Sphingosine-1-Phosphate-Cathelicidin Axis Plays a Pivotal Role in the Development of Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer caused by mutagenesis resulting from excess UVR or other types of oxidative stress. These stressors also upregulate the production of a cutaneous innate immune element, cathelicidin antimicrobial peptide (CAMP), through endoplasmic reticulum stress-initiated, sphingosine-1-phosphate (S1P) signaling pathway. Although CAMP has beneficial antimicrobial activities, it also can be proinflammatory and procarcinogenic. We addressed whether and how S1P-induced CAMP production leads to cSCC development. Our study demonstrated that (i) CAMP expression is increased in cSCC cells and skin from patients with cSCC; (ii) S1P levels are elevated in cSCC cells, whereas inhibition of S1P production attenuates CAMP-stimulated cSCC growth; (iii) exogenous CAMP stimulates cSCC but not normal human keratinocyte growth; (iv) blockade of FPRL1 protein, a CAMP receptor, attenuates cSCC growth as well as the growth and invasion of cSCC cells mediated by CAMP into an extracellular matrix-containing fibroblast substrate; (v) FOXP3+ regulatory T-cell (which decreases antitumor immunity) levels increase in cSCC skin; and (vi) CAMP induces endoplasmic reticulum stress in cSCC cells. Together, the endoplasmic reticulum stress-S1P-CAMP axis forms a vicious circle, creating a favorable environment for cSCC development, that is, cSCC growth and invasion impede anticancer immunity.

Predicting Sodium-Ion Battery Performance through Surface Chemistry Analysis and Textural Properties of Functionalized Hard Carbons Using AI.

Traditionally, the performance of sodium-ion batteries has been predicted based on a single characteristic of the electrodes and its relationship to specific capacity increase. However, recent studies have shown that this hypothesis is incorrect because their performance depends on multiple physical and chemical variables. Due to the above, the present communication shows machine learning as an innovative strategy to predict the performance of functionalized hard carbon anodes prepared from grapefruit peels. In this sense, a three-layer feed-forward Artificial Neural Network (ANN) was designed. The inputs used to feed the ANN were the physicochemical characteristics of the materials, which consisted of mercury intrusion porosimetry data (SHg and average pore), elemental analysis (C, H, N, S), ID/IG ratio obtained from RAMAN studies, and X-ray photoemission spectroscopy data of the C1s, N1s, and O1s regions. In addition, two more inputs were added: the cycle number and the applied C-rate. The ANN architecture consisted of a first hidden layer with a sigmoid transfer function and a second layer with a log-sigmoid transfer function. Finally, a sigmoid transfer function was used in the output layer. Each layer had 10 neurons. The training algorithm used was Bayesian regularization. The results show that the proposed ANN correctly predicts (R2 > 0.99) the performance of all materials. The proposed strategy provides critical insights into the variables that must be controlled during material synthesis to optimize the process and accelerate progress in developing tailored materials.

Feasibility of structuring electronic health record data to facilitate real-world data research: ICAREdata methods applied to multicenter cancer clinical trials.

BACKGROUND: The use of electronic health record (EHR) data for research is limited by a lack of structure and a standard data model. The objective of the ICAREdata (Integrating Clinical Trials and Real-World Endpoints Data) project was to structure key research data elements in EHRs using a minimal Common Oncology Data Elements (mCODE) data model to extract and transmit data. METHODS: The ICAREdata project captured two EHR data elements essential to clinical trials: cancer disease status and treatment plan change. The project was implemented in clinical sites participating in Alliance for Clinical Trials in Oncology trials. Data were extracted from EHRs and sent by secure Fast Healthcare Interoperability Resource messaging (a standard for exchanging EHRs) to a database. Selected elements were compared with corresponding data from the trial's electronic data capture (EDC) system, Medidata Rave. RESULTS: By December 2023, data were extracted and transmitted from 10 sites for 35 patients, involving 367 clinical encounters across 15 clinical trials. Data through March 2023 demonstrated that concordance for the elements treatment plan change and cancer disease status was 79% and 34%, respectively. When disease evaluation was reported by both EHR and EDC (n = 15), there was 87% agreement on cancer disease status. CONCLUSIONS: Documentation, extraction, and aggregation of structured data elements in EHRs using mCODE and ICAREdata methods is feasible in multi-institutional cancer clinical trials. EDC as a reference data set allowed assessment of the completeness of EHR data capture. Future initiatives will focus on elements with shared definitions in clinical and research environments and efficient workflows. PLAIN LANGUAGE SUMMARY: Clinical trials use electronic case report forms to report data, and data must be manually entered on these forms, which is costly and time consuming. ICAREdata methods use structured, organized data from clinical trials that can be more easily shared instead having to enter free text into electronic health records.

Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma.

BACKGROUND: Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. METHODS: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). RESULTS: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively. CONCLUSIONS: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.).

Decoding of the isotopic fingerprint of tequila 100% agave silver class and image analysis to evaluate differences between spirits.

This communication shows the decoding of Isotopic Fingerprint of Tequila 100% agave silver class (IFTequila100% agave) in three areas corresponding to isotopic variations due to: plant used as raw material, fermentation and distillation process, and hydrolysis process. Isotopic tracers that make them up correspond to the δ13CVPDB ethanol-δ13CVPDB ethyl acetate-δ13CVPDB isoamyl alcohol, δ13CVPDB ethyl acetate-δ13CVPDB isoamyl alcohol-δ13CVPDB n-propanol and δ13CVPDB ethyl acetate-δ13CVPDB n-propanol-δ13CVPDB methanol, respectively. Once the IFTequila100%agave has been decoded, an image comparison was performed against isotopic fingerprints of spirits (Tequila, Bacanora, Raicilla, Sotol, and Mezcal). Results show that it is possible classifies 100% of samples analyzed. Likewise, from decoding it is possible to determine the critical process stage to determine variations with respect to the IFTequila100%agave. The chemometric analysis developed corresponds to an auxiliary analytical tool useful for the inspection processes currently carried out by the authorities to determine the authenticity of the beverage.

Early exposure to glyphosate during larval development induces late behavioural effects on adult honey bees.

As the most abundant pollinator insect in crops, Apis mellifera is a sentinel species of the pollinator communities. In these ecosystems, honey bees of different ages and developmental stages are exposed to diverse agrochemicals. However, most toxicological studies analyse the immediate effects during exposure. Late effects during adulthood after early exposure to pollutants during larval development are poorly studied in bees. The herbicide glyphosate (GLY) is the most applied pesticide worldwide. GLY has been detected in honey and beebread from hives near treated crops. Alterations in growth, morphogenesis or organogenesis during pre-imaginal development could induce late adverse effects after the emergence. Previous studies have demonstrated that GLY alters honey bee development, immediately affecting survival, growth and metabolism, followed by late teratogenic effects. The present study aims to determine the late impact on the behaviour and physiology of adult bees after pre-imaginal exposure to GLY. For that, we reared brood in vitro or in the hive with sub-chronic exposure to the herbicide with the average detected concentration in hives. Then, all newly emerged bees were reared in an incubator until maturity and tested when they became nurse-aged bees. Three behavioural responses were assessed as markers of cognitive and physiological impairment. Our results show i) decreased sensitivity to sucrose regardless of the rearing procedure, ii) increased choice latency and locomotor alterations during chemotaxis and iii) impaired associative learning. These late toxicity signs could indicate adverse effects on task performance and colony efficiency.

Sugar-conditioned honey bees can be biased towards a nectarless dioecious crop.

The targeted pollination strategy has shown positive results in directing honey bees to crop flowers offering nectar along with pollen as reward. Kiwifruit is a functionally dioecious species, which relies on bees to transport pollen from staminate to pistillate nectarless flowers. Following the targeted pollination procedures recently validated, we first developed a mimic odor (KM) based on kiwifruit floral volatiles for which bees showed the highest level of generalization to the natural floral scent, although the response towards pistillate flowers was higher than towards staminate flowers. Then, in the field, feeding colonies KM-scented sucrose solution resulted in higher amounts of kiwifruit pollen collected by honey bees compared to control colonies fed unscented sucrose solution. Our results support the hypothesis that olfactory conditioning bees biases their foraging preferences in a nectarless crop, given the higher visitation to target flowers despite having provided the mimic odor paired with a sugar reward.

