Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation.

BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).

Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study.

BACKGROUND: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. METHODS: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. FINDINGS: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. INTERPRETATION: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. FUNDING: AstraZeneca and Daiichi Sankyo.

Electrical Conductivity Boost: In Situ Polypyrrole Polymerization in Monolithically Integrated Surface-Supported Metal-Organic Framework Templates.

Recent progress in synthesizing and integrating surface-supported metal-organic frameworks (SURMOFs) has highlighted their potential in developing hybrid electronic devices with exceptional mechanical flexibility, film processability, and cost-effectiveness. However, the low electrical conductivity of SURMOFs has limited their use in devices. To address this, researchers have utilized the porosity of SURMOFs to enhance electrical conductivity by incorporating conductive materials. This study introduces a method to improve the electrical conductivity of HKUST-1 templates by in situ polymerization of conductive polypyrrole (PPy) chains within the SURMOF pores (named as PPy@HKUST-1). Nanomembrane-origami technology is employed for integration, allowing a rolled-up metallic nanomembrane to contact the HKUST-1 films without causing damage. After a 24 h loading period, the electrical conductivity at room temperature reaches approximately 5.10-6 S m-1 . The nanomembrane-based contact enables reliable electrical characterization even at low temperatures. Key parameters of PPy@HKUST-1 films, such as trap barrier height, dielectric constant, and tunneling barrier height, are determined using established conduction mechanisms. These findings represent a significant advancement in real-time control of SURMOF conductivity, opening pathways for innovative electronic-optoelectronic device development. This study demonstrates the potential of SURMOFs to revolutionize hybrid electronic devices by enhancing electrical conductivity through intelligent integration strategies.

Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial.

OBJECTIVE: HER2 mutations are associated with poor prognosis and are detected in 3-6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT. METHODS: Eligible patients had HER2-mutant, metastatic or recurrent cervical cancer progressing after platinum-based treatment for advanced/recurrent disease. Patients received neratinib 240 mg/day; loperamide was mandatory during cycle 1. Confirmed objective response rate (ORR) was the primary endpoint. Duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints. RESULTS: Twenty-two patients were enrolled; 18 (81.8%) had endocervical adenocarcinoma; median two prior systemic chemotherapy regimens (range 1-4). The most common HER2 variant was S310F/Y mutation (n = 13; 59.1%). Four patients had confirmed partial responses (ORR 18.2%; 95% CI 5.2-40.3); 6 had stable disease ≥16 weeks (CBR 45.5%; 95% CI 24.4-67.8). Median DoR was 7.6 months (95% CI 5.6-12.3). Median PFS was 5.1 months (95% CI 1.7-7.2). All-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%) were the most common adverse events. Five patients (22.7%) reported grade 3 diarrhea. There were no grade 4 adverse events, no diarrhea-related treatment discontinuations, and two grade 5 adverse events, unrelated to neratinib: dyspnea (n = 1) and embolism (n = 1). CONCLUSIONS: Neratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted. TRIAL REGISTRATION NUMBER: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).

BODYFAT: a new calculator to determine the risk of being overweight validated in Spanish children between 11 and 17 years of age.

