Discovery of 4-aminopyrimidine analogs as highly potent dual P70S6K/Akt inhibitors.

Activation of the PI3K/Akt/mTOR kinase pathway is associated with human cancers. A dual p70S6K/Akt inhibitor is sufficient to inhibit strong tumor growth and to block negative impact of the compensatory Akt feedback loop activation. A scaffold docking strategy based on an existing quinazoline carboxamide series identified 4-aminopyrimidine analog 6, which showed a single-digit nanomolar and a micromolar potencies in p70S6K and Akt enzymatic assays. SAR optimization improved Akt enzymatic and p70S6K cellular potencies, reduced hERG liability, and ultimately discovered the promising candidate 37, which exhibited with a single digit nanomolar value in both p70S6K and Akt biochemical assays, and hERG activities (IC50 = 17.4 µM). This agent demonstrated dose-dependent efficacy in inhibiting mice breast cancer tumor growth and covered more than 90% pS6 inhibition up to 24 h at a dose of 200 mg/kg po.

MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates.

Brain-derived neurotrophic factor (BDNF) gene delivery to the entorhinal cortex is a candidate for treatment of Alzheimer's disease (AD) to reduce neurodegeneration that is associated with memory loss. Accurate targeting of the entorhinal cortex in AD is complex due to the deep and atrophic state of this brain region. Using MRI-guided methods with convection-enhanced delivery, we were able to accurately and consistently target AAV2-BDNF delivery to the entorhinal cortex of non-human primates; 86 ± 3% of transduced cells in the targeted regions co-localized with the neuronal marker NeuN. The volume of AAV2-BDNF (3 × 108 vg/µl) infusion linearly correlated with the number of BDNF labeled cells and the volume (mm3) of BDNF immunoreactivity in the entorhinal cortex. BDNF is normally trafficked to the hippocampus from the entorhinal cortex; in these experiments, we also found that BDNF immunoreactivity was elevated in the hippocampus following therapeutic BDNF vector delivery to the entorhinal cortex, achieving growth factor distribution through key memory circuits. These findings indicate that MRI-guided infusion of AAV2-BDNF to the entorhinal cortex of the non-human primate results in safe and accurate targeting and distribution of BDNF to both the entorhinal cortex and the hippocampus. These methods are adaptable to human clinical trials.

Characterization of selected municipal solid waste components to estimate their biodegradability.

Biological treatments of Residual Municipal Solid Waste (RMSW) allow to divert biodegradable materials from landfilling and recover valuable alternative resources. The biodegradability of the waste components needs however to be assessed in order to design the bioprocesses properly. The present study investigated complementary approaches to aerobic and anaerobic biotests for a more rapid evaluation. A representative sample of residual MSW was collected from a Mechanical Biological Treatment (MBT) plant and sorted out into 13 fractions according to the French standard procedure MODECOM™. The different fractions were analyzed for organic matter content, leaching behavior, contents in biochemical constituents (determined by Van Soest's acid detergent fiber method), Biochemical Oxygen Demand (BOD) and Bio-Methane Potential (BMP). Experimental data were statistically treated by Principal Components Analysis (PCA). Cumulative oxygen consumption from BOD tests and cumulative methane production from BMP tests were found to be positively correlated in all waste fractions. No correlation was observed between the results from BOD or BMP bioassays and the contents in cellulose-like, hemicelluloses-like or labile organic compounds. No correlation was observed either with the results from leaching tests (Soluble COD). The contents in lignin-like compounds, evaluated as the non-extracted RES fraction in Van Soest's method, was found however to impact negatively the biodegradability assessed by BOD or BMP tests. Since cellulose, hemicelluloses and lignin are the polymers responsible for the structuration of lignocellulosic complexes, it was concluded that the structural organization of the organic matter in the different waste fractions was more determinant on biodegradability than the respective contents in individual biopolymers.

Small Molecules Drive Big Improvements in Immuno-Oncology Therapies.

Immuno-oncology therapies have the potential to revolutionize the armamentarium of available cancer treatments. To further improve clinical response rates, researchers are looking for novel combination regimens, with checkpoint blockade being used as a backbone of the treatment. This Review highlights the significance of small molecules in this approach, which holds promise to provide increased benefit to cancer patients.

Recent progress towards clinically relevant ATP-competitive Akt inhibitors.

