Project Minerva: A low cost manned Mars mission based on indigenous propellant production

Project Minerva is a low-cost manned Mars mission designed to deliver a crew of four to the Martian surface using only two sets of two launches from the Kennedy Space Center. Key concepts which make this mission realizable are the use of near-term technologies and in-situ propellant production, following the scenario originally proposed by R. Zubrin. The first set of launches delivers two unmanned payloads into low Earth orbit (LEO): the first payload consists of an Earth Return Vehicle (ERV), a propellant production plant, and a set of robotic vehicles; the second payload consists of the trans-Mars injection (TMI) upper stage. In LEO, the two payloads are docked and the configuration is injected into a Mars transfer orbit. The landing on Mars is performed with the aid of multiple aerobraking maneuvers. On the Martian surface, the propellant production plant uses a Sabatier/electrolysis type process to combine nine tons of hydrogen with carbon dioxide from the Martian atmosphere to produce over a hundred tons of liquid oxygen and liquid methane, which are later used as the propellants for the rover expeditions and the manned return journey of the ERV. The systems necessary for the flights to and from Mars, as well as those needed for the stay on Mars, are discussed. These systems include the transfer vehicle design, life support, guidance and communications, rovers and telepresence, power generation, and propellant manufacturing. Also included are the orbital mechanics, the scientific goals, and the estimated mission costs

Demographics and Incident Location of Gunshot Wounds at a Single Level I Trauma Center

Introduction:  Little is known surrounding the demographic and geospatial factors of firearm-related traumas in the Midwest Region.  The purpose of this study was to describe the overall incidence of firearm-related traumas and examine any racial/ethnic disparities that may exist. Methods:  A retrospective review was conducted of all patients 14 years or older who were admitted with a gunshot wound (GSW) to a Level I trauma center between 2016 and 2017.  Results:  Forty-nine percent of patients were Caucasian, 26.5% African American, and 19.6% Hispanic/Latino.  Hispanic/Latino patients were the youngest (25.8 ± 8.8) and Caucasians were the oldest (34.3 ± 14.1, P = 0.002).  Compared to Caucasian patients, African American (42.0%) and Hispanic/Latino (54.1%) patients were more likely to be admitted to the intensive care unit (ICU) (P = 0.034) and experienced longer ICU lengths of stay (2.5 ± 6.3 and 2.4 ± 4.7, P = 0.031, respectively).  African American patients (96.0%) experienced more assaults while Caucasians were more likely to receive gunshot wounds accidentally (26.9%, P = 0.001).  More African American (86.0%) and Hispanic/Latino (89.2%) patients were injured with a handgun and Caucasians sustained the highest number of shotgun/rifle related injuries (16.1%, P = 0.012).  Most GSWs occurred in zip codes 67202, 67203, 67213, 67211, and 67214.  Geographical maps indicated that GSWs were concentrated in low-income areas and areas with high minority populations.                                                                                                                                                                                              Conclusions:  Racial differences were noted, however, unlike national trends, most of our patients were older Caucasian males

Low-Molecular-Weight Cyclin E Deregulates DNA Replication and Damage Repair To Promote Genomic Instability in Breast Cancer

Low-molecular-weight cyclin E (LMW-E) is an N-terminus deleted (40 amino acid) form of cyclin E detected in breast cancer, but not in normal cells or tissues. LMW-E overexpression predicts poor survival in breast cancer patients independent of tumor proliferation rate, but the oncogenic mechanism of LMW-E and its unique function(s) independent of full-length cyclin E (FL-cycE) remain unclear. In the current study, we found LMW-E was associated with genomic instability in early-stage breast tumors (n = 725) and promoted genomic instability in human mammary epithelial cells (hMECs). Mechanistically, FL-cycE overexpression inhibited the proliferation of hMECs by replication stress and DNA damage accumulation, but LMW-E facilitated replication stress tolerance by upregulating DNA replication and damage repair. Specifically, LMW-E interacted with chromatin and upregulated the loading of minichromosome maintenance complex proteins (MCMs) in a CDC6 dependent manner and promoted DNA repair in a RAD51- and C17orf53-dependent manner. Targeting the ATR-CHK1-RAD51 pathway with ATR inhibitor (ceralasertib), CHK1 inhibitor (rabusertib), or RAD51 inhibitor (B02) significantly decreased the viability of LMW-E-overexpressing hMECs and breast cancer cells. Collectively, our findings delineate a novel role for LMW-E in tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E-overexpressing breast cancers

TigerBase:A DNA registration system to enhance enforcement and compliance testing of captive tiger facilities

