Rationale for osteoporosis screening in men.

Unlabelled: The US Preventive Services Task Force has not recommended osteoporosis screening in men. Department of Veterans Affairs clinicians reviewed the literature on male osteoporosis screening and treatment. They concluded that targeted screening identifies men at risk and osteoporosis drugs reduce fracture risk similarly in men and women.

CC-96673 (BMS-986358), an affinity-tuned anti-CD47 and CD20 bispecific antibody with fully functional fc, selectively targets and depletes non-Hodgkin's lymphoma.

Cluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a "don't eat me" signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia.

Effect of Different Irrigant Activation Techniques on the Penetration of Calcium Hydroxide, an Intracanal Medicament: An In Vitro Study.

Background and objective The main goal of root canal treatment is to eliminate microorganisms from the canal and to prevent re-infection. To achieve these goals, instrumentation must be combined with adequate irrigation and the placement of intracanal medicament. This study aims to compare the effect of different irrigation activation techniques, i.

SMG1, a nonsense-mediated mRNA decay (NMD) regulator, as a candidate therapeutic target in multiple myeloma.

Early data suggested that CC-115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK) may have additional targets beyond TORK and DNA-PK. Therefore, we aimed to identify such target(s) and investigate a potential therapeutic applicability. Functional profiling of 141 cancer cell lines revealed inhibition of kinase suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA degradation mechanism nonsense-mediated mRNA decay (NMD), as an additional target of CC-115.

Risk factors for osteoporosis and fractures in rheumatoid arthritis.

People with rheumatoid arthritis (RA) have both disease-specific risk factors for osteoporosis and fractures in addition to those that affect the general population. Disease specific risks include directly pathogenic auto-antibodies, chronic exposure to systemic inflammation, and joint damage causing early disability. Risk factors that affect the general population which may have a higher prevalence in RA include smoking, calcium and vitamin D deficiency as well as hypogonadism.

Appropriate Use of Telehealth Visits in Endocrinology: Policy Perspective of the Endocrine Society.

Objective: This work aims to guide clinicians practicing endocrinology in the use of telehealth (synchronous patient-clinician visits conducted over video or telephone) for outpatient care.

Participants: The Endocrine Society convened a 9-member panel of US endocrinologists with expertise in telehealth clinical care, telehealth operations, patient-centered care, health care delivery research, and/or evidence-based medicine.

Evidence: The panel conducted a literature search to identify studies published since 2000 about telehealth in endocrinology.

Osteoporosis and fractures in rheumatoid arthritis - risk factors.

In this chapter, we emphasize among rheumatoid arthritis (RA) patients, whom and how to screen for osteoporosis. We highlight certain modalities, advancements in technology, secondary osteoporosis workup, and laboratory testing as well as their caveats. Finally, we discuss current guidance on how to direct the laboratory and radiology testing in the context of the individual patient with RA to guide and select from the osteoporosis treatment options currently available.

Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity.

TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (: TTK IC = 3.

Modulation of CD47-SIRPα innate immune checkpoint axis with Fc-function detuned anti-CD47 therapeutic antibody.

Cluster of differentiation 47 (CD47) is a transmembrane protein ubiquitously expressed on human cells but overexpressed on many different tumor cells. The interaction of CD47 with signal-regulatory protein alpha (SIRPα) triggers a "don't eat me" signal to the macrophage, inhibiting phagocytosis. Thus, overexpression of CD47 enables tumor cells to escape from immune surveillance via the blockade of phagocytic mechanisms.

Preliminary Evaluation of an Order Template to Improve Diagnosis and Testosterone Therapy of Hypogonadism in Veterans.

Background: Testosterone therapy is indicated for the treatment of hypogonadism. Evidence-based guidelines recommend testosterone treatment only for men with symptoms and signs of testosterone deficiency and consistently low serum testosterone concentrations; luteinizing hormone (LH) and follicle-stimulating hormone (FSH) measurements and discussion of risks and benefits of testosterone prior to therapy. However, the US Department of Veterans Affairs (VA) Office of the Inspector General (OIG) report found that health care providers were adhering poorly to guideline recommendations for the diagnosis and treatment of men with hypogonadism.

