Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.

Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1.

Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis.

Same-day discharge following lumbar spine neural decompression.

Introduction: The concept of same-day discharge following lumbar spine surgery for neural elements decompression, introduced in the 1980 s, represents a significant paradigm shift in postoperative care, offering potential benefits in terms of efficiency, convenience, and cost-effectiveness. However, concerns regarding patient safety and complications have persisted. This study aims to assess same-day discharge rates following lumbar spine decompression surgery, identify preoperative predictors, and compare outcomes between same-day discharge and hospitalization.

Periprocedural clinical outcomes of revision hip arthroplasty: a multi-centric comparison of current strategies based on the NSQIP.

Introduction: Recent projections suggest a substantial rise in demand for revision total hip arthroplasties, emphasizing the need for optimized perioperative care. Various revision techniques, such as isolated acetabular or femoral component revisions and total replacements, have garnered attention. Further research is needed to establish the most effective strategies for improving clinical outcomes.

Predictors and risk factors of pulmonary embolism after total hip arthroplasty: an NSQIP study.

Introduction: Pulmonary embolism (PE) is a well-known contributor to morbidity after total hip arthroplasty (THA). Considerable efforts have been invested in reducing PE occurrence through pharmacological and perioperative interventions. Nonetheless, the effectiveness of these strategies in reducing the incidence and overall mortality associated with pulmonary embolism events remains a matter of debate.

Selective recovery of antimony from Sb-bearing copper concentrates by integration of alkaline sulphide leaching solutions and microwave-assisted heating: A new sustainable processing route.

The technical feasibility of leaching antimony from an antimony-bearing copper sulphide concentrate, using alkaline sulphide solutions and microwave-assisted and non-assisted heating technology, is investigated at a laboratory scale. The leaching test examines the influence of selective leaching reagent (NaS and NaOH) concentrations, solid/liquid ratio, and temperature. The results indicate that antimony dissolution is highly selective (e.

Student survey after ten years of continuous blended teaching of echocardiography.

Objective: To analyse the impact of 10 years of blended echocardiography teaching.

Methods And Results: A questionnaire was emailed to all medical doctors who graduated from the blended learning diploma in echocardiography developed by the University of Chile and taught by a team from Chile and Spain. One hundred and forty of the 210 students who graduated from the program between 2011 and 2020 completed the questionnaire: 53.

Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.

Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer.

High-Sensitivity Troponin I after Cardiac Surgery and 30-Day Mortality.

Background: Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to ≥70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations.

Methods: We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery.

Coinfections among hospitalized patients with covid-19 in the first pandemic wave.

Background: COVID19 is the novel respiratory illness caused by SARS-CoV-2. The presence of other potentially pathogenic microorganisms could worsen the prognosis of these patients.

Aim: The study aims to describe coinfections in COVID-19 patients and contrast it between standard ward and critical care patients at Hospital Central de la Defensa Gómez Ulla (HCDGU).

Comparison of various serological assays for novel SARS-COV-2.

Coronavirus disease-19 (COVID19), the novel respiratory illness caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), is associated with severe morbidity and mortality. The aim of our study was to compare different immunoassays. We evaluated three immunochromatographic test (The StrongStep®SARS-CoV-2 IgG/IgM kit, AllTest COV-19 IgG/IgM kit, and Wondfo® SARS-CoV-2 Antibody) and two chemiluminescence immunoassays (CMIA) (Covid-19 VIRCLIA® IgM+IgA/IgG monotest and the Abbott SARS-CoV-2 IgG assay) in COVID-19 patients.

Treatment of faecal incontinence with autologous expanded mesenchymal stem cells: results of a pilot study.

Aim: Management of faecal incontinence (FI) remains challenging because no definitive optimal treatment for this condition has yet been determined. Regenerative medicine could be an attractive therapeutic alternative for treating FI. Here, we aimed to determine the safety and feasibility of autologous expanded mesenchymal stem cells derived from adipose tissue (AdMSCs) in the treatment of patients diagnosed with structural FI.

Intraoperative transesophageal echocardiography in cardiovascular surgery. Consensus document from the Spanish Society of Anesthesia and Critical Care (SEDAR) and the Spanish Society of Endovascular and Cardiovascular Surgery (SECCE).

Transesophageal echocardiography is a semi-invasive technique that allows an evaluation of cardiac morphology and function in real time and it is a quality standard in cardiovascular surgery. It has become a fundamental tool for both monitoring and diagnosis in the intraoperative period that allows decide the correct surgical planning and pharmacological management. The goal of this document is to answer the questions of when and how the perioperative TEE should be performed in cardiovascular surgery, what are their applications in the intraoperative, who should perform it and how the information should be transmitted.

Detect coastal disturbances and climate change effects in coralligenous community through sentinel stations.

