tbuckley/cabot-search huggingface dataset:
Host sirtuin 1 regulates mycobacterial immunopathogenesis and represents a therapeutic target against tuberculosis
Authors: Catherine Y. Cheng, Nuria M. Gutierrez, Mardiana B. Marzuki, Xiaohua Lu, Taylor W. Foreman, Bhairav Paleja, Bernett Lee, Akhila Balachander, Jinmiao Chen, Liana Tsenova, Natalia Kurepina, Karen W. W. Teng, Kim West, Smriti Mehra, Francesca Zolezzi, Michael Poidinger, Barry Kreiswirth, Deepak Kaushal, Hardy Kornfeld, Evan W. Newell, Amit Singhal
Journal: Science Immunology (2017)

Mycobacterium tuberculosis (Mtb) executes a plethora of immune-evasive mechanisms, which contribute to its pathogenesis, limited efficacy of current therapy, and the emergence of drug-resistant strains. This has led to resurgence in attempts to develop new therapeutic strategies/targets against tuberculosis (TB). We show that Mtb down-regulates sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, in monocytes/macrophages, TB animal models, and TB patients with active disease. Activation of SIRT1 reduced intracellular growth of drug-susceptible and drug-resistant strains of Mtb and induced phagosome-lysosome fusion and autophagy in a SIRT1-dependent manner. SIRT1 activation dampened Mtb-mediated persistent inflammatory responses via deacetylation of RelA/p65, leading to impaired binding of RelA/p65 on the promoter of inflammatory genes. In Mtb-infected mice, the use of SIRT1 activators ameliorated lung pathology, reduced chronic inflammation, and enhanced efficacy of anti-TB drug. Mass cytometry-based high-dimensional analysis revealed that SIRT1 activation mediated modulation of lung myeloid cells in Mtb-infected mice. Myeloid cell-specific SIRT1 knockout mice display increased inflammatory responses and susceptibility to Mtb infection. Collectively, these results provide a link between SIRT1 activation and TB pathogenesis and indicate a potential of SIRT1 activators in designing an effective and clinically relevant host-directed therapies for TB.
Studies of a novel modified E2F-targeted peptide with activity against castration-resistant prostate cancer.
Authors: Joseph R. Bertino, Zoltan Szekely, Kathleen W Scotto
Journal: Journal of Clinical Oncology (2017)

205 Background: The E2F family of genes encodes transcription factors that are key to the regulation of a number of target genes, including those encoding cyclins , CDKs , checkpoints regulators, and DNA repair and replication proteins. One of the primary functions of the E2Fs is to control the cell cycle, playing a major role in regulating the G1/S transition. One of the primary regulators of E2F expression is the retinoblastoma gene, RB, a chromatin associated protein that, in its unphosphorylated state, binds to and negatively regulates E2F; hyperphosphorylation of RB releases E2F, allowing cell cycle progression. Many tumor cells have mutant or dysfunctional RB, allowing the aberrant overexpression of the E2Fs and tumor cell proliferation; this aberrant overexpression is better tolerated when p53 is mutated, suppressing subsequent apoptosis. Overexpression of E2F, particularly E2F1, has thus been an attractive target for therapeutic intervention. However, this approach has not yet been successful, most likely due to the redundancy of the E2Fs and the lack of biomarkers for sensitivity. Methods: Using phage display, we have previously identified a novel peptide that, when coupled with penetratin (PEP) to enhance uptake), targets the E2F consensus site in E2F1,2 and 3a, leading to the downregulation of the activating E2Fs and their downstream targets. We have recently enhanced the stability and potency of this peptide by substituting L-Arg within the peptide with D-Arg. Results: Castrate resistant prostate cancer (CRPC) cells, DU-145, lack functional RB, have mutant p53, and are more sensitive to the D-Arg PEP than LnCap or PC-3 cells, with functional RB. Xenograft studies in mice show that the PEP, when encapsulated in PEGylated liposomes (PL-D-Arg PEP) , regresses DU-145 tumors without toxicity. Current studies are examining the combination of the (PL-D-Arg PEP) with taxotere, cisplatin and irradiation in prostate cancer xenografts and organoids from patients. Conclusions: A peptide that inhibits transcription of the activating E2Fs has promise to treat CRPC.
Evaluation of FDG-PET in pretreatment staging in locally advanced rectal cancer: A prospective study.
Authors: Jose G. Guillem, Jeannine Alberts Ruby, Tobias Leibold, Timothy J. Akhurst, Steven M. Larson, Marc Gollub, Michelle S. Ginsberg, Leonard Saltz
Journal: Journal of Clinical Oncology (2012)

