Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance

Establishing A Continuum of Care to Improve Follow-Up Rates for Survivors of Sexual Assault

Introduction. In 2011 there were over 1000 reported sexual assaults in Vermont. Current recommendations suggest that survivors of sexual assault (survivors) receive follow- up care within two weeks after an initial Sexual Assault Nurse Examiner (SANE) exam, but fewer than 15% receive documented follow-up. A published report has demonstrated increased follow-up to over 80% when appointments are scheduled prior to discharge from the emergency department (ED).https://scholarworks.uvm.edu/comphp_gallery/1082/thumbnail.jp

Measurement of radioactive contamination in the high-resistivity silicon CCDs of the DAMIC experiment

We present measurements of radioactive contamination in the high-resistivity silicon charge-coupled devices (CCDs) used by the DAMIC experiment to search for dark matter particles. Novel analysis methods, which exploit the unique spatial resolution of CCDs, were developed to identify $\alpha$ and $\beta$ particles. Uranium and thorium contamination in the CCD bulk was measured through $\alpha$ spectroscopy, with an upper limit on the $^{238}$U ($^{232}$Th) decay rate of 5 (15) kg$^{-1}$ d$^{-1}$ at 95% CL. We also searched for pairs of spatially correlated electron tracks separated in time by up to tens of days, as expected from $^{32}$Si-$^{32}$P or $^{210}$Pb-$^{210}$Bi sequences of $\beta$ decays. The decay rate of $^{32}$Si was found to be $80^{+110}_{-65}$ kg$^{-1}$ d$^{-1}$ (95% CI). An upper limit of $\sim$35 kg$^{-1}$ d$^{-1}$ (95% CL) on the $^{210}$Pb decay rate was obtained independently by $\alpha$ spectroscopy and the $\beta$ decay sequence search. These levels of radioactive contamination are sufficiently low for the successful operation of CCDs in the forthcoming 100 g DAMIC detector.Comment: 18 pages, 20 figure

The commodification of human reproductive materials.

This essay develops a framework for thinking about the moral basis for the commnodification of human reproductive nmaterials. It argues that selling and buyinlg gametes and genes is morally acceptable although there should not be a market for zygotes, embryos, or genomes. Also a market in gametes and genes shouild be regutlated in order to address concerns about the adverse social consequences of conmmodification. Originally published Journal of Medical Ethics, Vol. 24, No. 6, Dec 199

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

Mechanisms underlying the diminished sensitivity to prolactin negative feedback during lactation: Reduced STAT5 signaling and up-regulation of cytokine-inducible SH2 domain-containing protein (CIS) expression in tuberoinfundibular dopaminergic neurons

Hyperprolactinaemia during lactation is a consequence of the sucking stimulus and in part due to reduced prolactin (PRL) negative feedback. To date, the mechanisms involved in this diminished sensitivity to PRL feedback are unknown but may involve changes in PRL signal transduction within tuberoinfundibular dopaminergic (TIDA) neurons. Therefore, we investigated signal transducers and activators of transcription (STAT) 5 signaling in the TIDA neurons of lactating rats. Dual-label confocal immunofluorescence studies were used to determine the intracellular distribution of STAT5 within TIDA neurons in the dorsomedial arcuate nucleus. In lactating rats with pups removed for 16 h, injection of ovine PRL significantly (P < 0.05) increased the STAT5 nuclear/cytoplasmic ratio compared with vehicle-treated mothers. In contrast, ovine PRL injection did not increase the STAT5 nuclear/cytoplasmic ratio in lactating mothers with pups, demonstrating that PRL signal transduction through STAT5 is reduced in TIDA neurons in the presence of pups. To investigate possible mechanisms involved in reduced PRL signaling, we examined the expression of suppressors of cytokine signaling (SOCS) proteins. Northern analysis on whole hypothalamus showed that CIS (cytokine-inducible SH2 domain-containing protein), but not SOCS1 or SOCS3, mRNA expression was significantly (P < 0.01) up-regulated in suckled lactating rats. Semiquantitative RT-PCR on arcuate nucleus micropunches also showed up-regulation of CIS transcripts. Immunofluorescence studies demonstrated that CIS is expressed in all TIDA neurons in the dorsomedial arcuate nucleus, and the intensity of CIS staining in these neurons is significantly (P < 0.05) increased in lactating rats with sucking pups. Together, these results support the hypothesis that loss of sensitivity to PRL-negative feedback during lactation is a result of increased CIS expression in TIDA neurons

Acute nongonococcal infectious arthritis

A retrospective analysis of 71 nongonococcal joint infections in 63 patients in reported. Staphylococcus aureus was isolated from 59% of the patients. Five patients died as a result of infections. The outcome in Gram-n egative joint infections was similar to the overall outcome in the entire series of patients. All 11 joints with infected prostheses ultimately required removal of the prostheses. All patients were treated with appropriate parenteral antibiotics, and surgical intervention was used in 40 joints. Six patients underwent surgical treatment because of inability to sterilize the joint with antibiotics and because of repeated joint aspirations. The outcome with surgical intervention was good only in patients younger than 16 years of age. Medical therapy (parenteral antibiotics and frequent joint aspirations) led to good results in 74% of the patients. Outcome of joint infection was also influenced by factors which contribute to imparied host resistance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37749/1/1780230803_ftp.pd