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Introduction Despite the impact of the opioid overdose crisis on the United States, few physicians are trained to provide treatment with buprenorphine. While research has described some factors contributing to comfort in providing buprenorphine treatment, more research is needed to identify optimal strategies to produce physicians who prescribe this medication. Methods A community-based family medicine residency in Massachusetts sought to improve residents' comfort with prescribing buprenorphine by integrating patients treated with buprenorphine directly into resident continuity clinic panels in addition to existing mandatory didactic teaching. Results The program saw a significant increase in buprenorphine prescribing among residency graduates three years after graduation after integration of patients on buprenorphine into resident continuity panels. Conclusion Efforts to further increase the number of graduates prescribing buprenorphine nationwide should emphasize supervised management of patients treated with buprenorphine during residency.

Regulated apoptosis is essential for both the development and the subsequent maintenance of the immune system. Interleukins, including IL-2, IL-4, IL-7 and IL-15, heavily influence lymphocyte survival during the vulnerable stages of VDJ rearrangement and later in ensuring cellular homeostasis, but the genes specifically responsible for the development and maintenance of lymphocytes have not been identified. The antiapoptotic protein MCL-1 is an attractive candidate, as it is highly regulated, appears to enhance short-term survival and functions at an apical step in genotoxic deaths. However, Mcl-1 deficiency results in peri-implantation lethality. Here we show that mice conditional for Mcl-1 display a profound reduction in B and T lymphocytes when MCL-1 is removed. Deletion of Mcl-1 during early lymphocyte differentiation increased apoptosis and arrested the development at pro-B-cell and double-negative T-cell stages. Induced deletion of Mcl-1 in peripheral B- and T-cell populations resulted in their rapid loss. Moreover, IL-7 both induced and required MCL-1 to mediate lymphocyte survival. Thus, MCL-1, which selectively inhibits the proapoptotic protein BIM, is essential both early in lymphoid development and later on in the maintenance of mature lymphocytes.

BAX and BAK are “multidomain” proapoptotic proteins that initiate mitochondrial dysfunction but also localize to the endoplasmic reticulum (ER). Mouse embryonic fibroblasts deficient for BAX and BAK (DKO cells) were found to have a reduced resting concentration of calcium in the ER ([Ca 2+ ] er ) that results in decreased uptake of Ca 2+ by mitochondria after Ca 2+ release from the ER. Expression of SERCA (sarcoplasmic-endoplasmic reticulum Ca 2+ adenosine triphosphatase) corrected [Ca 2+ ] er and mitochondrial Ca 2+ uptake in DKO cells, restoring apoptotic death in response to agents that release Ca 2+ from intracellular stores (such as arachidonic acid, C 2 -ceramide, and oxidative stress). In contrast, targeting of BAX to mitochondria selectively restored apoptosis to “BH3-only” signals. A third set of stimuli, including many intrinsic signals, required both ER-released Ca 2+ and the presence of mitochondrial BAX or BAK to fully restore apoptosis. Thus, BAX and BAK operate in both the ER and mitochondria as an essential gateway for selected apoptotic signals.

The “BH3-only” proteins of the BCL-2 family require “multidomain” proapoptotic members BAX and BAK to release cytochrome c from mitochondria and kill cells. We find short peptides representing the α-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. Another subset characterized by the BH3 peptides from BAD and BIK cannot directly activate BAX, BAK but instead binds antiapoptotic BCL-2, resulting in the displacement of BID-like BH3 domains that initiate mitochondrial dysfunction. Transduced BAD-like and BID-like BH3 peptides also displayed synergy in killing leukemic cells. These data support a two-class model for BH3 domains: BID-like domains that “activate” BAX, BAK and BAD-like domains that “sensitize” by occupying the pocket of antiapoptotic members.

Cellular microtubules, polymers of tubulin, alternate relentlessly between phases of growth and shortening. We now show that noscapine, a tubulin-binding agent, increases the time that cellular microtubules spend idle in a paused state. As a result, most mammalian cell types observed arrest in mitosis in the presence of noscapine. We demonstrate that noscapine-treated murine melanoma B16LS9 cells do not arrest in mitosis but rather become polyploid followed by cell death, whereas primary melanocytes reversibly arrest in mitosis and resume a normal cell cycle after noscapine removal. Furthermore, in a syngeneic murine model of established s.c. melanoma, noscapine treatment resulted in an 85% inhibition of tumor volume on day 17 when delivered by gavage compared with untreated animals (Por= 0.01), without evidence of toxicity to the spleen, liver, duodenum, bone marrow, or peripheral blood. This inhibition was greater than that seen in vivo by paclitaxel (Taxol) alone and similar to the inhibition of tumor volume observed when noscapine was combined with paclitaxel. Importantly, noscapine also demonstrated the ability to significantly inhibit melanoma progression by 83% on day 18 when delivered in drinking water (Por= 0.01) and conferred a significant survival advantage (Por= 0.01). Our results demonstrate that p.o.-administered noscapine significantly inhibits the progression of melanoma cells through alterations in microtubule dynamics, with no detected toxicity to the host. Consequently, noscapine could be a valuable chemotherapeutic agent, alone or in combination, for the treatment of advanced melanoma.