Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness.

A multiparametric niche-like drug screening platform in acute myeloid leukemia.

Functional precision medicine in AML often relies on short-term in vitro drug sensitivity screening (DSS) of primary patient cells in standard culture conditions. We designed a niche-like DSS assay combining physiologic hypoxia (O 3%) and mesenchymal stromal cell (MSC) co-culture with multiparameter flow cytometry to enumerate lymphocytes and differentiating (CD11/CD14/CD15+) or leukemic stem cell (LSC)-enriched (GPR56+) cells within the leukemic bulk. After functional validation of GPR56 expression as a surrogate for LSC enrichment, the assay identified three patterns of response, including cytotoxicity on blasts sparing LSCs, induction of differentiation, and selective impairment of LSCs.

P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia.

Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment.

Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.

By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures.

Milnacipran in provoked vestibulodynia: efficacy and predictors of treatment success.

Objective: This study aimed to collect preliminary evidence on the efficacy of milnacipran in reducing pain in women with provoked vestibulodynia (PVD) and to identify which patient characteristics predict treatment success.

Materials And Methods: A 12-week open-label trial was conducted in 22 women with PVD. The Pain Rating Index of the McGill Pain Questionnaire was the primary outcome measure.

Guided outcomes in learned efficiency model in clinical medical education: a randomized controlled trial of self-regulated learning.

Objective: The guided outcomes in learned efficiency (GOLE) model emphasizes the use of evidence-based resources to understand the diagnosis, treatment, follow-up, and prevention of disease. We seek to determine whether presentations created using the GOLE model are superior to an unstructured approach in achieving Accreditation Council for Graduate Medical Education (ACGME) Core Competencies.

Study Design: Consenting medical students were randomized to GOLE or control groups to individually research a self-selected clinical topic.

Citalopram in the treatment of women with chronic pelvic pain: an open-label trial.

Objective: To determine the efficacy of citalopram in the treatment of chronic pelvic pain by measuring changes in pain severity, depressive symptoms and functional disability.

Study Design: Fourteen women between 18 and 50 years of age with chronic pelvic pain were enrolled in a 12-week, open-label, flexible-dose study. Following a single-blind washout, placebo nonresponders were treated with citalopram (20-60 mg/d).

A comparison of an interactive computer-based method with a conventional reading approach for learning pelvic anatomy.

Objective: This study was undertaken to assess the impact of interactive, computer-based versus conventional, paper-based format in student, resident, and fellow learning and retention of anatomy knowledge.

Study Design: Randomized longitudinal cohort design with scores repeated as pre-, post-, and follow-up tests. Subjects were randomly assigned to an anatomy module in computer-based (CD-ROM) format and 1 in paper-based format.

Assessment of a 360-degree instrument to evaluate residents' competency in interpersonal and communication skills.

Objective: To test the reliability of the 360-degree evaluation instrument for assessing residents' competency in interpersonal and communication skills.

Method: Ten-item questionnaires were distributed to residents and evaluators at Monmouth Medical Center in Long Branch, New Jersey, in March/April, 2002. The scoring scale was 1-5; the highest score was 50.

Pap smear noncompliance among female obstetrics-gynecology residents.

Objectives: We wish to determine how well female obstetrics and gynecology (OB/GYN) residents in the United States follow recommendations for routine Pap smears in managing their own health care and to identify the reasons for noncompliance.

Methods: A survey was mailed to 1693 female OB/GYN residents in the U.S.

Chiral recognition: design and preparation of chiral stationary phases using selectors derived from ugi multicomponent condensation reactions and a combinatorial approach.

Combinatorial approaches together with high-throughput screening have been used to develop highly selective stationary phases for chiral recognition. Libraries of potential chiral selectors have been prepared by the Ugi multicomponent condensation reactions and screened for their enantioselectivity using the reciprocal approach involving a chiral stationary phase with immobilized model target compound N-(3,5-dinitrobenzoyl)-alpha-l-leucine. The best candidates were identified from the library of phenyl amides of 2-oxo-azetidineacetic acid derivatives.

Efficacy of static magnetic field therapy in chronic pelvic pain: a double-blind pilot study.

Objective: The aim of the study was to determine the efficacy of static magnetic field therapy for the treatment of chronic pelvic pain (CPP) by measuring changes in pain relief and disability.

Study Design: Thirty-two patients with CPP completed 2 weeks and 19 patients completed 4 weeks of randomized double-blind placebo-controlled treatment at a gynecology clinic. Active (500 G) or placebo magnets were applied to abdominal trigger points for 24 hour per day.

Effect of multivalency on the performance of enantioselective separation media for chiral HPLC prepared by linking multiple selectors to a porous polymer support via aliphatic dendrons.

Chiral stationary phases (CSPs) containing L-proline indananilide chiral selectors attached through a multivalent dendritic linker to monodisperse macroporous poly(2-hydroxyethyl methacrylate-co-ethylene dimethacrylate) beads have been prepared using two different approaches. The convergent method involves the preparation of ligands in solution and their subsequent attachment to the support. The divergent approach is based on the stepwise "on-bead" formation of the linker using methods that are typical of solid-phase synthesis.

A new monophasic oral contraceptive containing drospirenone. Effect on premenstrual symptoms.

Objective: To determine whether a new monophasic oral contraceptive containing drospirenone/ethinyl estradiol reduces premenstrual symptoms.

Study Design: In an open-label study measuring intrasubject changes in premenstrual symptoms and comparing effects between women who were new users of oral contraceptives and those who switched from previous contraceptives, ethinyl estradiol (30 micrograms) and drospirenone (3 mg) were administered for 13 menstrual cycles to 326 healthy women aged 18-35 years. Subjects completed the 23-item Women's Health Assessment Questionnaire at baseline and at the end of the sixth cycle.