Altered Plasma Membrane Lipid Composition in Hypertensive Neutrophils Impacts Epithelial Sodium Channel (ENaC) Endocytosis.

Biological membranes are composed of a lipid bilayer with embedded proteins, including ion channels like the epithelial sodium channel (ENaC), which are critical for sodium homeostasis and implicated in arterial hypertension (HTN). Changes in the lipid composition of the plasma membrane can significantly impact cellular processes related to physiological functions. We hypothesized that the observed overexpression of ENaC in neutrophils from HTN patients might result from alterations in the structuring domains within the plasma membrane, disrupting the endocytic processes responsible for ENaC retrieval. This study assessed the structural lipid composition of neutrophil plasma membranes from HTN patients along with the expression patterns of key elements regulating ENaC at the plasma membrane. Our findings suggest alterations in microdomain structure and SGK1 kinase activity, which could prolong ENaC presence on the plasma membrane. Additionally, we propose that the proteasomal and lysosomal degradation pathways are insufficient to diminish ENaC presence at the plasma membrane in HTN. These results highlight the importance of understanding ENaC retrieval mechanisms and suggest that targeting these mechanisms could provide insights for developing drugs to prevent and treat HTN.

Impact of Insurance Type on Access to Pain Management Specialists for the Treatment of Lower Back Pain.

Background Low back pain is known to be one of the leading causes of disability among the young and elderly population. Low back pain can stem from multiple sources, including spinal degeneration, injury, herniated discs, sciatica, and other contributing causes. This symptom significantly influences the quality of life of affected individuals. Its implications include extensive social and economic costs. Economic considerations arise from the fact that not all healthcare facilities accept the insurance plans available to retired individuals under Medicare. This places an additional burden on patients who must bear the financial responsibility for healthcare services not covered by their insurance plan. Florida, renowned as a favored state for retirement, consists of a demographic composition wherein 21% of its residents are aged 65 or older. A significant proportion of this demographic qualifies for Traditional Medicare (TM) and/or Medicare Advantage (MA) plans. Thus, understanding the disparities in healthcare access between Medicare and Medicare Advantage plans is crucial. This study aims to evaluate different Medicare insurances available in the market and their impact on the ease of accessibility to pain management specialists for the treatment of lower back pain in Florida patients. Methods We analyzed the Florida Department of Health database to identify the four counties in Florida with the highest Medicare enrollment rates in 2022: Miami-Dade, Palm Beach, Broward, and Pinellas County. Using the U.S. News and Report directory, 25 Pain Management-trained anesthesiologists were randomly selected from each of the four counties. Each office was contacted four times via telephone by four different team members to assess appointment availability for a fictional 65-year-old grandfather seeking treatment for chronic low back pain. The study examined appointment availability and accepted insurance types, including Cigna (commercial insurance), TM, Humana Gold Plus HMO (Medicare Advantage plan), and Blue Medicare Select PPO (Medicare Advantage plan). Practices without contact information or retired physicians were excluded from the analysis. Time to appointment was measured in business days. Results Of the 100 Pain Management Physicians contacted, 44 fit the inclusion criteria of being non-retired physicians, still practicing in one of the four counties with open offices and valid contact information. Blue Medicare Select PPO was accepted by 47.73%, Humana Gold Plus HMO by 56.82%, TM by 93.18%, and Cigna by 93.18% of the encounters. Blue Medicare select PPO and Humana Gold Plus HMO were accepted at significantly lower rates when compared to Traditional Medicare and Cigna with P values of P < .00001 and P < .000176, respectively. There was no significant difference found in the time to appointment between insurances with P value < 7. Conclusion The study found that patients enrolled in Medicare Advantage plans have significantly decreased access to care when compared to those enrolled in TM or commercial insurance. Further research is needed to elucidate the reasons behind differences in access to care across different insurances, as identified in the study.

A Bibliometric Analysis of the 500 Most Cited Papers in Orthopaedic Oncology.