The illegal trade in tigers (Panthera tigris) and their derivatives, such as bones, teeth and pelts, is a major threat to the species' long-term persistence. As wild tiger populations have dwindled, a large proportion of trafficked tiger products now derive from captive breeding facilities found throughout Asia. Moreover, wild tigers have been poached and laundered into captive facilities, then falsely designated as captive-bred. The establishment of a DNA registration system is recognized as a key tool to monitor compliance of captive facilities, support tiger trade investigations and improve prosecution outcomes. Here, we present a standardised wildlife forensic DNA profiling system for captive tigers called TigerBase. TigerBase has been developed in four South-East Asia countries with captive tiger facilities: Malaysia, Vietnam, Thailand and Lao PDR. TigerBase DNA profile data is based on 60 single nucleotide polymorphism (SNP) markers, genotyped using two different TaqMan®-based approaches: OpenArray® chip (capable of genotyping 60 SNPs for 48 samples in a single chip), and singleplex TaqMan® assays (capable of genotyping one SNP for one sample per reaction). Of the 60 SNPs, 53 are autosomal nuclear markers, suitable for individualisation and parentage applications, two are sex-linked markers, suitable for sexing, and five are mtDNA markers, suitable for maternal subspecies identification. We conducted a series of validation experiments to investigate the reliability and limitations of these SNP genotyping platforms. We found that the OpenArray® chip platform is more appropriate for generating reference data given its greater throughput, while the singleplex TaqMan® assays are more appropriate for genotyping lower quality casework samples, given their higher sensitivity and throughput flexibility. Only 19 autosomal nuclear markers were validated as singleplex TaqMan® assays, which generally provides ample power for individualisation analysis (probability of identity among siblings was &lt;6.9 ×10-4), but may lack power for specific parentage questions, such as determining parentage of an offspring when one of the parent's genotypes is missing. Further, we have developed pipelines to support standardised SNP calling and decrease the chance of genotyping errors through the use of analytical workflows and synthetic positive controls. We expect the implementation of TigerBase will enhance enforcement of tiger trafficking cases and encourage compliance among captive tiger facilities, together contributing to combatting the illegal tiger trade.</p

Abemaciclib Is Effective in Palbociclib-Resistant Hormone Receptor-Positive Metastatic Breast Cancers

Cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression. To understand pathways leading to resistance to the CDK4/6is palbociclib and abemaciclib, we generated multiple in vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines as well as in vivo patient-derived xenografts (PDX) and ex vivo PDX-derived organoids (PDxO) from patients who progressed on CDK4/6i. PR and AR breast cancer cells exhibited distinct transcriptomic and proteomic profiles that sensitized them to different classes of inhibitors; PR cells upregulated G2-M pathways and responded to abemaciclib, while AR cells upregulated mediators of the oxidative phosphorylation pathway (OXPHOS) and responded to OXPHOS inhibitors. PDX and organoid models derived from patients with PR breast cancer remained responsive to abemaciclib. Resistance to palbociclib while maintaining sensitivity to abemaciclib was associated with pathway-specific transcriptional activity but was not associated with any individual genetic alterations. Finally, data from a cohort of 52 patients indicated that patients with HR-positive/HER2-negative MBC who progressed on palbociclib-containing regimens can exhibit a meaningful overall clinical benefit from abemaciclib-based therapy when administered after palbociclib. These findings provide the rationale for clinical trials evaluating the benefit of abemaciclib treatment following progression on a prior CDK4/6i

Cyclin E overexpression sensitizes triple negative breast cancer to Wee1 kinase Inhibition

Purpose: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in TNBC patients, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. Experimental Design: Mono and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cells lines. Results: Cyclin E overexpression (1) is enriched in TNBCs with high recurrence rates, (2) sensitizes TNBC cell lines and PDX models to AZD1775, (3) leads to CDK2-dependent activation of DNA replication stress pathways and (4) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy. Conclusions: Cyclin E is a potential biomarker of response (1) for AZD1775 as monotherapy in cyclin E high TNBC tumors and (2) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E low TNBC tumors

Sequential Targeting of Retinoblastoma and DNA Synthesis Pathways Is a Therapeutic Strategy for Sarcomas That Can Be Monitored in Real Time

Treatment strategies with a strong scientific rationale based on specific biomarkers are needed to improve outcomes in patients with advanced sarcomas. Suppression of cell-cycle progression through reactivation of the tumor suppressor retinoblastoma (Rb) using CDK4/6 inhibitors is a potential avenue for novel targeted therapies in sarcomas that harbor intact Rb signaling. Here, we evaluated combination treatment strategies (sequential and concomitant) with the CDK4/6 inhibitor abemacicib to identify optimal combination strategies. Expression of Rb was examined in 1,043 sarcoma tumor specimens, and 50% were found to be Rb-positive. Using in vitro and in vivo models, an effective two-step sequential combination strategy was developed. Abemaciclib was used first to prime Rb-positive sarcoma cells to reversibly arrest in G1 phase. Upon drug removal, cells synchronously traversed to S phase, where a second treatment with S-phase targeted agents (gemcitabine or Wee1 kinase inhibitor) mediated a synergistic response by inducing DNA damage. The response to treatment could be noninvasively monitored using real-time positron emission tomography imaging and serum thymidine kinase activity. Collectively, these results show that a novel, sequential treatment strategy with a CDK4/6 inhibitor followed by a DNA-damaging agent was effective, resulting in synergistic tumor cell killing. This approach can be readily translated into a clinical trial with noninvasive functional imaging and serum biomarkers as indicators of response and cell cycling

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin