tbuckley/cabot-search huggingface dataset:
MicroRNAs as a potential prognostic factor in gastric cancer.
Authors: O. Purim, M. Hoshen, G. Marshak, Y. Kundel, S. Morgenstern, M. Halpern, R. Aharonov, Y. Niv, M. Kushnir, B. Brenner
Journal: Journal of Clinical Oncology (2010)

10635 Background: Preliminary data suggest that microRNAs may have a prognostic role in gastric cancer and may thereby improve our ability to individualize its treatment. We therefore compared the microRNA profiles in the primary tumor of 45 patients with recurrent (14) and non-recurrent gastric cancer (31) and evaluated their prognostic impact. Methods: Eligible patients underwent curative gastrectomies, without adjuvant therapy. Total RNA was extracted from formalin-fixed paraffin embedded tumor samples preserving the small RNA fraction. Initial profiling using microRNA microarrays identified potential microRNA biomarkers for recurrence, verified by qRT-PCR. Results: Signal levels of three microRNAs, miR-451, miR-199a-3p, and miR-195 were found to be differentially expressed in tumors from patients with good prognosis vs. patients with bad prognosis (p-value<0.0002, 0.0027 and 0.0046 respectively). High expression of each microRNA was associated with poorer prognosis for both recurrence and survival. Using miR-451, the positive predictive value for non-recurrence was 100% (13/13). The expression of differential miRs was verified by qRT-PCR, showing high correlation to microarrays and similar separation into prognosis groups. Conclusions: This study identified three microRNAs, miR-451, miR-199a-3p, and miR-195 to be predictive of recurrence. Of these, miR-451 had the strongest prognostic impact. Based on these results, a validation study is planned. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Rosetta Genomics Rosetta Genomics
Safety and effectiveness of dose dense neoadjuvant chemotherapy in patients with stage II/III breast cancer
Authors: S. A. McDaniel, H. Krontiras, J. T. Carpenter, L. M. Nabell, K. I. Bland, M. M. Urist, C. I. Falkson, A. Forero
Journal: Journal of Clinical Oncology (2006)

10622 Background: NSABP B-18 randomized women with operable breast cancer to receive chemotherapy either pre- or postoperatively; OS and DSF rates at 9 years were identical. Importantly, pathologic complete response (pCR) was directly proportional to DFS and OS. Recently, dose dense adjuvant chemotherapy has shown a statistically significant improvement in DFS and OS. However, no data is available for the use of dose dense preoperative chemotherapy at this time. Methods: Women enrolled in the I-SPY correlative trial with newly diagnosed breast cancer, T ≥ 3cm, any N, M0 were evaluated to assess response rates and safety to dose dense neoadjuvant chemotherapy (doxorubicin 60 mg/m 2 IV Q2 wks × 4, paclitaxel 175 mg/m 2 IV Q2 wks × 4, and cyclophosphamide 600 mg/m 2 IV Q2 wks × 4). Results: Since 02/2003, 43 pts have been treated with dose dense neoadjuvant chemotherapy on the I-SPY trial at UAB (mean age 47.9). 47% of the pts were ER+, 37% were PR+ and 5% were Her2+ by FISH. 2 pts dropped out for personal reasons and 9 pts are actively undergoing treatment. Overall, 32 pts received dose dense chemotherapy and proceeded to surgery. Of those, 31 received dose dense sequential ATC and 1 received dose dense concurrent AC followed by T. 34% had a pCR (breast &amp; nodes) while an additional 10% had a pCR in the breast but residual disease in lymph nodes; 41% had a PR; 9% had SD; and 6% had PD. Hematologic toxicity consisted of grade 3 anemia in 2 pts, febrile neutropenia in 2 pts and no grade 4 thrombocytopenia. Non-hematologic grade 3–4 toxicity consisted of mediport-associated thrombosis in 2 pts, hyperglycemia in 2 pts, syncope in 1 pt, neuropathy in 1 pt, and disseminated varicella in 1 pt. Conclusion: Our results show that dose dense neoadjuvant chemotherapy achieves a pCR (breast &amp; nodes) in about 1/3 of patients (34%) with tolerable toxicity. No significant financial relationships to disclose.
More important than life and death
Authors: Kamran Abbasi
Journal: BMJ (2016)

