tbuckley/cabot-search huggingface dataset:
Abstract 54: MicroRNA Let-7d-3p in Heart Failure
Authors: Lee Lee Wong, Eng Leng Saw, Yue Zhou, Peipei Wang, Arthur M Richards
Journal: Circulation Research (2016)

Circulating microRNA (miRNAs) levels are dysregulated in heart failure (HF) suggesting possible diagnostic and prognostic applications. In addition, miRNAs may yield insights into the pathophysiology of HF and provide targets for therapeutic intervention. We sought to identify the diagnostic utility of miRNAs in HF and to further investigate selected miRNAs as potential targets for therapeutic intervention. We hypothesized that distinct dysregulated circulating miRNAs in HF may be potential therapeutic targets to improve outcomes for HF. Methods: Plasma from 338 well-characterized HF patients and 208 age-matched controls were collected for qPCR based miRNA profiling. Selected miRNAs of interest were further investigated using myocyte cell line, H9C2 and primary neonatal rat ventricular cardiomyocytes, NRVM. Results: Seventy-four miRNAs (AUC&gt;0.65, p&lt;0.001) were significantly dysregulated for discrimination of HF from non-HF controls on receiver-operator analysis. Seven miRNAs of interest were selected for further investigation. Of these, let-7d-3p had the most up regulated miRNA fold change=1.32 (p&lt;0.001 after FDR). Functional screening using mimic transfection demonstrated that let-7d-3p mimic increased CCK-8 activity and decreased LDH release in both H9C2 and NRVM during hypoxia. By in silico target prediction (miRDB, microRNA.org and Targetscan) and qPCR, mRNA targets YY1, KLF9, KLF12 and MEX3C were identified as candidate targets for let-7d-3p and were significantly downregulated by let-7d-3p mimic. This suggests that let-7d-3p may play a role in signaling pathways pertinent to cardiac development (YY1), cell proliferation/survival (KLF9 and KLF12) and adiposity (Mex3c). Conclusions: We identified miRNAs that were dysregulated in clinical HF and our preliminary data on let-7d-3p suggests roles in the pathophysiology of HF that warrant further investigation.
Abstract 3972: <i>Ex vivo</i> profiling of PD-1 blockade using organotypic tumor spheroids
Authors: David A. Barbie, Russell Jenkins, Kwok-Kin Wong
Journal: Cancer Research (2017)

Abstract Despite the impressive activity of PD-1/PD-L1 immune checkpoint blockade in melanoma, lung, and other cancers, the majority of patients are intrinsically resistant to this therapy. Furthermore, despite years of effort few robust biomarkers of response exist, and tumor PD-L1 expression and mutational load are only partially predictive of activity. Nearly all attempts at biomarker development have relied on fixed tumor tissue or studies in plasma. Meanwhile, emerging functional approaches to study patient derived samples, such as organoid development and circulating tumor cell culture, lack features of the native tumor immune microenvironment and thus are limited in the ability to assess ex vivo anti-PD-1 response. We have developed a novel approach to study short-term ex vivo response to immune checkpoint blockade based upon short term culture of murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS) in a 3-dimensional microfluidic system. Spheroids derived from fresh mouse and human tumor samples through partial collagenase digestion and filtration retain autologous tumor infiltrating immune cells, including PD-1 positive CD8 T lymphocytes. Using murine syngeneic mouse cancer models with known responsiveness or resistance to PD-1 blockade, we demonstrate the ability to recapitulate tumor killing ex vivo or lack thereof. Multiplexed cytokine profiling of conditioned media in this system further enables characterization of the cytokine and chemokine response to PD-1 and/or CTLA-4 blockade. We thus analyzed the secreted cytokine/chemokine response to PD-1 inhibition across a large panel of PDOTS, and observed pronounced induction of CCL19/CXCL13, which associated with % PD-1 positive CD8 T cells. This strategy further uncovered production of a class of myeloid attracting chemokines and cytokines in major proportion of samples, which clustered with the presence of plasmacytoid dendritic cells and myeloid derived suppressor cells. Importantly, the presence of this maladaptive cytokine/chemokine signature correlated with lack of response in the subset of patients that had been treated with PD-1 blockade. Together, these data demonstrate the ability to profile the functional response to tumor PD-1 blockade ex vivo and unveil a novel strategy to advance precision immuno-oncology. Citation Format: David A. Barbie, Russell Jenkins, Kwok-Kin Wong. Ex vivo profiling of PD-1 blockade using organotypic tumor spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3972. doi:10.1158/1538-7445.AM2017-3972
Cholesterol-Lowering Gene Therapy Counteracts the Development of Non-ischemic Cardiomyopathy in Mice
Authors: Ilayaraja Muthuramu, Ruhul Amin, Andrey Postnov, Mudit Mishra, Joseph Pierre Aboumsallem, Tom Dresselaers, Uwe Himmelreich, Paul P. Van Veldhoven, Olivier Gheysens, Frank Jacobs, Bart De Geest
Journal: Molecular Therapy (2017)
Abstract 1267: Emodin exerts its anticancer effect on colon cancer cells by inhibiting proliferation and inducing apoptosis
Authors: Ian T. Saunders, Hina Mir, Neeraj Kapur, Shailesh Singh
Journal: Cancer Research (2017)

