6-Methylquinazolin-4(3H)-one Based Compounds as BRD9 Epigenetic Reader Binders: A Rational Combination of in silico Studies and Chemical Synthesis

6-methylquinazolin-4(3H)-one-based compounds were here identified and synthesized as novel binders of bromodomain-containing protein 9 (BRD9) epigenetic reader. Accounting a fast and efficient synthetic route aimed to easily obtain differently 2- and 8-disubstituted 6-methylquinazolin-4(3H)-one derivatives, a virtual library of synthesizable items was built and submitted to molecular docking experiments. Based on two 3D structure-based pharmacophore models recently developed by us on BRD9, 16 compounds were selected and synthesized, using mild conditions with good yields in relatively short reaction times. Among them, 14, 16, 18, 22, and 26 emerged as the most potent compounds of these series, able to bind BRD9 at the low micromolar range of concentrations. These molecules also showed a promising selective behavior when tested against BRD4 bromodomain. These results highlighted the quinazolin-4(3H)-one chemical core as a valuable scaffold for developing promising BRD9 binders

Absent in melanoma 2 (AIM2) positive profile identifies a poor prognosis of lung adenocarcinoma patients.

The absent in melanoma 2 (AIM2) inflammasome has been demonstrated as involved in tumor growth. In this study we used human samples of lung adenocarcinoma (LUAD) patients, taking advantage of a mouse model of smoking cessation. Human samples were stratified according to the smoking status, high-risk factor for this type of tumor. Both public transcriptomic and human samples obtained by a clinical trial proved that AIM2 was upregulated either in terms of mRNA or protein, respectively, in the tumor mass according to the TNM stage, but it did not relate to the smoking status, age and sex. The upregulation of AIM2 was correlated to an immunosuppressive environment according to resting/non-active dendritic cells (DCs) and T regulatory cells, as demonstrated in both human samples and by means of an experimental model of smoking mice. Computational analysis showed that AIM2 upregulation was correlated to both an inflammasome profile, responsible for the poor prognosis of non-smoker and smoker LUAD patients, and to a non-inflammasome profile for former smoker. In conclusion, our study demonstrated that AIM2 is involved in lung carcinogenesis either in a canonical and non-canonical manner due to an immunosuppressive microenvironment associated to a dismal prognosis of LUAD patients

Starting Strong: Talent-Based Branching of Newly Commissioned U.S. Army Officers

Because the U.S. military\u27s long-held advantage in physical capital and equipment is waning, cutting-edge human capital management is more critical than ever before. The authors of Starting Strong argue that by gathering detailed information on the unique talents possessed by each newly commissioned Army officer, as well as on the unique talent demands of each Army basic branch, the Army can create a talent market that identifies and liberates the strengths of every officer, aligning each with the career field where they are most likely to be engaged, productive, and satisfied leaders. Strong evidence demonstrates that this talent-based approach better aligns officer talent with occupational requirements while simultaneously increasing individual branch satisfaction.https://press.armywarcollege.edu/monographs/1423/thumbnail.jp

Case Report: Pituitary metastasis from prostate adenocarcinoma: an integrated diagnosis via 68Ga-PSMA PET/CT and methylome analysis

BackgroundPituitary metastases are rare, accounting for only 1% of all pituitary tumor resections. Prostate adenocarcinoma, a common malignancy in men, seldom metastasizes to the pituitary gland, with only a few reported cases. Given their rarity and non-specific clinical presentation, pituitary metastases are often mistaken for primary sellar lesions. Advanced imaging techniques, including Prostate-Specific Membrane Antigen (PSMA) positron emission tomography (PET)/Computed Tomography (CT) and molecular diagnostics, such as DNA methylation profiling, can aid in accurate diagnosis and differentiation from pituitary adenomas.Case presentationWe report the case of a 71-year-old male with a history of prostate adenocarcinoma who presented with biochemical recurrence and underwent PSMA PET/CT imaging, revealing intense tracer uptake in the pituitary gland. Magnetic Resonance Imaging (MRI) findings were suggestive of a pituitary macroadenoma, and the patient developed bitemporal hemianopia, necessitating transsphenoidal surgical resection. Histopathological and immunohistochemical analyses were not compatible with a primary pituitary lesion, prompting further investigation via DNA methylation profiling. The analysis revealed a DNA-methylation signature consistent with prostate carcinoma, confirming pituitary metastasis. The patient subsequently received systemic treatment with androgen deprivation therapy, abiraterone, and docetaxel, achieving an excellent biochemical and imaging response.ConclusionThis case highlights the importance of considering metastatic prostate cancer in the differential diagnosis of pituitary lesions, particularly when PSMA PET/CT shows focal uptake in atypical locations. Integration of histopathological, immunohistochemical, and molecular techniques, such as DNA-methylation profiling, was essential for confirming the diagnosis. Clinicians should remain vigilant for atypical metastatic presentations and leverage advanced diagnostic tools to ensure accurate diagnosis and optimal patient management

