tbuckley/cabot-search huggingface dataset:
Integrated genomic analysis of recurrence-associated small non-coding RNAs in oesophageal cancer
Authors: Hee-Jin Jang, Hyun-Sung Lee, Bryan M Burt, Geon Kook Lee, Kyong-Ah Yoon, Yun-Yong Park, Bo Hwa Sohn, Sang Bae Kim, Moon Soo Kim, Jong Mog Lee, Jungnam Joo, Sang Cheol Kim, Ju Sik Yun, Kook Joo Na, Yoon-La Choi, Jong-Lyul Park, Seon-Young Kim, Yong Sun Lee, Leng Han, Han Liang, Duncan Mak, Jared K Burks, Jae Ill Zo, David J Sugarbaker, Young Mog Shim, Ju-Seog Lee
Journal: Gut (2016)

<h3>Objective</h3> Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict. A better understanding of the biology of ESCC recurrence is needed to improve patient care. Our goal was to identify small non-coding RNAs (sncRNAs) that could predict the likelihood of recurrence after surgical resection and to uncover potential molecular mechanisms that dictate clinical heterogeneity. <h3>Design</h3> We developed a robust prediction model for recurrence based on the analysis of the expression profile data of sncRNAs from 108 fresh frozen ESCC specimens as a discovery set and assessment of the associations between sncRNAs and recurrence-free survival (RFS). We also evaluated the mechanistic and therapeutic implications of sncRNA obtained through integrated analysis from multiple datasets. <h3>Results</h3> We developed a risk assessment score (RAS) for recurrence with three sncRNAs (microRNA (miR)-223, miR-1269a and nc886) whose expression was significantly associated with RFS in the discovery cohort (n=108). RAS was validated in an independent cohort of 512 patients. In multivariable analysis, RAS was an independent predictor of recurrence (HR, 2.27; 95% CI, 1.26 to 4.09; p=0<i>.</i>007). This signature implies the expression of ΔNp63 and multiple alterations of driver genes like PIK3CA. We suggested therapeutic potentials of immune checkpoint inhibitors in low-risk patients, and Polo-like kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase inhibitors in high-risk patients. <h3>Conclusion</h3> We developed an easy-to-use prognostic model with three sncRNAs as robust prognostic markers for postoperative recurrence of ESCC. We anticipate that such a stratified and systematic, tumour-specific biological approach will potentially contribute to significant improvement in ESCC treatment.
Correlation of DNA damage response (DDR) gene alterations with response to neoadjuvant (neo) dose-dense gemcitabine and cisplatin (ddGC) in urothelial carcinoma (UC).
Authors: Gopa Iyer, Arjun Vasant Balar, Matthew I. Milowsky, William C. Huang, Michael Woods, S. Machele Donat, Harry W. Herr, Guido Dalbagni, Bernard H. Bochner, Irina Ostrovnaya, Hikmat Al-Ahmadie, Tracy Lynn Rose, Jamie Cathleen Riches, Brooke Elizabeth Kania, Mariel Elena Boyd, Ashley Marie Regazzi, Asia S. McCoy, Anthony Drier, Jonathan E. Rosenberg, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2016)

5011 Background: Individual DDR genetic alterations have been reported to be predictive for neo chemotherapy response in UC. We sought to identify whether alterations in a DDR gene set correlate with response in UC patients (pts) enrolled onto a phase II study of neo ddGC. Methods: This trial evaluated 46 pts treated with 6 cycles of ddGC (Balar et al, GU ASCO 2016). 63% of pts undergoing cystectomy achieved pathological response defined as ≤ pT1. Exon capture sequencing (MSK-IMPACT) of 341 to 410 genes was performed on pre-treatment transurethral resection specimens and matched germline DNA on 24/46 pts. Fourteen of these 24 pts were responders to ddGC. Only deleterious alterations (truncating or functionally validated) in a pre-defined DDR gene set (Table 1) were considered when comparing responders vs non-responders. Results: The median number of somatic mutations (muts) per sample was 10 (range, 0-36) with an average coverage of 550X. The most frequently altered DDR genes were BRCA2 and ATR (12% each). Eleven samples (46%) harbored at least one DDR gene alteration (4 had 3 alterations, 1 had 2, and 6 had 1). The median number of DDR alterations in responders vs non-responders was similar (1 vs 2); however, 5 of 14 responders had deleterious DDR alterations vs 0 of 10 non-responders (p = 0.053). These included 4 nonsense muts, one each in BRCA2, ATR, ERCC5, and RECQL4, and one ERCC2 N238S point mut. This preponderance of deleterious DDR alterations in responders was similar to that observed in a previously published cohort (13 alterations in responders vs 4 in non-responders, p = 0.016) (Van Allen et al, Cancer Discovery 2014). Conclusions: Lack of deleterious DDR alterations in non-responders in this study is biologically plausible and worthy of further study. Sequencing of the remaining pts on this trial is ongoing to characterize the positive and negative values for this DDR gene set in this patient cohort. Clinical trial information: NCT01589094.DDR gene set. ATM CHEK2 MLH1 PMS1 RAD51D ATR ERCC2 MRE11A PMS2 RAD52 BARD1 ERCC3 MSH2 POLD1 RAD54L BLM ERCC4 MSH6 POLE RECQL4 BRCA1 ERCC5 MUTYH RAD50 XRCC2 BRCA2 FANCA NBN RAD51 BRIP1 FANCC PALB2 RAD51B CHEK1 MDC1 PARP1 RAD51C
Application of quality by design in the current drug development
Authors: Lan Zhang, Shirui Mao
Journal: Asian Journal of Pharmaceutical Sciences (2016)

Quality by Test was the only way to guarantee quality of drug products before FDA launched current Good Manufacturing Practice. To clearly understand the manufacture processes, FDA generalized Quality by Design (QbD) in the field of pharmacy, which is based on the thorough understanding of how materials and process parameters affect the quality profile of final products. The application of QbD in drug formulation and process design is based on a good understanding of the sources of variability and the manufacture process. In this paper, the basic knowledge of QbD, the elements of QbD, steps and tools for QbD implementation in pharmaceutics field, including risk assessment, design of experiment, and process analytical technology (PAT), are introduced briefly. Moreover, the concrete applications of QbD in various pharmaceutical related unit operations are summarized and presented.
Abstract 5184: MiXeno Humanized Mouse Model as an Efficient Tool to Evaluate in Vivo Activity of Anti-Cancer Immunotherapeutics
Authors: Juan Zhang, Meng Qiao, Jian Ding, Zhensheng Wang, zhongliang Li, Qian Shi
Journal: Cancer Research (2016)

Abstract Background: Fighting cancer by taking advantage of a patient's own immune system is showing considerable success in oncology research. Targeting therapeutic antibodies against tumor-associated antigens or the host immune system has been shown to prolong survival of patients in various tumor types. However, the lack of experimental immunotherapy models is a major obstacle toward better evaluating new immunotherapeutics and testing their exploratory combination strategies. To address this need, we set out to validate a new platform MiXenoTM by implanting human PBMC to immune-deficient mice. The MiXenoTM mice were partially reconstituted with human immune components. In vivo efficacy of several immunotherapeutics were evaluated. Results: We have reported before that several MiXenoTM models could be used to evaluate anti-human PD-1 or PD-L1 antibodies, where human T cells were well reconstituted in the mouse system. Here one of our MiXenoTM collection: HCC827 model was further optimized and identified as a PD-1/PD-L1 inhibitor highly sensitive model. Involvement of T cells in the tumor microenvironment was observed in HCC827 tumors. Furthermore, the dynamics of NK cell population in blood, tumor and other organs (e.g. spleen and lymph nodes) was established in MiXenoTM models. NK cell function was evaluated as well. Conclusion: The MiXenoTM model provides an alternative to the full stem cell reconstitution approach, and may allow various types of immunotherapies being evaluated in these partially humanized xenograft models. Citation Format: Juan Zhang, Meng Qiao, Jian Ding, Zhensheng Wang, zhongliang Li, Qian Shi. MiXeno Humanized Mouse Model as an Efficient Tool to Evaluate in Vivo Activity of Anti-Cancer Immunotherapeutics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5184.
First identified case of VIM-producing carbapenem-resistant Klebsiella pneumoniae in the Republic of Ireland associated with fatal outcome
Authors: A R Prior, C Roche, M Lynch, S Kelly, K O’Rourke, B Crowley
Journal: Eurosurveillance (2010)

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Abstract 1152: MUC1: A metabolic regulator in triple-negative breast cancer
Authors: Gennifer D. Goode, Nina Chaika, Vinee Purohit, Venugopal Gunda, Pankaj Singh
Journal: Cancer Research (2016)

Abstract Breast cancer, the second leading cause of cancer deaths in women, is the most common cancer among North American women, accounting for nearly 1 in 3 cancer cases diagnosed in the U.S. women. Triple negative breast cancer (TNBC) subtype accounts for approximately 15-25% of all breast cancer cases and has an increased incidence of metastasis, high recurrence within 1-3 years and a high mortality rate. Therefore, identifying factors that facilitate tumor growth and metastases have the potential to serve as novel molecular targets for breast cancer therapy. Mucin1 (MUC1), a glycoprotein associated with chemoresistance, is aberrantly overexpressed in TNBC and facilitates growth and metastasis of TNBC cells. This occurrence can be partially attributed to MUC1 interaction with hypoxia-inducible factor alpha (HIF1α), a key regulator of glycolysis. As metastasis is the leading cause of cancer related deaths, this process relies on the ability of tumor cells to adapt to the changing nutrient levels in the surrounding stroma. In the present study we examined how signaling through MUC1 facilitates metabolic phenotype in TNBC; thus facilitating tumor growth and metastasis. Our results indicate that MUC1 expression facilitates glucose and glutamine uptake in a panel of TNBC cell lines. Furthermore, metabolomic analysis through liquid chromatography-coupled tandem mass spectrometry approach revealed that MUC1 expression modulates metabolite levels in glycolysis, pentose phosphate pathway and TCA cycle in TNBC cells. Thus, our results support the notion that MUC1 serves as a metabolic regulator in TNBC, facilitating metabolic reprogramming that influences growth of TNBC. Citation Format: Gennifer D. Goode, Nina Chaika, Vinee Purohit, Venugopal Gunda, Pankaj Singh. MUC1: A metabolic regulator in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1152.
Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial
Authors: Eric P Moll van Charante, Edo Richard, Lisa S Eurelings, Jan-Willem van Dalen, Suzanne A Ligthart, Emma F van Bussel, Marieke P Hoevenaar-Blom, Marinus Vermeulen, Willem A van Gool
Journal: The Lancet (2016)
Idiopathic Pulmonary Hemosiderosis
Authors: F M Pedersen, N Milman
Journal: New England Journal of Medicine (2023)

Idiopathic pulmonary haemosiderosis (IPH) is a rare disease characterized by recurrent episodes of intrapulmonary bleeding, chronic iron deficiency anaemia and pulmonary fibrosis. IPH is a diagnosis made by exclusion of other causes. It occurs in both adults and children. Other conditions than IPH can cause pulmonary haemosiderosis. The etiology is unknown, but might be an immunological mechanism causing a defect in the basement membrane of the pulmonary capillary. IPH should be suspected in patients with recurrent episodes of coughing, haemoptysis, dyspnoea and anaemia. Chest X-ray shows pulmonary infiltrates during an acute attack. Examination of sputum or lung biopsy discloses large numbers of haemosiderin-laden pulmonary macrophages. The mortality-rate is high, but the prognosis is difficult to evaluate because many patients survive for a long time either with a course of recurrent attacks or with chronic symptoms, such as dyspnoea and persistent anaemia. Steroids may improve the condition of the patient during a bleeding episode.
Abstract 4480: Blood epigenetic age may predict cancer incidence and mortality
Authors: Yinan Zheng, Brian T. Joyce, Elena Colicino, Lei Liu, Wei Zhang, Qi Dai, Martha J. Shrubsole, Warren A. Kibbe, Tao Gao, Zhou Zhang, Nadereh Jafari, Joel Schwartz, Andrea A. Baccarelli, Lifang Hou
Journal: Cancer Research (2016)

