Delivering the National Diabetes Prevention Program: Assessment of Enrollment in In-Person and Virtual Organizations.

The aim of the US Centers for Disease Control and Prevention's (CDC) National Diabetes Prevention Program (National DPP) is to make an evidence-based lifestyle change program widely available to the more than 88 million American adults at risk for developing type 2 diabetes. The National DPP allows for program delivery using four delivery modes: in person, online, distance learning, and combination. The objective of this study was to analyze cumulative enrollment in the National DPP by delivery mode. We included all participants who enrolled in CDC-recognized organizations delivering the lifestyle change program between January 1, 2012, and December 31, 2019, and whose data were submitted to CDC's Diabetes Prevention Recognition Program. During this time, the number of participants who enrolled was 455,954. Enrollment, by delivery mode, was 166,691 for in-person; 269,004 for online; 4,786 for distance-learning; and 15,473 for combination. In-person organizations enrolled the lowest proportion of men (19.4%) and the highest proportions of non-Hispanic Black/African American (16.1%) and older (65+ years) participants (28.2%). Online organizations enrolled the highest proportions of men (27.1%), younger (18-44 years) participants (41.5%), and non-Hispanic White participants (70.3%). Distance-learning organizations enrolled the lowest proportion of Hispanic/Latino participants (9.0%). Combination organizations enrolled the highest proportions of Hispanic/Latino participants (37.3%) and participants who had obesity (84.1%). Most in-person participants enrolled in organizations classified as community-centered entities (41.4%) or medical providers (31.2%). Online and distance-learning participants were primarily enrolled (93.3% and 70.2%, respectively) in organizations classified as for-profit businesses or insurers. Participants in combination programs were enrolled almost exclusively in organizations classified as medical providers (89%). The National DPP has reached nearly half a million participants since its inception in 2012, but continued expansion is critical to stem the tide of type 2 diabetes among the many Americans at high risk.

Oxetanyl Sulfoxide MMS-350 Ameliorates Pulmonary Fibrosis In Vitro, In Vivo, and Ex Vivo.

Fibrosis is a common feature of several diseases, involves different organs, and results in significant morbidity and mortality. There are currently no effective therapies to halt the progression of fibrosis or reverse it. We have identified the highly water-soluble MMS-350, a novel bis-oxetanyl sulfoxide, as an antifibrotic agent. MMS-350 reduced the profibrotic phenotype induced in vitro in primary human fibroblasts and ameliorated bleomycin-induced pulmonary fibrosis in vivo. Furthermore, MMS-350 reversed fibrosis in human skin in organ culture. MMS-350 reduced levels of extracellular matrix proteins, the activation of fibroblasts, and the induction of pro-fibrotic factors. Similar effects at lower concentrations were observed with KRL507-031 and CL-613-091, two more lipophilic MMS-350 analogues. The fact that MMS-350 was effective at reducing pulmonary fibrosis induced by different triggers, the differential biological effects of its close structural analogues and its oral availability make it an attractive therapeutic candidate for organ fibrosis.

Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators.

Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.

Polyketide decarboxylative chain termination preceded by o-sulfonation in curacin a biosynthesis.

Biosynthetic innovation in natural product systems is driven by the recruitment of new genes and enzymes into these complex pathways. Here, an unprecedented decarboxylative chain termination mechanism is described for the polyketide synthase of curacin A, an anticancer lead compound isolated from the marine cyanobacterium Lyngbya majuscula. The unusual chain termination module containing adjacent sulfotransferase (ST) and thioesterase (TE) catalytic domains embedded in CurM was biochemically characterized. The TE was proved to catalyze a hydrolytic chain release of the polyketide chain elongation intermediate. Moreover, a selective ST-mediated sulfonation of the (R)-beta-hydroxyl group was found to precede TE-mediated hydrolysis, triggering a successive decarboxylative elimination and resulting in the formation of a rare terminal olefin in the final metabolite.