3563 Background: The utility of adding 18 F-Fluorodeoxyglucose-Positron Emission Tomography (PET) to the pre-treatment staging of patients with locally advanced rectal cancer has not been well evaluated. Methods: Following completion of standard work-up, including physical examination, endorectal ultrasound, CT of the abdomen and pelvis, and chest CT or chest x-ray, 150 patients with primary, resectable, biopsy-proven rectal adenocarcinoma requiring neoadjuvant chemoradiation were enrolled in a prospective, single-stage, phase II study evaluating the role of PET. All patients underwent a dedicated whole-body PET prior to initiation of neoadjuvant chemoradiation. The primary endpoint of this analysis was to determine the accuracy of PET in detecting extrapelvic metastatic disease in primary rectal cancer patients considered operable on the basis of currently-standard work-up. Results: Among the 117 eligible patients found to be stage II or III by standard staging techniques, none (0%) were found by PET to have extrapelvic metastatic disease. PET yielded a false positive result in 3 patients (2.6%). PET yielded a false-negative result in 3 patients who were subsequently diagnosed with metastatic disease: 2 pre-operatively (liver, lung) and 1 intra-operatively (obturator lymph node). In 1 patient, PET did identify a previously unappreciated obturator lymph node metastasis; left pelvic sidewall dissection at the time of rectal resection confirmed metastatic adenocarcinoma in one obturator lymph node. Conclusions: Of the 117 rectal cancer patients evaluated and found to have locoregional disease by standard examination and imaging techniques, none had extrapelvic metastatic disease accurately identified by PET. PET did not improve the accuracy of pre-treatment staging. As such, consistent with current NCCN guidelines, PET does not have a role in pre-treatment staging of locally advanced rectal cancer.
The prognostic impact of combined NPM1+/FLT3- mutational status in newly diagnosed acute myeloid leukemia (AML) patients with intermediate risk cytogenetics according to age and treatment modality.
Authors: Mehrdad Hefazi, Mustaqeem Ahmad Siddiqui, Mrinal M. Patnaik, Alexandra P. Wolanskyj, Hassan Alkhateeb, Darci Zblewski, Michelle A. Elliott, William J. Hogan, Mark Robert Litzow, Aref Al-Kali
Journal: Journal of Clinical Oncology (2015)

7064 Background: Combined NPM1+/FLT3- is associated with a favorable prognosis in adults with AML, treated with standard chemotherapy. The impact of this on outcome is however not well defined according to age and different treatment modalities, including chemotherapy with or without hematopoietic cell transplantation (HCT), and hypomethylating agents (HMA). Methods: Out of 620 newly diagnosed AML pts treated between 2007 and 2014, 169 with intermediate risk cytogenetics and known NPM1/FLT3 were analyzed. Results: Estimated 3-yr overall survival (OS) according to age, NPM1/FLT3 status, and treatments are shown in the table. Among adults and elderly treated with chemotherapy alone, those with NPM1+/FLT3- had a superior OS compared to those without this mutational status (P=0.004 and 0.0008, respectively). Adults without NPM1+/FLT3- had a significantly improved OS when treated with HCT in addition to chemotherapy (P<0.0001), and a comparable OS to those with NPM1+/FLT3- (P=0.43), when treated with chemotherapy alone. Similarly, elderly without NPM1+/FLT3- had a superior OS when treated with chemotherapy followed by HCT (P=0.028), and a comparable OS to those with NPM1+/FLT3- (P=0.83), when treated with chemotherapy alone. Among elderly pts without NPM1+/FLT3-, those treated with HMA alone (n=12) had a similar OS to those treated with chemotherapy without HCT (P=0.86). Conclusions: Combined NPM1+/FLT3- is associated with a favorable prognosis, irrespective of age, in newly diagnosed AML pts with intermediate risk cytogenetics, treated with chemotherapy. In pts without NPM1+/FLT3-, the OS improves with the addition of HCT to standard chemotherapy, irrespective of age. HMA seems to be comparable to chemotherapy alone in elderly pts without NPM1+/FLT3-. Elderly (>60 yrs.) N=84* Adults (18-60 yrs.) N=85 Chemo alone N=51 Chemo + HCT N=12 Chemo alone N=37 Chemo + HCT N=48 NPM1+/FLT3- N=17 Otherwise N=34 NPM1+/ FLT3- N=1 Otherwise N=11 NPM1+/ FLT3- N=13 Otherwise N=24 NPM1+/ FLT3- N=5 Otherwise N=43 Estimated 3-yr OS 59% 20% - 40% 64% 16% - 51% P=0.005 P<0.0001 *Other treatments: N=21.
A phase II trial of gemcitabine(G), capecitabine (C), and bevacizumab (B) in patients (pts) with metastatic renal cell carcinoma (RCC)
Authors: E. K. Chung, E. M. Posadas, K. Kasza, T. Karrison, E. Manchen, L. Michalak, O. M. Hahn, W. M. Stadler
Journal: Journal of Clinical Oncology (2009)