Abstract Despite state of the art diagnostic and therapeutic options offered in the clinics, colon cancer is still a major health care concern. Therapeutic outcome is often compromised due to late diagnosis and development of resistance against treatment options used to treat advanced disease. Hence, the need to explore new avenue to treat/prevent colon cancer more effectively still exist. In this study we have investigated potential impact of Emodin, an anthraquinone derived from plant (Rheum rhabarbarum) on colon cancer cell proliferation, survival and apoptosis. Our data show that emodin reduces the cell viability and inhibits proliferation of human colon cancer cell (COLO-201 and DLD-1) in a time-dependent manner. Furthermore, FACS analysis show higher percentage of apoptotic cells with Emodin treatment compared to untreated cells. Interestingly, pro-inflammatory and anti-inflammatory cytokines produced by colon cancer cells were modulated with Emodin treatment. Cancer cells often use these cytokines to achieve their goal to progress and escape the treatment. Our data implies Emodin could be a promising agent that could be used for chemoprevention as well as in therapeutic combination to improve efficacy of conventional therapy. Citation Format: Ian T. Saunders, Hina Mir, Neeraj Kapur, Shailesh Singh. Emodin exerts its anticancer effect on colon cancer cells by inhibiting proliferation and inducing apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1267. doi:10.1158/1538-7445.AM2017-1267
Abstract 4861: The role of PRAME in promoting uveal melanoma metastasis
Authors: Margaret I. Sanchez, Matthew G. Field, Jeffim N. Kuznetsov, Stefan Kurtenbach, Dien Pham, James W. Harbour
Journal: Cancer Research (2017)

Abstract Uveal melanoma (UM) is the most common primary eye cancer and has a predisposition for fatal metastasis. Our group has shown that UMs can be categorized by gene expression profiling (GEP) into two molecular classes associated with metastatic risk: Class 1 (low metastatic risk) and Class 2 (high metastatic risk). While the majority of Class 2 UMs (71%) metastasize, only 38% of Class 1 UMs metastasize. Our group was the first to identify the cancer-testis antigen PRAME as a biomarker for increased metastatic risk in Class 1 UMs, and sub-categorized these tumors into Class1 PRAME+ (intermediate metastatic risk) and Class1 PRAME- (low metastatic risk) subgroups. Further we identified PRAME+ was associated with shorter time to metastasis and worse prognosis in class 2 patients. We have now shown that this PRAME expression is correlated with hypomethylation in the promoter region of the gene, suggesting a mechanism for its expression. Since we have previously shown that PRAME is associated with early metastasis in Class 1 and Class 2 UMs, we hypothesized that PRAME plays a direct role in UM metastasis. To better understand the role of PRAME in UM, we used Class1PRAME+ (F41) and Class1PRAME– (Mel290) UM cell lines to develop in vitro models to study the role of PRAME. Since F41 cells are PRAME+ and highly metastatic, we constitutively silenced PRAME with a V5 tag (F41 shPRAME-V5). For Mel290 cells, we overexpressed PRAME to see whether this cell line, which does not induce metastatic death, became more malignant. We confirmed the silencing and overexpression of PRAME in our transformed cells with western blot. For cell proliferation, we found a slight increase in the Mel290 PRAME+ cells compared to non-transformed Mel290. Strikingly, in F41 cells, knockdown of PRAME led to complete cell death. In a xenograft animal model, NSG male mice were injected with either Mel290 PRAME-V5, Mel290, F41 shPRAME-V5 or F41 TET-empty vector cells. We found that PRAME overexpressing cell lines (Mel290 PRAME-V5 and F41 TET-empty vector) induced rapid, multiple and aggressive liver metastases that led to death, whereas the non-expressing PRAME cells (Mel290 and F41 shPRAME-V5) did not present macro or micrometastasis in any cases. This data highly suggests that PRAME overexpression is involved in UM metastasis. Thus, PRAME mRNA expression is not only a prognostic biomarker but also could be an important target for treatment. Citation Format: Margaret I. Sanchez, Matthew G. Field, Jeffim N. Kuznetsov, Stefan Kurtenbach, Dien Pham, James W. Harbour. The role of PRAME in promoting uveal melanoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4861. doi:10.1158/1538-7445.AM2017-4861
24-Hour Urine Calcium in the Evaluation and Management of Nephrolithiasis
Authors: Li Song, Naim M. Maalouf
Journal: JAMA (2017)