It is an interesting time to propose collaboration as a solution for the NHS. The United Kingdom may decide to leave the European Union, with unknown consequences for science and health (doi:10.1136/bmj.i1117). A state of emergency exists in primary care, where GPs are stressed (doi:10.1136/bmj.i693). Health and social care remain dysfunctional (doi:10.1136/bmj.i458). England’s health secretary has imposed a new contract on junior doctors (doi:10.1136/bmj.i1129; doi:10.1136/bmj.i1124). You might then reasonably conclude that collaboration isn’t in the air. Nor is the cup of goodwill overflowing. “Sustained effort” might not be …
Neuropilins 1 and 2 mediate neointimal hyperplasia and re-endothelialization following arterial injury
Authors: Caroline Pellet-Many, Vedanta Mehta, Laura Fields, Marwa Mahmoud, Vanessa Lowe, Ian Evans, Jorge Ruivo, Ian Zachary
Journal: Cardiovascular Research (2015)

AimsNeuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation.
Research Priorities, Measures, and Recommendations for Assessment of Tobacco Use in Clinical Cancer Research
Authors: Stephanie R. Land, Benjamin A. Toll, Carol M. Moinpour, Sandra A. Mitchell, Jamie S. Ostroff, Dorothy K. Hatsukami, Sonia A. Duffy, Ellen R. Gritz, Nancy A. Rigotti, Thomas H. Brandon, Sheila A. Prindiville, Linda P. Sarna, Robert A. Schnoll, Roy S. Herbst, Paul M. Cinciripini, Scott J. Leischow, Carolyn M. Dresler, Michael C. Fiore, Graham W. Warren
Journal: Clinical Cancer Research (2016)

There is strong evidence that cigarette smoking causes adverse outcomes in people with cancer. However, more research is needed regarding those effects and the effects of alternative tobacco products and of secondhand smoke, the effects of cessation (before diagnosis, during treatment, or during survivorship), the biologic mechanisms, and optimal strategies for tobacco dependence treatment in oncology. Fundamentally, tobacco is an important source of variation in clinical treatment trials. Nevertheless, tobacco use assessment has not been uniform in clinical trials. Progress has been impeded by a lack of consensus regarding tobacco use assessment suitable for cancer patients. The NCI-AACR Cancer Patient Tobacco Use Assessment Task Force identified priority research areas and developed recommendations for assessment items and timing of assessment in cancer research. A cognitive interview study was conducted with 30 cancer patients at the NIH Clinical Center to evaluate and improve the measurement items. The resulting Cancer Patient Tobacco Use Questionnaire (C-TUQ) includes "Core" items for minimal assessment of tobacco use at initial and follow-up time points, and an "Extension" set. Domains include the following: cigarette and other tobacco use status, intensity, and past use; use relative to cancer diagnosis and treatment; cessation approaches and history; and secondhand smoke exposure. The Task Force recommends that assessment occur at study entry and, at a minimum, at the end of protocol therapy in clinical trials. Broad adoption of the recommended measures and timing protocol, and pursuit of the recommended research priorities, will help us to achieve a clearer understanding of the significance of tobacco use and cessation for cancer patients.
Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1β and by the induction of endogenous IL-1Ra
Authors: Leo A B Joosten, Tania O Crişan, Tania Azam, Maartje C P Cleophas, Marije I Koenders, Frank L van de Veerdonk, Mihai G Netea, Soohyun Kim, Charles A Dinarello
Journal: Annals of the Rheumatic Diseases (2015)

