tbuckley/cabot-search huggingface dataset:
Expression of kruppel-like factor 5 mediates anchorage-independent growth and good prognosis in human lung cancer.
Authors: Jason Hasenstein, Avinash Baktula, Huajing Wan, Jeffrey Whitsett, Blake Gilks, H. Leighton Grimes
Journal: Cancer Research (2008)

84   Ras mutations have been identified in human lung adenocarcinoma; however, attempts to clinically target mutant Ras have encountered significant problems. The Ras/Erk pathway is responsible for much of the oncogenicty of the Ras oncoproteins, providing rationale for the analysis of Ras/Erk downstream signaling targets such as the transcription factor Kruppel-like Factor 5 (KLF5). The Ras/Erk pathway mediates the expression of KLF5. KLF5 may facilitate cell entry into the S phase of the cell cycle, and may regulate downstream mediators of Ras function in cell proliferation such as cyclin D1; however, KLF5 may also act in a tumor suppressive manner. We have generated a KLF5 specific antisera, and have determined that KLF5 is expressed in several mouse lung tumor models which stimulate Ras signaling. Moreover, we have applied this reagent to a tissue array of primary human lung cancer biopsies and found that patients with tumors expressing high levels of KLF5 have significantly better prognosis than those without KLF5 expression. To understand the molecular basis of this observation we overexpressed KLF5 in Ras-mutant human lung adenocarcinoma cell lines. In comparison to empty vector controls, growth rates of KLF5 overexpressing cells increased after (but not before) cultures became confluent. In contrast, knockdown of KLF5 expression limited growth. Moreover, soft agar assays showed a significant reduction in colony formation of KLF5 knockdown cells. These findings indicate that the KLF5 transcription factor may mediate anchorage independent growth in human lung cancer cells. Interestingly, anchorage independent growth is one function mutant Ras signaling. Gene expression analyses reveal that the putative KLF5 target gene cyclin D1 is deregulated upon manipulation of KLF5 in human lung adenocarcinoma cell lines. In mice, conditional deletion of Klf5 in the lung dramatically ablates cyclin D1 expression, but only in a subset of cells. These data provide the first validation of a Klf5 target gene in primary lung cells, and the first indication of the prognostic value of KLF5 expression in human lung cancer.
Predictive role of [18F]FDG-PET early evaluation in patients (pts) undergoing preoperative chemotherapy (PCT) for breast cancer (BC).
Authors: A. Martoni, C. Zamagni, S. Quercia, M. Rosati, N. Cacciari, A. Bernardi, M. Castellucci, D. Santini, M. Taffurelli
Journal: Journal of Clinical Oncology (2010)

635 Background: Pathologic complete response (pCR) and minimal residual disease (pMRD) after PCT for BC correlate with a good prognosis. Early identification of pts who will achieve pCR/pMRD or who will not, could change the therapeutic strategy. The role of [18F]FDG PET in the prediction of pathological response in this clinical setting remains unclear. Methods: Pts with newly diagnosed early and locally advanced BC were submitted to 6-8 cycles of anthracycline and taxane-based PCT and there after operated. Pathological response was assessed according to Miller and Payne's classification. Pts with pCR or pMRD in the tumour and absence of cancer cells in ipsilateral axillary nodes were defined as having obtained an optimal pathological response (pR), while all the other conditions were classified as pathological nonresponse (pNR). [18F]FDG-PET/CT scan was included in the baseline work-up and repeated after 2 cycles of chemotherapy. Maximal standardized uptake value (SUVmax) was measured at the breast tumor and at the ipsilateral axilla and its percentage change (Δ-SUV) after 2 cycles was compared with the pathological response. Results: Out of forty-one pts, 10 (24%) achieved pR (5 pCR and 5 pMRD). With Δ- SUV reduction cut off of 50% sensitivity, specificity, negative predictive value and positive predictive value in order to identify pR were 100%, 26%, 100% and 30%, respectively. Thirty-three pts (80%) presented Δ-SUV reduction > 50% including all 10 pts with pR and 23 pts with pNR. On the contrary, all 8 pts with Δ-SUV reduction ≤ 50% presented pNR. All these 8 pts had ER+ tumors. Hence, out of a total of 24 pts with ER+ tumors, one third was correctly identify early as pNR. Conclusions: After 2 cycles of PCT, [18F]FDG-PET has a too high rate of false positive results to be recommended as standard predictor of pR. However, it could have a role in early identification of pts with ER+ tumours not candidate to obtain optimal pathologic response. No significant financial relationships to disclose.
Phase II Weekly Vinblastine for Chemotherapy-Naïve Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study
Authors: Alvaro Lassaletta, Katrin Scheinemann, Shayna M. Zelcer, Juliette Hukin, Beverley A. Wilson, Nada Jabado, Anne Sophie Carret, Lucie Lafay-Cousin, Valerie Larouche, Cynthia E. Hawkins, Gregory Russell Pond, Ken Poskitt, Daniel Keene, Donna L. Johnston, David D. Eisenstat, Rahul Krishnatry, Matthew Mistry, Anthony Arnoldo, Vijay Ramaswamy, Annie Huang, Ute Bartels, Uri Tabori, Eric Bouffet
Journal: Journal of Clinical Oncology (2016)