e16072 Background: RCC is resistant to most traditional DNA and DNA repair targeted chemotherapy; although modest response rates to nucleotide analog based therapy, including GC, have been reported. Bevacizumab has activity in RCC. We thus performed a single center phase II trial of GCB in pts with metastatic RCC. Methods: Eligibility included clear cell or unclassified histologies, performance status 0–1, measurable disease, normal organ function and no prior treatment with VEGF binding agents or pyramidine analogs. Following significant hematotoxicity in the first 7 of 8 pts, chemotherapy was modified to G 1,000 mg/m2 (days 1, 8), C 1,000 mg po bid (days 1–14) and B 15 mg/kg (day 1) on a 21 day cycle with disease re-evaluation every 3 cycles. Primary endpoint was objective response rate (ORR) using a Bayesian continuous reassessment method designed to detect an improvement in the ORR from a 15% historical rate to 27%. Maximum planned enrollment = 55. Results: 30 pts enrolled from March 2005-May 2008 of which 29 were evaluable: 1 never treated. Pt characteristics: male 83%, median age 58 (36–82), prior nephrectomy 83%, prior radiation 52%, prior cytokine therapy 28%, prior VEGFR tyrosine kinase inhibitor 69%. MSKCC prognostic group: good 24%, intermediate 66%, poor 10%. 7 pts had a partial response (24%). Median overall and progression free survival were 9.8 mo (95%CI: 6.2, 14.9) and 5.3 mo (95%CI: 3.9, 9.9). Grade 3 or 4 toxicities: leucopenia 17%, neutropenia 31%, thrombocytopenia 7%, anemia 14%, proteinuria 3%, rash/hand foot syndrome 7%, fatigue 21%. Average change in mean arterial pressure after 2 cycles: 5.6 (p = 0.040). Serious adverse events: bowel perforation resulting in death 1 pt (3%), sepsis 1 pt (3%), PE/DVT 3 pts (10%), seizure 1 pt (3%). Conclusions: The trial was terminated early despite not meeting protocol criteria for success or futility due to slow accrual and the fact that the historical response rate on which the trial was based became irrelevant with emerging data using sequential VEGF pathway directed therapies. Nevertheless, the observed progression free and overall survival compare favorably to other phase II trials in this population. [Table: see text]
Phase II trial of PF-03084014 in adults with desmoid tumors/aggressive fibromatosis.
Authors: Shivaani Kummar, Khanh Tu Do, Geraldine Helen O'Sullivan Coyne, Baris Turkbey, Paul S. Meltzer, Eric Polley, Yvonne Horneffer, Lamin Juwara, Ramya Antony, Peter L. Choyke, Sandra A. Mitchell, Lee J. Helman, Alice Chen, James H. Doroshow
Journal: Journal of Clinical Oncology (2015)

10563 Background: Desmoids are rare, invasive, slow growing soft tissue tumors that are sporadic or associated with familial genetic syndromes, such as familial adenomatous polyposis. Desmoids are characterized by stabilization and abnormal nuclear localization of β-catenin. Mutations in the CTNNB1 gene are found in 85-90% of desmoids. Gamma-secretase cleaves intracellular Notch resulting in Notch signaling. PF-030844014 (PF) is an oral reversible γ-secretase inhibitor (GSI) that is well tolerated. Based on encouraging data from a phase I trial, we conducted a phase II study of PF in patients (pts) with symptomatic desmoid tumors progressing following at least one line of therapy. Objectives: determine the response rate (RR); assess symptom measures and perform genotyping for germline/somatic mutations in APC and CTNNB1 genes. Methods: PF was administered orally at 150mg BID; for 21 day cycles. Archival samples were sequenced for germline and somatic mutations in APC and CTNNB1genes. Dynamic contrast-enhanced MRI (DCE-MRI) was obtained at baseline and restaging. Single stage; 90% power to rule out unacceptably low RR of 10% in favor of 35% RR. The validated MD Anderson Symptom Inventory (MDASI) was used to assess symptoms. Results: Accrual completed. 13/17 pts (76.4%) remain on study; 4 pts stopped treatment by choice/co-morbid conditions. No pt has progressed to date. Median follow-up time is 10 months (range 2-14), 6 pts remain on study ≥ 1year. Grade 3 toxicities include hypophosphatemia (3 pts, 17.6%) and diarrhea (1 pt, 5.8%). Dose reduction to 100mg BID daily occurred in 2 pts. 16 pts (94%) have stable disease with 1 (5.8%) unconfirmed PR. In 15/17 pts (88.2%), a somatic or germ line mutation was identified. DCE-MRI and symptom scale analysis ongoing. Conclusions: PF is active at the selected dose, with a manageable side effect profile. Copy number analysis, transcriptome sequencing and DNA methylation analysis of archival samples as well as 2 paired biopsies obtained on study is ongoing. Clinical trial information: NCT01981551. % change in tumor measurements by MRI Pt p C 1 p C 6 p C 12 1010001 -3% -15% 1010002 -5% -25% -28% 1010003 -11% -25% -34% 1010005 -5% -3% -3% 1010006 -14% -15% -13% 1010007 0% -21% 1010009 3% -3% 6% 1010010 -7% 1010011 -12% -2% -16% 1010015 3% 3% 1010017 0% -12%
Enhanced ability of daniplestim and mpo-1 to suppress apoptosis and stimulate cytokine-inducible gene expression
Authors: James A. McCubrey, Oussama A. Saleh, Patrick M. Navolanic, Marianne L. Pearce, William L. Blalock, Linda S. Steelman, Carla J. Burrows, John T. Lee, Richard A. Franklin, Parul D. Doshi, John P. McKearn
Journal: Blood (2000)
Ovarian cancer stem cells: still an elusive entity?
Authors: Michela Lupia, Ugo Cavallaro
Journal: Molecular Cancer (2017)

The cancer stem cell (CSC) model proposes that tumor development and progression are fueled and sustained by undifferentiated cancer cells, endowed with self-renewal and tumor-initiating capacity. Ovarian carcinoma, based on its biological features and clinical evolution, appears as a prototypical example of CSC-driven disease. Indeed, ovarian cancer stem cells (OCSC) would account not only for the primary tumor growth, the peritoneal spread and the relapse, but also for the development of chemoresistance, thus having profound implication for the treatment of this deadly disease. In the last decade, an increasing body of experimental evidence has supported the existence of OCSC and their pathogenic role in the disease. Nevertheless, the identification of OCSC and the definition of their phenotypical and functional traits have proven quite challenging, mainly because of the heterogeneity of the disease and of the difficulties in establishing reliable biological models. A deeper understanding of OCSC pathobiology will shed light on the mechanisms that underlie the clinical behaviour of OC. In addition, it will favour the design of innovative treatment regimens that, on one hand, would counteract the resistance to conventional chemotherapy, and, on the other, would aim at the eradication of OC through the elimination of its CSC component.
Context-Specific KLF-1 Mediated Transcriptional Activation at the Alpha Hemoglobin-Stabilizing Protein and Dematin Promoters in Erythroid Cells.
Authors: Aurelie Desgardin, Valerie M. Jansen, Eun-Hee Shim, Tatiana Abramova, Shaji Ramachandran, Stephen Jane, John M Cunningham
Journal: Blood (2009)
Comparison of next-generation sequencing methodologies and direct sequencing for the detection of <i>EGFR</i> mutations in non-small-cell lung carcinoma: Implications for optimal clinical testing.
Authors: Hye Sook Kim, Yeul Hong Kim, Jae Sook Sung, Seung Tae Kim, Kyong Hwa Park, Jung Sun Kim, Yoon Ji Choi
Journal: Journal of Clinical Oncology (2013)