Abstract Biological measures of aging are important for understanding age-related cancers as the population ages. Since the epigenome is closely related to aging, epigenetics may help predict these and other age-related diseases. We aimed to prospectively examine whether blood Δage (the discrepancy between epigenetic and chronological age) can predict cancer incidence/mortality. In a prospective cohort (the Normative Aging Study), Δage and its rate of change over time were calculated using Illumina Human Methylation 450K array data in 834 blood leukocyte samples longitudinally collected from 442 participants free of cancer at the blood draw. About 3-5 years before cancer onset or death, Δage was associated with cancer risks in a dose-responsive manner (test for trend P = 0.02) and time-dependent Cox models showed a one-year increase in Δage was associated with all-cancer incidence (HR (hazard ratio): 1.06, 95% CI: 1.02-1.10) and mortality (HR: 1.17, 95% CI: 1.07-1.28). Participants with smaller Δage and decelerated epigenetic aging over time had the lowest risks of cancer incidence (log-rank P = 0.003) and mortality (log-rank P = 0.02). Spline analysis suggested Δage was associated with cancer incidence in a ‘J-shaped’ manner, and with cancer mortality in a time-varying manner. We conclude that blood epigenetic age may mirror epigenetic abnormalities related to cancer early development or the immune response to it. Those with older epigenetic age relative to their chronological age have an elevated risk of cancer events within 3-5 years. Thus, epigenetic age could potentially serve as a novel, minimally invasive biomarker for cancer prediction. Citation Format: Yinan Zheng, Brian T. Joyce, Elena Colicino, Lei Liu, Wei Zhang, Qi Dai, Martha J. Shrubsole, Warren A. Kibbe, Tao Gao, Zhou Zhang, Nadereh Jafari, Joel Schwartz, Andrea A. Baccarelli, Lifang Hou. Blood epigenetic age may predict cancer incidence and mortality. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4480.
Mycophenolate Mofitil (MMF) As Salvage Graft-Versus-Host Diseases (GVHD) Prophylaxis In Allogeneic Hematopoietic Stem Cell Transplantation (HCT) After Early Discontinuation Of Tacrolimus and/Or Sirolimus Due To Toxicities
Authors: Joycelynne Palmer, Zeynep Eroglu, Tracey Stiller, Sandra H. Thomas, Mbbch Samer Khaled, Sepideh Shayani, Pablo Parker, Stephen J. Forman, Ryotaro Nakamura
Journal: Blood (2013)
Abstract 2719: ADA3, a cell cycle regulator, regulates chromosome segregation
Authors: Shashank Srivastava, Shakur Mohibi, June Wang-France, Sameer Mirza, Xiangshan Zhao, Hamid Band, Vimla Bnad
Journal: Cancer Research (2016)

Abstract The RNA polymerase II mediated transcription requires the higher degree structure of chromatin to be relieved so that general transcription machinery can access the DNA. The acetylation of DNA bound histones at specific loci is the major epigenetic modification by which opening of chromatin is achieved. HATs (Histone Acetyl Transferase) are the enzymes that catalyze the acetylation of histones and require association with mediator proteins for their function. One such mediator protein is ADA3 (Alteration/Deficiency in Activation 3), which was initially discovered as a component of multi-protein complex that contains either GCN5 (General Control Non-repressed 5) or PCAF (p300/CBP Associated Factor) as HAT and subsequent studies showed that ADA3 associates with another HAT, p300. As a HAT interacting protein, ADA3 enhances the acetylation of histones as well as non-histone proteins, such as p53. We have recently shown that ADA3 is a cell cycle regulatory protein and is important for both G1 to S phase transition as well as mitosis. Conditional deletion of Ada3 from Ada3FL/FL MEFs (Mouse Embryonic Fibroblasts) causes cell cycle arrest and severe mitotic defects. To further explore the mechanism of ADA3 mediated mitosis, we performed ChIP-seq analyses and found that ADA3 bound to higher order repeat region of the centromere across most of the chromosomes. Further studies showed ADA3 interaction with centromere was mediated by a centromeric protein CENP-B. More importantly, siRNA mediated knockdown of ADA3 decreases the occupancy of CENP-B at centromere and causes chromosomal segregation defects during mitosis. These studies demonstrate a novel function of ADA3 in cell cycle regulation. Our current studies are focused on defining the exact mechanism of recruitment of ADA3 complex to CENP-B to regulate mitosis and its effect on genomic stability. Citation Format: Shashank Srivastava, Shakur Mohibi, June Wang-France, Sameer Mirza, Xiangshan Zhao, Hamid Band, Vimla Bnad. ADA3, a cell cycle regulator, regulates chromosome segregation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2719.
An open label, multicenter clinical study of cetuximab combined with concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: Preliminary results of a phase II trial.
Authors: J. M. Yu, J. H. Wang, X. Sun, L. H. Wang, G. Y. Zhu, P. B. Feng, M. Ye, Y. Lu, S. C. Zhu, Z. X. Liao
Journal: Journal of Clinical Oncology (2010)