A 29-year-old man presented with recurrent nephrolithiasis with 95% calcium oxalate and 5% calcium phosphate. His maternal family history was significant for nephrolithiasis, but his laboratory studies showed normal results. How would you proceed?
Abstract 5732: PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer
Authors: Sami Blom, Petra Mäki-Teeri, Andrew Erickson, Lassi Paavolainen, Tuomas Mirtti, Antti Rannikko, Swapnil Potdar, Päivi Östling, Wytske van Weerden, Olli Kallioniemi, Teijo Pellinen
Journal: Cancer Research (2017)

Abstract Activation of PI3K/Akt pathway is associated with adverse outcome and aggressive disease in many cancers. In prostate cancer (PCa), the activity of this pathway has been shown to promote disease progression and metastasis. However, it is still controversial how PI3K/Akt regulates androgen receptor (AR), a central signaling molecule in prostate pathophysiology, and whether it has an active role in hormone naïve non-metastatic PCa. Here, we show using immunohistochemistry (IHC) and advanced quantitative multiplexed IHC that the expression of phosphorylated-Akt(S473) and AR are highly correlated in clinical PCa, even at the cellular level. Furthermore, we found that high expression of p-Akt(S473) predicts poor clinical outcome in two independent hormone-naïve non-metastatic PCa cohorts. To study whether PI3K/Akt regulates AR expression, we performed an in vitro drug screen with 32 PI3K/Akt/mTOR inhibitors in PC346C, an AR expressing cell line derived from a hormone-naïve primary tumor of prostate. We observed a strong correlation between p-Akt(S473) and AR also in vitro in individual cells independent of the inhibitor used. Although both PI3K and Akt specific inhibition reduced cell viability, the response in nuclear expression of AR was highly dependent on the target of inhibition: Akt specific inhibition reduced AR nuclear expression and resulted in large, spindle-shaped cells, whereas PI3K specific inhibition increased AR nuclear expression and resulted in smaller, round-shaped cells. These data suggest that PI3K and Akt have different roles in sustaining AR activity in PCa as perturbations of the two components leads to differential responses in terms of AR nuclear expression and cell morphology. In conclusion, activated Akt associates with AR expression and predicts poor clinical outcome in hormone-naïve non-metastatic PCa. Furthermore, the differing roles of PI3K and Akt in AR regulation warrants for further studies as it may have implications in the design of PCa therapy targeting PI3K/Akt, especially when the inhibitors are administered in combination with anti-androgens. Citation Format: Sami Blom, Petra Mäki-Teeri, Andrew Erickson, Lassi Paavolainen, Tuomas Mirtti, Antti Rannikko, Swapnil Potdar, Päivi Östling, Wytske van Weerden, Olli Kallioniemi, Teijo Pellinen. PI3K/Akt activity regulates androgen receptor expression and predicts poor clinical outcome in non-metastatic hormone-naïve prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5732. doi:10.1158/1538-7445.AM2017-5732
Abstract 4868: RD3 reprogramming in N-MYC non-amplified neuroblastoma evolution
Authors: Dinesh Babu Somasundaram, Karthikeyan Subramanian, Sheeja Aravindan, Terence Herman, Aravindan Natarajan
Journal: Cancer Research (2017)