This study was implemented to assess the Sessile Bioindicators in Permanent Quadrats (SBPQ) underwater environmental alert method. The SBPQ is a non-invasive and low-cost protocol; it uses sessile target species (indicators) to detect environmental alterations (natural or anthropic) at either the local or global (i.e.

Validation of a Novel Fecal Incontinence Scale: The Rapid Assessment Fecal Incontinence Score (RAFIS).

Objective: The development and validation of a new version of the fecal incontinence (FI) scale "Rapid Assessment Fecal Incontinence Score" (RAFIS) incorporating domains for severity, type of stool loss, and global perception of the effect of incontinence on quality of life (QoL).

Background: FI negatively impacts on QoL. Currently used incontinence questionnaires have outstanding limitations on the global assessment of the impact of the disease on QoL that patients perceive.

Associations Between Self-Determined Motivation, Team Potency, and Self-Talk in Team Sports.

The current study aimed to evaluate the determinant factors of athletes´ internal positive self-talk that might lead to decreased anxiety and increased performance. The sample consisted of 191 male and female athletes ranging in age from 14 to 35 years old. They played soccer, volleyball and basketball and they were cadets (43%), juniors (29.

Platelet-rich plasma (PRP) versus fibrin glue in cryptogenic fistula-in-ano: a phase III single-center, randomized, double-blind trial.

Purpose: To compare the clinical outcome of autologous platelet-rich growth factor (PRP) with commercial fibrin glue in the management of high cryptogenic fistulae-in-ano.

Method: The study was conducted at a single center between July 2012 and July 2015 and performed as a phase III, randomized, double-blind comparison of autologously prepared PRP versus fibrin glue for cryptoglandular anal fistulae without active sepsis. Patients were assessed with clinical and endosonographic follow-up.

Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation.

Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a Ser/Thr kinase that operates via the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways to dampen the T-cell response and antitumor immunity. Accordingly, selective HPK1 inhibition is considered a means to enhance antitumor immunity. Sunitinib, a multi-receptor tyrosine kinase (RTK) inhibitor approved for the management of gastrointestinal stromal tumors (GISTs), renal cell carcinoma (RCC), and pancreatic cancer, has been reported to inhibit HPK1 In this report, we describe the crystal structures of the native HPK1 kinase domain in both nonphosphorylated and doubly phosphorylated states, in addition to a double phosphomimetic mutant (T165E,S171E), each complexed with sunitinib at 2.

Local Mesenchymal Stem Cell Therapy in Experimentally Induced Colitis in the Rat.

Background: Multipotent mesenchymal stem cells (MSCs) have been used in inflammatory bowel diseases because of their immunomodulatory and regenerative properties. We investigated their local use in an experimental model of colitis in the rat.

Materials And Methods: Colitis was induced into 20 Wistar rats with local TNBS instillation.

Treatment of transsphincteric fistula-in-ano with growth factors from autologous platelets: results of a phase II clinical trial.

Purpose: The aim of this paper is to evaluate to the safety, feasibility and efficacy of a novel treatment for transsphincteric cryptoglandular fistula: injection of autologous plasma rich in growth factors (PRGF) into the fistula tract accompanied by sealing using a fibrin plug created from the activated platelet-poor fraction of the same plasma.

Method: This article is a prospective, phase II clinical trial. The procedure was externally audited.

Factibility and security study of the PICS-AF™ plug for the treatment of cryptoglandular anal fistula.

Introduction: The PICS-AF™ (Curaseal Inc.) device is a new plug made of collagen that has a retention system in the internal orifice. This pilot study was designed to assess both the feasibility and safety of this plug in the treatment of trans-sphincteric anal fístulas.

Ultrasonographic evidence of Gatekeeper™ prosthesis migration in patients treated for faecal incontinence: a case series.

Background: Faecal incontinence (FI) is both a medical and social problem, with an underestimated incidence. For patients with internal anal sphincter damage, implantation of biomaterial in the anal canal is a recognised treatment option. One such material, Gatekeeper™, has previously shown promising short- and medium-term results without any major complications, including displacement.

Prognostic Value of High-Sensitivity Troponin-T to Identify Patients at Risk of Left Ventricular Graft Dysfunction After Heart Transplantation.

Primary graft dysfunction after heart transplantation (HTx) has a very high mortality rate, especially if the left ventricle (PGD-LV) is involved. Early diagnosis is important to select the appropriate therapy to improve prognosis. The value of high-sensitivity troponin T (HS-TNT) measurement obtained at patient arrival at the intensive care unit was analyzed in 71 HTx patients.

Validation of a new scoring system: Rapid assessment faecal incontinence score.

Aim: To implement a quick and simple test - rapid assessment faecal incontinence score (RAFIS) and show its reliability and validity.

Methods: From March 2008 through March 2010, we evaluated a total of 261 consecutive patients, including 53 patients with faecal incontinence. Demographic and comorbidity information was collected.

Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.

There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e.