Objectives In the present study, we generated a new protein, recombinant human alpha-1-anti-trypsin (AAT)-IgG1 Fc fusion protein (AAT-Fc), and evaluated its properties to suppress inflammation and interleukin (IL)-1β in a mouse model of gouty arthritis. Methods A combination of monosodium urate (MSU) crystals and the fatty acid C16.0 (MSU/C16.0) was injected intra-articularly into the knee to induce gouty arthritis. Joint swelling, synovial cytokine production and histopathology were determined after 4 h. AAT-Fc was evaluated for inhibition of MSU/C16.0-induced IL-1β release from human blood monocytes and for inhibition of extracellular IL-1β precursor processing. Results AAT-Fc markedly suppressed MSU/C16.0-induced joint inflammation by 85–91% (p&lt;0.001). Ex vivo production of IL-1β and IL-6 from cultured synovia were similarly reduced (63% and 65%, respectively). The efficacy of 2.0 mg/kg AAT-Fc in reducing inflammation was comparable to 80 mg/kg of plasma-derived AAT. Injection of AAT-Fc into mice increased circulating levels of endogenous IL-1 receptor antagonist by fourfold. We also observed that joint swelling was reduced by 80%, cellular infiltration by 95% and synovial production of IL-1β by 60% in transgenic mice expressing low levels of human AAT. In vitro, AAT-Fc reduced MSU/C16.0-induced release of IL-1β from human blood monocytes and inhibited proteinase-3-mediated extracellular processing of the IL-1β precursor into active IL-1β. Conclusions A single low dose of AAT-Fc is highly effective in reducing joint inflammation in this model of acute gouty arthritis. Considering the long-term safety of plasma-derived AAT use in humans, subcutaneous AAT-Fc emerges as a promising therapy for gout attacks.
Variations in organic cation transporter (OCT) expression in bronchial epithelial cell layers after environmental insults
Authors: Manali Mukherjee, David I. Pritchard, Cynthia Bosquillon
Journal: European Respiratory Journal (2011)

OCTs are transmembrane carriers that mediate the transport of endogenous amines in both directions. They are essential for the preservation of several organs and have been associated with chronic inflammatory disorders like Crohn9s disease and rheumatoid arthritis. They are also dysregulated in the lung of allergic rodents after an acute ovalbumin challenge (Lips, K.S., et al. Life Sciences, 2007; 80:2263-2269). The airway epithelium is the primary protection barrier in lung defence and its role in the pathogenesis of chronic inflammatory respiratory diseases is becoming evident. Variations in OCT expression in response to environmental insults were quantified in bronchial epithelial cell layers in vitro. Layers of the human cell line Calu-3 and normal human bronchial epithelial (NHBE) cells showed similar OCT gene expression pattern after differentiation at an air-liquid interface for 21days. Calu-3 layers were exposed to the aeroallergen house dust mite or they were physically injured in a scrape wound model. Cells were harvested after recovery for real-time PCR analysis. Significant fold-increases in the expression of OCT1, OCT3, OCTN2 and the pro-inflammatory markers CCL17 and COX-2 were measured. “In-cell” western blotting confirmed OCT up-regulation at the protein level. It was shown OCT expression in bronchial epithelial cells is enhanced after allergen abuse and physical damage. Although further investigation into OCT functions in bronchial epithelial cells is needed, this study suggests a possible role of the transporters in the protection and regeneration of the bronchial epithelium.
On our watch
Authors: R. Coombes
Journal: BMJ (2015)

“Doctors can always do harm, even—and especially—when well intentioned,” writes our GP columnist Margaret McCartney this week, with typical frankness (doi:10.1136/bmj.h5830). Her subject is female genital mutilation and a new law in England and Wales that directs doctors, among others, to report signs of any cases in children to the police. Invading “the land behind the consulting room door” is a mistake because there “the ground is fragile,” she says. “The space is precious.” And patients’ “freedom to speak is permissible often only because of an implicit assurance of privacy.”

It’s a point …
Coming Out of Their Evolutionary Shells: New Turtle Genomic Study Reveals Clues to Defense by Skin Adaptations
Authors: Joseph Caspermeyer
Journal: Molecular Biology and Evolution (2015)

Twenty-one percent, that is the amount of oxygen in the air that we breathe—with the exception of the extreme high-altitude dwellers on the Tibetan or Andean mountains. To get at the genetic roots of these thin air thrivers, a collaborative research team led by University of Chicago Professor Kevin White and University of California San Diego’s Jha et al. 2015 turned to a research workhorse, the fruit fly and identified a treasure trove of new genes—all told, over 100 genes that may be critical to high-altitude adaptation, with more than 40 similar genes found in humans. The results were published in the advanced online edition of Molecular Biology and Evolution. Using experimental evolution followed by whole-genome sequencing (dubbed “evolve and resequence”), the research team grew three fruit fly populations under severely hypoxic conditions over many generations. Sequencing the hypoxiatolerant flies (surviving on just 5% oxygen by the 13th generation) they identified 3,800 single mutations many of which mapped within 66 genomic regions and prioritized a total of 99 candidate fruit fly genes. Many of these were primarily associated with development of respiratory system in fruit flies. In addition, gene knockdown experiments of the targets significantly enhanced survival under severe hypoxic conditions. “In a tribute to legendary Sherpa mountaineers of Nepal, we named three of the previously unnamed fruit fly genes implicated in metabolic rewiring as Pasang Lhamu, Tenzing Norgay, and Phurba Tashi,” said Jha et al. (2015), a graduate student in Kevin White’s lab and the first author of the study. When the research team examined similar genes in highaltitude populations, they found several single mutation differences between high-altitude human populations and their lowland neighbors. Human comparative data from Andeans (n = 10), Sherpas (69) Tibetans (96), and Ethiopian highlanders (165) showed that of the 102 human genes that are similar to the 55 hypoxia genes in fruit fly, more than 40 appear to enable hypoxia tolerance in Sherpas, Tibetans, and Ethiopian highlanders. A smaller number (n = 21) of genes were shared in the Andean population, which may have been due to the small sample size (just ten individuals). Professor White explains, “These results show that, to our surprise, genetic variation in the same types of genes can produce hypoxia resistance in both humans and fruit flies. This result implies that even across hundreds of millions years of evolution, organisms can arrive at convergent solutions during adaptation to similar types of environmental change.” Armed with the new data, the team will pursue teasing out the individual contributions and functions of the candidate genes they have identified.
Corrigendum to “Longterm -ostomy as a quality marker: Comparison of outcomes from a six year series of laparoscopic surgery in MRI defined low rectal cancer” [Int. J. Surg. 23 (2015) 108–114]
Authors: Omotolani A.O. Lewis, Iain J.D. McCallum, Steve Dixon, Mark Katory
Journal: International Journal of Surgery (2015)
Abstract 332: Mitochondrial Inner-Membrane Potential Instability Promotes Sarcolemmal Electrical Instability after Ischemia-Reperfusion in Monolayers of Cardiac Myocytes
Authors: Soroosh Solhjoo, Brian O’Rourke
Journal: Circulation Research (2013)

Mitochondrial uncoupling due to oxidative stress can, through opening of sarcolemmal KATP channels, alter cellular electrical excitability, and it has been proposed that mitochondrial function is a major factor in arrhythmogenesis during ischemia-reperfusion. Here, we examine the effects of ischemia-reperfusion on mitochondrial inner membrane potential (ΔΨm) and corresponding changes in electrical excitability and wave propagation in monolayer cultures of neonatal rat ventricular myocytes. Changes in ΔΨm were observed using TMRM and changes in the sarcolemmal voltage were recorded with a 464-element photodiode array using di-4-ANEPPS. Ischemia was induced by covering the center part of the monolayer (D = 22 mm) with a coverslip (D = 15 mm). Cell contractions ceased after approximately 6 min of ischemia; however, electrical activity continued for 11.3 ± 4.2 min (N = 5). Amplitude and conduction velocity of the action potentials in the ischemic region decreased over the same time period. ΔΨm was lost in two phases: a reversible phase of partial depolarization, after 11.2 ± 1.3 min of ischemia, and a nonreversible phase, which happened after 30 ± 6 min of ischemia, during which the whole mitochondrial network of the myocyte became depolarized and the cells underwent contracture (N = 4). Reperfusion after the long ischemia resulted in only partial recovery and the observance of oscillations of ΔΨm in the mitochondrial network or rapid flickering of individual mitochondrial clusters and was associated with heterogeneous electrical recovery, and formation of wavelets and reentry (4/5 monolayers). In contrast, mitochondria fully recovered and reentry was rare (1/5 monolayers) for reperfusion after the short ischemia (10-12 min). 4’-chlorodiazepam, an inhibitor of inner membrane anion channels, stabilized mitochondrial function after the long ischemia, and prevented wavelets (5/5 monolayers) and reentry (4/5 monolayers). In conclusion, incomplete or unstable recovery of mitochondrial function after ischemia correlates with reentrant arrhythmias in monolayers of cardiac myocytes. Our findings suggest that stabilization of mitochondrial network dynamics is an important strategy for preventing ischemia/reperfusion-related arrhythmias.
Molecular and genomic predictors of response to single-agent doxorubicin (ADR) versus single-agent docetaxel (DOC) in primary breast cancer (PBC).
Authors: M. Martin, A. Romero, J. Lopez Garcia-Asenjo, M. C. Cheang, B. Oliva, J. Garcia Saenz, X. He, T. Caldes, E. Diaz-Rubio, C. M. Perou
Journal: Journal of Clinical Oncology (2010)

