The Horizon for Treating Cutaneous Vascular Lesions

Dermatologists encounter a wide range of cutaneous vascular lesions, including infantile hemangiomas, port-wine stain birthmarks, arteriovenous malformations, venous malformations, Kaposi sarcomas, angiosarcomas, and angiofibromas. Current treatment modalities to reduce these lesions include topical and/or intralesional steroids, laser therapy, surgical resection, and endovascular therapy. However, each method has limitations owing to recurrence, comorbidities, toxicity, or lesion location. Photodynamic therapy, antiangiogenic therapy, and evolving methods of sclerotherapy are promising areas of development that may mitigate limitations of current treatments and offer exciting options for patients and their physicians

Investigating undergraduate students’ engagement in systems thinking and modeling using causal maps

IntroductionTo develop a foundation of scientific understanding, undergraduate biology students need to integrate ideas about individual concepts into thinking about complex biological systems.MethodsTo investigate the extent to which undergraduate students engage in systems thinking, we conducted a pre-post study with students in a required undergraduate botany course at a small liberal arts college in the Midwest. All students in the study completed a causal map at the beginning and end of the course. Casual maps are similar to concept maps but demonstrate cause and effect relationships rather than other connections included in a concept map.ResultsAnalysis showed that the majority of students did see some connections within the system but did not reach a high level of systems thinking.DiscussionThis work highlights the difficulties undergraduate students have with engaging in systems thinking but provides important insight into the particular areas in which students do engage in more complex thinking and areas in which we can specifically target with instruction and intervention

Using Bcr-Abl to Examine Mechanisms by Which Abl Kinase Regulates Morphogenesis in Drosophila

Signaling by the nonreceptor tyrosine kinase Abelson (Abl) plays key roles in normal development, whereas its inappropriate activation helps trigger the development of several forms of leukemia. Abl is best known for its roles in axon guidance, but Abl and its relatives also help regulate embryonic morphogenesis in epithelial tissues. Here, we explore the role of regulation of Abl kinase activity during development. We first compare the subcellular localization of Abl protein and of active Abl, by using a phosphospecific antibody, providing a catalog of places where Abl is activated. Next, we explore the consequences for morphogenesis of overexpressing wild-type Abl or expressing the activated form found in leukemia, Bcr-Abl. We find dose-dependent effects of elevating Abl activity on morphogenetic movements such as head involution and dorsal closure, on cell shape changes, on cell protrusive behavior, and on the organization of the actin cytoskeleton. Most of the effects of Abl activation parallel those caused by reduction in function of its target Enabled. Abl activation leads to changes in Enabled phosphorylation and localization, suggesting a mechanism of action. These data provide new insight into how regulated Abl activity helps direct normal development and into possible biological functions of Bcr-Abl

A Phase 1a/b Trial of Luxeptinib (CG-806) in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia and Evaluation of New G3 Formulation

INTRODUCTION: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively. AIMS: The primary objectives of these studies are to assess the safety, tolerability, and pharmacokinetics (PK) of LUX and determine recommended phase 2 doses for relapsed or refractory (R/R) AML and B cell malignancy patients. METHODS: In two studies (NCT04477291; NCT03893682), LUX (original formulation, G1) was administered continuously as oral capsules BID in 28-day cycles of ascending cohorts (relapsed or refractory de novo, secondary, or therapy-related AML or higher risk myelodysplastic syndrome (MDS), and relapsed and refractory for B cell lymphoma and chronic lymphocytic/small lymphocytic leukemia). A novel generation 3 (G3) formulation of LUX designed to increase bioavailability was tested at a single-dose (sub-study) for relative bioavailability (RBA), followed by continuous dosing in subsequent R/R AML patients. RESULTS: In the B-cell study (as of 15 th May 2023), LUX has been administered to 36 patients at dose levels from 150 mg to 900 mg BID in patients with a median of 3 lines of prior treatment, with 47.2% having received a BTK-inhibitor. Only one (2.8%) patient had a DLT of hypertension and 14 (38.9%) experienced at least one drug related ≥Grade3 treatment emergent adverse event (TEAE). Two patients (900 mg) are currently on study with no DLT and no ≥Grade 3 related TEAEs. A Follicular lymphoma patient is at cycle 28, and achieved a best response as partial response (PR) with a decrease in lesion size of 76.2%; an SLL patient is at cycle 13, and achieved stable disease (SD) showing a decrease in lesion size of 43.1% (Figure A). The overall best response achieved among the 17 patients who have been on treatment for more than 12 weeks are stable disease (SD) (n=11), partial response (PR) (n=3), minor response (n=2) and complete response (CR) (n=1). As of 5 th June 2023, in the AML trial, a total of 40 patients (16 (40%) FLT3-ITD, 21 (52.5%) FLT3-WT, 2 (5.0%) FLT3-TKD, and 1 (2.5%) unknown mutations) with a median of 3 prior treatments (range, 1 - 10) have been treated with LUX G1 formulation at dose levels from 450 mg - 900 mg BID (n=34) or with 50 mg BID of G3 formulation (n=6). Four (10%) experienced drug related SAE and 7 (17.5%) had a drug related grade ≥3 TEAEs. The most common related TEAEs were lymphocyte count decrease, platelet count decrease, and anemia (n=2; 5% patients each). One (2.5%) patient at 450 mg dose, reported complete remission without minimum residual disease (CRmrd) and remained on study for 56 weeks. In the RBA sub-study, G3 (50 mg) produced comparable exposures to G1 (450-900 mg range) (Figure B) and was, therefore, selected as the starting dose for use in the R/R AML study. Six patients were treated with a continuous dosing of 50 mg BID G3; with plasma levels of 274 ng/mL and 195 ng/mL LUX observed by the end of C1D15 and C1D22 respectively. No drug related Grade ≥3 TEAEs or DLTs were observed in 50 mg BID G3 LUX treated patients; with no new safety signals observed for the G3 formulation. Based on these findings and expected exposures for higher dose levels, the cohort safety review committee has approved escalation of G3 dosing to 200 mg BID at which dosing is ongoing. CONCLUSIONS: LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition

©2019American Society for Bone andMineral Research. Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease)