tbuckley/cabot-search huggingface dataset:
Rising homelessness is public health emergency, say doctors
Authors: Richard Hurley
Journal: BMJ (2019)

Doctors have expressed serious concern at increases in homelessness in the UK and the consequent harm to health, urging governments to fund better access to healthcare for homeless people.

The BMA’s annual representative meeting in Belfast on 26 June unanimously passed an unopposed motion calling for action.

David Clayton, a final year medical student at Glasgow University and co-chair of BMA …
A phase III trial to evaluate the efficacy of uproleselan (GMI-1271) with chemotherapy in patients with relapsed/refractory acute myeloid leukemia.
Authors: Daniel J. DeAngelo, Harry Paul Erba, Brian Andrew Jonas, Michael O'Dwyer, Paula Marlton, Gerwin A Huls, Jane Liesveld, Brenda W. Cooper, Bhavana Bhatnagar, Michael Armstrong, William Fogler, Mary Chen, John Magnani, Helen M. Thackray, Anjali S. Advani, Pamela Sue Becker
Journal: Journal of Clinical Oncology (2019)

TPS7066 Background: Binding of E-selectin (E-sel) to sialyl Le x , the E-sel ligand (E-sel-L), on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Expression of E-sel-L is associated with increased relapse and poor survival. Uproleselan (GMI-1271), a novel E-sel antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity such as mucositis with improved survival in vivo. Preclinical data support combination with multiple agents to achieve improved chemosensitivity and toxicities. A phase I/II study of uproleselan added to chemotherapy in R/R AML showed promising remission rates (CR/CRi) and survival outcomes, and reduced rates of mucositis. High E-sel-L expression on leukemic blasts in the bone marrow, rather than connoting treatment resistance and poor survival, instead correlated with longer survival than expected with addition of uproleselan. Breakthrough Therapy Designation was granted by FDA for treatment of patients with R/R AML. A pivotal phase 3 study (NCT03616470) is underway to assess the efficacy and safety of uproleselan with standard salvage chemotherapy in R/R AML. Methods: This study is a global, randomized, double-blind, phase 3 trial in adults aged 18-75 years with R/R AML and fit for chemotherapy. Patients may have primary refractory AML (received 1 prior induction containing an anthracycline and cytarabine), or be in untreated first or second relapse; prior HSCT is allowed. Treatment is MEC (mitoxantrone, etoposide, cytarabine) or FAI (fludarabine, cytarabine, idarubicin) induction regimen with blinded study drug (Uproleselan:placebo at 1:1 ratio) administered 1 day prior (sentinel dose) and then BID through 2 days post chemotherapy. Consolidation (HIDAC/IDAC) with uproleselan/placebo (same assignment) up to 3 cycles is allowed. The primary endpoint is overall survival; key secondary endpoints include the incidence of severe oral mucositis during induction and CR/CRh rate. Measurable residual disease, E-sel-L expression on leukemic cells, event free survival, safety, and pharmacokinetics will also be evaluated. Clinical trial information: NCT03616470.
Abstract 2193: AXL inhibitor TP-0903 attenuates AXL-TGFbeta Hippo signaling axis in lung adenocarcinoma cells
Authors: Josephine Amalia Taverna, Chia-Nung Hung, Chun-Lin Lin, Pawel Osmulski, Meizhen Chen, Chiou-Miin Wang, Nicholas L. L. Lucio, Nameer Kirma, Chih-Wei Chou, Maria E. Gaczynska, Alia Nazarullah, Mark Wade, Lars Mouritsen, Tim Huang
Journal: Cancer Research (2019)