e14520 Background: In China, more than 95% of esophageal malignancies are squamous cell carcinoma (ESCC). We hypothesized that cetuximab would be efficacious for ESCC when given together with concurrent chemoradiation. We conducted a multicenter, phase II study to investigate the safety and efficacy of cetuximab combined with concurrent chemoradiotherapy for patients with locally advanced ESCC. Methods: Patients aged 18-70 years with stage II-III cervical, upper thoracic and midthoracic locally advanced nonresectable ESCC, ECOG performance status (PS) ≤ 1 were recruited to received cetuximab (400 mg/m2 on day1 before chemo-radiotherapy and then q1w×7 weeks) plus paclitaxel (45 mg/m2 q1w×7 weeks) and cisplatin (20 mg/m2 q1w×7 weeks). Radiotherapy consisted of 59.4 Gy in 33 fractions in 7 weeks. The primary endpoint was overall response rate and secondary endpoints included time to disease progression, overall survival at 1 year and 3 year, toxicity and K-ras status. Planned accrual was 44 patients. Results: Preliminary data are available for 39 patients, including 31 male and 8 female. Median age was 58 years old. 32 of all included patients finished the planned treatment. The overall response rate was 93.8% (complete response, n = 15; partial response, n = 15). Stable disease was observed in 1 patient, and 1 patient has not been evaluated. The most relevant NCI-CTC grade 3 hematologic events were neutropenia (12.8%), febrile neutropenia (5.1%), and anemia (2.5%). Major nonhematologic toxicities were acneiform skin eruptions (≥ grade 2 in 17.9% of patients) and dermatitis (64.1%). The acneiform skin eruptions mainly started at the third week of cetuximab treatment. At the fourth week of radiotherapy, 15.3% and 25.6% of the patients began to suffer from grade 1-2 dermatitis and mucositis, respectively. No grade 4 adverse event was observed. The K-ras status of all patients was wild-type genetype. Conclusions: The combined treatment modality of cetuximab plus concurrent chemoradiotherapy in locally advanced ESCC in China were well tolerated and resulted in promising response rates and a predictable toxicity profile. No significant financial relationships to disclose.
Abstract B37: RNAi and CRISPR/Cas9-based in vivo models for drug discovery
Authors: Prem K. Premsrirut, Chia-Lin Wang, Yu-ting Yang, Rafii Pelossof, Christina Leslie, Christof Fellmann, Lukas Dow, Johannes Zuber, Scott Lowe
Journal: Cancer Research (2018)

Abstract With the advent of RNAi and more recently CRISPR/Cas9 technologies, the speed and precision by which genetically engineered mouse models of cancer can be created is unprecedented. Having previously engineered a miRE scaffold for enhanced shRNA processing and now with the introduction of a powerful new SplashRNA algorithm for accurate shRNA prediction, we have brought RNAi technology to its peak by increasing potency and reducing off-target effects, such that it can be effectively exploited to preclinically mimic drug therapy and even combination therapy not only in vitro but also in live mice. Here, we take advantage of Cas9-expressing mice and demonstrate that in situ delivery of sgRNAs can lead to somatic mutagenesis to promote rapid tumorigenesis in mice. By combining this approach with inducible and reversible RNAi-mediated gene silencing to mimic drug therapy in the same mice, we now have an advanced platform to perform target validation and toxicity assessment of novel candidate targets in vivo. Here, we showcase how synergizing our RNAi and CRISPR/Cas9 genetic toolbox will help facilitate cancer drug discovery research and increase our confidence in predicting drug responses in humans into a new era. Citation Format: Prem K. Premsrirut, Chia-Lin Wang, Yu-ting Yang, Rafii Pelossof, Christina Leslie, Christof Fellmann, Lukas Dow, Johannes Zuber, Scott Lowe. RNAi and CRISPR/Cas9-based in vivo models for drug discovery [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B37.