Soft drug inhibitors for the epigenetic targets lysine-specific demethylase 1 and histone deacetylases.

Epigenetic modulators such as lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are drug targets for cancer, neuropsychiatric disease, or inflammation, but inhibitors of these enzymes exhibit considerable side effects. For a potential local treatment with reduced systemic toxicity, we present here soft drug candidates as new LSD1 and HDAC inhibitors. A soft drug is a compound that is degraded in vivo to less active metabolites after having achieved its therapeutic function.

Structure-Activity Studies of 1,2,4-Oxadiazoles for the Inhibition of the NAD-Dependent Lysine Deacylase Sirtuin 2.

The NAD-dependent lysine deacylase sirtuin 2 (Sirt2) is involved in multiple pathological conditions such as cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purposes. Furthermore, the orthologue from (Sirt2) has been considered for the potential treatment of the neglected tropical disease schistosomiasis.

Lysine Methyltransferase 9 (KMT9) Is an Actionable Target in Muscle-Invasive Bladder Cancer.

Novel treatment modalities are imperative for the challenging management of muscle-invasive and metastatic BC to improve patient survival rates. The recently identified KMT9, an obligate heterodimer composed of KMT9α and KMT9β, regulates the growth of various types of tumors such as prostate, lung, and colon cancer. While the overexpression of KMT9α was previously observed to be associated with aggressive basal-like MIBC in an analysis of patients' tissue samples, a potential functional role of KMT9 in this type of cancer has not been investigated to date.

LSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice.

Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators.

Phosphate buffering in mangrove sediment pore water under eutrophication and deforestation influences.

Phosphorus (P) behavior was evaluated in mangrove wetlands impacted by urban sewage, including a deforested site. Sediment cores were analyzed for grain size, organic carbon, total nitrogen, stable isotopes (δC and δN), P contents, and pore water PO concentrations and net consumption/production rates. Under stronger eutrophication influence, significantly higher P (1390 vs.

Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity.

Inhibition of epigenetic regulators by small molecules is an attractive strategy for cancer treatment. Recently, we characterised the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observation that the enzymatic activity was required for tumour cell proliferation identified KMT9 as a potential therapeutic target.

Biomarkers of neurodegeneration and neural injury as potential predictors for delirium.

Objectives: Determine if biomarkers of Alzheimer's disease and neural injury may play a role in the prediction of delirium risk.

Methods: In a cohort of older adults who underwent elective surgery, delirium case-no delirium control pairs (N = 70, or 35 matched pairs) were matched by age, sex and vascular comorbidities. Biomarkers from CSF and plasma samples collected prior to surgery, including amyloid beta (Aβ) , Aβ , total (t)-Tau, phosphorylated (p)-Tau , neurofilament-light (NfL), and glial fibrillary acid protein (GFAP) were measured in cerebrospinal fluid (CSF) and plasma using sandwich enzyme-linked immunosorbent assays (ELISAs) or ultrasensitive single molecule array (Simoa) immunoassays.

Association of Loneliness With Change in Physical and Emotional Health of Older Adults During the COVID-19 Shutdown.

Objectives: To examine factors influencing loneliness and the effect of loneliness on physical and emotional health, in the context of the COVID-19 pandemic.

Design: Prospective, observational cohort.

Setting: Community-dwelling participants.

Vanishing lead in the Loire River estuary: An example of successful environmental regulation.

The behavior, and history of lead (Pb) contamination in the ecosystem of the Loire estuary was examined using elemental concentrations and Pb isotope data in water, sediment, bivalves, shrimps, and fish. In the estuary and in the surrounding coastal area, Pb concentrations in water and sediment decreased compared to concentrations determined in the 1980s, with concentrations ranging from 15.8 to 65.

Trends in use of antipsychotics and psychoactive drugs in older patients after major surgery.

Background: Professional society guidelines recommend limiting the use of antipsychotics in older patients with postoperative delirium. How these recommendations affected the use of antipsychotics and other psychoactive drugs in the postoperative period has not been studied.

Methods: This retrospective cohort study included patients 65 years or older without psychiatric diagnoses who underwent major surgery in community hospitals (CHs) and academic medical centers (AMCs) in the United States.

Comparative Safety Analysis of Oral Antipsychotics for In-Hospital Adverse Clinical Events in Older Adults After Major Surgery : A Nationwide Cohort Study.

Background: Antipsychotics are commonly used to manage postoperative delirium. Recent studies reported that haloperidol use has declined, and atypical antipsychotic use has increased over time.

Objective: To compare the risk for in-hospital adverse events associated with oral haloperidol, olanzapine, quetiapine, and risperidone in older patients after major surgery.

Personalized Cancer Monitoring Assay for the Detection of ctDNA in Patients with Solid Tumors.

Background: Highly sensitive molecular assays have been developed to detect plasma-based circulating tumor DNA (ctDNA), and emerging evidence suggests their clinical utility for monitoring minimal residual disease and recurrent disease, providing prognostic information, and monitoring therapy responses in patients with solid tumors. The Invitae Personalized Cancer Monitoring assay uses a patient-specific, tumor-informed variant signature identified through whole exome sequencing to detect ctDNA in peripheral blood of patients with solid tumors.

Methods: The assay's tumor whole exome sequencing and ctDNA detection components were analytically validated using 250 unique human specimens and nine commercial reference samples that generated 1349 whole exome sequencing and cell-free DNA (cfDNA)-derived libraries.

Two-Dimensional Mapping of Arsenic Concentration and Speciation with Diffusive Equilibrium in Thin-Film Gels.

We present a new approach combining diffusive equilibrium in thin-film gels and spectrophotometric methods to determine the spatial distribution of arsenite, arsenate, and phosphate at submillimeter resolution. The method relies on the simultaneous deployment of three gel probes. Each retrieved gel is exposed to malachite green reagent gels differing in acidity and oxidant addition, leading to green coloration dependent on analyte speciation and concentration.

Overexpression of KMT9α Is Associated with Aggressive Basal-like Muscle-Invasive Bladder Cancer.

Muscle-invasive bladder cancer (MIBC) is associated with limited response rates to systemic therapy leading to a significant risk of recurrence and death. A recently discovered histone methyltransferase KMT9, acts as an epigenetic regulator of carcinogenesis in different tumor entities. In this study, we investigated the presence and association of histological and molecular subtypes and their impact on the survival of KMT9α in MIBC.

Structural insight into halide-coordinated [FeSXY] clusters (X, Y = Cl, Br, I) by XRD and Mössbauer spectroscopy.

Iron sulphur halide clusters [FeSBr] and [FeSXY] (X, Y = Cl, Br, I) were obtained in excellent yields (77 to 78%) and purity from [Fe(CO)], elemental sulphur, I and benzyltrimethylammonium (BTMA) iodide, bromide and chloride. Single crystals of (BTMA)[FeSBr] (1), (BTMA)[FeSBrCl] (2), (BTMA)[FeSClI] (3), and (BTMA)[FeSBrI] (4) were isostructural to the previously reported (BTMA)[FeSI] (5) (monoclinic, ). Instead of the chloride cubane cluster [FeSCl], we found the prismane-shaped cluster (BTMA)[FeSCl] (6) (1̄).

Methodology of the INVestigating traIning assoCiated blasT pAthology (INVICTA) study.

Background: Subconcussive blast exposure during military training has been the subject of both anecdotal concerns and reports in the medical literature, but prior studies have often been small and have used inconsistent methods.

Methods: This paper presents the methodology employed in INVestigating traIning assoCiated blasT pAthology (INVICTA) to assess a wide range of aspects of brain function, including immediate and delayed recall, gait and balance, audiologic and oculomotor function, cerebral blood flow, brain electrical activity and neuroimaging and blood biomarkers.

Results: A number of the methods employed in INVICTA are relatively easy to reproducibly utilize, and can be completed efficiently, while other measures require greater technical expertise, take longer to complete, or may have logistical challenges.

Experimental in vitro, ex vivo and in vivo models in prostate cancer research.

Androgen deprivation therapy has a central role in the treatment of advanced prostate cancer, often causing initial tumour remission before increasing independence from signal transduction mechanisms of the androgen receptor and then eventual disease progression. Novel treatment approaches are urgently needed, but only a fraction of promising drug candidates from the laboratory will eventually reach clinical approval, highlighting the demand for critical assessment of current preclinical models. Such models include standard, genetically modified and patient-derived cell lines, spheroid and organoid culture models, scaffold and hydrogel cultures, tissue slices, tumour xenograft models, patient-derived xenograft and circulating tumour cell eXplant models as well as transgenic and knockout mouse models.

Perioperative Gabapentin Use and In-Hospital Adverse Clinical Events Among Older Adults After Major Surgery.

Importance: Gabapentin has been increasingly used as part of a multimodal analgesia regimen to reduce opioid use in perioperative pain management. However, the safety of perioperative gabapentin use among older patients remains uncertain.

Objective: To examine in-hospital adverse clinical events associated with perioperative gabapentin use among older patients undergoing major surgery.

Now showing: The presentation. Using video recording to enhance Balint leadership training.

Review of video recorded sessions is a powerful teaching tool in medical education, helping students appreciate both spoken and unspoken communications not fully appreciated in the moment. For many years, the American Balint Society has used video review in its Leadership Training Intensive courses, however technical challenges around setting up and operating the equipment have led some faculty to question whether the benefits are worth the effort and anxiety. We describe here an approach to video review in Intensives with a focus on the case presentation.

Parental Education and Delirium Risk after Surgery in Older Adults.

Objectives: Efforts to conceptualize risk factors for postoperative delirium in older adults have focused on the time proximate to the episode, but how early-life exposures influence delirium risk is poorly understood.

Methods: An observational cohort of 547 patients aged 70+undergoing major non-cardiac surgery at two academic medical centers in Boston. Demographic characteristics, cognition, parental education, health, and participation in cognitively stimulating activities were assessed prior to surgery.

Drivers for primary producers' dynamics: New insights on annual benthos pelagos monitoring in anthropised freshwater marshes (Charente-Maritime, France).

Wetlands, especially marshes, support many services such as carbon catchment control or water purification led by primary producers such as phytoplankton and microphytobenthos (PB). The impact of the sedimentary compartment, as source and sink of essential nutrients for the water column, is often neglected in the study of their dynamics and water purification capacity of the systems. This work compared monthly (between February 2020 and April 2021) the benthic and pelagic primary producers' dynamics in two anthropised freshwater marshes (Marans and Genouillé), with the simultaneous follow-up of physico-chemical parameters of the water column and nutrient fluxes at the sediment-water (SWI) interface.