BACKGROUND: Despite notable progress over time, broad insight into the scientific landscape of orthopaedic oncology is lacking. We conducted a bibliometric analysis of the 500 most cited papers in the field. METHODS: We searched the Science Citation Index Expanded database of the Web of Science Core Collection to find the 500 most cited articles in the field. RESULTS: Citation count ranged from 81 to 1,808. Articles were published from 1965 to 2018. Over half of all articles were published in the United States (53.6%). The 2000s was the most productive decade with 170 (34%) articles. All articles were written in English and were published across 29 journals. Female participation as first authors significantly increased from the 1960s to the 2010s (0% vs 14.6%, P = 0.0434). Similarly, female involvement as senior authors grew from the 1960s to the 2010s (0% vs 12.2%, P = 0.0607). Primary bone sarcomas were the most cited topic among articles from the 1970s to the 1980s. From studies produced in the 1990s up until the 2010s, reconstruction procedures were the most cited topic. CONCLUSION: Trends over the years have resulted in an emphasis on a surgical technique. Notable progress has been made regarding gender diversity, yet disparities still exist.

Time Period of Treatment's Effect on the Association Between Race and Survival in Patients With Malignant Colorectal Adenocarcinoma.

BACKGROUND: Colorectal cancer is one of the most common malignancies diagnosed in the United States, with 126,240 new cases diagnosed in 2020. Past studies have shown that disparities may exist between certain patient populations, but it is unknown how they are affected over time as treatments evolve. The purpose of this study was to determine whether the decade of treatment modifies the association between race and five-year survival in adults diagnosed and treated for malignant colorectal adenocarcinomas since the 1970s. METHODS: This was a non-concurrent retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. The inclusion criteria involved patients with primary malignant colorectal adenocarcinoma between the years 1975 and 2018. Exclusion criteria included previous malignancies or missing information on any of the variables. The exposure variable was the patient's race, and the main outcome variable was average five-year survival rates. The effect modifier was the time period in which the patient received treatment. The covariates of the study included age, sex, Hispanic status, surgical intervention recommendation, and disease stage. Unadjusted and adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated using Cox regression models. RESULTS: As the interaction term between race/ethnicity and year of diagnosis was statistically significant, the data were stratified according to year of diagnosis. Black patients in both time periods had a higher mortality rate from malignant colorectal carcinoma after adjustment for the covariates (1975-1990: HR 1.10, 95% CI 1.06-1.15; 1991-2018: HR 1.19, 95% CI 1.16-1.23) when compared with White patients. American Indian, Alaskan Native, and Asian patients were found to have lower mortality in both time periods when compared with White patients (1975-1990: HR 0.90, 95% CI 0.85-0.95; 1991-2018: HR 0.93, 95% CI 0.89-0.96). CONCLUSION: Our data found that despite the evolution in the standard of care treatment for malignant colorectal adenocarcinoma since the year 1975, Black patients had lower five-year survival rates when compared with their White counterparts as well as increased rates of being diagnosed with this disease. Overall, addressing these disparities in colorectal cancer outcomes is critical for improving public health and reducing healthcare costs.

Foot and Ankle Soft Tissue Sarcomas-Treatment and Oncologic Outcomes: A Systematic Review of the Literature.

BACKGROUND: Foot and ankle soft tissue sarcomas (STSs) are rare neoplasms associated with a high risk of local recurrence and metastasis. Although amputation is often performed, its impact on prognosis remains unknown. The aims of our systematic review were identifying risk factors for (1) disease-specific death, (2) local recurrence, (3) metastasis, and assessing (4) whether the type of surgery (amputation or limb-salvage) affected disease-specific survival. METHODS: This systematic review was conducted following PRISMA guidelines. The PubMed, Embase, and Scopus databases were searched. Our study was registered in PROSPERO (ID: 415624). Quality appraisal was done using STROBE guidelines. RESULTS: A total of 7 studies and 123 patients were included. Metastasis was the only risk factor for disease-specific death (OR = 107.85, P< .001). Previous unplanned excision (OR = 22.29, P = .009) and positive margins (OR = 64.48, P = .011) were associated with higher risk of local recurrence. Patients with high-grade tumors (OR = 13.22, P = .023) and tumors ≥6 cm (OR = 7.40, P = .022) were more likely to develop metastases. After adjusting for confounders (age, sex, and presence of metastasis), amputation was not associated with poorer disease-specific survival. CONCLUSION: Metastasis was the single most important risk factor for death with foot and ankle soft tissue sarcoma. Positive margins and history of previous unplanned excision are risk factors for local recurrence. The most important risk factors for metastasis are tumor grade and size ≥6 cm. Amputation was not associated with poorer disease-specific survival.