The frequency of PI3K/Akt/mTOR (PAM) Pathway mutations in human cancers sparked interest to determine if the pathway is druggable. The modest clinical benefit observed with mTOR rapalogs (temsirolimus and everolimus) provided further motivation to identify additional nodes of pathway inhibition that lead to improved clinical benefit. Akt is a central signaling node of the PAM pathway and could be an ideal target for improved pathway inhibition. Furthermore, inhibitors of Akt may be especially beneficial in tumors with Akt1 mutations. Recently, multiple ATP-competitive Akt inhibitors have been identified and are currently in clinical development. This review details the medicinal chemistry efforts towards identification of these molecules, highlights relevant preclinical data supporting clinical evaluation, and summarizes current clinical development plans.

Anaerobic digestion of lignocellulosic biomasses pretreated with Ceriporiopsis subvermispora.

Fungal pretreatment by Ceriporiopsis subvermispora of two forest residues (hazel and acacia branches) and two agricultural lignocellulosic residues (barley straw and sugarcane bagasse) were studied as a pretreatment to improve their subsequent anaerobic digestion for methane production. Biomass samples were grinded to 2 ranges of particle sizes (<4 or 1 mm), autoclaved, inoculated with two strains of C. subvermispora (ATCC 90467 and ATCC 96608) and incubated at 28 °C for 28 days. The effects of fungal pretreatment were assessed by analyzing the samples before and after incubations for dry solids mass, biochemical composition, bio-methane production (BMP) and availability of cellulose to hydrolysis. The production of ligninolytic enzymes MnP and/or laccase was observed with both strains during incubation on most of the samples tested. It almost doubled the hazel branches BMP per unit mass of dry solids but did not improve however the BMP of the agricultural residues and acacia branches. These observations were explained by the fact that although both strains were able to degrade 20-25% of lignin in <1 mm and <4 mm hazel branches samples, none of them was successful however to significantly degrade lignin in the other samples, except for sugarcane bagasse.

Surgical Management of Spinal Cysticercosis: 2-Dimensional Operative Video.

Neurocysticercosis is a notorious-albeit relatively rare-parasitic infection of the nervous system caused by ingestion of embryonated eggs or gravid proglottids of the pork tapeworm Taenia solium.1 Most cases appear intracranially and can present with seizures and/or headache; far fewer affect the spinal canal alone.1-6 We describe a case of a 66-year-old Hispanic man with isolated spinal cysticercosis presenting to the emergency department initially with axial back pain. After lumbar x-rays and a computed tomography scan failed to find any pathology, he was discharged home without neurosurgical consultation. A week later he would re-present to the same emergency department with worsening back pain and new neurologic deficits, prompting an MRI revealing pathology within the lumbar spinal canal. After consultation, the neurosurgical team discussed management strategies and eventually opted for surgical exploration of the patient's lumbar spine. This exploration eventually culminated in an intradural exploration, revealing an impressive string of interconnected larval cysts of the T. solium tapeworm within the cauda equina. The patient's neurologic condition improved immediately after surgery, and final pathologic examination supported a diagnosis of spinal cysticercosis, prompting the appropriate workup and medical treatment. He would ultimately make a full recovery and continues to follow-up with infectious disease at our institution. The patient consented to the surgical intervention described herein after a discussion of its risks, benefits, and alternatives. Institutional review board and ethics committee approval was not sought because the intervention did not constitute experimental surgery, but rather represented standard of care given the patient's condition on presentation.

Machine learning predicts cerebral vasospasm in patients with subarachnoid haemorrhage.