The assessment of body fat of children in primary care requires consideration of the dynamic changes in height, weight, lean mass, and fat mass during childhood growth. To achieve this, we aim to develop a predictive equation based on anthropometric values, with optimal diagnostic utility. This is a cross-sectional observational study, involving schoolgoers aged 11-17 years in the Vigo metropolitan area. Out of 10,747 individuals, 577 were randomly recruited. VARIABLES: age, sex, ethnicity/country of origin, weight, height, 8 skinfolds, 3 diameters, 7 perimeters, and 85% percentile of body fat mass as the gold standard. Generalized additive regression was selected by cross-validation and compared using receiver operating characteristic curves (ROC curves). Sensitivity, specificity, positive and negative predictive values, true positive and true negative values, false positive and false negative values, accuracy, and positive and negative likelihood ratios were calculated. Two models were identified. The optimal model includes sex, weight, height, leg perimeter, and arm perimeter, with sensitivity of 0.93 (0.83-1.00), specificity of 0.91 (0.83-0.96), accuracy of 0.91 (0.84-0.96), and area under the curve (AUC) of 0.957 (0.928-0.986). The second model includes sex, age, and body mass index, with sensitivity of 0.93 (0.81-1.00), specificity of 0.90 (0.80-0.97), accuracy of 0.90 (0.82-0.96), and an AUC of 0.944 (0.903-0.984). CONCLUSION: Two predictive models, with the 85th percentile of fat mass as the gold standard, built with basic anthropometric measures, show very high diagnostic utility parameters. Their calculation is facilitated by a complementary online calculator. WHAT IS KNOWN: • In routine clinical practice, mainly in primary care, BMI is used to determine overweight and obesity. This index has its weaknesses in the assessment of children. WHAT IS NEW: • We provide a calculator whose validated algorithm, through the determination of fat mass by impedanciometry, makes it possible to determine the risk of overweight and obesity in the community setting, through anthropometric measurements, providing a new practical, accessible and reliable model that improves the classification of overweight and obesity in children with respect to that obtained by determining BMI.

Infective endocarditis in pediatric patients: a decade of insights from a leading Spanish heart surgery reference center.

Infective endocarditis (IE) is a rare disease in children and is associated with significant morbidity and mortality. In recent years, significant changes have occurred in pediatric care that could have influenced the microbiology and presentation of IE. The aim of this work was to study epidemiological, microbiological, and clinical features of IE treated at a Pediatric Cardiac Surgery Reference Center located in Madrid (Spain) in a 10-years' period. A descriptive observational retrospective study was performed, including pediatric patients < 16 years old with definite or possible IE admitted to a reference center between January 2012 and December 2021. Thirty-two IE episodes were identified. Twenty-eight (87.5%) had congenital heart disease (CHD), 8 (25.0%) were preterm infants, 1 (3.1%) was immunocompromised and 6 (18.8%) had other chronic conditions; in 11 (34.4%) episodes more than one underlying condition was associated. In 20 (62.5%) episodes there was an indwelling central venous catheter (CVC); children with other comorbidities (preterm, immunocompromised, other chronic conditions) were more likely to have a CVC at diagnosis compared with patients with isolated CHD (p < 0.001). Thirty-six microbiological isolates were obtained in the 32 episodes; 4 (12.5%) episodes had 2 isolated microorganisms. Microbiological isolates were 20 (55.6%) Gram-positive bacteria (GPB), 10 (27.8%) non-HACEK Gram-negative bacteria (GNB), 1 (2.8%) HACEK-group bacterium, 4 (11.1%) fungi and 1 (2.8%) Coxiella burnetii. In 10 (31.3%) episodes, patients were colonized by multidrug-resistant bacteria (MDRB) and the etiology of IE in 3 (30.0%) of those episodes was the colonizing MDRB. MDRB colonization was associated with MDRB IE (p = 0.007). The most common complication was septic embolism: 11 (34.4%) episodes (9 pulmonary and 2 cerebral). In-hospital mortality was 6.3% (n = 2), all of them due to underlying conditions and not to IE or its complications. Clinical features and complications of IE episodes caused by non-HACEK GNB and those caused by GPB were compared, finding no statistically significant differences.    Conclusion: Risk factors for developing IE, the proportion of embolic complications, and mortality rate were consistent with previously published findings. Proportion of IE cases attributed to non-HACEK GNB was higher than previously reported, suggesting an evolving epidemiology of IE. One-third of children colonized with MDRB subsequently developed IE caused by the same MDRB strains, so empirical coverage of MDRB organisms must be considered when IE is suspected in MDRB colonized patients. No significant differences in clinical features and complications were observed when comparing IE episodes caused by non-HACEK GNB and those caused by GPB, however larger cohort studies are needed. What is Known: • Infective endocarditis (IE) is a rare disease in children, associated with significant morbidity and mortality. • The main risk factor for developing IE in children is an underlying congenital heart disease. What is New: • With current changing epidemiology in pediatric IE, a higher proportion of IE caused by non-HACEK Gram-negative bacteria should be expected. • A significant percentage of children colonized by multidrug-resistant bacteria can develop an IE due to those bacteria.

A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer.

BACKGROUND: WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose--escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions. PATIENTS AND METHODS: Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose-limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety. RESULTS: Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response. CONCLUSION: Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02278133.

Efficacy of [177Lu]Lu-DOTATATE in metastatic neuroendocrine neoplasms of different locations: data from the SEPTRALU study.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282). RESULTS: The sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7-not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8-28.1) in pancreatic, and 17.6 months (14.4-33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity. CONCLUSION: This study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

Parents' Experiences of Having a Child with Down Syndrome and Sleep Difficulties.

OBJECTIVES: Sleep disorders are prevalent in children with Down Syndrome (DS). However, sleep treatment is not always readily accessed by this group. This study aims to understand families' experiences of having a child with DS and sleep difficulties, and in particular, their healthcare experiences, with the goal of informing practice improvements. METHODS: We conducted semi-structured interviews with 34 parents (fathers n = 4 and mothers n = 30) with open-ended questions about parents' experiences of sleep, family dynamics, and healthcare. We operationalized a reflexive Thematic Analysis. RESULTS: Parents normalized their experiences of having a child with DS and sleep problems. Parents acknowledged that sleep disruption has adverse and pervasive impacts on their wellbeing and family dynamics, but also found this difficult to identify as a health problem. They accepted sleep difficulties as a regular part of bringing up any child, particularly one with a disability. When they did seek treatment for their child's sleep difficulties, parents often reported encountering insensitive and inadequate care and described that, at times, healthcare professionals also normalized children's sleep difficulties, resulting in sub-optimal treatment. This included at times failure to refer to tertiary sleep medicine services when required. CONCLUSIONS: Parents' and healthcare professionals' normalization of sleeping difficulties denies that they are both deleterious and modifiable. Practice implications include raising healthcare professionals' awareness of the importance of proactively addressing sleep, with sensitivity to families' normalization strategies, recognizing that families may require prompting to report concerns.

A Different Processing of Time-Domain Induced Polarisation: Application for Investigating the Marine Intrusion in a Coastal Aquifer in the SE Iberian Peninsula.

This study presents the developments regarding the time-domain induced polarisation method as a supporting tool for resistivity soundings during investigations of coastal detrital aquifers that are salinized by marine intrusion. The interpretation of resistivity measurements in such aquifers, which have variable hydrochemistry and lithology, involves uncertainties owing to the presence of low-resistivity lithologies, such as clays. To reduce these uncertainties, the use of other geophysical parameters is necessary; hence, this study focuses on induced polarisation since it can be measured simultaneously with resistivity. In detail, we propose the determination of induced polarisation using 1D techniques while developing a different algorithm for processing the induced polarisation data. The aim is to extend the results of this phenomenon, using, instead of chargeability, the concepts of polarisability and decay time, which are extracted from the decay curve, given that they represent more intrinsic properties of the various analyzed subsurface media. Results were obtained by applying this methodology to a Quaternary aquifer of the Costa del Sol in the SE Iberian Peninsula (in the province of Almería) during two different campaigns, one in mid-autumn and one late winter (i.e., in October and February, respectively) are presented. The results reveal the position of the saline front during each campaign while reflecting the seasonal movement of the marine intrusion.

Correlation of Boreholes through Well Logs: Application to the Western Sector of Madrid.