Purpose Vinblastine monotherapy has shown promising activity and a low-toxicity profile in patients with pediatric low-grade glioma (PLGG) who experienced treatment failure after initial treatment with chemotherapy and/or radiation. The aim of this study was to assess the activity of vinblastine in therapy-naïve children. Patients and Methods Patients &lt; 18 years old with unresectable and/or progressive therapy-naïve PLGG were eligible. Vinblastine was administered once per week at a dose of 6 mg/m 2 intravenously over a period of 70 weeks. Vision, quality of life, neurofibromatosis type 1 (NF1) status, and BRAF mutation/fusion status were also determined and correlated with outcome. Results Fifty-four patients were enrolled onto the study, with a median age of 8 years (range, 0.7 to 17.2 years). Most patients had chiasmatic/hypothalamic tumors (55.5%), and 13 patients (24.1%) had NF1. The most common histology was pilocytic astrocytoma (46.3%). Seventeen patients were diagnosed using radiologic criteria alone. Best response to chemotherapy was centrally reviewed with a response rate (complete, partial, or minor response) of 25.9%. Disease stabilization (complete, partial, or minor response or stable disease) was achieved in 47 patients (87.0%). Visual improvement was observed in 20% of patients with optic pathway glioma. Five-year overall survival and progression-free survival (PFS) rates were 94.4% (95% CI, 88.5% to 100%) and 53.2% (95% CI, 41.3% to 68.5%), respectively, for the entire cohort. Patients with NF1 had a significantly better PFS (85.1%; 95% CI, 68.0% to 100%) when compared with patients without NF1 (42.0%; 95% CI, 29.1% to 60.7%; P = .012). Age&lt; 3 years or &gt; 10 years was not associated with poor outcome. Treatment was well tolerated, and quality of life was not affected during treatment. In this trial, there was no correlation between BRAF alterations and outcome. Conclusion Vinblastine administered once per week is well tolerated in children with treatment naïve PLGG. Overall survival and PFS are comparable to current therapies, with a favorable toxicity profile and a maintained quality of life.
Early Improvement in Work Productivity Predicts Future Clinical Course in Depressed Outpatients: Findings From the CO-MED Trial
Authors: Manish K. Jha, Abu Minhajuddin, Tracy L. Greer, Thomas Carmody, A. John Rush, Madhukar H. Trivedi
Journal: American Journal of Psychiatry (2016)

Depression symptom severity, the most commonly studied outcome in antidepressant treatment trials, accounts for only a small portion of burden related to major depression. While lost work productivity is the biggest contributor to depression's economic burden, few studies have systematically evaluated the independent effect of treatment on work productivity and the relationship between changes in work productivity and longer-term clinical course.
A Crispr/Cas9 Drop-out Screen Identifies Genome-Wide Genetic Valnerubilities in Acute Myeloid Leukaemia
Authors: Konstantinos Tzelepis, Hiroko Koike-Yusa, Etienne De Braekeleer, Yilong Li, Emmanouil Metzakopian, Oliver M. Dovey, Annalisa Mupo, Vera Grinkevich, Milena M. Mazan, Malgorzata Gozdecka, Jonathan L. Cooper, Miten Patel, Thomas David Hardman McKerrell, Bin Chen, Hannes Ponstingl, Brian J.P Huntly, Ultan McDermott, Julio Saez-Rodriguez, Francesco Iorio, Kosuke Yusa, George S. Vassiliou
Journal: Blood (2015)
Primary Biliary Cholangitis — A New Name and a New Treatment
Authors: Daniel S. Pratt
Journal: New England Journal of Medicine (2016)