Wastewater surveillance of pharmaceuticals during the COVID-19 pandemic in Mexico City and the Mezquital Valley: A comprehensive environmental risk assessment.

This study tracked five pharmaceutically active compounds (PhACs) in Mexico City's sewage, namely, famotidine, indomethacin, dexamethasone, azithromycin, and ivermectin, which were used to treat COVID-19. The monitoring campaign was carried out over 30 months (May 2020 to November 2022), covering the five COVID-19 waves in Mexico. In the Central Emitter, the main sewage outflow, famotidine displayed levels of 132.57 ± 28.16 ng L-1 (range from < LOQ to 189.1 ng L-1), followed by indomethacin (average 672.46 ± 116.4 ng L-1, range from 516.7 to 945.2 ng L-1), dexamethasone (average 610.4 ± 225.7 ng L-1, range from 233.4 to 1044.5 ng L-1), azithromycin (average 4436.2 ± 903.6 ng L-1, range from 2873.7 to 5819.6 ng L-1), and ivermectin (average 3413.3 ± 1244.6 ng L-1, range from 1219.8 to 4622.4 ng L-1). The concentrations of dexamethasone, azithromycin and ivermectin were higher in sewage from a temporary COVID-19 care unit, by a factor of 3.48, 3.52 and 2.55, respectively, compared with those found in municipal wastewater. In the effluent of the Atotonilco Wastewater Treatment Plant (AWWTP), which treats near 60 % of the Mexico City's sewage, famotidine was absent, while concentrations of indomethacin, dexamethasone, azithromycin and ivermectin were 78.2 %, 76.7 %, 74.4 %, and 88.1 % lower than those in the influent, respectively. The occurrence of PhACs in treated and untreated wastewater resulted in medium to high environmental risk since Mexico City's wastewater is reused for irrigation in the Mezquital Valley. There, PhACs were found in irrigation canals at lower levels than those observed in Mexico City throughout the monitoring. On the other hand, famotidine, indomethacin, and dexamethasone were not found in surface water resulting from the infiltration of wastewater through soil in Mezquital Valley, while azithromycin and ivermectin sporadically appeared in surface water samples collected through 2021. Using an optimized risk assessment based on a semi-probabilistic approach, the PhACs were prioritized as ivermectin > azithromycin > dexamethasone > famotidine > indomethacin.

Estimation of Ground Contact Time with Inertial Sensors from the Upper Arm and the Upper Back.

Ground contact time (GCT) is one of the most relevant factors when assessing running performance in sports practice. In recent years, inertial measurement units (IMUs) have been widely used to automatically evaluate GCT, since they can be used in field conditions and are friendly and easy to wear devices. In this paper we describe the results of a systematic search, using the Web of Science, to assess what reliable options are available to GCT estimation using inertial sensors. Our analysis reveals that estimation of GCT from the upper body (upper back and upper arm) has rarely been addressed. Proper estimation of GCT from these locations could permit an extension of the analysis of running performance to the public, where users, especially vocational runners, usually wear pockets that are ideal to hold sensing devices fitted with inertial sensors (or even using their own cell phones for that purpose). Therefore, in the second part of the paper, an experimental study is described. Six subjects, both amateur and semi-elite runners, were recruited for the experiments, and ran on a treadmill at different paces to estimate GCT from inertial sensors placed at the foot (for validation purposes), the upper arm, and upper back. Initial and final foot contact events were identified in these signals to estimate the GCT per step, and compared to times estimated from an optical MOCAP (Optitrack), used as the ground truth. We found an average error in GCT estimation of 0.01 s in absolute value using the foot and the upper back IMU, and of 0.05 s using the upper arm IMU. Limits of agreement (LoA, 1.96 times the standard deviation) were [-0.01 s, 0.04 s], [-0.04 s, 0.02 s], and [0.0 s, 0.1 s] using the sensors on the foot, the upper back, and the upper arm, respectively.

Reporte de caso: vólvulo de sigmoides en un adulto joven, una manifestación de enfermedad de Hirschsprung.

BACKGROUND: Hirschsprung's disease is characterized by the absence of enteric ganglia in the distal digestive tract; being usually diagnosed in neonates, it rarely debuts during adulthood, where it presents as chronic constipation refractory to treatment. CASE REPORT: 24-year-old female patient with Hirschsprung's disease who arrives to the emergency room with a sigmoid volvulus requiring urgent surgical therapy. CONCLUSIONS: Hirschsprung's disease doesn't frequently debut in adulthood, presenting a diagnostic and therapeutic challenge for the general surgeon, especially when dealing with its complications.

ANTECEDENTES: La enfermedad de Hirschsprung se caracteriza por un defecto de las células nerviosas en el intestino distal. Suele diagnosticarse durante los primeros años de vida, rara vez debutando en adultos, en quienes se manifiesta como una constipación crónica refractaria al tratamiento. CASO CLÍNICO: Mujer de 24 años con enfermedad de Hirschsprung no diagnosticada, quien acude a urgencias por un cuadro de vólvulo de sigmoides que requiere intervención quirúrgica. CONCLUSIONES: La enfermedad de Hirschsprung rara vez debuta en la edad adulta y generalmente se diagnostica secundaria a sus complicaciones, por lo que supone un reto diagnóstico y terapéutico para el cirujano general.

The visible-light-driven photocatalytic reduction of Cr6+ using BiVO4: assessing the effect of Au deposition and the reaction parameters.

In this work, fern-leaf-like BiVO4 was used to photocatalytically reduce Cr6+ in water. Nanosized BiVO4 displayed bandgap energy and specific surface area of 2.49 eV and 5.65 m2 g-1, respectively. Metallic Au nanoparticles were deposited on the BiVO4 to increase the photocatalytic performance. To optimize the reaction conditions, the sacrificial agents methanol, ethanol, formic acid, dimethyl sulfoxide, and KI were tested, while different catalyst dosages and Au loadings were assessed. The best sacrificial agent was formic acid, which was used at an optimal concentration of 0.01 mol L-1. The complete removal of Cr6+ was attained after 90 min of visible light irradiation using a catalyst dosage of 1.5 g L-1. Depositing metallic Au nanoparticles barely improved the photocatalytic performance, thus unmodified BiVO4 was used to remove Cr6+ in tap water. The matrix effect slowed the photocatalytic process, and the complete removal of Cr6+ was achieved in 120 min. Cr3+ and Cr6+ species were precipitated on the catalyst surface at the end of the photocatalytic process; still, BiVO4 displayed high stability after three reaction cycles.

Real-Time Short-Term Pedestrian Trajectory Prediction Based on Gait Biomechanics.

The short-term prediction of a person's trajectory during normal walking becomes necessary in many environments shared by humans and robots. Physics-based approaches based on Newton's laws of motion seem best suited for short-term predictions, but the intrinsic properties of human walking conflict with the foundations of the basic kinematical models compromising their performance. In this paper, we propose a short-time prediction method based on gait biomechanics for real-time applications. This method relays on a single biomechanical variable, and it has a low computational burden, turning it into a feasible solution to implement in low-cost portable devices. We evaluate its performance from an experimental benchmark where several subjects walked steadily over straight and curved paths. With this approach, the results indicate a performance good enough to be applicable to a wide range of human-robot interaction applications.

Assessment of the Mechanical Support Characteristics of a Light and Wearable Robotic Exoskeleton Prototype Applied to Upper Limb Rehabilitation.

Robotic exoskeletons are active devices that assist or counteract the movements of the body limbs in a variety of tasks, including in industrial environments or rehabilitation processes. With the introduction of textile and soft materials in these devices, the effective motion transmission, mechanical support of the limbs, and resistance to physical disturbances are some of the most desirable structural features. This paper proposes an evaluation protocol and assesses the mechanical support properties of a servo-controlled robotic exoskeleton prototype for rehabilitation in upper limbs. Since this prototype was built from soft materials, it is necessary to evaluate the mechanical behavior in the areas that support the arm. Some of the rehabilitation-supporting movements such as elbow flexion and extension, as well as increased muscle tone (spasticity), are emulated. Measurements are taken using the reference supplied to the system's control stage and then compared with an external high-precision optical tracking system. As a result, it is evidenced that the use of soft materials provides satisfactory outcomes in the motion transfer and support to the limb. In addition, this study lays the groundwork for a future assessment of the prototype in a controlled laboratory environment using human test subjects.

Synthesis of BiOI/Mordenite Composites for Photocatalytic Treatment of Organic Pollutants Present in Agro-Industrial Wastewater.

Recently, bismuth oxyiodide (BiOI) is an attractive semiconductor to use in heterogeneous photocatalysis processes. Unfortunately, BiOI individually shows limited photocatalytic efficiency, instability, and a quick recombination of electron/holes. Considering the practical application of this semiconductor, some studies show that synthetic zeolites provide good support for this photocatalyst. This support material permits a better photocatalytic efficiency because it prevents the quick recombination of photogenerated pairs. However, the optimal conditions (time and temperature) to obtain composites (BiOI/ synthetic zeolite) with high photocatalytic efficiency using a coprecipitation-solvothermal growth method have not yet been reported. In this study, a response surface methodology (RSM) based on a central composite design (CCD) was applied to optimize the synthesis conditions of BiOI/mordenite composites. For this purpose, eleven BiOI/mordenite composites were synthesized using a combined coprecipitation-solvothermal method under different time and temperature conditions. The photocatalytic activities of the synthesized composites were evaluated after 20 min of photocatalytic oxidation of caffeic acid, a typical organic pollutant found in agro-industrial wastewater. Moreover, BiOI/mordenite composites with the highest and lowest photocatalytic activity were physically and chemically characterized using nitrogen adsorption isotherms, scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and diffuse reflectance spectroscopy (DRS). The optimal synthesis conditions prove to be 187 °C and 9 h. In addition, the changes applied to the experimental conditions led to surface property modifications that influenced the photocatalytic degradation efficiency of the BiOI/mordenite composite toward caffeic acid photodegradation.

Metrological Evaluation of Human-Robot Collaborative Environments Based on Optical Motion Capture Systems.

In the context of human-robot collaborative shared environments, there has been an increase in the use of optical motion capture (OMC) systems for human motion tracking. The accuracy and precision of OMC technology need to be assessed in order to ensure safe human-robot interactions, but the accuracy specifications provided by manufacturers are easily influenced by various factors affecting the measurements. This article describes a new methodology for the metrological evaluation of a human-robot collaborative environment based on optical motion capture (OMC) systems. Inspired by the ASTM E3064 test guide, and taking advantage of an existing industrial robot in the production cell, the system is evaluated for mean error, error spread, and repeatability. A detailed statistical study of the error distribution across the capture area is carried out, supported by a Mann-Whitney U-test for median comparisons. Based on the results, optimal capture areas for the use of the capture system are suggested. The results of the proposed method show that the metrological characteristics obtained are compatible and comparable in quality to other methods that do not require the intervention of an industrial robot.

Selection of rhizobacteria isolates with bioherbicide potential against Palmer amaranth (Amarathus palmeri S. Wats.).

Crop yield and quality are affected by the presence of weeds such as Palmer amaranth. Chemical control is the most commonly used method to eradicate weeds, due to its quickness and efficacy. However, the inappropriate use of chemical herbicides can lead to resistant weed biotypes, as well as problems related to environmental pollution and human health hazards. One ecological alternative to combat weeds is the use of deleterious rhizobacteria (DRB). We evaluated the potential bioherbicidal effect in 15 DRB isolates from the rhizosphere of Palmer amaranth, both in vitro and in greenhouse tests. Isolates TR10 and TR18 inhibited seed germination in vitro, whereas the TR25 and TR36 isolates showed the potential to inhibit Palmer amaranth plant development in growth room assays without affecting maize and common bean germination and growth. These four isolates were molecularly identified as either Pseudomonas sp. (TR10 and TR36), Enterobacter sp. (TR18), or Bacillus sp. (TR25). In addition, the production of volatiles and diffusible metabolites were identified as possible mechanisms of germination arrestment and plant development inhibition. This study suggests the bioherbicide potential of some indigenous rhizobacteria against Palmer amaranth.

Conformational Strain of Macrocyclic Peptides in Ligand-Receptor Complexes Based on Advanced Refinement of Bound-State Conformers.