This study correlates the results obtained from the resistivity and spontaneous potential well logs in six boreholes for water extraction, located in the multilayer siliciclastic basin in the Madrid region, in the center of the Iberian Peninsula. Given the small lateral continuity that the layers considered in isolation show in this type of multilayer aquifer, geophysical stretches, with their corresponding average lithological assignments, have been established to achieve this objective from the well logs. These stretches allow for mapping the internal lithology in the studied area, obtaining a correlation of greater geological scope than that provided by the correlation between layers. Subsequently, the possible correlation of the lithological stretches selected in each of the boreholes was analyzed, verifying their lateral continuity and establishing an NNW-SSE section in the study area. In this work, the transcendence of the correlation of wells up to great distances (about 8 km in total, and average distance of 1.5 km between wells) is focused on the fact that, if there is a presence of pollutant in certain aquifer stretches in a part of the studied area, overexploitation in the Madrid basin will cause the mobilization of this pollutant to the whole basin, with a possible impact on non-polluted areas.

Derivation of Limbal Stem Cells from Human Adult Mesenchymal Stem Cells for the Treatment of Limbal Stem Cell Deficiency.

Approximately 10 million individuals have blindness due to limbal stem cell (LSCs) deficiency, one of the most challenging problems in ophthalmology. To replenish the LSC pool, an autologous extraocular cell source is appropriate, thereby avoiding the risk of immune rejection, the need for immunosuppression and the risk of damaging the contralateral eye. In recent years, adipose-derived mesenchymal stem cells (ADSCs) have been a key element in ocular regenerative medicine. In this study, we developed a protocol for deriving human LSCs from ADSCs compatible with the standard carrier human amniotic membrane, helping provide a stem cell pool capable of maintaining proper corneal epithelial homeostasis. The best protocol included an ectodermal induction step by culturing ADSCs with media containing fetal bovine serum, transforming growth factor-ß inhibitor SB-505124, Wnt inhibitor IWP-2 and FGF2 for 7 days, followed by an LSC induction step of culture in modified supplemental hormonal epithelial medium supplemented with pigment epithelium-derived factor and keratinocyte growth factor for 10 additional days. The optimal differentiation efficiency was achieved when cells were cultured in this manner over vitronectin coating, resulting in up to 50% double-positive αp63/BMI-1 cells. The results of this project will benefit patients with LSC deficiency, aiding the restoration of vision.

Comparison of Methods for Testing Mismatch Repair Status in Endometrial Cancer.

Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing has become part of the routine diagnosis. The aim of this study was to establish and compare the MMR status using various approaches. Immunohistochemistry (IHC), PCR-based MSI, and the detection of defects in the four key MMR genes (MLH1, PMS2, MSH2, and MSH6) via methylation-specific multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) were performed. MSH3 expression was also evaluated. A set of 126 early-stage EC samples were analyzed, 53.2% of which were dMMR and 46.8% of which were proficient MMR (pMMR) as determined using IHC, whereas 69.3% were classified as microsatellite stable, while 8.8% and 21.9% were classified MSI-low (MSI-L) and MSI-high (MSI-H), respectively. In total, 44.3% of the samples showed genetic or epigenetic alterations in one or more genes; MLH1 promoter methylation was the most common event. Although acceptable concordance was observed, there were overall discrepancies between the three testing approaches, mainly associated with the dMMR group. IHC had a better correlation with MMR genomic status than the MSI status determined using PCR. Further studies are needed to establish solid conclusions regarding the best MMR assessment technique for EC.

Phase I study of lurbinectedin in combination with weekly paclitaxel with or without bevacizumab in patients with advanced solid tumors.

