to the corresponding original tumours, and assessment of platinum sensitivity in these preclinical models replicated the clinical setting of the corresponding GSC patients. Differential gene expression profiling of a panel of 770 genes representing major canonical cancer pathways, comparing platinum-sensitive and platinum-resistant PDOs, revealed cellular response to DNA damage stimulus as the principal biological process associated with the acquisition of resistance to the first-line therapy for GSC. Additionally, candidate genes involved in regulation of cell adhesion, cell cycles, and transcription emerged from this proof-of-concept study. In conclusion, we describe the generation of PDOs from liquid biopsies in the context of gynaecological serous carcinomas to explore the molecular determinants of platinum resistance.

Liquid biopsy-based microRNA models as potential biomarkers of bowel conditions.

MicroRNAs detected in liquid biopsies have demonstrated to have potential as biomarkers of benign and malignant bowel conditions. Numerous studies have reported on the combination of different microRNAs to improve the diagnostic capabilities in the detection of bowel conditions. This editorial will be reviewing the best scientific evidence available to this date on studies showing microRNA models with sensitivity and specificity values. Also, the current challenges on how to implement microRNAs in the routine clinical practice are exposed.

Early Use of Sarilumab in Patients Hospitalized with COVID-19 Pneumonia and Features of Systemic Inflammation: the SARICOR Randomized Clinical Trial.

The objective of this study was to investigate the efficacy and safety of early treatment with sarilumab, added to standard of care (SOC), in hospitalized adults with COVID-19. Methods included phase II, open-label, randomized, controlled clinical trial of hospitalized patients with COVID-19 pneumonia and interleukin (IL)-6 levels ≥ 40 pg/mL and/or d-dimer > 1,500 ng/mL. Participants were randomized (1:1:1) to receive SOC (control group), SOC plus a single subcutaneous dose of sarilumab 200 mg (sarilumab-200 group), or SOC plus a single subcutaneous dose of sarilumab 400 mg (sarilumab-400 group). The primary outcome variable was the development of acute respiratory distress syndrome (ARDS) requiring high-flow nasal oxygenation (HFNO), non-invasive mechanical ventilation (NIMV) or invasive mechanical ventilation (IMV) at day 28. One-hundred and 15 participants (control group, n = 39; sarilumab-200, n = 37; sarilumab-400, n = 39) were included. At randomization, 104 (90%) patients had supplemental oxygen and 103 (90%) received corticosteroids. Eleven (28%) patients in the control group, 10 (27%) in sarilumab-200, and five (13%) in sarilumab-400 developed the primary outcome (hazard ratio [95% CI] of sarilumab-400 vs control group: 0.41 [0.14, 1.18]; P = 0.09). Seven (6%) patients died: three in the control group and four in sarilumab-200. There were no deaths in sarilumab-400 (P = 0.079, log-rank test for comparisons with the control group). In patients recently hospitalized with COVID-19 pneumonia and features of systemic inflammation, early IL-6 blockade with a single dose of sarilumab 400 mg was safe and associated with a trend for better outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT04357860.).