PELP1 inhibition by SMIP34 reduces endometrial cancer progression via attenuation of ribosomal biogenesis.

Endometrial carcinoma (ECa) is the fourth most common cancer among women. The oncogene PELP1 is frequently overexpressed in a variety of cancers, including ECa. We recently generated SMIP34, a small-molecule inhibitor of PELP1 that suppresses PELP1 oncogenic signaling.

Thermal behavior of astrophysical amorphous molecular ices.

Ice is a major component of astrophysical environments - from interstellar molecular clouds through protoplanetary disks to evolved solar systems. Ice and complex organic matter coexist in these environments as well, and it is thought primordial ice brought the molecules of life to Earth four billion years ago, which could have kickstarted the origin of life on Earth. To understand the journey of ice and organics from their origins to becoming a part of evolved planetary systems, it is important to complement high spatial and spectral resolution telescopes such as JWST with laboratory experimental studies that provide deeper insight into the processes that occur in these astrophysical environments.

A Comparison of Presolar Isotopic Signatures in Laboratory-Studied Primitive Solar System Materials and Comet 67P/Churyumov-Gerasimenko: New Insights from Light Elements, Halogens, and Noble Gases.

Comets are considered the most primitive planetary bodies in our Solar System. ESA's Rosetta mission to Jupiter family comet 67P/Churyumov-Gerasimenko (67P/CG) has provided a wealth of isotope data which expanded the existing data sets on isotopic compositions of comets considerably. In a previous paper (Hoppe et al.

Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34.

Purpose: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Oncogenic PELP1 is frequently overexpressed in TNBC, and it has been demonstrated that PELP1 signaling is essential for TNBC progression. The therapeutic utility of targeting PELP1 in TNBC, however, remains unknown.

Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth.

Endometrial cancer (EC) is the fourth most common cancer in women, and half of the endometrioid EC (EEC) cases are attributable to obesity. However, the underlying mechanism(s) of obesity-driven EEC remain(s) unclear. In this study, we examined whether LIF signaling plays a role in the obesity-driven progression of EEC.

A First-in-Class Inhibitor of ER Coregulator PELP1 Targets ER+ Breast Cancer.

Unlabelled: Most patients with estrogen receptor alpha-positive (ER+) breast cancers initially respond to treatment but eventually develop therapy resistance with disease progression. Overexpression of oncogenic ER coregulators, including proline, glutamic acid, and leucine-rich protein 1 (PELP1), are implicated in breast cancer progression. The lack of small molecules that inhibits PELP1 represents a major knowledge gap.

Identification and characterization of a new ensemble of cometary organic molecules.

In-situ study of comet 1P/Halley during its 1986 apparition revealed a surprising abundance of organic coma species. It remained unclear, whether or not these species originated from polymeric matter. Now, high-resolution mass-spectrometric data collected at comet 67P/Churyumov-Gerasimenko by ESA's Rosetta mission unveil the chemical structure of complex cometary organics.

SETDB1 interactions with PELP1 contributes to breast cancer endocrine therapy resistance.

Background: Methyltransferase SETDB1 is highly expressed in breast cancer (BC), however, the mechanisms by which SETDB1 promotes BC progression to endocrine therapy resistance remains elusive. In this study, we examined the mechanisms by which SETDB1 contribute to BC endocrine therapy resistance.

Methods: We utilized therapy sensitive (MCF7 and ZR75), therapy resistant (MCF7-TamR, MCF7-FR, MCF7-PELP1cyto, MCF7-SETDB1) estrogen receptor alpha positive (ER)BC models and conducted in vitro cell viability, colony formation, 3-dimensional cell growth assays to investigate the role of SETDB1 in endocrine resistance.

Global Genomic and Proteomic Analysis Identified Critical Pathways Modulated by Proto-Oncogene PELP1 in TNBC.

The PELP1 oncogene is commonly overexpressed in many cancers, including triple negative breast cancer (TNBC). However, the mechanisms by which PELP1 contributes to TNBC progression are not well understood. To elucidate these mechanisms, we generated CRISPR-Cas9 mediated PELP1 knockout TNBC cell lines, and alterations in the proteome were examined using global data-independent acquisition mass spectrometry (DIA-MS).

LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer.

Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells.

Role of estrogen receptor coregulators in endocrine resistant breast cancer.

Breast cancer (BC) is the most ubiquitous cancer in women. Approximately 70-80% of BC diagnoses are positive for estrogen receptor (ER) alpha (ERα). The steroid hormone estrogen [17β-estradiol (E2)] plays a vital role both in the initiation and progression of BC.

Histone deacetylase inhibitors enhance estrogen receptor beta expression and augment agonist-mediated tumor suppression in glioblastoma.

Background: Glioblastomas (GBMs) are the most lethal primary brain tumors. Estrogen receptor β (ERβ) function as a tumor suppressor in GBM, however, ERβ expression is commonly suppressed during glioma progression. In this study, we examined whether drugs that reverse epigenetic modifications will enhance ERβ expression and augment ERβ agonist-mediated tumor suppression.

LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer.

Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC.

Interaction of transcription factor AP-2 gamma with proto-oncogene PELP1 promotes tumorigenesis by enhancing RET signaling.

A significant proportion of estrogen receptor-positive (ER+) breast cancer (BC) initially responds to endocrine therapy but eventually evolves into therapy-resistant BC. Transcription factor AP-2 gamma (TFAP2C) is a known regulator of ER activity, and high expression of TFAP2C is associated with a decreased response to endocrine therapies. PELP1 is a nuclear receptor coregulator, commonly overexpressed in BC, and its levels are correlated with poorer survival.

On the Origin and Evolution of the Material in 67P/Churyumov-Gerasimenko.

Primitive objects like comets hold important information on the material that formed our solar system. Several comets have been visited by spacecraft and many more have been observed through Earth- and space-based telescopes. Still our understanding remains limited.

Comparison of neutral outgassing of comet 67P/Churyumov-Gerasimenko inbound and outbound beyond 3 AU from ROSINA/DFMS.

Context: Pre-equinox measurements of comet 67P/Churyumov-Gerasimenko with the mass spectrometer ROSINA/DFMS on board the Rosetta spacecraft revealed a strongly heterogeneous coma. The abundances of major and various minor volatile species were found to depend on the latitude and longitude of the nadir point of the spacecraft. The observed time variability of coma species remained consistent for about three months up to equinox.

PELP1 signaling contributes to medulloblastoma progression by regulating the NF-κB pathway.

Medulloblastoma (MB) is the most common and deadliest brain tumor in children. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein and its oncogenic signaling is implicated in the progression of several cancers. However, the role of PELP1 in the progression of MB remains unknown.

The Surface Distributions of the Production of the Major Volatile Species, HO, CO, CO and O, from the Nucleus of Comet 67P/Churyumov-Gerasimenko throughout the Rosetta Mission as Measured by the ROSINA Double Focusing Mass Spectrometer.

The Rosetta Orbiter Spectrometer for Ion and Neutral Analysis (ROSINA) suite of instruments operated throughout the over two years of the Rosetta mission operations in the vicinity of comet 67P/Churyumov-Gerasimenko. It measured gas densities and composition throughout the comet's atmosphere, or coma. Here we present two-years' worth of measurements of the relative densities of the four major volatile species in the coma of the comet, HO, CO, CO and O, by one of the ROSINA sub-systems called the Double Focusing Mass Spectrometer (DFMS).

Ammonium Salts as a Source of Small Molecules Observed with High-Resolution Electron-Impact Ionization Mass Spectrometry.

Recent high-resolution in situ mass spectrometry at comet 67P/Churyumov-Gerasimenko visited by European Space Agency's Rosetta spacecraft raised the question, if sublimating ammonium salts can unequivocally be detected in the cometary coma. In laboratory experiments with the twin model of the space instrument, two prototypic ammonium salts NHB, namely, ammonium chloride (B = Cl) and ammonium formate (B = HCOO) (as well as methodologically relevant isotopologues), were allowed to sublimate in vacuum while mass spectra were collected. High-resolution electron-impact ionization mass spectrometry provides an outstanding experimental tool to investigate the complex physicochemical processes occurring during the sublimation of ammonium salts.

EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer.

Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Here, we describe a rationally designed first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibits antiproliferative effects, reduces invasiveness and stemness, and promotes apoptosis in triple-negative breast cancer (TNBC) cell lines.

Water Reservoirs in Small Planetary Bodies: Meteorites, Asteroids, and Comets.

Asteroids and comets are the remnants of the swarm of planetesimals from which the planets ultimately formed, and they retain records of processes that operated prior to and during planet formation. They are also likely the sources of most of the water and other volatiles accreted by Earth. In this review, we discuss the nature and probable origins of asteroids and comets based on data from remote observations, in situ measurements by spacecraft, and laboratory analyses of meteorites derived from asteroids.

Krypton isotopes and noble gas abundances in the coma of comet 67P/Churyumov-Gerasimenko.

The Rosetta Orbiter Spectrometer for Ion and Neutral Analysis mass spectrometer Double Focusing Mass Spectrometer on board the European Space Agency's Rosetta spacecraft detected the major isotopes of the noble gases argon, krypton, and xenon in the coma of comet 67P/Churyumov-Gerasimenko. Earlier, it was found that xenon exhibits an isotopic composition distinct from anywhere else in the solar system. However, argon isotopes, within error, were shown to be consistent with solar isotope abundances.

Presolar Isotopic Signatures in Meteorites and Comets: New Insights from the Rosetta Mission to Comet 67P/Churyumov-Gerasimenko.

Comets are considered the most primitive planetary bodies in our Solar System, i.e., they should have best preserved the solid components of the matter from which our Solar System formed.