Primary biliary cholangitis, previously called primary biliary cirrhosis, is a cholestatic autoimmune liver disease that is marked by the progressive lymphocytic destruction of the smallest intralobular bile ducts.1,2 In the absence of effective therapy, it progresses inexorably to cirrhosis and liver failure.Ursodiol, a hydrophilic bile acid with an excellent safety profile, was approved by the Food and Drug Administration (FDA) in 1988 for the dissolution of gallstones. On the basis of early promising data in the management of primary biliary cholangitis and the unmet clinical need, the FDA granted ursodiol orphan status in 1991 for the management of . . .
Clinical Features and Treatment Response of Light Chain (AL) Amyloidosis Diagnosed in Patients with Previous Diagnosis of Multiple Myeloma (MM).
Authors: Sumit Madan, Angela Dispenzieri, Martha Q. Lacy, Francis Buadi, Suzanne R. Hayman, Kristin Detweiler, Steven R. Zeldenrust, David Dingli, Philip R Greipp, Stephen J. Russell, John A. Lust, Robert A Kyle, S. Vincent Rajkumar, Morie A Gertz, Shaji K Kumar
Journal: Blood (2009)
P-149 Changes of quality of life in elderly gastrointestinal cancer patients after curative surgery in South Korea.
Authors: D.R. Choi, B. Han, J.H. Kim, H.S. Kim, G. Jang, J.H. Kwon, H.Y. Kim, H.J. Kim, J.Y. Jung, H.J. Kim, I. Nam, H. Yoon, H.-S. Bae, Y.-S. Park, H.W. Lee, S.Y. Kang, J.W. Cho, H.H. Song, D.Y. Zang
Journal: Annals of Oncology (2015)
The many faces of interleukin-17 in inflammatory skin diseases
Authors: R. Speeckaert, J. Lambert, L. Grine, M. Van Gele, S. De Schepper, N. van Geel
Journal: British Journal of Dermatology (2016)

Interleukin (IL)‐17 is an emerging target for inflammatory skin disorders. Given the remarkable success of its therapeutic inhibition in psoriasis, the pathogenic role of this cytokine is being explored in other immune‐mediated diseases. Interestingly, IL‐17 is linked to particular skin conditions where its activation coincides with disease flares. The leading hypothesis for its contribution to proinflammatory signalling cascades is driving inflammasome activation. However, IL‐17 stimulation also releases a range of noninflammasome‐related cytokines from human skin. Furthermore, a role in cytotoxic responses and an important interplay with the microbiome is hypothesized. While treatment failure would be surprising in neutrophilic dermatoses, the picture might be more complex in lymphocyte‐mediated conditions. Nonetheless, increasing insights into the pathogenesis suggest that beneficial responses are also probable in the latter conditions. Study of this pathway in the skin reveals some intriguing aspects of the IL‐17‐related immunological network.
Physician associates—what do they do?
Authors: Abi Rimmer
Journal: BMJ (2016)

Abi Rimmer looks at the roles carried out by this new breed of healthcare worker

Physician associate roles have been proposed as a way of filling workforce gaps and freeing doctors’ time. But doctors themselves have raised concerns about the scope of physician associates’ practice, their length of training, and the possibility that their training will encroach on that of junior doctors.

The first UK trained physician associates graduated from the University of Birmingham in 2009. Health Education England announced in 2014 that it would create a further 205 posts to support emergency medicine and primary care.1 The next year, the National Physician Associate Expansion Programme (npaep.com) was launched in England, seeking to employ 200 physician associates to work in the NHS for one to two years.

Currently 27 UK universities offer postgraduate training for physician associates, with further courses in the process of development. Most require at least a 2:1 honours degree for entry into the postgraduate diploma course, as well as some prior health or social care experience.

Alison Carr is director of postgraduate studies at Plymouth University Peninsula …
Phase II study of gemcitabine/vinorelbine (GV) as first or second line chemotherapy in patients with metastatic soft tissue sarcoma (STS)
Authors: J. A. Morgan, S. George, J. Desai, M. St. Amand, D. Horton, E. Wilkins, J. Manola, G. D. Demetri
Journal: Journal of Clinical Oncology (2004)