BACKGROUND: Cerebral vasospasm (CV) is a feared complication which occurs after 20-40% of subarachnoid haemorrhage (SAH). It is standard practice to admit patients with SAH to intensive care for an extended period of resource-intensive monitoring. We used machine learning to predict CV requiring verapamil (CVRV) in the largest and only multi-center study to date. METHODS: Patients with SAH admitted to UCLA from 2013 to 2022 and a validation cohort from VUMC from 2018 to 2023 were included. For each patient, 172 unique intensive care unit (ICU) variables were extracted through the primary endpoint, namely first verapamil administration or no verapamil. At each institution, a light gradient boosting machine (LightGBM) was trained using five-fold cross validation to predict the primary endpoint at various hospitalization timepoints. FINDINGS: A total of 1750 patients were included from UCLA, 125 receiving verapamil. LightGBM achieved an area under the ROC (AUC) of 0.88 > 1 week in advance and ruled out 8% of non-verapamil patients with zero false negatives. Our models predicted "no CVRV" vs "CVRV within three days" vs "CVRV after three days" with AUCs = 0.88, 0.83, and 0.88, respectively. From VUMC, 1654 patients were included, 75 receiving verapamil. VUMC predictions averaged within 0.01 AUC points of UCLA predictions. INTERPRETATION: We present an accurate and early predictor of CVRV using machine learning with multi-center validation. This represents a significant step towards optimized clinical management and resource allocation in patients with SAH. FUNDING: Robert E. Freundlich is supported by National Center for Advancing Translational Sciences federal grant UL1TR002243 and National Heart, Lung, and Blood Institute federal grant K23HL148640; these funders did not play any role in this study. The National Institutes of Health supports Vanderbilt University Medical Center which indirectly supported these research efforts. Neither this study nor any other authors personally received financial support for the research presented in this manuscript. No support from pharmaceutical companies was received.

From the importance of organic carbon in reproduction tests with Eisenia fetida.

The standard Eisenia fetida chronic toxicity reproduction test is normalized and needs up to 8 weeks of experimentation. Many matrixes have shown toxic effects on the earthworms' survey, growth and reproduction. But the food factor may affect the organisms' responses to contaminated media in such tests. We try to evaluate the effect, or not, of the organic carbon content present in the environment, as spreadable organic wastes added in soil, on the reproduction test of Eisenia fetida. We confirm the influence of the organic matter content on earthworm reproduction. This "food" factor must be considered when studying environmental samples rich in organic matter, since that could mask potentially harmful effects. To minimize this potential "food" effect during reproduction tests, we recommend an inverse gradient of organic matter contribution by the "horse dung" food applied in all conditions according to the dose of agricultural amendments tested.

Early Postoperative Opioid Requirement Is Associated With Later Pain Control Needs After Supratentorial Craniotomies.

BACKGROUND: Despite a renewed focus in recent years on pain management in the inpatient hospital setting, postoperative pain after elective craniotomy remains under investigated. This study aims to identify which perioperative factors associate most strongly with postoperative pain and opioid medication requirements after inpatient craniotomy. MATERIALS AND METHODS: Using an existing dataset, we selected a restricted cohort of patients who underwent elective craniotomy surgery requiring an inpatient postoperative stay during a 7-year period at our institution (n=1832). We examined pain scores and opioid medication usage and analyzed the relative contribution of specific perioperative risk factors to postoperative pain and opioid medication intake (morphine milligram equivalents). RESULTS: Postoperative pain was found to be highest on postoperative day 1 and decreased thereafter (up to day 5). Factors associated with greater postoperative opioid medication requirement were preoperative opioid medication use, duration of anesthesia, degree of pain in the preoperative setting, and patient age. Notably, the most significant factor associated with a higher postoperative pain score and Morphine milligram equivalents requirement was the time elapsed between the end of general anesthesia and a patient's first intravenous opioid medication. CONCLUSION: Postcraniotomy patients are at higher risk for requiring opioid pain medications if they have a history of preoperative opioid use, are of younger age, or undergo a longer surgery. Moreover, early requirement of intravenous opioid medications in the postoperative period should alert treating physicians that a patient's pain may require additional or alternative methods of pain control than routinely administered, to avoid over-reliance on opioid medications.

The Role of Vancomycin Powder During Spinal Cord Stimulator Implantation: A Case Series and Review of the Literature.