Lurbinectedin and paclitaxel showed synergism in preclinical studies and have non-completely overlapping toxicity profiles. This phase I trial evaluated a combination of paclitaxel and lurbinectedin with/without bevacizumab in advanced tumors. This trial was divided into Group A, which evaluated weekly paclitaxel (60 or 80 mg) plus lurbinectedin (3.0-5.0 mg flat dose [FD] or 2.2 mg/m2) every 3 weeks in advanced solid tumors; and Group B, which evaluated bevacizumab (BEV, 15 mg/kg) added to the recommended dose (RD) defined in Group A in advanced epithelial ovarian or non-small cell lung cancer (NSCLC). 67 patients (A, n = 55; B, n = 12) were treated. The RD was paclitaxel 80 mg/m2 on Day (D)1,D8 plus lurbinectedin 2.2 mg/m2 on D1. At this RD, myelotoxicity was reversible and manageable, and most non-hematological toxicities were mild/moderate. Adding BEV did not notably change tolerability. Twenty-five confirmed responses were observed: 20/51 evaluable patients in Group A (overall response rate [ORR] = 39% at all dose levels and at the RD), and 5/10 evaluable patients in Group B (ORR = 50%). Most responders had breast (n = 7/12 patients), small cell lung (SCLC) (n = 5/7), epithelial ovarian (n = 3/9) and endometrial cancer (n = 3/11) in Group A, and epithelial ovarian (n = 3/4) and NSCLC (n = 2/6) in Group B. Clinical benefit rate was 61% in Group A (58% at the RD), and 90% in Group B. No major pharmacokinetic drug-drug interactions were observed. Paclitaxel/lurbinectedin and paclitaxel/lurbinectedin/BEV are feasible combinations. Further development is warranted of paclitaxel/lurbinectedin in SCLC, breast, and endometrial cancer, and of paclitaxel/lurbinectedin/BEV in epithelial ovarian cancer.

A Brucella melitensis H38ΔwbkF rough mutant protects against Brucella ovis in rams.

Brucella melitensis and Brucella ovis are gram-negative pathogens of sheep that cause severe economic losses and, although B. ovis is non-zoonotic, B. melitensis is the main cause of human brucellosis. B. melitensis carries a smooth (S) lipopolysaccharide (LPS) with an N-formyl-perosamine O-polysaccharide (O-PS) that is absent in the rough LPS of B. ovis. Their control and eradication require vaccination, but B. melitensis Rev 1, the only vaccine available, triggers anti-O-PS antibodies that interfere in the S-brucellae serodiagnosis. Since eradication and serological surveillance of the zoonotic species are priorities, Rev 1 is banned once B. melitensis is eradicated or where it never existed, hampering B. ovis control and eradication. To develop a B. ovis specific vaccine, we investigated three Brucella live vaccine candidates lacking N-formyl-perosamine O-PS: Bov::CAΔwadB (CO2-independent B. ovis with truncated LPS core oligosaccharide); Rev1::wbdRΔwbkC (carrying N-acetylated O-PS); and H38ΔwbkF (B. melitensis rough mutant with intact LPS core). After confirming their attenuation and protection against B. ovis in mice, were tested in rams for efficacy. H38ΔwbkF yielded similar protection to Rev 1 against B. ovis but Bov::CAΔwadB and Rev1::wbdRΔwbkC conferred no or poor protection, respectively. All H38ΔwbkF vaccinated rams developed a protracted antibody response in ELISA and immunoprecipitation B. ovis diagnostic tests. In contrast, all remained negative in Rose Bengal and complement fixation tests used routinely for B. melitensis diagnosis, though some became positive in S-LPS ELISA owing to LPS core epitope reactivity. Thus, H38ΔwbkF is an interesting candidate for the immunoprophylaxis of B. ovis in B. melitensis-free areas.

A keystone mutualism promotes resistance to invasion.

It is not uncommon for one or a few species, and their interactions, to have disproportionate effects on other species in ecological communities. Such keystone interactions might affect how communities respond to the invasion of non-native species by preventing or inhibiting the establishment, spread or impact of non-native species. We explore whether a keystone mutualism among a hummingbird-mistletoe-marsupial promotes ecological resistance to an invasive pollinator, the bumblebee Bombus terrestris, by comparing data collected at sites prior to bumblebee invasion to data collected 11 years after the invasion in sites with and without the keystone mutualism. We built pollination networks and focused on network motifs, regarded as building blocks of networks, to identify the central pollinators and estimate the change in their interactions after invasion of B. terrestris. We also estimated the interaction rewiring across the season in post-invasion networks and tested it as a possible mechanism explaining how the keystone mutualism increased ecological resistance to invasion. We found two times more species in post-invasion sites with the keystone mutualism than in post-invasion sites without the keystone mutualism. Moreover, we found that invasive bumblebee reduced the strength and interaction niche of the five central pollinator species while increasing its own strength and interaction niche, suggesting a replacement of interactions. Also, we found that the keystone mutualism promoted resistance to B. terrestris invasion by reducing its negative impacts on central species. In the presence of the keystone mutualism, central species had three times more direct interactions than in sites without this keystone mutualism. The higher interaction rewiring, after invasion of B. terrestris, in sites with the keystone mutualism indicates greater chances of central pollinators to form new interactions and reduces their competence for resources with the non-native bumblebee. Our results demonstrate that a keystone mutualism can enhance community resistance against the impacts of a non-native invasive pollinator by increasing species diversity and promoting interaction rewiring in the community. This study suggests that the conservation of mutualisms, especially those considered keystone, could be essential for long-term preservation of natural communities under current and future impacts of global change.

Es común que una o unas pocas especies y sus interacciones tengan efectos desproporcionado sobre otras especies en las comunidades. Estas especies y sus interacciones claves podrían afectar el modo en que las comunidades responden a la invasión de especies no nativas al prevenir o disminuir su establecimiento, su propagación o el impacto de las mismas. En este estudio evaluamos si un mutualismo clave entre un colibrí, un muérdago y un marsupial promueve la resistencia de la comunidad frente a un polinizador invasor, el abejorro Bombus terrestris, mediante la comparación de datos colectados en sitios previos a la invasión del abejorro y datos colectados 11 años después de su invasión, en sitios con y sin el mutualismo clave. Construimos redes ecológicas planta-polinizador y nos centramos en los modos de interacción ("interaction motifs"), los cuales son usados como bloques en la construcción de las redes, para identificar los polinizadores centrales y estimar el cambio en sus interacciones después de la invasión de B. terrestris. Además, en las redes posteriores a la invasión estimamos la reconexión de interacciones a lo largo de la temporada y la evaluamos como un posible mecanismo mediante la cual el mutualismo clave aumentó la resistencia a la invasión. En sitios posteriores a la invasión con el mutualismo clave encontramos dos veces más especies que en sitios posteriores a la invasión ausentes de éste. Además, en los sitios ausentes del mutualismo clave, encontramos que el abejorro invasor redujo la fuerza y el nicho de interacción de los cinco polinizadores centrales mientras incrementó su propia fuerza y nicho de interacciones, sugiriendo un reemplazo de interacciones. Asimismo, encontramos que el mutualismo clave promovió la resistencia de la comunidad a la invasión de B. terrestris al reducir sus impactos negativos sobre las especies centrales. En presencia del mutualismo clave, las especies centrales presentaron tres veces más interacciones directas que en sitios ausentes de esta interacción. La gran reconexión de interacciones encontrada en sitios posteriores a la invasión con el mutualismo clave indica mayores probabilidades de que los polinizadores centrales formen nuevas interacciones y reduzcan la competencia por recursos con el abejorro no nativo. Nuestros resultados demuestran que un mutualismo clave puede mejorar la resistencia de la comunidad frente a los impactos de especies invasoras al incrementar la diversidad de especies y promover la reconexión de interacciones en la comunidad. Este estudio sugiere que la conservación de las interacciones mutualistas, principalmente aquellas consideradas claves, podría ser esencial para preservar las comunidades naturales frente a los impactos del cambio global.

The Roadmap for Implementing Value-Based Healthcare in European University Hospitals-Consensus Report and Recommendations.