Abstract N-MYC amplification is restricted to ~30% of the high-risk neuroblastoma (NB), while the remaining 70% is N-MYC non-amplified (N-MYC-NA), yet still has a poor outcome with only 37% 5 Year OS and a miserable 9% 10Y OS. Recently, we demonstrated, Retinal Degeneration Protein 3 (RD3) regulates metastatic state of NB cells and its loss associates with poor prognosis. Herein, utilizing bed-to-bench approach coupled with in vitro, in vivo and ex vivo NB models, we investigated the role of RD3 reprogramming in the evolution of N-MYC-NA-NB. Assessing 15 different human derived stage-4 N-MYC-NA-NB cell lines demonstrated: transcriptional/translational loss of RD3 compared to neural crest cells; cell specific loss and; association of RD3 loss to cellular progressive disease, cellular therapy resistance and disease relapse. Further, in silico analysis demonstrated that RD3-loss was intrinsically associated with reduced OS and abridged relapse-free survival in N-MYC-NA-NB patient cohorts. We also demonstrated the complete loss of RD3 in metastatic site-derived aggressive cells (regardless of CSC status) ex vivo and in reproducible aggressive disease models in vivo. RD3-loss correlated with the heightened metastatic state (tumor cell migration, invasion and tumorosphere formation) of the N-MYC-NA-NB cells. Further, re-expressing RD3 in aggressive cells reverted their metastatic potential both in vitro and in vivo. These results demonstrate the loss of RD3 in high-risk N-MYC-NA-NB, its novel tumor evolution stabilization function and further imply that continuous ongoing acquisition of RD3-loss in therapy resistant cells may directly relate to tumor progression and poor clinical outcomes. Citation Format: Dinesh Babu Somasundaram, Karthikeyan Subramanian, Sheeja Aravindan, Terence Herman, Aravindan Natarajan. RD3 reprogramming in N-MYC non-amplified neuroblastoma evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4868. doi:10.1158/1538-7445.AM2017-4868
Impact of the PROCESS guideline on the reporting of surgical case series: A before and after study
Authors: R.A. Agha, M.R. Borrelli, R. Farwana, T. Kusu-Orkar, M.C. Millip, R. Thavayogan, J. Garner, N. Darhouse, D.P. Orgill
Journal: International Journal of Surgery (2017)
Emerging understanding of the mechanism of action of Bronchial Thermoplasty in asthma
Authors: J.N.S. d'Hooghe, N.H.T. ten Hacken, E.J.M. Weersink, P.J. Sterk, J.T. Annema, P.I. Bonta
Journal: Pharmacology & Therapeutics (2017)

Bronchial Thermoplasty (BT) is an endoscopic treatment for moderate-to-severe asthma patients who are uncontrolled despite optimal medical therapy. Effectiveness of BT has been demonstrated in several randomized clinical trials. However, the asthma phenotype that benefits most of this treatment is unclear, partly because the mechanism of action is incompletely understood. BT was designed to reduce the amount of airway smooth muscle (ASM), but additional direct and indirect effects on airway pathophysiology are expected. This review will provide an overview of the different components of airway pathophysiology including remodeling, with the ASM as the key player. Current concepts in the understanding of BT clinical effectiveness with a focus on its impact on airway remodeling will be reviewed.
Abstract 5632: Thyroid carcinoma in The Sudan
Authors: Mohamed ElMakki Ahmed
Journal: Cancer Research (2017)