Osteoporosis care amidst the prolonged pandemic.

As SARS-CoV-2 stunned and overtook everyone's lives, multiple daily briefings, protocols, policies and incident command committees were mobilized to provide frontline staff with the tools, supplies and infrastructure needed to address the COVID-19 pandemic. Medical resources were immediately shifted. In light of the necessity for self-isolation, telemedicine was expanded, although there has been concern than non-pandemic disorders were being ignored.

CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009.

Gender-Affirming Hormone Therapy and Bone Health: Do Different Regimens Influence Outcomes in Transgender Adults? A Narrative Review and Call for Future Studies.

Background: Gender-affirming hormone therapy (GAHT) influences bone health in transgender individuals. Several hormone preparations and administration routes are available for GAHT, but no studies have compared clinical and laboratory bone health measures across different GAHT regimens.

Content: We searched PubMed (MEDLINE), Embase, and Google Scholar for studies measuring bone turnover markers and bone mineral density before and during GAHT in transgender adults.

Structural and Metabolic Assessment of Bone.

The assessment of bone structure and metabolism should focus on the bone strength. Many factors are involved, and although bone density is an important component, it is not the same as bone strength. Other aspects of bone quality include bone volume, micro-architecture, material composition, and ability to repair damage.

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma.

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e.

Urinary cross-linked carboxyterminal telopeptide, a bone resorption marker, decreases after vaso-occlusive crises in adults with sickle cell disease.

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode.

Metabolic Consequences of Obstructive Sleep Apnea Especially Pertaining to Diabetes Mellitus and Insulin Sensitivity.

Obstructive sleep apnea (OSA) and diabetes has been known to be closely related to each other and both diseases impact highly on the public health. There are many evidence of reports that OSA is associated with diabetes with a bidirectional correlation. A possible causal mechanism of OSA to diabetes is intermittent hypoxemia and diabetes to OSA is microvascular complication.

Suboptimal osteoporosis evaluation and treatment in older men with and without additional high-risk factors for fractures.

We compared osteoporosis case-finding, evaluation and treatment in groups of Older Men and Older Women with age alone as a significant risk for fracture and Older Men with Higher Risk (older men additionally having previous hip fracture, corticosteroid use or androgen deprivation therapy). We studied 13,704 older men and women (≥70 years old) receiving care at a Veterans Affairs medical center from January 2000 to August 2010 whose 10-year hip fracture risk was assessed by limited FRAX score. The main outcome measures were the proportion of patients who had bone mineral density (by dual-energy X-ray absorptiometry [DXA]) and serum 25-hydroxy vitamin D (25-OH D) measurements performed, and calcium/vitamin D or bisphosphonates prescribed.

Bones and the sex hormones.

Sex hormones act in multiple ways to maintain a strong skeleton. In men, estrogen regulates cortical bone turnover, but testosterone maintains trabecular turnover. In normal men, sex hormone-binding protein is an independent risk factor for fractures.

Synthetic Lethal Strategy Identifies a Potent and Selective TTK and CLK1/2 Inhibitor for Treatment of Triple-Negative Breast Cancer with a Compromised G-S Checkpoint.

Historically, phenotypic-based drug discovery has yielded a high percentage of novel drugs while uncovering new tumor biology. CC-671 was discovered using a phenotypic screen for compounds that preferentially induced apoptosis in triple-negative breast cancer cell lines while sparing luminal breast cancer cell lines. Detailed kinase profiling shows CC-671 potently and selectively inhibits two kinases-TTK and CLK2.

The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen.

Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing).

Pomalidomide in combination with dexamethasone results in synergistic anti-tumour responses in pre-clinical models of lenalidomide-resistant multiple myeloma.

Pomalidomide is an IMiD(®) immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, ; San Miguel et al, 2013; Richardson et al, 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti-proliferative and pro-apoptotic activity in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single-agent treatment in xenografts of lenalidomide-resistant H929 R10-1 cells.

Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115.

We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo.