bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multisite prospective investigation of psychological outcomes following cataract surgery in Vietnam
Authors: Berle David , Steel Zachary , Essue Beverley M , Keay Lisa , Jan Stephen , Tan Phuc Huynh , Hackett Maree L 
Published: January 2017

BackgroundCataract surgery is a low-cost and effective intervention. There is increasing evidence to suggest that cataract surgery is associated with improvements in mobility, overall functioning and reductions in psychological distress. Within low-income and middle-income countries, cataract surgery has also been documented to lead to reductions in psychological distress; however, differences in economic activity and engagement in paid and domestic work in these countries may moderate such reductions. We aimed to examine the psychological outcomes following cataract surgery among a diverse Vietnamese sample.MethodsWe report findings from the VISIONARY study, a 12-month multisite prospective study of cataract surgery outcomes conducted in Vietnam (N=462). Generalised estimating equations (GEEs) were used to identify the variables which were associated with reduced psychological distress.ResultsA high proportion of participants (56.6%) reported psychological distress before surgery and severity of psychological distress had decreased by 12 months following surgery (95% CI (4.13 to 4.95)). There were regional differences in the extent of improvement in psychological distress and change in paid and unpaid work. The extent of improvement in visual acuity, male gender, and increase in paid and unpaid work hours were significant predictors of reductions in psychological distress.ConclusionsCataract surgery appears to result in the greatest reductions in psychological distress in communities where work engagement is highest.FundingThe VISIONARY study was funded by a grant provided by the Fred Hollows Foundation, Australia. During the course of this work, BME was in receipt of an Ian Potter Foundation Fellowship and a National Health and Medical Research Council (NHMRC) fellowship (1072148), SJ received an NHMRC Senior Research Fellowship, MLH was in receipt of a National Heart Foundation Future Leader Fellowship 100034.
Abstract A11: Therapeutic targeting of GCB- and ABC-DLBCLS by rationally designed BCL6 inhibitors
Authors: Cardenas Mariano Gonzalo , Yu Wenbo , Beguelin Wendy , Matthew Teater R. , Geng Huimin , Goldstein Rebecca , Oswald Erin , Hatzi Katerina , Yang Shao-Ning , Cohen Joanna , Shaknovich Rita , Vanommeslaeghe Kenno , Cheng Huimin , Liang Dongdong , Cho Hyoje , Abbott Joshua , Tam Wayne , Leonard John P. , Cerchietti Leandro , Cierpicki Tomasz , Xue Fengtian , MacKerell Alexander D. , Melnick Ari 
Published: January 2017

Abstract
Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors.
Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL.
Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo.
Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands.
Citation Format: Mariano Gonzalo Cardenas, Wenbo Yu, Wendy Beguelin, Teater R. Matthew, Huimin Geng, Rebecca Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyoje Cho, Joshua Abbott, Wayne Tam, John P. Leonard, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell, Jr., Ari Melnick. Therapeutic targeting of GCB- and ABC-DLBCLS by rationally designed BCL6 inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A11.
Abstract A30: Kinome dynamics in triple negative breast cancer in response to chemotherapy
Authors: Velarde Sara H. , Usary Jerry , Perou Chuck , Johnson Gary L. 
Published: January 2017

Abstract
Triple negative breast cancers (TNBC) have lower expression levels of the receptors (estrogen, progesterone, Her2) used in targeted therapy than other breast cancer subtypes. This makes chemotherapy the main option for treatment for TNBC patients. Only about 22% of TNBC patients respond to chemotherapy, so it is important to understand the tumor cell response involved in TNBC chemo-resistance in order to develop more effective therapies. We have studied the kinome response to paclitaxel and carboplatin in tumor samples derived from TNBC patients in both HIM PDXs (Human-In-Mouse Patient Derived Xenografts) and cell lines derived from HIM PDX lines. Integration of RNAseq and Multiplexed Inhibitor Bead/Mass Spectrometry (MIB/MS) analysis of kinome dynamics in HIM PDXs in response to carboplatin and paclitaxel treatment identified multiple pathways whose expression and/or MIB binding dynamics were changed or altered after chemotherapy. Multiple survival and apoptotic regulators, including NFkB, JNK, ErbB, Sonic Hedgehog and Hippo pathways, were altered over the course of chemotherapy treatment. We are interrogating these pathways in both the HIM PDXs and HIM cell lines to determine each pathway's role in chemosensitivity with the goal of developing pharmacological strategies to increase the efficacy of chemotherapy, as well as kinase inhibitors, in the clinic.
Citation Format: Sara H. Velarde, Jerry Usary, Chuck Perou, Gary L. Johnson. Kinome dynamics in triple negative breast cancer in response to chemotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A30.
Abstract B01: Integrated genomic analysis identifies two subsets of cervical cancer with potentially distinct therapeutic profiles
Authors: Banister Carolyn E. , Pirisi Lucia , Creek Kim E. , Buckhaults Phillip J. 
Published: January 2017