502 Background: ADR and DOC improve disease-free survival (DFS) of PBC, but patients (pts) who actually obtain a benefit with either of these agents cannot be identified. Predictors of response to ADM and DOC are necessary. Methods: ER, PR, Ki-67, topoIisomerase IIα protein (topoII), tau and p27 proteins, bcl-2, EGFR, and CK 5/6 (all determined by IHC), topoIIα and her2 gen alterations (by FISH) and a genomic profiling (PAM50/claudin low classifier, using Agilent 44K microarrays) were studied as predictors of response to ADR (75mg/m2 × 4 cy) vs DOC (100mg/m2 × 4 cy) q3w in a neoadjuvant phase II study in pts with PBC (www.ClinTrials.gov, NCT 00123929). Pathological responses (PatRes) and residual cancer burden (RCB) were estimated according to Symmans et al. (J Clin Oncol 25:4414,2007). PCR+class I were considered good PatRes. Multivariable logistic regression analysis was used to determine the odds ratio to response. Results: 204 pts (104 ADR, 100 DOC) were analyzed. PatRes were 19% (ADR) vs 20% (DOC), p=1.0. In multivariate analysis, high topoII expression (but not topoII gene alterations) and ER+ status (for ADM) and ER+ status and tumor size (T) >5cm (for DOC) were associated with poorer PatRes. The odd ratios of PatRes for ADR were 10.4 (95% CI 2.0-55.1) for normal vs high topoII (p=0.006) and 4.6 (95% CI 1.4-15.3) for ER—; vs ER+ tumors (p=0.012); and for DOC 8.3 (2.25-30.73) for ER— vs ER+ tumors (p=0.001) and 13.9 (3.4-56.3) for T≤5 cm vs >5cm (p<0.001). Genomic profiles were possible in 94 pts. Basal-like tumors were selectively sensitive to DOC and resistant to ADR; no differences were seen in other subtypes. Conclusions: Normal topoIIα protein expression and ER-negative status were predictive of response to ADR, while ER-negative status and T≤5cm were predictive of response to DOC. Basal-like tumors are sensitive to DOC and resistant to ADR. Good PatRes (PCR+I) RCB (mean) Genomic subtype ADR DOC P* ADR DOC P* Luminal A 1/12 (8%) 0/5 (0%) NS 3.386 2.839 NS Luminal B 2/14 (14%) 0/11 (0%) NS 2.378 2.806 NS HER2-enriched 1/5 (20%) 2/5 (40%) NS 2.822 1.670 NS Basal 0/7 (0%) 5/9 (56%) 0.034 3.245 1.626 0.039 Claudin low 3/12 (25%) 1/5 (20%) NS 2.626 2.538 NS Normal 1/4 (25%) 2/5 (40%) NS 2.183 2.821 NS Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration University Genomics
Induction of Tumors With Cycasin in Newborn and Preweanling Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: R Fukunishi, A Kadota, A Yoshida, N Hirota
Journal: JNCI Journal of the National Cancer Institute (1985)

Comprehensive studies of carcinogenesis in newborn or preweanling SD rats were conducted under various dose schedules of cycasin (CAS: 14901-08-7) administration. When cycasin was given sc to newborn rats at day 0, tumors were detected in more than 80% of rats of both sexes; kidney tumors were by far the most common. The incidences of tumors declined in the older groups, namely, over 60% in both sexes in the 7-day group, 55% in males and 8.3% in females in 14-day rats, and 0% in 21-day groups. By multiple administration, tumor incidences elevated considerably. Administration ip of cycasin also gave rise to tumor induction in newborn rats. A total of 435 kidney tumors found in the experiments were studied pathologically. Most of them were classified as mesenchymal tumor; some of them metastasized. A few other tumors were found in the liver and colon.