9009 Background: Both single agent gemcitabine and vinorelbine have efficacy for treatment of STS. Combination GV is active therapy for metastatic carcinoma, with acceptable toxicity. This single institution phase II trial has been undertaken to determine response rates and toxicity of combination GV for treatment of metastatic STS. Methods: Pts with PS 0–2, unresectable or metastatic STS, adequate end organ function, and no more than 1 prior regimen were eligible. Gemcitabine at 800mg/m2 was infused over 90 minutes on days 1 and 8 of a 21 day cycle, following vinorelbine at 25mg/m2. Pts with grade 3 or 4 toxicity were subsequently treated at the same doses on days 1 and 15 of a 28 day cycle. Results: An initial 18 pts have been accrued, following standard two-stage design by the method of Simon. Histology was uterine or extremity leiomyosarcoma (LMS) in 9, high grade pleomorphic sarcoma in 2, and 1 each with carcinosarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor (MPNST), desmoplastic small round cell tumor, rhabdomyosarcoma, and small round cell sarcoma. As expected, toxicity has been moderate. 57 cycles have been administered. No treatment related deaths have occurred. Only 3 grade 4 toxicities have been noted, all hematologic. Of 19 episodes of grade 3 toxicity, 10 have been hematologic. Of the remaining 9, 4 have been treatment related, including cough, nausea, vomiting, and SGPT elevation. 3 pts have experienced clinical benefit defined as partial response (PR) or stable disease for greater than 4 months. There have been two confirmed PRs, one high grade uterine LMS progressing after single agent doxorubicin, and one small round cell tumor recurring within 6 months of completion of a 5 drug Ewing's regimen. One metastatic MPNST has exhibited stable disease for greater than 4 months. Median time to progression has been 4.2 months and median survival 6.25 months. Conclusions: GV appears to be a well-tolerated and potentially effective regimen for first or second line treatment of metastatic STS. Further accrual to this Phase II study is warranted. No significant financial relationships to disclose.
Economic evaluation for the United States (US) of gemcitabine (GEM), nab-paclitaxel plus gemcitabine (NAB-P+GEM), and FOLFIRINOX as first-line treatment for metastatic pancreatic cancer (MPC).
Authors: Mahdi Gharaibeh, Ali McBride, J. Lyle Bootman, Lee D. Cranmer, Ivo Abraham
Journal: Journal of Clinical Oncology (2015)

6605 Background: Both NAB-P+GEM and FOLFIRINOX have shown superior survival efficacy over GEM alone as first-line treatment for MPC. Independent cost effectiveness/utility analyses for the US of NAB-P+GEM and FOLFIRINOX have not been performed. Methods: AMarkov model of outcomes and total costs estimated the life years (LY) and quality-adjusted life years (QALY) gained and incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) for patients with MPC using probabilistic sensitivity analyses, discounted at 3%/year, with full lifetime horizon, from a payer perspective, and expressed in 2015 US$. Lacking 3-way head-to-head trial results, comparative efficacy and safety of NAB-P+GEM and FOLFIRINOX were estimated using Bucher indirect comparisons. Total costs included chemotherapy, administration, disease monitoring, adverse reactions and supportive care measures. Results: In direct comparison, NAB-P+GEM was associated with differentials of +0.27 LY and +0.16 QALY gained over GEM at an incremental total cost of $23,031; yielding ICER of $80,562/LY and ICUR of $141,338/QALY. In direct comparison, FOLFIRINOX was associated with differentials of +0.50 LY and +0.26 QALY gained over GEM at an incremental total cost of $42,846; yielding ICER of $83,978/LY and ICUR of $164,495/QALY. In indirect comparison, FOLFIRINOX was associated with differentials of +0.23 LY and +0.16 QALY gained over NAB-P+GEM at an incremental total cost of $19,815; yielding ICER of $88,031/LY and ICUR of $202,187/QALY. HR for NAB-P+GEM vs. FOLFIRINOX was 1.26 (95%CI = 0.95-1.67, p = ns) indicating no superiority in survival outcome of either regimen. Conclusions: In this independent economic analysis, the superior survival efficacy of both NAB-P+GEM and FOLFIRINOX over GEM in the management of MPC is associated with positive cost-effectiveness and cost-utility. With NAB-P+GEM and FOLFIRINOX not differing statistically in survival benefit, the cost differential of $-4053/LY and $-37,692/QALY gained associated with NAB-P+GEM over FOLFIRINOX renders NAB-P+GEM the most economical of both regimens as first-line treatment for MPC.
Effect of neoadjuvant alternating taxane- and anthracycline-based dose-dense regimen for operable breast cancer on prognosis in triple-negative tumors with a complete histological response.
Authors: J. Medioni, C. Huchon, M. le Frere-Belda, H. Hoffman, A. Bats, D. Eme, J. Andrieu, S. Oudard, E. Levy, F. Lecuru
Journal: Journal of Clinical Oncology (2010)