Abstract
Background and Significance: The continuous expression of HPV oncogenes is responsible for initiating and driving cervical cancer. Current treatments include radiation and Cisplatin-based chemotherapy. Targeted therapies can be directed to specific subset of tumors if they are known.
Methods: Molecular genetic data generated by The Cancer Genome Atlas (TCGA) were analyzed.
Results: We discovered and characterized a subset of HPV positive cervical cancers that do not express HPV transcripts, including the E6 and E7 oncogenes. These tumors more commonly appear in women with a median age of diagnosis 9 years later (54 vs. 45 years) (p-value = 0.023) and reveal worse survival (p-value 0.06). Gene expression profiles of HPV expressing tumors (HPV-active) are distinct from those tumors that do not express HPV (HPV-inactive). Gene Set Enrichment Analysis of the HPV-active tumors show enrichment for E2F target genes, as expected based on the activity of HPV E7. HPV-inactive tumors show enrichment for WNT/beta-catenin target genes. Additionally, this analysis reveals that the HPV-active tumors have increased AKT/MTOR signaling and HPV-inactive tumors have increased sonic hedgehog signaling indicating different potential therapeutic targets for these two classes of tumors. The majority of differentially expressed genes can be explained by DNA hyper methylation and silencing of expression. Somatic mutation landscapes are significantly different. HPV-inactive tumors are significantly enriched for non-synonymous somatic mutations (p-value &lt;0.0000001) compared to HPV-active tumors.
Conclusions: Many of the somatic mutations found in non-expressing tumors mimic the functions of the E6 and E7 viral oncoproteins, such as TP53, CTNNB1, EGFR and KRAS somatic mutations. Unexpectedly, BRCA1 and BRCA2 somatic mutations are more frequent in the HPV-inactive tumors. Therapeutic strategies based on PARP inhibition may be effective against this category of cervical cancers. Application of therapeutics routinely used in other cancer types could be used to exploit the weaknesses we discovered in the HPV-inactive tumors and may improve survival for these cervical cancer patients.
Citation Format: Carolyn E. Banister, Lucia Pirisi, Kim E. Creek, Phillip J. Buckhaults. Integrated genomic analysis identifies two subsets of cervical cancer with potentially distinct therapeutic profiles. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B01.
Abstract B07: Differential roles for AKT isoforms in BRAF mutant melanoma
Authors: McRee Siobhan K. , Pietruska Jodie R. , Dignan Elisabeth , Hinds Philip W. 
Published: January 2017

Abstract
Despite recent advances, melanoma remains the deadliest form of skin cancer, and new therapeutic strategies are urgently needed. The MAP kinase (MAPK) and PI3K/AKT pathways are central to both disease progression and chemoresistance in melanoma, with dual targeting approaches yielding promising results that would benefit from increased target specificity and selectivity. The AKT family of serine/threonine kinases comprises three highly homologous and functionally distinct isoforms (AKT1, AKT2, and AKT3) that play unique roles in melanoma but have not yet been leveraged for isoform-specific targeting.
Our lab has engineered a unique mouse model of melanoma, in which mutant BRAFV600E is constitutively targeted to mouse melanocytes, resulting in spontaneous malignant disease upon additional loss of tumor suppressor genes, and faithfully recapitulates the human disease. We have identified differential and dynamic activation of AKT isoforms in our mouse melanoma model, which supports the hypothesis that AKT isoforms may play both non-redundant and compensatory roles in melanoma progression. To systematically address this question, we have genetically ablated each AKT isoform individually in melanoma-prone mice in order to elucidate the individual and unique contribution of each isoform to melanoma progression.
In parallel, we performed in vitro studies using shRNA mediated conditional knockdown of AKTs in a wide variety of human melanoma cell lines. Our results support an isoform-specific role for AKT1 in promoting melanoma cell proliferation, while AKT2 stimulates cell migration. Further studies utilizing the precision genome editing technology CRISPR/Cas9 allows us to interrogate the effects of AKT isoform specific knockout (KO) on in vivo tumor formation. This work moves toward establishing the contribution of AKT isoforms to tumor progression in melanoma, using both human melanoma cell lines and mouse models, to advance our understanding of the role of AKT in melanomagenesis. With AKT inhibitors in clinical trials for melanoma, our findings could yield novel therapeutic strategies and increase the efficiency of existing therapies to improve treatment options and outcome for this devastating disease.
Citation Format: Siobhan K. McRee, Jodie R. Pietruska, Elisabeth Dignan, Philip W. Hinds. Differential roles for AKT isoforms in BRAF mutant melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B07.
Abstract B10: Synthetic lethal screen to identify novel therapies targeting TP53-mutant colon cancer cells
Authors: Weige Charles C. , Anderson Erin L. , Richardson Joseph , Contreras Carlo , Buckhaults Phillip J. 
Published: January 2017

Abstract
We have performed a genome-wide synthetic lethal screen for pathways that are essential for the survival of colon cancer cells with TP53 mutations. RKO colon cancer cells are wild-type for TP53, and display robust p53-dependent growth arrest and apoptosis. We have utilized an isogenic pair of RKO cells differing only in TP53 gene status (Wild Type vs homozygous null derivative) to screen a genome-wide GeCKO CRISPR library and identified pathways that are novel therapeutic targets for TP53-mutant colon cancers. After infection of these cells with the GeCKO CRISPR library and one week of culturing in vitro, we performed deep GeCKO CRIPSR amplicon sequencing to enumerate and identify all CRISPRs that were underrepresented in TP53 mutant compared to wild type cells. We identified multiple CRISPRs targeting the CHEK1 and the SHH genes which were underrepresented in TP53 knockout cells. We then tested small molecule inhibitors of CHEK1 (UCN01) and the SHH receptor SMO (Cyclopamine) against isogenic pairs of RKO, HCT116, and DLD1 cells and confirmed that each molecule is significantly more toxic to cells with mutant TP53 than to those with wild-type TP53. Future studies will focus on testing these and additional targets alone and in combination against primary colon tumor and normal avatars, and preclinical models of TP53-mutant colon cancer.
Citation Format: Charles C. Weige, Erin L. Anderson, Joseph Richardson, Carlo Contreras, Phillip J. Buckhaults. Synthetic lethal screen to identify novel therapies targeting TP53-mutant colon cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B10.
Abstract B13: Reprogramming glioblastoma multiforme cells to neurons by protein kinase inhibitors
Authors: Yuan Jie , Zhang Fan , You Meng , Yang Qin 
Published: January 2017

Abstract
Reprogramming healthy somatic cells into pluripotent stem (iPS) cells with defined factors has been intensively investigated. However, reprogramming cancer cells has fallen much behind. Direct reversion of cancers into normal tissues is an ideal strategy for cancer treatment. Recent reports have showed that defined factors can induce reprogramming of cancer cells into iPS cells, supporting this notion. Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor, with a median survival of just 14.2 months. Therefore, developing novel therapeutic strategy is an emergent task. The tumor suppressor p53 is considered today the most important tumor suppressor protein in humans and it suppresses both reprogramming and oncogenic transformation. p53 inactivation or mutations are the most common in GBM, and this p53 deficient GBM subgroup is currently the most difficult to treat, typically associated with rapid local recurrence after treatment. p53 mutations result in loss-of-function, gain-of-function, and dominant-negative mutational effects for p53. Thus, different p53 mutants may have various effects on reprogramming, promoting or inhibiting GBM reprogramming. Furthermore, p53 activity is often inactivated in GBM with wild-type p53 that may also affect reprogramming.
We have demonstrated that the depletion of p53 reprograms human somatic cells into neurons by regulation of a set of transcription factors (Nature Communications, 2014; Cell Reports, 2014, International Journal of Stem Cell Research & Therapy, 2016). Integration-free reprogramming cancer cells would be safer and preferable for clinical use. Along those lines, we screened a protein kinase inhibitor library and found that the kinase inhibitors can substitute for all transcription factors and convert human p53-deficient GBM cells into “normal” neurons (functional neurons). In vitro and in vivo tumorigenesis assays showed that induced neurons lose tumorigenicity. Moreover, the inhibitor reprogramming prevents GBM local recurrence in mice. Currently these inhibitors are used as anti-tumor drugs in patients, so this reprogramming strategy has significant potential to move rapidly toward clinical trials.
Note: This abstract was not presented at the conference.
Citation Format: Jie Yuan, Fan Zhang, Meng You, Qin Yang. Reprogramming glioblastoma multiforme cells to neurons by protein kinase inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B13.
Abstract B22: Novel dual regulation of epithelial-mesenchymal transition and anoikis resistance prevents metastases of triple negative breast cancer
Authors: Ito Koichi , Park Sun Hee , Nayak Anupma , Irie Hanna Y. 
Published: January 2017