Abstract Background: Non-small cell lung cancer (NSCLC) is a molecularly heterogeneous disease with a high propensity for drug resistance and metastasis. AXL, a member of the Tyro3-AXL-Mer family of receptor tyrosine kinases, is a central regulator of epithelial-to-mesenchymal transition (EMT) and enables tumor cells to invade and acquire drug resistance. AXL is overexpressed in lung tumors, correlates positively with tumor invasion, drug resistance, and negatively predicts overall survival. We mechanistically interrogate the effects of AXL inhibitor TP-0903 on EMT in lung adenocarcinoma cells using transcriptomic and proteomic profiling. Methods: Atomic force microscopy, Western blot analysis, RNA sequencing and mass cytometry (CyTOF) were all used to scrutinize the biomechanical properties, phenotypic, transcriptomic and proteomic profiles of A549 cells treated with 40nM TP0903 or shAXL knockdown. Results: TP-0903 attenuates total AXL/AXL phosphorylation and blunts transcriptional responses to TGFβ-Hippo signaling by disrupting the transcriptional complexes formed by SMAD2/3, SMAD4, YAP1 and TAZ. AXL knockdown or TP-0903 reverses EMT phenotype and reduces migration potential in A549 and H2009 adenocarcinoma cell lines. CyTOF data also identified resistant clones that overexpress TGFβ receptor II, TAZ protein and display hybrid EMT phenotypes. Conclusions: We are the first to report the interplay between AXL and TGFβ-Hippo signaling axis. TP-0903 study agent has excellent therapeutic promise in NSCLC and we speculate that TP-0903 drug can target epithelial to mesenchymal transitional states in lung cancer cells possibly through the inhibition of the AXL-TGFβ-Hippo signaling axis. Citation Format: Josephine Amalia Taverna, Chia-Nung Hung, Chun-Lin Lin, Pawel Osmulski, Meizhen Chen, Chiou-Miin Wang, Nicholas L. L. Lucio, Nameer Kirma, Chih-Wei Chou, Maria E. Gaczynska, Alia Nazarullah, Mark Wade, Lars Mouritsen, Tim Huang. AXL inhibitor TP-0903 attenuates AXL-TGFbeta Hippo signaling axis in lung adenocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2193.
Expression of Ptn increases the areas of invasive scirrhous carcinoma in MMTV-PyMT transgenic mouse model of breast cancer
Authors: Yunchao Chang, Masahiko Zuka, Zhaoyi Wang, Thomas F. Deuel
Journal: Cancer Research (2006)

1774  Pleiotrophin (PTN, Ptn is the gene) is an 18 KDa heparin-binding cytokine. The Ptn gene is regulated both temporally and in cell type specificity during development but, in adults, Ptn gene expression is constitutive and limited to few cell types, except in inflammatory and endothelial cells in injured tissue and early tissue repair. The Ptn gene is an oncogene; Ptn expression is found in glioblastoma, breast cancer, melanoma and many other tumors. In these studies, we wished to identify the role of PTN in breast cancer. We generated transgenic mice in which the Ptn gene was driven by the mouse mammary tumor virus promoter (MMTV) and bred these mice with MMTV-Polyoma middle T (PyMT) gain of function breast cancer predisposition mice. The MMTV-Ptn gain of function mice breed and lactate normally and histological abnormalities in breast tissue have not been found. There is no significant difference in the onset of palpable tumors between MMTV-PyMT single transgenic mice and MMTV-PyMT/Ptn double transgenic mice; although the average tumor size in MMTV-PyMT/Ptn double transgenic mice was larger, the difference was not statistically significant. However, the morphological pattern of the MMTV-PyMT/Ptn double transgenic mice differed; we observed a significant increase of epithelial islands characteristic of invasive scirrhous carcinoma in areas within the tumor. The levels of expression of the Ptn gene were higher in these areas with a scirrhous carcinoma pattern. Furthermore, these areas were surrounded by collagen and elastin and increased numbers of new blood vessels were found in the microenvironment surrounding the tumors. Increased levels of activated ERK1/2 were found and the expression of ER1-46, the 46 KD isoform of Estrogen Receptor 1 that has lost the N-terminal estrogen-independent transactivation domain was also increased. These data support the conclusion that expression of Ptn initiates a significant switch to aggressive growth in MMTV-PyMT breast cancer in mice.
Abstract 4203: Race and triple-negative breast cancer survival: A population-based study
Authors: Ying Liu, Min Lian, Graham A. Colditz
Journal: Cancer Research (2019)

