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. Randomized controlled trials have also demonstrated similar findings. Recent refinements in procedural technique, increased operator experience and advancements in procedural technology have facilitated marked reduction in the risk of complications following BPA. Current guidelines recommend BPA for patients with inoperable CTEPH and persistent pulmonary hypertension following PEA. The pulmonary arterial endothelium plays a vital role in the pathophysiologic development and progression of CTEPH.

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. In particular, we describe the components of our evidence-based protocol, ways in which evidence-based assessment may need to be modified when working with this population, and discuss policy and clinical implications relevant to increasing access to evidence-based assessment among incarcerated adolescents.

Restricting Human Movement During the COVID-19 Pandemic: New Research Avenues in the Study of Mobility, Migration, and Citizenship.

Every government in the world introduced restrictions to human mobility - that is, the movement of persons across and within state borders - in response to the COVID-19 pandemic. Such restrictions thus constituted a global phenomenon, but they were by no means globally uniform; rather, they varied significantly between and within states, as well as over time. This research note presents different data sources for studying the drivers and outcomes of mobility restrictions, highlighting specific ways in which the data can be used. We begin by surveying seven new databases capturing various aspects of the regulation of human movement during the COVID-19 pandemic. Drawing inspiration from research on previous pandemics, we then outline five possible research avenues prompted by these data. We suggest that explaining the causes and consequences of such restrictions, as well as the differences between them, can significantly advance research on the governance of mobility, migration, and citizenship.

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 (11) and rilzabrutinib (PRN1008, 12). These compounds have exhibited potent and durable inhibition of BTK, in vivo efficacy in rodent arthritis models, and clinical efficacy in canine pemphigus foliaceus. Compound 11 has completed phase 1 trials as a topical agent, and 12 is in phase 3 trials for pemphigus vulgaris and immune thrombocytopenia.

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. A first-in-human randomized, double-blind, placebo-controlled study of tolebrutinib was conducted. The trial design consisted of five single ascending dose arms with oral administration of a single dose of 5, 15, 30, 60, and 120 mg (n = 6 per arm, n = 2 placebo), five multiple ascending dose arms with oral administration of 7.5, 15, 30, 60, and 90 mg (n = 8 per arm, n = 2 placebo) over 10 days, and one arm (n = 4) in which cerebral spinal fluid (CSF) exposure was measured 2 h after a single 120 mg dose. Tolebrutinib was well-tolerated in the study and all treatment-related treatment emergent adverse events were mild. Tolebrutinib was rapidly absorbed following oral administration with a rapid half-life of ~ 2 h. Peripheral BTK occupancy was assessed at various timepoints by an enzyme-linked immunosorbent assay-based readout using an irreversible probe. Assessments demonstrated extensive and prolonged peripheral BTK occupancy at steady-state with once daily doses as low as 7.5 mg. Further, CSF exposure was demonstrated 2 h after administration at 120 mg.

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. Through quality improvement cycles, changes were made to enhance the curriculum by utilizing the outcome measures of participant questionnaires and feedback from a steering committee of clinical experts. Male youth at the state's juvenile detention center were asked to participate in pilot groups, as they were identified as a high-risk population of adolescents to become involved. The curriculum was modified by adding sessions, including additional community guest speakers, and providing a more holistic educational experience that involves trafficking prevention from both a victimization and perpetration standpoint. Our goal is to expand this educational opportunity to be utilized in multiple settings (e.g., schools, hospitals) across the country.

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. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell-dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib's unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of 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.S. borders. There is limited knowledge and research in regard to male involvement in DMST outside the context of homelessness and runaway youth. To our knowledge, no research specifically examines at-risk or involved male youth from a larger dataset of youth who present to a child abuse outpatient medical clinic. The objective of the present case series was to describe the demographic, psychosocial, medical, and psychiatric characteristics of natal male participants (who did not identify as transgender) suspected of DMST involvement. Six medical records of male patients under the age of 18 who were referred to a child protection clinic for concern of DMST involvement between 8/1/13 and 12/31/18 were retrospectively reviewed. Our case series demonstrates that male participants present for concern of sex trafficking and have complex behavioral, medical, and psychiatric concerns similar to what has been identified in research focused on female victims. Therefore, testing (e.g., sexually transmitted infection (STI)/HIV testing, urine toxicology screening), DMST screening, and interventions (e.g., STI prophylaxis, referrals to mental health counselors) should be completed in male patients.

