Chronic thromboembolic pulmonary hypertension and balloon pulmonary angioplasty - Where are we in 2024?

Pulmonary endarterectomy (PEA) is the first-line treatment for patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, some patients with CTEPH are considered inoperable, and in the last decade, balloon pulmonary angioplasty (BPA) has emerged as a viable therapeutic option for these patients with prohibitive surgical risk or recurrent pulmonary hypertension following PEA. Numerous international centers have increased their procedural volume of BPA and have reported improvements in pulmonary hemodynamics, patient functional class and right ventricular function.

Piloting an Evidence-Based Assessment Protocol for Incarcerated Adolescents.

Although evidence-based assessment is considered an essential component of evidence-based practice, few adolescents have access to evidence-based assessment. Despite experiencing high rates of mental health disorders, incarcerated justice-involved adolescents are rarely able to access evidence-based psychiatric care. In this article, we discuss the components of an evidence-based assessment protocol designed and piloted with incarcerated adolescents involved in Rhode Island's juvenile justice system.

Discovery of Reversible Covalent Bruton's Tyrosine Kinase Inhibitors PRN473 and PRN1008 (Rilzabrutinib).

Bruton's tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved BTK inhibitors are irreversible covalent inhibitors and limited to oncology indications. Herein, we describe the design of covalent reversible BTK inhibitors and the discoveries of PRN473 () and rilzabrutinib (PRN1008, ).

Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168).

Bruton's tyrosine kinase (BTK), expressed in B cells and cells of innate immunity, including microglia, is an essential signaling element downstream of the B-cell receptor and Fc-receptors. Tolebrutinib (PRN2246, SAR442168) is a potent BTK inhibitor that covalently binds the kinase, resulting in durable inhibition with the potential to target inflammation in the periphery and central nervous system (CNS). Tolebrutinib crosses the blood-brain barrier and potently inhibits BTK in microglial cells isolated from the CNS.

Development of a Multi-Session Curriculum Addressing Domestic Minor Sex Trafficking for High-Risk Male Youth.

Males, in particular adolescents and young adults, have been increasingly recognized as involved in domestic minor sex trafficking (DMST). However, there are very sparse resources and organizations that provide prevention, identification, and interventions for boys and young men who are involved in or at-risk for DMST involvement. The objective was to develop and assess an educational curriculum to prevent adolescent male involvement in DMST through a three-pronged educational approach: as victims of sexual exploitation; receiving financial benefit as exploiters; as buyers of sex.

Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease.

Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases.

Domestic Minor Sex Trafficking: A Case Series of Male Pediatric Patients.

Domestic minor sex trafficking (DMST) is the commercial sexual exploitation of children (<18 years old) who are U.S. citizens or lawful permanent residents, victimized within U.

Evaluation of the etiology of persistent iritis after cataract surgery.

Background: The purpose of this study was to evaluate patients with persistent iritis after cataract surgery to determine its incidence and risk factors. Adjusting the management of patients at risk could allow for a more predictable post-operative course and outcome. A retrospective chart review was performed of patients who had post-operative iritis longer than 1 month after cataract surgery during a 2-year period at Storm Eye Institute at the Medical University of South Carolina (MUSC) in Charleston, South Carolina.

Co-inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity.

Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible proteasome variant comprising the proteolytic subunits LMP2 (β1i), MECL-1 (β2i), and LMP7 (β5i). Targeting the immunoproteasome in pre-clinical models of autoimmune diseases with the epoxyketone inhibitor ONX 0914 has proven to be effective. ONX 0914 was previously described as a selective LMP7 inhibitor.

The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance.

An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site.

Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors.

Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications.

Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton's tyrosine kinase (BTK).

Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.

A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression.

In T cells, the Tec kinases IL-2-inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4(+) T cells from Itk(-/-) and Itk(-/-)Rlk(-/-) mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice.

Prolonged and tunable residence time using reversible covalent kinase inhibitors.

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d.

Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.

Interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK or TXK) are essential mediators of intracellular signaling in both normal and neoplastic T-cells and natural killer (NK) cells. Thus, ITK and RLK inhibitors have therapeutic potential in a number of human autoimmune, inflammatory, and malignant diseases. Here we describe a novel ITK/RLK inhibitor, PRN694, which covalently binds to cysteine residues 442 of ITK and 350 of RLK and blocks kinase activity.

Finding the perfect spot for fluorine: improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.

A rational fluorine scan based on co-crystal structures was explored to increase the potency of a series of selective BTK inhibitors. While fluorine substitution on a saturated bicyclic ring system yields no apparent benefit, the same operation on an unsaturated bicyclic ring can increase HWB activity by up to 40-fold. Comparison of co-crystal structures of parent molecules and fluorinated counterparts revealed the importance of placing fluorine at the optimal position to achieve favorable interactions with protein side chains.

Giant, completely calcified lumbar juxtafacet cyst: report of an unusual case.

Study Design Case report. Objective To report the case of one patient who developed a giant, completely calcified, juxtafacet cyst. Methods A 57-year-old woman presented with a 2-year history of progressively worsening lower back pain, left leg pain, weakness, and paresthesias.

Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis.

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J.

Symptomatic Rathke's cleft cyst with a co-existing pituitary tumor; Brief review of the literature.

Pituitary adenomas and Rathke's cleft cysts (RCCs) share a common embryological origin. Occasionally, these two lesions can present within the same patient. We present a case of a 39-year-old male who was found to have a large sellar lesion after complaints of persistent headaches and horizontal nystagmus.

Impact of subsidence on clinical outcomes and radiographic fusion rates in anterior cervical discectomy and fusion: a systematic review.

Study Design: Systematic review.

Objective: To provide a systematic review of published literature on the impact of subsidence on clinical outcomes and radiographic fusion rates after anterior cervical discectomy and fusion with plates or without plates.

Background: Subsidence of interbody implants is common after anterior cervical spine fusions.

Spinal cord astrocytomas: a modern 20-year experience at a single institution.

Study Design: Retrospective cohort analysis.

Objective: To examine the effect of resection on survival and neurological outcome in a modern cohort of patients with spinal cord astrocytomas and identify prognostic factors for survival.

Summary Of Background Data: There are currently no clear treatment guidelines for the management of spinal cord astrocytomas.

Outcome and prognostic factors in adult cerebellar glioblastoma.

Cerebellar glioblastoma multiforme (GBM) occurs rarely in adults, accounting for 0.4-3.4% of all GBM.

Timing of tracheostomy after anterior cervical spine fixation.

Background: Patients with cervical spinal cord injury frequently undergo early anterior cervical spine fixation (ACSF) and tracheostomy procedures to reduce further deterioration, to reduce risk of pulmonary complications, and to improve patient mobilization. However, tracheostomy is often delayed because of the risk of cross contamination as a result of the proximity to the ACSF incision site. Currently, there is a paucity of studies evaluating this outcome to determine the safety of early tracheostomy after ACSF.

Thickness of subcutaneous fat as a risk factor for infection in cervical spine fusion surgery.

Background: Surgical site infections increase the incidence of morbidity and mortality as well as health-care expenses. The cost of care increases threefold to fourfold as a consequence of surgical site infection after spinal surgery. The aim of the present study was to determine the role of subcutaneous fat thickness in the development of surgical site infection following cervical spine fusion surgery.

Spinal cavernous and capillary hemangiomas in adults.

Study Design: Retrospective cohort analysis.

Objective: To evaluate the neurological outcomes after resection of intramedullary, intradural extramedullary, and extradural hemangiomas.

Summary Of Background Data: Spinal hemangiomas most commonly arise in the vertebral bodies and are typically asymptomatic.