OBJECTIVE: We examined the role of intrawound vancomycin powder as prophylaxis against postoperative surgical site infection (SSI) after spinal cord stimulator (SCS) implantation. METHODS: We performed a retrospective analysis of 153 consecutive patients who had undergone permanent SCS implantation surgery via open laminectomy between 2014 and 2020. We queried the patients' medical records for patient age, sex, relevant medical history, and whether intrawound vancomycin had been administered. We compared the rates of SSI (primary outcome) and seroma (secondary outcome) within 3 months after surgery between the vancomycin and no-vancomycin groups. Finally, we conducted multivariable logistic regression analyses to identify independent predictors of postoperative SSI or seroma. RESULTS: Of the 153 patients, 59% were women, and the average age was 65.4 years. Overall, 3 patients (2%) had developed an SSI: 2 (methicillin-resistant Staphylococcus aureus, Klebsiella) in the vancomycin group and 1 (methicillin-sensitive Staphylococcus aureus) in the no-vancomycin group. This difference in SSI rate between the 2 groups was insignificant (P = 0.73). Three seromas, all in the no-vancomycin group, accounted for a statistically significant difference in seroma formation between the 2 groups (P = 0.04). Multivariate logistic regression failed to identify any perioperative characteristics as independent predictors of postoperative SSI or seroma. CONCLUSIONS: Our experience suggests open laminectomy for SCS implantation surgery can be performed with a low postoperative SSI rate, with or without the use of powdered vancomycin. We found no evidence suggesting that the use of powdered vancomycin is unsafe or related to postoperative seroma formation. We failed to draw any definitive conclusions regarding its efficacy, despite referencing the largest single case series of SCS implantation to date.

Characterization of municipal biowaste categories for their capacity to be converted into a feedstock aqueous slurry to produce methane by anaerobic digestion.

Biowaste material is a good candidate for the production of energy in urban territories. The presence of undesirable or constituents mixed with the biowaste collected by municipalities makes it difficult to recycle organic matter of sufficient quality for agricultural uses. Methane production is particularly attractive for energy recovery notably because this energy vector can be distributed using the grid already in place for natural gas in many cities. Depending on the origin and biochemical composition of biowaste, methane can be produced using thermochemical (gasification then syngas methanation) or biological processes (anaerobic digestion). The objective of this work was to characterize the ability of biowaste to be used as a feedstock for anaerobic digestion. Based on considerations such as the quantities produced and the availability, four categories of biowaste produced in the city of Lyon were identified as potential key resources: Garden biowaste (GBW), restauration biowaste (RBW), household biowaste (HBW) and supermarkets biowaste (SMBW). Representative samples were taken from the sites of production and analyzed for parameters including biomethane potential (BMP). Each sample was then fractioned by leaching and the distribution of the BMP between the particulate fraction and the readily soluble fraction was assessed. GBW organic matter exhibited high hemicellulose content (over 81% of VS) and a low BMP which was very poorly distributed into its soluble fraction (2 NL·kgTS-1). RBW, HBW and SMBW showed a much higher BMP with a strong distribution in the soluble fraction (100 NL·kgTS-1). Plastic materials were found to account for up to 40% of the mass of SMBW sample. Altogether, GBW was identified as non-favorable for anaerobic digestion and recommended rather for thermochemical conversion. HBW, RBW and SMBW revealed adapted to anaerobic. Pulping was shown to be applicable in order to convert the 3 biowaste materials into a pumpable slurry with high biomethane potential.

Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases.

Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

Mass balance to assess the efficiency of a mechanical-biological treatment.

Using mechanical-biological treatment of residual municipal solid waste, it is possible to significantly lower landfill volume and gas and leachate emissions. Moreover, the landfill characteristics are improved. The performance of the Mende (France) mechanical-biological treatment plant is assessed via mass balances coupled with manual sorting according to the MODECOM methodology and biochemical methane potential after 90 days of incubation. The site includes mechanical sorting operations, a rotary sequential bioreactor, controlled aerobic stabilisation corridors, maturation platforms, and a sanitary landfill site for waste disposal in separated cells. Results showed that several steps could be improved: after a first sieving step, about 12% of the potentially biodegradable matter is landfilled directly without any treatment; mechanical disintegration of papers and cardboards in the rotary sequential bioreactor is insufficient and leads to a high proportion of papers and cardboards being landfilled without further treatment. Two fine fractions go through stabilisation and maturation steps. At the end of the maturation step, about 54% of the potentially biodegradable matter is degraded. The biochemical methane potential after 90 days of incubation is reduced by 81% for one of the two fine fractions and reduced by 88% for the other one. Considering the whole plant, there is a reduction of nearly 20% DM of the entering residual municipal solid waste.

Effect of biological pretreatment of coarse MSW on landfill behaviour: laboratory study.

