findings may explain how PDE inhibitors can affect symptoms of the overactive bladder.Cancer cells have differential metabolic dependencies compared to their nonmalignant counterparts. However, few metabolism-targeting compounds have been successful in clinical trials. Infigratinib clinical trial Here, we investigated the metabolic vulnerabilities of triple-negative breast cancer (TNBC), particularly those metabolic perturbations that increased mitochondrial apoptotic priming and sensitivity to BH3 mimetics (drugs that antagonize antiapoptotic proteins). We used high-throughput dynamic BH3 profiling (HT-DBP) to screen a library of metabolism-perturbing small molecules, which revealed inhibitors of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) as top candidates. In some TNBC cells but not in nonmalignant cells, NAMPT inhibitors increased overall apoptotic priming and induced dependencies on specific antiapoptotic BCL-2 family members. Treatment of TNBC cells with NAMPT inhibitors sensitized them to subsequent treatment with BH3 mimetics. The combination of a NAMPT inhibitor (FK866) and an MCL-1 antagonist (S63845) reduced tumor growth in a TNBC patient-derived xenograft model in vivo. We found that NAMPT inhibition reduced NAD+ concentrations below a critical threshold that resulted in depletion of adenine, which was the metabolic trigger that primed TNBC cells for apoptosis. These findings demonstrate a close interaction between metabolic and mitochondrial apoptotic signaling pathways and reveal that exploitation of a tumor-specific metabolic vulnerability can sensitize some TNBC to BH3 mimetics.Integrin activation by the intracellular adaptor proteins talin1 and kindlin-3 is essential for lymphocyte adhesion. These adaptors cooperatively control integrin activation through bidirectional (inside-out and outside-in) activation signals. Using single-molecule measurements, we revealed the distinct dynamics of talin1 and kindlin-3 interactions with the integrin LFA1 (αLβ2) and their functions in LFA1 activation and LFA1-mediated adhesion. The kinetics of talin1 binding to the tail of the β2 subunit corresponded to those of LFA1 binding to its ligand ICAM1. ICAM1 binding induced transient interactions between the membrane-proximal cytoplasmic region of the β2 subunit with an N-terminal domain of kindlin-3, leading to disruption of the association between the integrin subunits (the α/β clasp) and unbending of the ectodomains of the α/β heterodimer. These conformational changes promoted high-affinity talin1 binding to the β2 tail that required the talin rod domain and the actomyosin cytoskeleton. Inside-out signaling induced by the GTPase Rap1 did not markedly stabilize the binding of talin1 and kindlin-3 to LFA1. In contrast, ligand-induced outside-in signaling, the stabilization of open LFA1 conformers, or shear force substantially altered the dynamics of talin1 and kindlin-3 association with LFA1 and enhanced both Rap1 and LFA1 activation. In migrating lymphocytes, asymmetrical distribution of talin1 and kindlin-3 correlated with the maturation of LFA1 from a low-affinity conformation at the leading edge to a high-affinity conformation in the adherent mid-body. Our results suggest that kindlin-3 spatiotemporally mediates a positive feedback circuit of LFA1 activation to control dynamic adhesion and migration of lymphocytes.

Research demonstrates that policies aimed at retailers who sell to minors must be strongly enforced to have an impact on youth usage rates.

In the USA, the Food and Drug Administration (FDA) conducts compliance checks, issues fines, and can order retailers to stop selling tobacco products (ie, no-tobacco-sale orders (NTSOs)) to enforce the Family Smoking Prevention and Tobacco Control Act. We sought to assess FDA’s utilisation of NTSOs.

We conducted a quantitative content analysis of FDA’s enforcement actions for inspections decided between 1 October 2015 and 29 March 2019. From the 536 134 inspection records we identified 148 NTSOs and 249 720 unique retailer locations, of which 2095 had three or more violations. We randomly sampled NTSOs (n=76) and retail locations (n=152) with frequent violations. We calculated the proportion of NTSOs that could have been issued earlier by FDA. We then calculated the proportion of retailers that could have been issued an NTSO, and the proportion actually issued an NTSO using FDA’s approach and a more stringent approach.

Among NTSOs, 94.7% (95% CI 89.8% to 97.4%) of NTSOs could have been issued earlier under a more stringent approach. On average, when an NTSO could have been issued earlier, it could have been issued 453 days earlier (95% CI 418 to 489; range 89-1159). Among frequently violating retail locations, 73.6% (95% CI 66.0% to 80.0%) were eligible for an NTSO. Of those, 1.9% (95% CI 0.5% to 7.0%) had received an NTSO.

The FDA’s failure to fully leverage its powers to address retailers’ underage sales of tobacco products has weakened efforts to curb the youth e-cigarette epidemic.

The FDA’s failure to fully leverage its powers to address retailers’ underage sales of tobacco products has weakened efforts to curb the youth e-cigarette epidemic.

Little is known on whether cigarette filter-related knowledge or beliefs are associated with support for policies to reduce their environmental impact.

A cross-sectional, population-based sample of US adults aged 18-64 years (n=2979) was used to evaluate filter-related knowledge and beliefs by smoking status using data collected between 24 October 2018 and 17 December 2018. Multivariate logistic regression models explored whether these knowledge and belief items were associated with support for two policies, a US$0.75 litter fee and a ban on sales of filtered cigarettes, controlling for demographic characteristics and smoking status.

Regardless of smoking status, 71% did not know plastic was a cigarette filter component and 20% believed filters were biodegradable. Overall, 23% believed filters reduce health harms and 60% believed filters make it easier to smoke; 90% believed cigarette butts are harmful to the environment. Individuals believing cigarette butts harmed the environment were more likely to support a litter fee (adjusted OR (aOR)=2.