Abstract Introduction: Goiter is endemic in Sudan and thyroidectomy is a daily practice in most surgical lists across the country. The most common indications are cosmoses and pressure with respiratory choking. In 10% of cases a surprise histopathology on cancer is reported . This study aims to report on thyroid carcinoma on patients presenting to the surgical department in Khartoum Teaching Hospital. Methods: This study is an overview on pattern, clinical presentation a management of thyroid carcinoma in Khartoum during the period 2007 - 2014. Thyroidectomy was the standard procedure when feasible and postoperative radio iodine given. External radiotherapy was given in aggressive anaplastic carcinoma. Results: 166 patients with thyroid cancer were studied. The mean age was 51 +/-SD 17yrs and the age range between 15 - 85 years. Male to female ratio was 1.0:2.4. Clinical presentation was a goiter that was showing a recent rapidly growth with either respiratory choking, pain and dysphagia. Follicular carcinoma was 43%,papillary 27%, anaplastic 10% 2%medullary. Sarcoma and lymphoma 5% and missing data in 13%. Six per cent of patients presented with lung and bone metastasis. 20 patients had long standing goiter before development of cancer. Different types of total thyroidectomy done in 81%, no surgery in 7% and missing data in 12%. 18 patients needed postoperative tracheostomy, 7 developed permanent hypocalcaemia, 15 recurrent nerve palsy and a 30 days mortality was 10% and all were anaplastic carcinoma where recurrence occurred within weeks following thyroidectomy or dublking in most cases. Conclusion: Patients with thyroid cancer presents late. The dominance of follicular type indicates the significance of underlying endemic goiter in its etiology. Anaplastic is very aggressive and lethal outcome. Citation Format: Mohamed ElMakki Ahmed. Thyroid carcinoma in The Sudan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5632. doi:10.1158/1538-7445.AM2017-5632
Abstract 2225: Green tea polyphenols suppress tumor growth and invasion by targeting matrix metalloproteinases, RECK and TIMP-3, in a mouse model implanted with prostate tumors
Authors: Eswar Shankar, Natarajan Bhaskaran, Rajnee Kanwal, Sanjay Gupta
Journal: Cancer Research (2017)

Abstract Green tea polyphenols (GTP) and its major constituent, epigallocatechin-3-gallate (EGCG) reactivate epigenetically silenced genes in cancer cells that reduces invasiveness and migration capabilities; however, the mechanisms whereby these effects occur are not well understood. RECK, a novel tumor suppressor and the tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) genes negatively regulates matrix metalloproteinases (MMPs) and inhibits tumor invasion, angiogenesis and metastasis. In the present study, we demonstrate that GTP mediate epigenetic induction of RECK and TIMP-3 thereby playing a key role in suppressing invasiveness and gelatinolytic activity of MMP-2 and MMP-9 in vivo in an orthotopic implantation model of human prostate cancer. Athymic nude mice were implanted with human prostate cancer LNCaP tumor in the ventral prostate for 2 weeks and later treated DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (AZA), histone deacetylase inhibitor, trichostatin A (TSA) and histone methyltransferase inhibitor, 3-Deazaneplanocin A (DZNep) individually at 0.1 mg/kg body weight intraperitoneally at alternate days/week; and combination of AZA+TSA and DZNep+TSA at similar doses and times; whereas GTP was provided peroral by gavage at 7.5 and 15.0 mg/kg body weight freshly prepared in 100µl PBS. Treatment of mice with GTP resulted in marked decrease in tumor growth and its local invasion in dose dependent manner, compared to treatment with epigenetic inhibitors and their combination after 8 weeks of intervention. GTP treatment significantly reduced serum levels of MMP-2, MMP-9 and VEGF, compared to treatment with epigenetic inhibitors alone. Combination of AZA+TSA exhibited similar effect which was equivalent to the lower dose of GTP treatment. Furthermore, GTP treatment significantly reduced EZH2 and H3K27me3 and class I HDAC protein levels in tumors. GTP partially reversed the hypermethylation status of RECK and TIMP3 gene and significantly enhanced their protein expression in the tumor tissue. Inhibition of VEGF, MMP-2 and MMP-9 levels were also noted after GTP treatment in tumor tissue in dose-dependent manner. Our findings suggest that induction of RECK and TIMP-3 are key epigenetic events modulated by GTP that results in suppression of matrix degradation and angiogenesis to delay prostate cancer invasion and its subsequent progression. Citation Format: Eswar Shankar, Natarajan Bhaskaran, Rajnee Kanwal, Sanjay Gupta. Green tea polyphenols suppress tumor growth and invasion by targeting matrix metalloproteinases, RECK and TIMP-3, in a mouse model implanted with prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2225. doi:10.1158/1538-7445.AM2017-2225