Abstract Tripe-negative breast cancer (TNBC) is characterized by lacking the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, and thereby has poor prognosis. A higher incidence of TNBC in Black women than in White women has been well documented. However, it remains uncertain if there are racial differences in TNBC outcomes. Using the Surveillance, Epidemiology, and End Results dataset, we identified 23,077 women diagnosed with non-metastatic invasive TNBC, including 5,839 non-Hispanic Blacks and 17,238 non-Hispanic Whites, between 2010 and 2015. Cox proportional hazards regression was used to estimate relative risks (RRs) of breast cancer-specific death. During a median follow-up of 29 months, 2,494 cases died from breast cancer. The racial difference in estimated 5-year breast cancer-specific survival was 6.8% for younger (&amp;lt;65 years) women and 4.7% for older (≥65 years) women. The RR of breast cancer-specific death was 1.22 (95% CI 1.10-1.34) in Black women compared with White women after adjustment for age, insurance status, cancer registries, tumor characteristics, treatment, neighborhood socioeconomic deprivation, and rural locations. The race-associated higher risk was observed in women under 65 (RR=1.29, 95% CI 1.14-1.45), in less socioeconomically deprived counties (RR=1.33, 95% CI 1.18-1.49), and in urban counties (RR=1.27, 95% CI 1.15-1.41). The higher risk in Black women did not significantly vary by health insurance within age strata; the RR was 1.34 (95% CI 1.06-1.69) in younger patients having no insurance or Medicaid, 1.27 (95% CI 1.10-1.47) in younger patients having non-Medicaid insurance, 1.10 (95% CI 0.67-1.81) in older patients having no insurance or Medicaid, and 1.09 (95% CI 0.90-1.33) in older patients having non-Medicaid insurance. Black women with TNBC had worse survival compared with White counterparts, which was unlikely attributed to insurance coverage and was not evenly distributed across geographic areas. This warrants further research to investigate nonbiological and biological mechanisms for racial differences in TNBC outcomes, particularly in women under 65. Citation Format: Ying Liu, Min Lian, Graham A. Colditz. Race and triple-negative breast cancer survival: A population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4203.
Abstract 4649: Duplex Sequencing detects rare subclonal variants that mark early carcinogenesis and preneoplastic clonal evolution
Authors: Charles C. Valentine, Mark Fielden, Robert Young, Jake Higgins, Lindsey Williams, Tan Li, Rohan Kulkarni, Sheroy Minocherhomji, Rosana Risques, Patrick Danaher, Jesse Salk
Journal: Cancer Research (2019)

Abstract Cancer is a disease of somatic evolution, characterized by the natural selection of genomic mutations that facilitate enhanced cell survival and proliferation. Although many thousands of tumor genomes have now been sequenced, our ability to identify early genetic patterns of clonal selection in both humans and model organisms have been hampered by inadequately sensitive methodologies for identifying mutations during the long period between their occurrence and the final outgrowth of a clinically apparent tumor. Sensitive molecular tests are capable of measuring minute levels of cancer cells in tissue samples, however no existing method is satisfactory at scaling to high-throughput detection at the rate of one cancer-associated variant per more than a million normal cells. NGS is used to study the genetic variation in cell populations, although the accuracy of standard NGS methods limit our ability to detect sub-clones below ~1%. Duplex Sequencing (DS) is a sensitive NGS error-correction method which increases the accuracy of base calls by more than 100,000-fold. DS enables precise reconstruction of the original double-stranded source molecule while overcoming both chemical and technical artifacts that arise during library preparation and sequencing. Here we present the use of Duplex Sequencing, in both human and mouse tissues, for measuring sub-clones at allelic fractions less than 1×10-4 for an early glimpse into pre-neoplastic evolution. We illustrate how, merely weeks after mutagen exposure, we observe emerging clones of cells bearing cancer-driving mutations in histologically normal mouse tissue. Furthermore, we illustrate how similar patterns of clonal selection can be seen in multiple otherwise healthy tissues of humans as part of normal aging. We discuss how variations in the pattern and rate of accumulation of rare cancer-associated mutations offers a new preclinical tool for evaluating carcinogenicity of chemicals, as well as a potential clinical tool for assessing life-integrated carcinogenic processes and cancer risk in humans. Citation Format: Charles C. Valentine, Mark Fielden, Robert Young, Jake Higgins, Lindsey Williams, Tan Li, Rohan Kulkarni, Sheroy Minocherhomji, Rosana Risques, Patrick Danaher, Jesse Salk. Duplex Sequencing detects rare subclonal variants that mark early carcinogenesis and preneoplastic clonal evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4649.
Abstract 214: Preclinical evaluation of a novel MET antibody-drug conjugate in uveal melanoma models
Authors: Oliver Surriga, John DaSilva, Gary K. Schwartz
Journal: Cancer Research (2019)