Clinical decision making in prostate cancer care-evaluation of EAU-guidelines use and novel decision support software.

Keeping up to date with the latest clinical advances in prostate cancer can be challenging. We investigated the impact of guideline use on quality of treatment decisions as well as the impact of a novel, CE-certified clinical decision support tool (Siemens AIPC software) on the amount of time clinicians spend on decision-making in a multicenter setting. Ten urologists assessed ten clinical cases (screening and localized prostate cancer) in three settings: without support, using a digital version of the EAU guidelines, and with the AIPC tool, resulting in 300 clinical decisions. Comparison involved time spent, decision correct- and completeness. Using AIPC compared to digital guidelines led to a significant reduction of expenditure of time at a per case level (3.57 min and 0:14 min, p < 0.01) and for overall time per urologist (39.45 min and 02:20 min, p < 0.01). Decision options without guidelines support, online guideline usage and usage of AIPC were complete in 61%, 80% and 100%, respectively (p < 0.01). Decision making without guidelines support, online guideline usage and usage of AIPC was correct including all options in 28%, 66% and 100%, respectively (p < 0.01).Clinical decision support systems have the potential to reduces decision-making time and to enhance decision quality.

Microbial diversity and gene abundance in denitrifying bioreactors: A comparison of the woodchip surface biofilm versus the interior wood matrix.

Excessive amounts of nitrogen (N) and phosphorus (P) can lead to eutrophication in water sources. Woodchip bioreactors have shown success in removing N from agricultural runoff, but less is known regarding P removal. Woodchip bioreactors are subsurface basins filled with woodchips installed downgradient of agricultural land to collect and treat drainage runoff. Microorganisms use the woodchips as a carbon (C) source to transform N in the runoff, with unresolved biological impacts on P. This study aims to explore microbial communities present in the bioreactor and determine whether milling woodchips to probe the microbial communities within them reveals hidden microbial diversities or potential activities. Metagenomic sequencing and bioinformatic analyses were performed on six woodchip samples (i.e., three unmilled and three milled) collected from a 10-year-old woodchip bioreactor treating agricultural tile drainage. All samples had similar DNA purity, yield, quality, and microbial diversity regardless of milling. However, when sequences were aligned against various protein libraries, our results indicated greater relative abundance of denitrification and P transformation proteins on the outside of the woodchips (unmilled), while the interior of woodchips (milled) exhibited more functional gene abundance for carbohydrate breakdown. Thus, it may be important to characterize microbial communities both within woodchips, and on woodchip surfaces, to gain a more holistic understanding of coupled biogeochemical cycles on N, P, and C in woodchip bioreactors. Based on these findings, we advise that future microbial research on woodchips (and potentially other permeable organic materials) examine both the surface biofilm and the interior organic material during initial studies. Once researchers determine where specific proteins or enzymes of interest are most prevalent, subsequent studies may then focus on either one or both aspects, as needed.

Groundwater inputs could be a significant but often overlooked source of phosphorus in lake ecosystems.

Freshwater lakes are severely threatened, due largely to excess inputs of nutrients and other contaminants. Phosphorus (P) is receiving renewed attention due to recent increases in toxic cyanobacteria blooms in lakes worldwide. We investigated groundwater seepage for its role in P loading dynamics at Oneida Lake, New York, USA-one of the most well-studied lakes globally. P loading was measured at representative sites along the 88 km shoreline over three summers by directly measuring groundwater flow using seepage meters and porewater samplers. Groundwater seepage was a continuous and significant source of dissolved P over the summer months, comparable to tributary sources to the lake during that time. This constant input has enriched the concentrations of P in the nearshore surface waters, significantly above levels in the pelagic zone. Pore Total Phosphorus (TP) concentrations and loads reached extremely high values (up to 100 mg/L), with inorganic P representing only ~ 10% of TP per site. Groundwater seepage flows and P loadings were highly variable across space and time, partially explained by adjacent land uses and precipitation. Our research concludes that groundwater seepage is a significant, but overlooked, source of dissolved P and a crucial factor driving summer primary production at Oneida Lake, and likely other temperate lakes.

