PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding.

ABSTRACT Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and increase metabolism. Progesterone receptor membrane component 1 (Pgrmc1) is related to cytochrome b 5 , binds to heme, and is associated with DNA damage resistance and apoptotic suppression. Pgrmc1 is induced by carcinogens, including dioxin, and is up-regulated in multiple types of cancer. In the present study, we found that Pgrmc1 increased in vivo tumor growth, anchorage-independent growth, and migration. Pgrmc1 also promoted proliferation in the absence of serum in A549 non-small cell lung cancer cells but enhanced proliferation regardless of serum concentration in MDA-MB-468 breast cancer cells. Pgrmc1 promotes cholesterol synthesis and binds to Insig (insulininduced gene), Scap (sterol regulatory element binding protein cleavage activating protein), and P450 proteins, but Pgrmc1 did not affect cholesterol synthesis in lung cancer cells. Pgrmc1 is also associated with progesterone signaling and plasminogen activator inhibitor (PAI1) RNA binding protein, but neither progesterone activity nor PAI1 transcript levels were altered in Pgrmc1-knockdown lung cancer cells. Pgrmc1 homologues bind to aryl ligands identified in an in silico screen, and we have found that a Pgrmc1 ligand induced cell death in a Pgrmc1-specific manner in multiple breast and lung tumor cell lines. Our data support a role for Pgrmc1 in promoting cancer-associated phenotypes and provide a therapeutic approach for targeting Pgrmc1 with a small molecule in lung and breast cancer

Pgrmc1 (Progesterone Receptor Membrane Component 1) Associates with Epidermal Growth Factor Receptor and Regulates Erlotinib Sensitivity*

Tumorigenesis requires the concerted action of multiple pathways, including pathways that stimulate proliferation and metabolism. Epidermal growth factor receptor (EGFR) is a transmembrane receptor-tyrosine kinase that is associated with cancer progression, and the EGFR inhibitors erlotinib/tarceva and tyrphostin/AG-1478 are potent anti-cancer therapeutics. Pgrmc1 (progesterone receptor membrane component 1) is a cytochrome b5-related protein that is up-regulated in tumors and promotes cancer growth. Pgrmc1 and its homologues have been implicated in cell signaling, and we show here that Pgrmc1 increases susceptibility to AG-1478 and erlotinib, increases plasma membrane EGFR levels, and co-precipitates with EGFR. Pgrmc1 co-localizes with EGFR in cytoplasmic vesicles and co-fractionates with EGFR in high density microsomes. The findings have therapeutic potential because a Pgrmc1 small molecule ligand, which inhibits growth in a variety of cancer cell types, de-stabilized EGFR in multiple tumor cell lines. EGFR is one of the most potent receptor-tyrosine kinases driving tumorigenesis, and our data support a role for Pgrmc1 in promoting several cancer phenotypes at least in part by binding EGFR and stabilizing plasma membrane pools of the receptor

Impact of a Novel, Low-Cost and Sustainable Health Education Program on the Knowledge, Attitudes, and Practices Related to Intestinal Schistosomiasis in School Children in a Hard-to-Reach District of Madagascar.

Schistosomiasis control requires multisectoral approaches including praziquantel treatment, access to safe water, sanitation and hygiene, and health education. Community input can help ensure health education programs are culturally appropriate to effectively direct protective behavior change. This study reports on the three-stage development of an education program for Malagasy children, with an impact evaluation on their knowledge, attitudes, and practices (KAP) related to intestinal schistosomiasis. A cross-sectional study took place in 2017 with follow-up in 2018 in the hard-to-reach Marolambo district, Madagascar. A novel schistosomiasis education program (SEP) was designed in collaboration with researchers, stakeholders, and local community and included cartoon books, games, songs, puzzles, and blackboard lessons, costing $10 USD per school. KAP questionnaires were completed by 286 children pre-SEP and 273 children post-SEP in 2017, and by 385 and 337 children pre-SEP and post-SEP, respectively, in 2018. Improvements were observed in responses to all questions between pre- and post-education answers in 2017 (53-77%, P < 0.0001) and 2018 (72-98%, P < 0.0001) and in the pre-education answers between years (53-72%, P < 0.0001). Praziquantel mass drug administration attendance improved, rising from 64% to 91% (P < 0.0001), alongside improved latrine use, from 89% to 96% (P = 0.005). This community-consulted and -engaged SEP resulted in substantial improvements in children's understanding of schistosomiasis, with improvements in praziquantel uptake and latrine use. Socioculturally tailored education programs can help gain schistosomiasis control. Continued investment in SEP will help promote the future well-being of children through increased participation in control and treatment activities

Search for a charged Higgs boson decaying into a heavy neutral Higgs boson and a W boson in proton-proton collisions at s=\sqrt{s} = 13 TeV

A search for a charged Higgs boson ${\mathrm{\tilde{H}^{\pm}}}$ decaying into a heavy neutral Higgs boson H and a W boson is presented. The analysis targets the H decay into a pair of tau leptons with at least one of them decaying hadronically and with an additional electron or muon present in the event. The search is based on proton-proton collision data recorded by the CMS experiment during 2016-2018 at $\sqrt{s} =$ 13 TeV, corresponding to an integrated luminosity of 138 fb$^{-1}$. The data are consistent with standard model background expectations. Upper limits at 95% confidence level are set on the product of the cross section and branching fraction for an ${\mathrm{\tilde{H}^{\pm}}}$ in the mass range of 300-700 GeV, assuming an H with a mass of 200 GeV. The observed limits range from 0.085 pb for an ${\mathrm{\tilde{H}^{\pm}}}$ mass of 300 GeV to 0.019 pb for a mass of 700 GeV. These are the first limits on ${\mathrm{\tilde{H}^{\pm}}}$ production in the ${\mathrm{\tilde{H}^{\pm}}} \to \mathrm{H} \mathrm{W^{\pm}}$ decay channel at the LHC.A search for a charged Higgs boson H$^{±}$ decaying into a heavy neutral Higgs boson H and a W boson is presented. The analysis targets the H decay into a pair of tau leptons with at least one of them decaying hadronically and with an additional electron or muon present in the event. The search is based on proton-proton collision data recorded by the CMS experiment during 2016–2018 at $\sqrt{s}$ = 13 TeV, corresponding to an integrated luminosity of 138 fb$^{−1}$. The data are consistent with standard model background expectations. Upper limits at 95% confidence level are set on the product of the cross section and branching fraction for an H$^{±}$ in the mass range of 300–700 GeV, assuming an H with a mass of 200 GeV. The observed limits range from 0.085 pb for an H$^{±}$ mass of 300 Ge V to 0.019 pb for a mass of 700 GeV. These are the first limits on H$^{±}$ production in the H$^{±}$→ HW$^{±}$ decay channel at the LHC.[graphic not available: see fulltext]A search for a charged Higgs boson H$^\pm$ decaying into a heavy neutral Higgs boson H and a W boson is presented. The analysis targets the H decay into a pair of tau leptons with at least one of them decaying hadronically and with an additional electron or muon present in the event. The search is based on proton-proton collision data recorded by the CMS experiment during 2016-2018 at $\sqrt{s}$ = 13 TeV, corresponding to an integrated luminosity of 138 fb$^{-1}$. The data are consistent with standard model background expectations. Upper limits at 95% confidence level are set on the product of the cross section and branching fraction for an H$^\pm$ in the mass range of 300-700 GeV, assuming an H with a mass of 200 GeV. The observed limits range from 0.085 pb for an H$^\pm$ mass of 300 GeV to 0.019 pb for a mass of 700 GeV. These are the first limits on H$^\pm$ production in the H$^\pm$ $\to$ HW$^\pm$ decay channel at the LHC

Search for CPCP violation in ttH and tH production in multilepton channels in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceThe charge-parity (CP) structure of the Yukawa interaction between the Higgs (H) boson and the top quark is measured in a data sample enriched in the t$\overline{\textrm{t}}$H and tH associated production, using 138 fb$^{−1}$ of data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV by the CMS experiment at the CERN LHC. The study targets events where the H boson decays via H → WW or H → ττ and the top quarks decay via t → Wb: the W bosons decay either leptonically or hadronically, and final states characterized by the presence of at least two leptons are studied. Machine learning techniques are applied to these final states to enhance the separation of CP -even from CP -odd scenarios. Two-dimensional confidence regions are set on κ$_{t}$ and $\overset{\sim }{\kappa } _{t}$, which are respectively defined as the CP -even and CP -odd top-Higgs Yukawa coupling modifiers. No significant fractional CP -odd contributions, parameterized by the quantity |${f}_{CP}^{\textrm{Htt}}$| are observed; the parameter is determined to be |${f}_{CP}^{\textrm{Htt}}$| = 0.59 with an interval of (0.24, 0.81) at 68% confidence level. The results are combined with previous results covering the H → ZZ and H → γγ decay modes, yielding two- and one-dimensional confidence regions on κ$_{t}$ and $\overset{\sim }{\kappa } _{t}$, while |${f}_{CP}^{\textrm{Htt}}$| is determined to be |${f}_{CP}^{\textrm{Htt}}$| = 0.28 with an interval of |${f}_{CP}^{\textrm{Htt}}$| < 0.55 at 68% confidence level, in agreement with the standard model CP -even prediction of |${f}_{CP}^{\textrm{Htt}}$| = 0.[graphic not available: see fulltext