Abstract Uveal melanoma is the most common primary intraocular malignant tumor in adults. These tumors are characterized by mutations in G-proteins (GNAQ and GNA11) and high expression of MET, a receptor tyrosine kinase. While inhibition of MET signaling delays the development of uveal melanoma metastases in preclinical models (possibly by inhibiting cell migration), primary tumor growth is not inhibited, indicating a lack of dependence on the MET pathway. Thus, treatment of established metastatic uveal melanoma with MET signal blockers is unlikely to be effective. However, the high expression of MET protein in metastatic uveal melanoma presents an opportunity to directly kill tumor cells with a MET-targeted antibody drug conjugate (ADC). METxMET-ADC is a novel bispecific antibody that binds to two distinct epitopes on MET and is conjugated to a maytansinoid payload via a cleavable linker. The METxMET-ADC potently induces receptor internalization and mitotic arrest of cancer cells. Our in vitro studies show that the METxMET-ADC significantly and specifically decreases the viability of MET expressing uveal melanoma cell lines in a dose-dependent manner with an IC50 of less than 1 nM. A longer 7-day cell viability assay shows significantly enhanced inhibition of proliferation of several MET expressing cell lines (Mel270, Mel202, OMM1.3 and MP65) but not of OCM3 cells which express low levels of MET. Apoptosis is also induced up to 40% in the MET-expressing cell lines when treated with 10 nM of the METxMET-ADC for 48 hours. Cell cycle analysis shows a significant increase of OMM1.3 and Mel202 cells in mitosis after 6-24 hours of treatment and appearance of a sub-G1 population after 24-48 hours. Western blots confirm a decrease of MET protein levels, presumably due to receptor internalization and trafficking to lysosomes. Finally, treatment with the METxMET ADC is associated with induction of PARP cleavage and phosphorylation of histone H3 after 24 hours in OMM1.3 and Mel202 cells, but not in OCM3 cells. In summary, conjugation of a METxMET bispecific antibody with a cytotoxic payload allows for potent and selective killing of MET-expressing uveal melanoma cells. The METxMET-ADC demonstrates promising therapeutic potential for the treatment of uveal melanoma. Citation Format: Oliver Surriga, John DaSilva, Gary K. Schwartz. Preclinical evaluation of a novel MET antibody-drug conjugate in uveal melanoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 214.
Abstract #LB-117: Peroxiredoxin 5 as a mediator for de-silencing of BRCA2 gene expression in dividing human breast cells
Authors: Smita Misra, Gautam Chaudhuri
Journal: Cancer Research (2009)

The DNA double stranded break repair protein BRCA2 is not expressed in the quiescent breast cells but is expressed in abundance in the dividing cells. We have shown previously that cell cycle dependent regulation of human BRCA2 gene expression is mediated through the transcriptional repressor protein SLUG (Tripathi M. K. et al., J. Biol. Chem. 280, 17163-17171, 2005). We report here the identification of the BRAC2 silencer binding protein in the dividing human breast cells as peroxiredoxin 5 (PRDX5). While all three alternatively spliced mRNAs (PRDX5A, -B and -C) are present in the breast cells analyzed, we only could detect a ~19 kDa protein with PRDX5 antibody. This protein is located in the cytoplasm as well as in the nucleus. In the nucleus of the dividing breast cells PRDX5 binds to the BRCA2 gene silencer preferentially over SLUG as was shown by DNA affinity pull down and quantitative chromatin immuno-precipitation assays. Knockdown of PRDX5 using siRNA leads to the restoration of silencer activity as well as the down regulation of BRCA2 mRNA and protein in the dividing breast cells. We propose that PRDX5 competes with SLUG to bind to the BRCA2 gene silencer in the dividing human breast cells to alleviate the BRCA2 gene repressor activity of SLUG. Supported by the DOD-CDMRP IDEA Grant# W81XWH-06-1-0466 and the Susan G. Komen Breast Cancer Foundation grant# BCTR0707627 to GC.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-117.
Abstract 4683: Targeting GPCR signaling in HER2+ breast cancer suppresses cancer stem cell tumorigenicity and sensitizes HER2-targeted therapies
Authors: Wei Wang, Dharmendra Bhargava, Yuan Chao Ye, Songhai Chen
Journal: Cancer Research (2019)