Mechanical and biological pre-treatment (MBT) of residual Municipal Solid Waste (MSW) is considered as a promising technical option prior to landfilling. The aim of MBT is to control the biological landfill activity to minimize biogas and leachate production. Laboratory-scale bioreactors were set up to study the behaviour of untreated and pre-treated residues. The bioreactors were designed to simulate the anaerobic condition of sanitary landfill. Initial water addition has been performed to ensure optimal condition of biological degradation. The incubation time was 400 days to achieve the biodegradation. Experiments have been carried out with untreated or treated waste collected from a mechanical-aerobic biological treatment plant located in middle south of France. Chemical and biological analyses have been performed to characterise the waste samples before and after the incubation. Results showed that a residual anaerobic activity does exist for the pre-treated waste when incubated in optimal moisture condition: biogas production does still exist even after a long period of aerobic hot fermentation and maturation.

Cumulative Intracranial Tumor Volume Augments the Prognostic Value of Diagnosis-Specific Graded Prognostic Assessment Model for Survival in Patients with Melanoma Cerebral Metastases.

BACKGROUND: The diagnosis-specific graded prognostic assessment scale (ds-GPA) for patients with melanoma brain metastasis (BM) utilizes only 2 key prognostic variables: Karnofsky performance status and the number of intracranial metastases. We wished to determine whether inclusion of cumulative intracranial tumor volume (CITV) into the ds-GPA model for melanoma augmented its prognostic value. OBJECTIVE: To determine whether or not CITV augments the ds-GPA prognostic scale for melanoma. METHODS: We analyzed the survival pattern of 344 melanoma patients with BM treated with stereotactic radiosurgery (SRS) at separate institutions and validated our findings in an independent cohort of 201 patients. The prognostic value of ds-GPA for melanoma was quantitatively compared with and without the addition of CITV using the net reclassification index (NRI > 0) and integrated discrimination improvement (IDI) metrics. RESULTS: The incorporation of CITV into the melanoma-specific ds-GPA model enhanced its prognostic accuracy. Addition of CITV to the ds-GPA model significantly improved its prognostic value, with NRI > 0 of 0.366 (95% CI: 0.125-0.607, P = .002) and IDI of 0.024 (95% CI: 0.008-0.040, P = .004). We validated these findings that CITV improves the prognostic utility of melanoma ds-GPA in an independent cohort of 201 melanoma cohort. CONCLUSION: The prognostic value of the ds-GPA scale for melanoma BM is enhanced by the incorporation of CITV.

Comprehensive two-dimensional gas chromatography for biogas and biomethane analysis.

The gas industry is going to be revolutionized by being able to generate bioenergy from biomass. The production of biomethane - a green substitute of natural gas - is growing in Europe and the United-States of America. Biomethane can be injected into the gas grid or used as fuel for vehicles after compression. Due to various biomass inputs (e.g. agricultural wastes, sludges from sewage treatment plants, etc.), production processes (e.g. anaerobic digestion, municipal solid waste (MSW) landfills), seasonal effects and purification processes (e.g. gas scrubbers, pressure swing adsorption, membranes for biogas upgrading), the composition and quality of biogas and biomethane produced is difficult to assess. All previous publications dealing with biogas analysis reported that hundreds of chemicals from ten chemical families do exist in trace amounts in biogas. However, to the best of our knowledge, no study reported a detailed analysis or the implementation of comprehensive two-dimensional gas chromatography (GC×GC) for biogas matrices. This is the reason why the benefit of implementing two-dimensional gas chromatography for the characterization of biogas and biomethane samples was evaluated. In a first step, a standard mixture of 89 compounds belonging to 10 chemical families, representative of those likely to be found, was used to optimize the analytical method. A set consisting of a non-polar and a polar columns, respectively in the first and the second dimension, was used with a modulation period of six seconds. Applied to ten samples of raw biogas, treated biogas and biomethane collected on 4 industrial sites (two MSW landfills, one anaerobic digester on a wastewater treatment plant and one agricultural biogas plant), this analytical method provided a "fingerprint" of the gases composition at the molecular level in all biogas and biomethane samples. Estimated limits of detection (far below the µgNm-3) coupled with the resolution of GC×GC allowed the comparison of the real samples considered. This first implementation of GC×GC for the analysis of biogas and biomethane demonstrated unambiguously that it is a promising tool to provide a "fingerprint" of samples, and to monitor trace compounds by families.