Abstract
Triple negative breast cancers (TNBC) are associated with a higher rate of metastatic recurrence and poorer prognosis due to intrinsic biological aggressiveness and lack of targeted therapies. Novel strategies to prevent metastasis are needed to improve outcomes for patients diagnosed with TNBC. Epithelial-mesenchymal transition (EMT) and anoikis resistance are processes recognized as contributing to treatment resistance and enhanced metastatic potential. In a functional genomic screen, we identified several candidates as novel dual regulators of EMT and anoikis sensitivity of triple negative breast cancer cells, that can be pharmacologically targeted to prevent metastases. One highly validated candidate, PTK6/Brk, specifically enhances anoikis resistance and metastatic potential of triple negative breast cancer cells via E-cadherin regulation. Overexpression of PTK6 in non-transformed immortalized breast epithelial cells is sufficient to promote an EMT, whereas PTK6 inhibition (either PTK6 shRNA or kinase inhibitor treatment) enhances E-cadherin expression and suppresses migration and lung colonization of TNBC cells. PTK6-dependent E-cadherin regulation and anoikis resistance is specifically dependent on levels of SNAIL, a transcriptional repressor. SNAIL down-regulation by PTK6 inhibition is directly responsible for modulation of anoikis sensitivity, which is in turn causally linked to lung colonization potential. PTK6 inhibition promotes the degradation of SNAIL via a novel mechanism independent of GSK3β and Fbox proteins known to regulate Snail ubiquitination. Using an siRNA screening approach, we identified novel E3 ligase candidates responsible for SNAIL ubiquitination and degradation downstream of PTK6 inhibition. PTK6 is a representative novel regulator of EMT and anoikis resistance that can be targeted to prevent metastases of patient triple negative tumors.
Citation Format: Koichi Ito, Sun Hee Park, Anupma Nayak, Hanna Y. Irie. Novel dual regulation of epithelial-mesenchymal transition and anoikis resistance prevents metastases of triple negative breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B22.
Abstract B24: Regulation of mutant p53 stability by the mevalonate pathway-Hsp40-CHIP axis
Authors: Parrales Alejandro , Ranjan Atul , Iyer Swathi V. , Weir Scott , Roy Anuradha , Iwakuma Tomoo 
Published: January 2017

Abstract
Missense mutations in the p53 gene result in accumulation of dysfunctional p53 proteins in tumors with oncogenic gain-of-function activities, such as metastasis and chemotherapy resistance. Increasing evidence indicates that stabilization of mutant p53 (mutp53) in tumors is crucial for its oncogenic activities, while its knockdown reduces malignant progression. Thus, malignant properties of cancer cells are dependent on the presence of mutp53, providing a rationale to identify compounds that deplete mutp53 with minimal effects on wild-type p53 (wtp53). Toward this goal, we performed luciferase assay-based high-throughput screening of ~9,000 chemical compounds using cells expressing a chimeric fusion protein of p53R175H and a luciferase reporter. This screening led us to identify statins, a class of cholesterol-lowering drugs, as degradation inducers of conformational p53 mutants. Interestingly, statins showed minimal effects on wtp53 and DNA contact mutants. Moreover, CHIP ubiquitin ligase, but not MDM2, mediated statin-induced nuclear export, ubiquitination, and degradation of mutp53. Surprisingly, degradation of mutp53 by statins was independent of protein prenylation/lipidation or cholesterol synthesis, and specific reduction of mevalonte-5-phosphate (MVP) triggered mutp53 degradation. We also demonstrated that downregulation of a molecular chaperone Hsp40/DNAJA1 mirrored statin's effects on mutp53, while its overexpression nullified them. Moreover, statin-induced reduction of MVP inhibited the DNAJA1-mutp53 interaction. Biologically, statins preferentially suppressed malignant properties of mutp53-expressing cancer cells in vitro and in vivo. Our study proposes a novel role of DNAJA1 in inhibiting CHIP-mediated degradation of mutp53 induced by statins and highlights the significance of p53 status in impacting the efficacy of statins in cancer therapy and of DNAJA1 as a viable target for inducing mutp53 degradation.
Citation Format: Alejandro Parrales, Atul Ranjan, Swathi V. Iyer, Scott Weir, Anuradha Roy, Tomoo Iwakuma. Regulation of mutant p53 stability by the mevalonate pathway-Hsp40-CHIP axis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B24.
Walking Out for Yizkor
Authors: Ron Zvi 
Published: January 2017

Abstract
In many synagogues it is customary for people with living parents to walk out of the sanctuary for the Yizkor memorial service. This has been explained in many ways, with most explanations involving the evil eye or liturgical concerns. This article examines the origin of the Yizkor service and its connection to the collection of monetary donations in honor of the deceased. This practice, connecting Yizkor with donations, is proposed as a significant factor that those with living parents would not participate in this service.