Abstract G protein coupled receptors (GPCRs) are the largest family of cell surface receptors with over 800 members. Aberrant activation of GPCRs has been implicated in cancer initiation and development. However, many of GPCRs are overexpressed in cancer cells, making it difficult to target individual GPCRs for cancer treatment. In this study, we have tested a new approach of targeting GPCRs in HER2+ breast cancer by blocking their common pathways downstream of G proteins. By mammary gland-specific expression of the pertussis toxin (PTx) catalytic subunit, a selective inhibitor that uncouples a subgroup of GPCRs from activating Gi/o proteins, we demonstrated that blocking GPCR downstream signaling delayed the onset of HER2-driven spontaneous mammary tumor formation and suppressed lung metastasis. Moreover, we showed that aberrant HER2 signaling upregulated Gi/o-GPCR expression in breast cancer cells, which in turn activated the ErbB/HER family of protein-tyrosine kinases via Src and PI3K pathways to maintain cancer stem cell tumorigenicity. Targeting Gi/o-GPCR signaling by PTx, Src or PI3K inhibitors sensitizes HER2+ breast cancer to HER2-targeted therapies. Together, our data demonstrate that targeting GPCR downstream signal pathways may represent a new approach to ablate CSCs to block tumor progression and augment HER2-targeted therapeutics. Citation Format: Wei Wang, Dharmendra Bhargava, Yuan Chao Ye, Songhai Chen. Targeting GPCR signaling in HER2+ breast cancer suppresses cancer stem cell tumorigenicity and sensitizes HER2-targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4683.
Abstract 117: Pharmacological targeting of activated PSC decreases resistance to gemcitabine and increases survival in murine PDA
Authors: Ravi Chakra Turaga, Malvika Sharma, Falguni Mishra, Zhi-Ren Liu
Journal: Cancer Research (2019)

Abstract Background: Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of cancer owing to its insensitivity to many chemotherapeutic drugs. Gemcitabine remains a cornerstone of PDA treatment despite suboptimal efficacy in clinics. One major mechanism by which PDA becomes resistant to gemcitabine is its conversion to inactive derivative, dFdU by upregulation of the enzyme, cytidine deaminase (Cda) in cancer cells. Activated pancreatic stellate cells (PSC) are the major source of IGF1 in the tumor microenvironment, which may be responsible for an increase in Cda expression in cancer cells. We previously reported a rationally designed protein, ProAgio that targets integrin αVβ3 at a novel site. Here we demonstrate that ProAgio specifically induces apoptosis of integrin αVβ3-expressing activated PSC and therefore circumvents gemcitabine resistance in murine PDA models. Objective: To test whether targeting activated PSC restores chemotherapeutic sensitivity in previously unresponsive PDA tumors in a murine model. Methods: To study the effect of ProAgio and gemcitabine combination in PDA, we used two murine PDA models: a) KP orthotopic mouse model where KPC cells were orthotopically injected into the pancreas and, b) LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model. Mice were treated with 20 doses of ProAgio (10mg/kg; i.p.) and 10 doses of gemcitabine twice weekly (50mg/kg; i.p.). IGF1 and Cda levels were analyzed by ELISA and immunohistochemistry. The intratumoral levels of the gemcitabine prodrug 2′,2′-difluorodeoxcytidine (dFdC) and the inactivated and activated metabolites (2′,2′-difluorodeoxyuridine (dFdU) and gemcitabine triphosphate (dFdCTP) respectively were determined by LCMS. Results: Our data in murine PDA models clearly demonstrate that pharmacological targeting of activated PSC by ProAgio can stabilize PDA, and when combined with gemcitabine significantly increased the survival benefit by 3-fold (p&amp;lt;0.001). Pharmacological targeting of activated PSC by ProAgio consequently decreases IGF1R signaling in cancer cells. As a result, there is a decrease in Cda expression leading to an increase in active metabolite, dfdCTP in the tumor, which contributes to the enhanced efficacy of gemcitabine. In conclusion, our findings for the first time demonstrate the mechanistic approach to target activated PSC, resulting in decreased Cda expression and enhanced gemcitabine delivery, thereby restoring chemotherapeutic sensitivity in murine PDA models. Citation Format: Ravi Chakra Turaga, Malvika Sharma, Falguni Mishra, Zhi-Ren Liu. Pharmacological targeting of activated PSC decreases resistance to gemcitabine and increases survival in murine PDA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 117.