OBJECTIVES: Value-based healthcare (VBHC) aims at improving patient outcomes while optimizing the use of hospitals' resources among medical personnel, administrations, and support services through an evidence-based, collaborative approach. In this article, we present a blueprint for the implementation of VBHC in hospitals, based on our experience as members of the European University Hospital Alliance. METHODS: The European University Hospital Alliance is a consortium of 9 large hospitals in Europe and aims at increasing the quality and efficiency of care to ultimately drive better outcomes for patients. RESULTS: The blueprint describes how to prepare hospitals for VBHC implementation; analyzes gaps, barriers, and facilitators; and explores the most effective ways to turn patient pathways into a process that results in high-value care. Using a patient-centric approach, we identified 4 core minimum components that must be established as cornerstones and 7 organizational enablers to waive the barriers to implementation and ensure sustainability. CONCLUSION: The blueprint guides through pathway implementation and establishment of key performance indicators in 6 phases, which hospitals can tailor to their current status on their way to implement VBHC.

New Checkpoint Inhibitors on the Road: Targeting TIM-3 in Solid Tumors.

PURPOSE OF REVIEW: Even though checkpoint inhibitors have become a recent milestone for the treatment of many different tumor types, eventually, most part of patients will develop resistance mechanisms and their disease will progress. New generations of checkpoint inhibitors, as the ones directed to TIM-3, are on research. RECENT FINDINGS: TIM-3 expression has been associated with more advanced stages and shorter survival in several tumor types, due to its association with T-cell dysfunction, and has become an interesting target to explore. Early phase clinical trials with different anti-TIM-3 monoclonal antibodies have shown a safe toxicity profile, as cobolimab, LY3321367, or sabatolimab; however, the general antitumor activity remains to be determined and further investigations are needed. TIM-3 is implicated in resistance to immunotherapy due to its role in T cell exhaustion. However, the TIM-3 pathway is highly complex in terms of non-canonical signaling, broad expression by different immune cells and multiple ligands. Different anti-TIM-3 inhibitors are currently on research, either as monotherapy or in combination with other immunotherapies or chemotherapy, aiming to overcome resistance.

Biological Properties of Latex, Aqueous Extracts and Bee Products of Euphorbia officinarum L.: A Short Review.

Euphorbia officinarum L. is a Moroccan endemic plant known as "Tikiout" and "Daghmus" that can also be found in Mauritania, Western Sahara, and Algeria. In the present review, "Euphorbia officinarum", "metabolites" "hemisynthesis" were the keywords used for the research in the Web search engine Google Scholar and in the database Web of Science. Triterpenes, phytosterols and ingol diterpenes were isolated and identified in the latex of Moroccan E. officinarum. More than sixty triterpenes were obtained by hemisynthesis from natural triterpenes. Some of these derivatives had insecticidal and antimicrobial activity (phytopathogenic bacteria). The total phenol content and the antioxidant and anti-α-glucosidase activities were dependent on the time and temperature of extractions and also on the plant solvent ratio. The antioxidant activity of monofloral honey of E. officinarum origin was attributed to the phenol fraction (this fraction, previously isolated from honey samples, had better activity than the entire honey).

Priming human adipose-derived mesenchymal stem cells for corneal surface regeneration.

Limbal stem cells (LSC) maintain the transparency of the corneal epithelium. Chemical burns lead the loss of LSC inducing an up-regulation of pro-inflammatory and pro-angiogenic factors, triggering corneal neovascularization and blindness. Adipose tissue-derived mesenchymal stem cells (AT-MSC) have shown promise in animal models to treat LSC deficiency (LSCD), but there are not studies showing their efficacy when primed with different media before transplantation. We cultured AT-MSC with standard medium and media used to culture LSC for clinical application. We demonstrated that different media changed the AT-MSC paracrine secretion showing different paracrine effector functions in an in vivo model of chemical burn and in response to a novel in vitro model of corneal inflammation by alkali induction. Treatment of LSCD with AT-MSC changed the angiogenic and inflammatory cytokine profile of mice corneas. AT-MSC cultured with the medium that improved their cytokine secretion, enhanced the anti-angiogenic and anti-inflammatory profile of the treated corneas. Those corneas also presented better outcome in terms of corneal transparency, neovascularization and histologic reconstruction. Priming human AT-MSC with LSC specific medium can potentiate their ability to improve corneal wound healing, decrease neovascularization and inflammation modulating paracrine effector functions in an in vivo optimized rat model of LSCD.