610 Background: Neoadjuvant antitumour activity of an alternating taxane- and anthracycline-based dose-dense regimen in patients with operable, noninflammatory large breast cancer was investigated. Methods: Women (n = 74) with clinical stage II or III breast cancer were enrolled in this open-label, multicentre study to receive six twice-weekly courses of: gemcitabine 1,000 mg/m2 plus docetaxel 75 mg/m2 on days 1 and 15 and vinorelbine 25 mg/m2 plus epirubicin 100 mg/m2 on days 29 and 43. Patients with an objective response on day 56 then received another cycle of gemcitabine/docetaxel on day 57 and of vinorelbine/epirubicin on day 71. Conservative surgery was scheduled for all patients. Results: Of the patients enrolled, 30% had triple-negative breast cancer (TNBC). Thepathological complete response (pCR) rate was 22% overall, but was higher in TNBC than non-TNBC patients (40.9% versus 14.0%; p = 0.028). Among patients with a pCR, TNBC patients had similar recurrence-free survival (RFS) and overall survival (OS) to non-TNBC patients. Among those without a pCR, RFS rates for TNBC patients were significantly lower than for non-TNBC patients (p = 0.04). The most common severe haematological toxicity was neutropenia. Conclusions: Administering four drugs in a dose-dense alternating sequence gave a high pCR in patients with operable, invasive breast cancer. TNBC patients with a pCR had similar OS to non-TNBC patients, whereas TNBC patients without a pCR had poorer survival than their non-TNBC counterparts. No significant financial relationships to disclose.
Intron Length Coevolution across Mammalian Genomes
Authors: Peter A. Keane, Cathal Seoighe
Journal: Molecular Biology and Evolution (2016)

Although they do not contribute directly to the proteome, introns frequently contain regulatory elements and can extend the protein coding potential of the genome through alternative splicing. For some genes, the contribution of introns to the time required for transcription can also be functionally significant. We have previously shown that intron length in genes associated with developmental patterning is often highly conserved. In general, sets of genes that require precise coordination in the timing of their expression may be sensitive to changes in transcript length. A prediction of this hypothesis is that evolutionary changes in intron length, when they occur, may be correlated between sets of coordinately expressed genes. To test this hypothesis, we analyzed intron length coevolution in alignments from nine eutherian mammals. Overall, genes that belong to the same protein complex or that are coexpressed were significantly more likely to show evidence of intron length coevolution than matched, randomly sampled genes. Individually, protein complexes involved in the cell cycle showed the strongest evidence of coevolution of intron lengths and clusters of coexpressed genes enriched for cell cycle genes also showed significant evidence of intron length coevolution. Our results reveal a novel aspect of gene coevolution and provide a means to identify genes, protein complexes and biological processes that may be particularly sensitive to changes in transcriptional dynamics.
Cardiac and renal biomarker responses in a phase 1/2 study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction.
Authors: Morie A. Gertz, Heather Jolie Landau, Ray Comenzo, David C. Seldin, Brendan M. Weiss, Jeffrey A. Zonder, Jackie Walling, Gene Kinney, Marty Koller, Michaela Liedtke
Journal: Journal of Clinical Oncology (2015)

8514 Background: Light chain (AL) amyloidosis is caused by an accumulation of misfolded proteins that induce the dysfunction of vital organs (e.g., heart and kidneys). NEOD001, a monoclonal antibody that targets these misfolded proteins, is hypothesized to neutralize circulating soluble protein aggregates and to clear insoluble aggregates from organs. We report data from a phase I/II dose-escalation/expansion study of NEOD001 in patients (pts) with AL amyloidosis and persistent organ dysfunction (NCT01707264). Methods: Pts who completed ≥ 1 prior anti-plasma cell systemic therapy, had partial response or better, did not require additional chemotherapy, and had persistent organ dysfunction received NEOD001 intravenously every 28 days (q28d). Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3+3 study design). Primary study objectives were to determine safety/tolerability and maximum tolerated dose/recommended phase II dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), immunogenicity, and hematologic and best organ responses based on consensus criteria. Results: As of September 30, 2014, 27 pts in seven cohorts received 209 infusions. No deaths, drug-related serious adverse events (AEs), discontinuations due to drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. Most frequently reported AEs were fatigue, cough, and dyspnea. 24 mg/kg was selected as RP2D. PK data support intravenous dosing q28d. Of the 14 pts evaluable for cardiac biomarker assessment, 50% met criteria for cardiac response (NT-proBNP: 30% reduction), and 50% achieved disease stabilization. Of the 14 renal-evaluable pts, 43% met criteria for renal response (24-hour urine protein: 50% reduction) and 57% achieved disease stabilization. Conclusions: Monthly infusions of NEOD001 were safe and well tolerated. 24 mg/kg was RP2D. Cardiac response rate was 50% and renal response rate was 43%. These organ response rates compare favorably to those reported with traditional chemotherapy. The phase II expansion phase is ongoing. A phase III study has been initiated. Antibody therapy may represent a new therapeutic platform for management of AL amyloidosis. Clinical trial information: NCT01707264.