Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors.

Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.

Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity.

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays.

Managing Pregnancy and Nursing Affecting African American Women with Inflammatory Bowel Disease: Clinical Outcomes and Parenthood.

Inflammatory bowel disease (IBD) is a term for two autoimmune diseases encompassing Crohn's disease (CD) and ulcerative colitis (UC) which are lifelong diseases affecting more than 3 million adults (1.3%) in the United States. IBD is characterized by chronic inflammation of the whole digestive system which results in damage to the gastrointestinal (GI) tract. IBD often emerges during adolescence and young adulthood. Maternal morbidity includes physical and psychological conditions that result from or are aggravated by pregnancy and have an adverse effect on a woman's health, the baby's health or both. Some women have health challenges that arise before or during pregnancy that could lead to complications. It is recommended for women to receive health care counseling before and during pregnancy. Compared to other developed countries, the United States has the highest rate of women dying of pregnancy related complications. During the past 25 years maternal mortality has been getting worse. African American women (AAW) with and/or without IBD are dying at significantly higher rates than other groups. This is linked to several factors, i.e., systemic, institutionalized, and structural racism in health-care delivery and subsequent toxic stress from people's lived experiences of racism, limited knowledge about healthcare system function, lack of access to healthcare, (inclusiveness and insurance policies) all of which negatively impact these patients. African Americans (AAs) are also up to three times as likely to experience severe maternal morbidity: unexpected outcomes of labor and delivery, deficient or lacking prenatal care and social determinants of health like lack of transportation, adequate employment, limited literacy, and limited healthcare access contribute to poor health outcomes. Studies on IBD patients indicate Medicaid expansion is associated with reduced rates of maternal morbidity, particularly for African American Women (AAW) and increased access to preconception and prenatal services that make pregnancy and childbirth safer for parent and baby. Herein we examine the physiological changes of pregnancy in patients diagnosed with inflammatory bowel disease and their relationship perinatal outcomes and parenthood.

Bioprocess decision support tool for scalable manufacture of extracellular vesicles.

Newly recognized as natural nanocarriers that deliver biological information between cells, extracellular vesicles (EVs), including exosomes and microvesicles, provide unprecedented therapeutic opportunities. Large-scale and cost-effective manufacturing is imperative for EV products to meet commercial and clinical demands; successful translation requires careful decisions that minimize financial and technological risks. Here, we develop a decision support tool (DST) that computes the most cost-effective technologies for manufacturing EVs at different scales, by examining the costs of goods associated with using published protocols. The DST identifies costs of labor and consumables during EV harvest as key cost drivers, substantiating a need for larger-scale, higher-throughput, and automated technologies for harvesting EVs. Importantly, we highlight a lack of appropriate technologies for meeting clinical demands, and propose a potentially cost-effective solution. This DST can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes when commercializing EV products.

Personally Identifiable Information in State Laws: Use, Release, and Collaboration at Health Departments.

Despite benefits to sharing data among public health programs, confidentiality laws are often presumed to obstruct collaboration or data sharing. We present an overview of the use and release of confidential, personally identifiable information as consistent with public health interests and identify opportunities to align data-sharing procedures with use and release provisions in state laws to improve program outcomes. In August 2013, Centers for Disease Control and Prevention staff and legal researchers from the National Nurse-Led Care Consortium conducted a review of state laws regulating state and local health departments in 50 states and the District of Columbia. Nearly all states and the District of Columbia employ provisions for the general use and release of personally identifiable information without patient consent; disease-specific use or release provisions vary by state. Absence of law regarding use and release provisions was noted. Health departments should assess existing state laws to determine whether the use or release of personally identifiable information is permitted. Absence of direction should not prevent data sharing but prompt an analysis of existing provisions in confidentiality laws.

Are managed care organizations in the United States impeding the delivery of primary care by nurse practitioners? A 2012 update on managed care organization credentialing and reimbursement practices.

In 2014, the Affordable Care Act will create an estimated 16 million newly insured people. Coupled with an estimated shortage of over 60,000 primary care physicians, the country's public health care system will be at a challenging crossroads, as there will be more patients waiting to see fewer doctors. Nurse practitioners (NPs) can help to ease this crisis. NPs are health care professionals with the capability to provide important and critical access to primary care, particularly for vulnerable populations. However, despite convincing data about the quality of care provided by NPs, many managed care organizations (MCOs) across the country do not credential NPs as primary care providers, limiting the ability of NPs to be reimbursed by private insurers. To assess current credentialing practices of health plans across the United States, a brief telephone survey was administered to 258 of the largest health maintenance organizations (HMOs) in the United States, operated by 98 different MCOs. Results indicated that 74% of these HMOs currently credential NPs as primary care providers. Although this represents progress over prior assessments, findings suggest that just over one fourth of major HMOs still do not recognize NPs as primary care providers. Given the documented shortage of primary care physicians in low-income communities in the United States, these credentialing policies continue to diminish the ability of NPs to deliver primary care to vulnerable populations. Furthermore, these policies could negatively impact access to care for thousands of newly insured Americans who will be seeking a primary care provider in 2014.

Healthcare employers' policies on nurse education.

The 2010 recommendation that the proportion of registered nurses with BSN (bachelor of science in nursing) degrees in the nursing workforce should increase from the current 40% to 80% by the year 2020 has shifted the focus on nurses educational progression from state legislatures-where changes in entry-level requirements were debated for decades-to the executive suites of large healthcare providers. The recommendation, contained in the report titled The Future of Nursing: Leading Change, Advancing Health, by the Robert Wood Johnson Foundation Initiative on the Future of Nursing at the Institute of Medicine, suggests that human resources policies for nurses have the potential to double the rates of college degree completions (IOM, 2010). We surveyed 447 nurse executives in hospitals, nurse-led clinics, and home and hospice companies to explore the current practices of healthcare employers with regard to this recommendation. Almost 80% of respondents reported that their institution either preferred or required newly hired nurses to have a bachelor's degree, and 94% of the facilities offered some level of tuition reimbursement. Only 25%, however, required their nurses to earn a BSN or offered salary differentials on the basis of educational attainment (9%). We conclude that if employers are serious about wanting a more highly educated nurse workforce, they need to adopt requirements for degree completion and wage differentials in the coming years. The likelihood that such policies will be widely adopted, however, is dramatically affected by the dynamics of nursing supply and demand.