Transfusional approach in multi-ethnic Sickle Cell patients: real-world practice data from a Multicenter survey in Italy

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder characterized by recurrent acute vaso-occlusive crises (VOCs and anemia). Gold standard treatments are hydroxycarbamide (HC) and/or different red blood cell (RBC) transfusion regimens to limit disease progression. Here, we report a retrospective study on 1,579 SCD patients (median age 23 years; 802 males/777 females), referring to 34 comprehensive Italian centers for hemoglobinopathies. Although we observed a similar proportion of Caucasian (47.9%) and African (48.7%) patients, Italian SCD patients clustered into two distinct overall groups: children of African descent and adults of Caucasian descent. We found a subset of SCD patients requiring more intensive therapy with a combination of HC plus chronic transfusion regimen, due to partial failure of HC treatment alone in preventing or reducing sickle cell-related acute manifestations. Notably, we observed a higher use of acute transfusion approaches for SCD patients of African descent when compared to Caucasian subjects. This might be related to (i) age of starting HC treatment; (ii) patients' low social status; (iii) patients' limited access to family practitioners; or (iv) discrimination. In our cohort, alloimmunization was documented in 135 patients (8.5%) and was more common in Caucasians (10.3%) than in Africans (6.6%). Alloimmunization was similar in male and female and more frequent in adults than in children. Our study reinforces the importance of donor-recipient exact matching for ABO, Rhesus, and Kell antigen systems for RBC compatibility as a winning strategy to avoid or limit alloimmunization events that negatively impact the clinical management of SCD-related severe complications

The invisible plan: how English teachers develop their expertise and the special place of adapting the skills of lesson planning

This paper analyses how English teachers learn to become expert designers of learning and why sharing that expertise is increasingly vital. Its conceptual framework is the widely recognised, empirically tested, five-stage developmental Dreyfus model of skill acquisition, exemplifying the development of teacher expertise, constituted by the “milestone” [m] and “transitory” [t] phases connecting with the five stages of: Novice [m], Advanced Beginner [t], Competent [m], Proficient [t] and Expert [m]. Teacher planning is analysed as one key tacit or non-tangible component of developing expertise. Focusing specifically on English teachers as key participants in this pioneer teacher cognition study, the defining characteristics of milestone stages of expertise development are explored with specific attention to the remarkably under-researched area of planning. We introduce three new categories, defining modes of planning: (i) visible practical planning, (ii) external reflective planning and (iii) internal reflective planning, demonstrating their role in teacher development through the Dreyfus five stages. English is a subject which suffers from frequent disruptive changes to curriculum and assessment: new learning designs are constantly demanded, making planning an ongoing challenge. The implications for practice include the importance of an explicit understanding of how teachers’ planning moves through the three phases from the very “visible” novice phase to the internal relatively “automatic” competent teacher and finally the seemingly “invisible” expert phase. Further research is needed to explore how English teachers can share planning expertise between the three phases to improve teachers’ skills and student learning

Real-Time High Resolution 3D Imaging of the Lyme Disease Spirochete Adhering to and Escaping from the Vasculature of a Living Host

Pathogenic spirochetes are bacteria that cause a number of emerging and re-emerging diseases worldwide, including syphilis, leptospirosis, relapsing fever, and Lyme borreliosis. They navigate efficiently through dense extracellular matrix and cross the blood–brain barrier by unknown mechanisms. Due to their slender morphology, spirochetes are difficult to visualize by standard light microscopy, impeding studies of their behavior in situ. We engineered a fluorescent infectious strain of Borrelia burgdorferi, the Lyme disease pathogen, which expressed green fluorescent protein (GFP). Real-time 3D and 4D quantitative analysis of fluorescent spirochete dissemination from the microvasculature of living mice at high resolution revealed that dissemination was a multi-stage process that included transient tethering-type associations, short-term dragging interactions, and stationary adhesion. Stationary adhesions and extravasating spirochetes were most commonly observed at endothelial junctions, and translational motility of spirochetes appeared to play an integral role in transendothelial migration. To our knowledge, this is the first report of high resolution 3D and 4D visualization of dissemination of a bacterial pathogen in a living mammalian host, and provides the first direct insight into spirochete dissemination in vivo