Macrocyclic peptides are an important modality in drug discovery, but molecular design is limited due to the complexity of their conformational landscape. To better understand conformational propensities, global strain energies were estimated for 156 protein-macrocyclic peptide cocrystal structures. Unexpectedly large strain energies were observed when the bound-state conformations were modeled with positional restraints. Instead, low-energy conformer ensembles were generated using xGen that fit experimental X-ray electron density maps and gave reasonable strain energy estimates. The ensembles featured significant conformational adjustments while still fitting the electron density as well or better than the original coordinates. Strain estimates suggest the interaction energy in protein-ligand complexes can offset a greater amount of strain for macrocyclic peptides than for small molecules and non-peptidic macrocycles. Across all molecular classes, the approximate upper bound on global strain energies had the same relationship with molecular size, and bound-state ensembles from xGen yielded favorable binding energy estimates.

Occurrence of perfluorinated carboxylic acids in Mexico City's wastewater: A monitoring study in the sewerage and a mega wastewater treatment plant.

An analytical method based on liquid chromatography coupled to mass spectrometry was validated to quantify five perfluorinated carboxylic acids (PFCA) namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), and perfluoroundecanoic acid (PFUnA), in wastewater produced in a megacity. Sampling was performed on a monthly basis, obtaining samples from the undergrounded sewerage system and the main open-air canal transporting wastewater out the city. Steady levels of the sum of the target PFCA (Æ©PFCA) were determined on both sites through the study: 419.4 ± 24.3 ng L-1 in undergrounded sewage and 591.1 ± 39 ng L-1 in the open-air canal. Short-chain PFCA (PFBA, PFHxA, and PFHpA) were abundant, while concentrations of PFOA and PFUnA remained lower in both sampling sites. The open-air canal was transected in four sampling points, which were sampled throughout the monitoring campaign, finding that furtive discharges of municipal and industrial wastewater increased the levels of short-chain PFCA, while those of PFOA and PFUnA were depleted. Relevant concentrations of PFBA (176.9 ± 3.3 ng L-1), PFHxA (133.4 ± 2.5 ng L-1), PFHpA (116.6 ± 3.9 ng L-1), PFOA (133.1 ± 3.5 ng L-1), and PFUnA (23.5 ± 6.5 ng L-1) were found 60 km downstream, where the wastewater transported by the open-air canal is used in irrigation. A fraction of sewage is treated in a conventional wastewater treatment plant. The concentration of short-chain PFCA increased in effluent, adding extra loads of PFBA, PFHxA, and PFHpA to the environment.

Evaluation of a Spanish language version of the Asthma Trigger Inventory.

Background: Perceptions of asthma triggers provide important guidance for patients' disease management. A psychometrically valid instrument, the Asthma Trigger Inventory (ATI), is available in English and German language versions, however, a version in Spanish as major world language has been missing.Method: A Spanish-language version of the ATI was evaluated in 339 adult patients with asthma, 223 of these in Peru and 107 in the USA. Principal Component analysis (PCA) with Varimax rotation was used to identify coherent trigger domains across and within samples. Resulting subscales were evaluated for internal consistency.Results: PCA suggested differences in factor structures between sites. Whereas the USA sample largely replicated original factors for animal allergens, pollen allergens, physical activity, air pollution/irritants, infections, and psychology, the initial analysis of the Peru sample suggested substantial overlap of air pollution/irritant, infection, and allergen items. Subsequent analysis of an expanded research form of the ATI for the Peru site culminated in extraction of five factors related to psychology, climate/temperature, combined pollen and animal allergens, physical activity, and infection. Internal consistencies were in an acceptable to excellent range (α = 0.74 to 0.94). Additional free trigger responses confirmed the importance of climate variables for patients in Peru. Psychological triggers were reported by 26% (Peru) and 31% (USA) of patients.Conclusion: Coherent trigger domains are readily identified and measured reliably by a Spanish-language ATI version. However, factor structures vary between samples from different Hispanic/Latino cultural and geographic domains. Culturally adapted versions of this instrument are therefore required for Hispanic/Latino population studies.

ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy.