Development of an artificial neural network (ANN) for the prediction of a pilot scale mobile wastewater treatment plant performance.

Productive activities such as pig farming are a fundamental part of the economy in Mexico. Unfortunately, because of this activity, large quantities of wastewater are generated that have a negative impact in the environment. This work shows an alternative for treating piggery wastewater based on advanced oxidation processes (Fenton and solar photo Fenton, SPF) that have been probed successfully in previous works. In the first stage, Fenton and SPF were carried out on a laboratory scale using a Taguchi L9-type experimental design. From the statistical analysis of this design, the operating parameters: pH, time, hydrogen peroxide concentration [H2O2], and iron ferrous concentration [Fe2+] that maximize the response variables: Chemical Oxygen Demand (COD), Total Organic Carbon (TOC), and color were chosen. From these, a cascade forward neural network was implemented to establish a correlation between data from the variables to the physicochemical parameters to be measure being that a great fit of the data was obtained having a correlation coefficient of 0.99 which permits to optimize the pollutant degradation and predict the removal efficiencies at pilot scale but with a projection to a future industrial scale. A relevant result, it was found that the optimal values for maximizing the removal of physicochemical parameters were pH = 3, time = 60 min, H2O2/COD = 1.5 mg L-1, and H2O2/Fe2+ = 2.5 mg L-1. With these conditions degradation percentages of 91.44%, 47.14%, and 97.89% for COD, TOC, and color were obtained from the Fenton process, while for SPF the degradation percentage increased moderately. From the ANN analysis, the possibility to establish an intelligent system that permits to predict multiple results from operational conditions has been achieved.

A revision of the genus Wrangelia (Wrangeliaceae, Ceramiales) in Bermuda resolves six new species including W. ryancraigii from the mesophotic zone.

Four species of the genus Wrangelia are presently known from the western Atlantic Ocean: W. argus, W. bicuspidata, W. penicillata, and W. gordoniae, with the first three historically being reported from Bermuda. Morphological and molecular barcode (COI-5P) and phylogenetic analyses used in this study (SSU, LSU, rbcL) indicated eight species groupings of Wrangelia in Bermuda, excluding two of the historically recognized species, retaining only W. argus while adding seven new species, of which six are formally described. What had been historically reported as W. penicillata from Bermuda was shown to be distinct from Mediterranean Sea specimens (type locality) and was shown to be a mixture of W. hesperia sp. nov. and W. incrassata sp. nov. Along with these two, three other new species (W. laxa sp. nov., W. ryancraigii sp. nov., and W. secundiramea sp. nov.) have complete rhizoidal cortication tightly covering axial cells of indeterminate axes below the apices, distinguishing them from the two local incompletely corticated congeners W. argus and W. abscondita sp. nov., the latter a morphologically cryptic sister species with W. bicuspidata from the Caribbean Sea. Only one of the new species, W. ryancraigii, has thus far been observed in the mesophotic zone off the Bermuda platform, and it is morphologically cryptic with the euphotic zone's W. laxa.

Ghrelin for Neuroprotection in Post-Cardiac Arrest Coma: A Randomized Clinical Trial.