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. Patient demographics and various pre-operative, intra-operative, and post-operative factors were analyzed for trends. RESULTS: Thirty-nine patients (49 eyes) met the inclusion criteria, and this group was compared to a control cohort of 40 patients (66 eyes) who did not have persistent iritis after cataract surgery. The overall incidence of post-operative iritis was 1.75%. In all patients with post-operative iritis lasting greater than 1 month, African American race and pupil expansion device use were statistically significant factors. After excluding patients with a history of ocular inflammation or known inflammatory or autoimmune diagnosis (1.20% incidence), there were still a significantly higher proportion of African Americans compared to the control group. When patients with post-operative iritis of less than 6 months in duration were additionally excluded, the incidence was 0.32%, and history of diabetes was statistically significant in addition to race. CONCLUSIONS: Risk factors for persistent iritis after cataract surgery include being diabetic, of African American racial background, and pupil expansion device use. These patients can be better informed of the higher risk of prolonged inflammation in their post-operative course, and peri-operative management can be tailored accordingly.

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 (ß1i), MECL-1 (ß2i), and LMP7 (ß5i). 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. Here, we show that PRN1126, developed as an exclusively LMP7-specific inhibitor, has limited effects on IL-6 secretion, experimental colitis, and experimental autoimmune encephalomyelitis (EAE). We demonstrate that prolonged exposure of cells with ONX 0914 leads to inhibition of both LMP7 and LMP2. Co-inhibition of LMP7 and LMP2 with PRN1126 and LMP2 inhibitors LU-001i or ML604440 impairs MHC class I cell surface expression, IL-6 secretion, and differentiation of naïve T helper cells to T helper 17 cells, and strongly ameliorates disease in experimental colitis and EAE. Hence, co-inhibition of LMP2 and LMP7 appears to be synergistic and advantageous for the treatment of autoimmune diseases.

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. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668-76. ©2017 AACR.

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. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor.

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.g. compound 1 has a value of 459pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26pmol/mg protein.

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. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4(+) T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases.

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. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.

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. Molecular modeling was utilized to design molecules that interact with cysteine while binding to the ATP binding site in the kinase domain. PRN694 exhibits extended target residence time on ITK and RLK and is highly selective for a subset of the TEC kinase family. In vitro cellular assays confirm that PRN694 prevents T-cell receptor- and Fc receptor-induced cellular and molecular activation, inhibits T-cell receptor-induced T-cell proliferation, and blocks proinflammatory cytokine release as well as activation of Th17 cells. Ex vivo assays demonstrate inhibitory activity against T-cell prolymphocytic leukemia cells, and in vivo assays demonstrate durable pharmacodynamic effects on ITK, which reduces an oxazolone-induced delayed type hypersensitivity reaction. These data indicate that PRN694 is a highly selective and potent covalent inhibitor of ITK and RLK, and its extended target residence time enables durable attenuation of effector cells in vitro and in vivo. The results from this study highlight potential applications of this dual inhibitor for the treatment of T-cell- or NK cell-mediated inflammatory, autoimmune, and malignant diseases.

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.

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. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.

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. Imaging showed a giant, completely calcified mass arising from the left L5-S1 facet joint, with coexisting grade I L5 on S1 anterolisthesis. The patient was treated with laminectomy, excision of the mass, and L5-S1 fixation and fusion. Results The patient had an uncomplicated postoperative course and had complete resolution of her symptoms as of 1-year follow-up. Conclusions When presented with a solid-appearing, calcified mass arising from the facet joint, a completely calcified juxtafacet cyst should be considered as part of the differential diagnosis.

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. Additionally there is no conclusive evidence for the surgical resection of these tumors, with some studies even demonstrating worse survival with surgery. However, most studies have examined patients treated prior to the routine use of magnetic resonance imaging and advanced microsurgical techniques. METHODS: We performed a retrospective review of 46 consecutive patients with spinal cord astrocytomas treated at our institution from 1992 to 2012. Univariate and multivariate analyses were used to identify variables associated with survival. RESULTS: The majority of patients (67.4%) underwent surgical resection, with the remaining only receiving biopsy. Of those who underwent resection, only 12.5% of patients underwent gross total resection, all of whom had low-grade astrocytomas. Of all patients, 30.7% worsened compared with their preoperative baseline. The occurrence of worsening increased with high tumor grade (52.9% vs. 27.6%, P = 0.086) and an increased extent of resection (66.7% vs. 18.8%, P = 0.0069). Resection did not provide a survival benefit compared with biopsy alone (P = 0.53). Multivariate analysis revealed high-grade histology (hazard ratio, 11.3; 95% confidence interval, 2.41-53.2; P = 0.0021), tumor dissemination (hazard ratio, 4.24; 95% confidence interval, 1.22-14.8; P = 0.023), and an increasing number of tumor involved levels (hazard ratio, 1.31; 95% confidence interval, 0.99-1.74; P = 0.058) to be associated with worse survival. CONCLUSION: As surgical intervention is associated with a higher rate of neurological complications and lacks a clear benefit, the resection of spinal cord astrocytomas should be reserved for select cases and should be used sparingly.