e22025 Background: The efficacy of next-generation sequencing (NGS) for the prediction of clinical benefits from EGFR TKIs in non small cell lung cancer(NSCLC) has yet to be fully established. The purpose of the present study was to evaluate the predictive effect of EGFR-evaluating methodologies on the use of EGFR TKIs in patients with NSCLC. Methods: cTumor samples were obtained from patients with NSCLC at 5 institutions in Korea. Study cohort A consisted of surgically resected or biopsy NSCLC samples enriched with adenocarcinoma histology. Study cohort B consisted of patients who received EGFR TKI during the treatment period. EGFR status was tested with direct sequencing, Peptide nucleic acid-locked nucleic acid PCR clamp (PNA-LNA PCR Clamp) method, and Personal genome machine (PGM) sequencing using the Ion AmpliSeq Cancer Panel on the Ion Torrent. Results: EGFR mutations in cohort A were identified in 16 (28.1%), 27 (47.4%), and 29 (50.9%) of 57 patients by direct sequencing, PNA-LNA clamping, and the Ion Torrent PGM, respectively. In 2 cases of EGFR mutant detected by Ion Torrento PGM in contrast to EGFR wild type by PNA-LNA clamping, EGFR mutation was found on novel sequence other than classical EGFR mutations. In total, 33 out of 37 patients in cohort B whose frozen NSCLC tissue was available were examined. Patients with EGFR mutations tested by PNA-LNA clamping did not show a significantly higher response rate than did patients with the wild-type EGFR (P=0.607). Mutational status detected by 2 methods did not significantly predict overall survival and progression free survival. However, curves showed a greater differentiation when the mutation was detected by PNA-LNA clamp as compared to mutations detected by direct sequencing. Conclusions: Though this study was conducted in a small number of cases, the results suggest that both PNA-LNA clamping and the Ion Torrent PGM are highly sensitive procedures relative to direct sequencing, and are useful screening tools for the detection of EGFR mutations in clinical practice.
Proteomic and metabolic signaling pathways in different prognosis of gastric cancer.
Authors: Guodong Lian, Daguang Wang, Chang Shu, Chengguo Wei, Fei Ye, David Y. Zhang, Jian Suo
Journal: Journal of Clinical Oncology (2014)

e15087 Background: Gastric cancer (GC) remains the fourth most common cancer and the second most common cause of cancer-related death worldwide. To tailor treatment regimens individually on the basis of patients’ chemosensitivity is a more effective strategy. Methods: After assessing the chemosensitivity status through survival time after surgery and adjuvant chemotherapy, 140 stage III (AJC) GC patients were split into two groups: chemosensitive (67 cases) and chemoresistant (73 cases). The differentially expressed proteins between those two groups were assessed using Protein Pathway Array (PPA). Data were analyzed by Significance Analysis of Microarrays (SAM) and BRB Array Tools software v.3.3.0. Ingenuity Pathway Analysis (IPA) was explored to further analysis the relevant signaling pathways. Results: Among 292 protein-specific or phosphorylation site-specific proteins tested, 147 were detected in cancer tissues. SAM analysis showed that 23 of these proteins/phosphorproteins had significant difference (q<5%) between chemosensitive and chemoresistant groups. We further carried out supervised K-fold cross validation (K=10) analysis using support vector machine (SVM), and 18 proteins (PLk1, FKHR, HDAC1, calpain 2, WT1, cdk4, β3 Tubulin, HMG-1, NMT1, Bcl-xL, V-ATPase H, tsg 101, calpastatin, P-cadherin, ADH, p-JNK, DACH1 and E-cadherin) were selected to separate gastric cancer of chemosensitive group from chemoresistant group with 94% correct rate, 94.8% sensitivity and 93% specificity. Six proteins (ERCC1, FKHR, PLK1, DACH1, E-Cadherin and ADH) were identified as independent predictors of chemoresistance. Using these 6 proteins, a risk score model was established to determine the risk of chemoresistance for each individual gastric cancer patient. Conclusions: Our current study indicated that some proteins differentially expressed in gastric cancer can be selected as clinically useful biomarkers. The risk score model is useful for determining patients’ risk of chemoresistance after radical surgery.
Bariatric Surgery and Risk for Perinatal Complications—Reply
Authors: Brodie Parent, Noel Weiss, Ali Rowhani-Rahbar
Journal: JAMA Surgery (2017)

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