Importance: Out-of-hospital cardiac arrest survival rates have markedly risen in the last decades, but neurological outcome only improved marginally. Despite research on more than 20 neuroprotective strategies involving patients in comas after cardiac arrest, none have demonstrated unequivocal evidence of efficacy; however, treatment with acyl-ghrelin has shown improved functional and histological brain recovery in experimental models of cardiac arrest and was safe in a wide variety of human study populations. Objective: To determine safety and potential efficacy of intravenous acyl-ghrelin to improve neurological outcome in patients in a coma after cardiac arrest. Design, Setting, and Participants: A phase 2, double-blind, placebo-controlled, multicenter, randomized clinical trial, Ghrelin Treatment of Comatose Patients After Cardiac Arrest: A Clinical Trial to Promote Cerebral Recovery (GRECO), was conducted between January 18, 2019, and October 17, 2022. Adult patients 18 years or older who were in a comatose state after cardiac arrest were assessed for eligibility; patients were from 3 intensive care units in the Netherlands. Expected death within 48 hours or unfeasibility of treatment initiation within 12 hours were exclusion criteria. Interventions: Patients were randomized to receive intravenous acyl-ghrelin, 600 µg (intervention group), or placebo (control group) within 12 hours after cardiac arrest, continued for 7 days, twice daily, in addition to standard care. Main Outcomes and Measures: Primary outcome was the score on the Cerebral Performance Categories (CPC) scale at 6 months. Safety outcomes included any serious adverse events. Secondary outcomes were mortality and neuron-specific enolase (NSE) levels on days 1 and 3. Results: A total of 783 adult patients in a coma after cardiac arrest were assessed for eligibility, and 160 patients (median [IQR] age, 68 [57-75] years; 120 male [75%]) were enrolled. A total of 81 patients (51%) were assigned to the intervention group, and 79 (49%) were assigned to the control group. The common odds ratio (OR) for any CPC improvement in the intervention group was 1.78 (95% CI, 0.98-3.22; P = .06). This was consistent over all CPC categories. Mean (SD) NSE levels on day 1 after cardiac arrest were significantly lower in the intervention group (34 [6] µg/L vs 56 [13] µg/L; P = .04) and on day 3 (28 [6] µg/L vs 52 [14] µg/L; P = .08). Serious adverse events were comparable in incidence and type between the groups. Mortality was 37% (30 of 81) in the intervention group vs 51% (40 of 79) in the control group (absolute risk reduction, 14%; 95% CI, -2% to 29%; P = .08). Conclusions and Relevance: In patients in a coma after cardiac arrest, intravenous treatment with acyl-ghrelin was safe and potentially effective to improve neurological outcome. Phase 3 trials are needed for conclusive evidence. Trial Registration: Clinicaltrialsregister.eu: EUCTR2018-000005-23-NL.

Development and Validation of a Prediction Model for 1-Year Mortality in Patients With a Hematologic Malignancy Admitted to the ICU.

OBJECTIVES: To develop and validate a prediction model for 1-year mortality in patients with a hematologic malignancy acutely admitted to the ICU. DESIGN: A retrospective cohort study. SETTING: Five university hospitals in the Netherlands between 2002 and 2015. PATIENTS: A total of 1097 consecutive patients with a hematologic malignancy were acutely admitted to the ICU for at least 24 h. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We created a 13-variable model from 22 potential predictors. Key predictors included active disease, age, previous hematopoietic stem cell transplantation, mechanical ventilation, lowest platelet count, acute kidney injury, maximum heart rate, and type of malignancy. A bootstrap procedure reduced overfitting and improved the model's generalizability. This involved estimating the optimism in the initial model and shrinking the regression coefficients accordingly in the final model. We assessed performance using internal-external cross-validation by center and compared it with the Acute Physiology and Chronic Health Evaluation II model. Additionally, we evaluated clinical usefulness through decision curve analysis. The overall 1-year mortality rate observed in the study was 62% (95% CI, 59-65). Our 13-variable prediction model demonstrated acceptable calibration and discrimination at internal-external validation across centers (C-statistic 0.70; 95% CI, 0.63-0.77), outperforming the Acute Physiology and Chronic Health Evaluation II model (C-statistic 0.61; 95% CI, 0.57-0.65). Decision curve analysis indicated overall net benefit within a clinically relevant threshold probability range of 60-100% predicted 1-year mortality. CONCLUSIONS: Our newly developed 13-variable prediction model predicts 1-year mortality in hematologic malignancy patients admitted to the ICU more accurately than the Acute Physiology and Chronic Health Evaluation II model. This model may aid in shared decision-making regarding the continuation of ICU care and end-of-life considerations.