BACKGROUND: Interleukin-2 (IL-2) plays a pivotal role in immune homeostasis due to its ability to stimulate numerous lymphocyte subsets including natural killer (NK) cells, effector CD4+ and CD8+ T cells, and regulatory T cells (Tregs). Low concentrations of IL-2 induce signaling through the high-affinity IL-2 receptor (IL-2R) comprised of IL-2Rα, IL-2Rß, and common γ chain (γc), preferentially expressed on Tregs. Higher concentrations of IL-2 are necessary to induce signaling through the intermediate-affinity IL-2R, composed of IL-2Rß and γc, expressed on memory CD8+ T cells and NK cells. Recombinant human IL-2 (rhIL-2) is approved for treatment of metastatic melanoma and renal cell carcinoma (RCC), but adverse events including capillary leak syndrome, potentially mediated through interaction with the high-affinity IL-2R, limit its therapeutic use. Furthermore, antitumor efficacy of IL-2 may also be limited by preferential expansion of immunosuppressive Tregs. ALKS 4230 is an engineered fusion protein comprised of a circularly-permuted IL-2 with the extracellular domain of IL-2Rα, designed to selectively activate effector lymphocytes bearing the intermediate-affinity IL-2R. RESULTS: ALKS 4230 was equipotent to rhIL-2 in activating human cells bearing the intermediate-affinity IL-2R, and less potent than rhIL-2 on cells bearing the high-affinity IL-2R. As observed in vitro with primary human cells from healthy donors and advanced cancer patients, ALKS 4230 induced greater activation and expansion of NK cells with reduced expansion of Tregs relative to rhIL-2. Similarly, in mice, ALKS 4230 treatment stimulated greater expansion of NK cells and memory-phenotype CD8+ T cells at doses that did not expand or activate Tregs. ALKS 4230 treatment induced significantly lower levels of proinflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, and interferon gamma relative to rhIL-2. Furthermore, ALKS 4230 exhibited superior antitumor efficacy in the mouse B16F10 lung tumor model, where ALKS 4230 could be administered via multiple routes of administration and dosing schedules while achieving equivalent antitumor efficacy. CONCLUSIONS: ALKS 4230 exhibited enhanced pharmacokinetic and selective pharmacodynamic properties resulting in both improved antitumor efficacy and lower indices of toxicity relative to rhIL-2 in mice. These data highlight the potential of ALKS 4230 as a novel cancer immunotherapy, and as such, the molecule is being evaluated clinically.

Current and Future Roles of Artificial Intelligence in Medicinal Chemistry Synthesis.

Artificial intelligence and machine learning have demonstrated their potential role in predictive chemistry and synthetic planning of small molecules; there are at least a few reports of companies employing in silico synthetic planning into their overall approach to accessing target molecules. A data-driven synthesis planning program is one component being developed and evaluated by the Machine Learning for Pharmaceutical Discovery and Synthesis (MLPDS) consortium, comprising MIT and 13 chemical and pharmaceutical company members. Together, we wrote this perspective to share how we think predictive models can be integrated into medicinal chemistry synthesis workflows, how they are currently used within MLPDS member companies, and the outlook for this field.

Alterations to the contents of plasma membrane structural lipids are associated with structural changes and compartmentalization in platelets in hypertension.

Arterial hypertension (HTN) can lead to serious organ damage. Several mechanisms have been implicated in the pathogenesis of HTN including constitutive activation of platelets, which increases the risk of aggregation and clot formation. We recently demonstrated the plasma membranes of platelets from patients with HTN exhibit modified structural and physicochemical properties; Raman and Fourier transform infrared by attenuated total reflectance (FTIR-ATR) spectroscopy also indicated lipid content and protein structure alterations. This study aimed to precisely quantify the constituents of the main structural phospholipids and cholesterol in the plasma membranes of platelets from patients with HTN and normotensive individuals. We also assessed the consequence of these alterations on platelet structure and function. Liquid chromatography coupled to triple quadrupole mass spectrometry revealed the plasma membranes of HTN platelets contained less cholesterol and phosphatidylcholine, more phosphatidylserine and phosphatidylethanolamine and had similar sphingosine contents. Atomic force microscopy revealed HTN platelets exhibited increased surface roughness and more pleats. Transmission electron microscopy revealed diminution of the internal membranous structures in HTN platelets. Our findings strongly suggest plasma membrane lipid content alterations-including cholesterol depletion-occur in HTN, and these alterations may induce morphological and physiological abnormalities that participate in the functional changes associated with hypertension.