There Is More to Length of Survival Than Survival: Endpoints in Oncology Trials.

Progression-free survival as a primary endpoint for comparative trials does not fully capture the therapeutic risk/benefit ratio. Additionally, summarization of the treatment effect via a hazard ratio is problematic when the proportional hazards assumption is violated. Restricted mean survival time metrics may address these challenges but have other limitations. See related article by Chang et al., p. 3282.

Egyptian Dynasties to Biologics: A Historical Review of Nasal Polyposis.

The history of nasal polyposis originates even before Hippocrates described a nasal mass that he likened to a sea polyp. References to sinonasal disease and treatment can be found in ancient texts, such as the Ebers Papyrus and the Edwin Smith Papyrus of Ancient Egypt, as well as in the foundational texts of Ayurvedic medicine. Greek philosophers marked a significant shift away from the belief that illness was a result of divine intervention and embraced medical theory. Over the subsequent millennia, the understanding of nasal polyposis expanded, resulting in notable progress in surgical procedures and medical treatments. However, the complex pathophysiology of this condition remained enigmatic until breakthroughs in basic science and immunology. This historical journey takes us from the tomb of the first rhinologist in 2500 BC to the development of immune-modulating biologics.

Understanding the Electronic Transport of Al-Si and Al-Ge Nanojunctions by Exploiting Temperature-Dependent Bias Spectroscopy.

Understanding the electronic transport of metal-semiconductor heterojunctions is of utmost importance for a wide range of emerging nanoelectronic devices like adaptive transistors, biosensors, and quantum devices. Here, we provide a comparison and in-depth discussion of the investigated Schottky heterojunction devices based on Si and Ge nanowires contacted with pure single-crystal Al. Key for the fabrication of these devices is the selective solid-state metal-semiconductor exchange of Si and Ge nanowires into Al, delivering void-free, single-crystal Al contacts with flat Schottky junctions, distinct from the bulk counterparts. Thereof, a systematic comparison of the temperature-dependent charge carrier injection and transport in Si and Ge by means of current-bias spectroscopy is visualized by 2D colormaps. Thus, it reveals important insights into the operation mechanisms and regimes that cannot be exploited by conventional single-sweep output and transfer characteristics. Importantly, it was found that the Al-Si system shows symmetric effective Schottky barrier (SB) heights for holes and electrons, whereas the Al-Ge system reveals a highly transparent contact for holes due to Fermi level pinning close to the valence band with charge carrier injection saturation due to a thinned effective SB. Moreover, thermionic field emission limits the overall electron conduction, indicating a distinct SB for electrons.

Identification of chemosensory genes in the stingless bee Tetragonisca fiebrigi.

Reception of chemical information from the environment is crucial for insects' survival and reproduction. The chemosensory reception mainly occurs by the antennae and mouth parts of the insect, when the stimulus contacts the chemoreceptors located within the sensilla. Chemosensory receptor genes have been well-studied in some social hymenopterans such as ants, honeybees, and wasps. However, although stingless bees are the most representative group of eusocial bees, little is known about their odorant, gustatory, and ionotropic receptor genes. Here, we analyze the transcriptome of the proboscis and antennae of the stingless bee Tetragonisca fiebrigi. We identified and annotated 9 gustatory and 15 ionotropic receptors. Regarding the odorant receptors, we identified 204, and we were able to annotate 161 of them. In addition, we compared the chemosensory receptor genes of T. fiebrigi with those annotated for other species of Hymenoptera. We found that T. fiebrigi showed the largest number of odorant receptors compared with other bees. Genetic expansions were identified in the subfamilies 9-exon, which was also expanded in ants and paper wasps; in G02A, including receptors potentially mediating social behavior; and in GUnC, which has been related to pollen and nectar scent detection. Our study provides the first report of chemosensory receptor genes in T. fiebrigi and represents a resource for future molecular and physiological research in this and other stingless bee species.

A Phase I Trial of Enzalutamide Plus Selective Glucocorticoid Receptor Modulator Relacorilant in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.