tbuckley/cabot-search huggingface dataset:
NUMB phosphorylation destabilizes p53 and promotes self‐renewal of tumor‐initiating cells by a NANOG‐dependent mechanism in liver cancer
Authors: Hifzur R. Siddique, Douglas E. Feldman, Chia‐Lin Chen, Vasu Punj, Hiroshi Tokumitsu, Keigo Machida
Journal: Hepatology (2015)

Stem cell populations are maintained through self-renewing divisions in which one daughter cell commits to a particular fate whereas the other retains the multipotent characteristics of its parent. The NUMB, a tumor suppressor, in conjunction with another tumor-suppressor protein, p53, preserves this property and acts as a barrier against deregulated expansion of tumor-associated stem cells. In this context, NUMB-p53 interaction plays a crucial role to maintain the proper homeostasis of both stem cells, as well as differentiated cells. Because the molecular mechanism governing the assembly and stability of the NUMB-p53 interaction/complex are poorly understood, we tried to identify the molecule(s) that govern this process. Using cancer cell lines, tumor-initiating cells (TICs) of liver, the mouse model, and clinical samples, we identified that phosphorylations of NUMB destabilize p53 and promote self-renewal of TICs in a pluripotency-associated transcription factor NANOG-dependent manner. NANOG phosphorylates NUMB by atypical protein kinase C zeta (aPKCζ), through the direct induction of Aurora A kinase (AURKA) and the repression of an aPKCζ inhibitor, lethal (2) giant larvae. By radioactivity-based kinase activity assays, we showed that NANOG enhances kinase activities of both AURKA and aPKCζ, an important upstream process for NUMB phosphorylation. Phosphorylation of NUMB by aPKCζ destabilizes the NUMB-p53 interaction and p53 proteolysis and deregulates self-renewal in TICs.Post-translational modification of NUMB by the NANOG-AURKA-aPKCζ pathway is an important event in TIC self-renewal and tumorigenesis. Hence, the NANOG-NUMB-p53 signaling axis is an important regulatory pathway for TIC events in TIC self-renewal and liver tumorigenesis, suggesting a therapeutic strategy by targeting NUMB phosphorylation. Further in-depth in vivo and clinical studies are warranted to verify this suggestion.
Solving the Conundrum: Immunogenetics of Sarcoidosis
Authors: Naftali Kaminski, Wonder P. Drake
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

conducted during very brief periods (only 2 h of respiratory electrodialysis), and that further complications may arise when performing the technique over clinically meaningful periods.Moreover, the technical setup is complex and will need to be as safe as possible before it can be deployed in human trials. ConclusionsDuring the last decades, we have learned that the iatrogenic effects of invasive mechanical ventilation may negatively influence outcomes.Minimally invasive extracorporeal lung assist devices markedly reducing the need for alveolar ventilation would or could play a pivotal role in mitigating these negative influences.The innovative approach of Zanella and colleagues opens the possibility of ensuring sufficient CO 2 removal with a less-invasive way of using positive pressure ventilation than the current standard, or by eliminating invasive mechanical ventilation altogether.Doubling the amount of extracorporeal CO 2 removal would allow a considerable decrease in invasiveness by enabling lower flow rates and vascular access with smaller cannulae.Moreover, it offers the opportunity to widely apply and evaluate the concept of ultraprotective ventilation to reduce VILI, as well as a potential alternative to invasive mechanical ventilation for the support of hypercapnic respiratory failure.If the technique of Zanella and colleagues could be successfully transferred to the clinical setting, it might mark a quantum jump in the treatment of respiratory failure of different etiologies.
A microRNA-based diagnostic assay distinguishes squamous from non-squamous non small-cell lung carcinoma
Authors: Danit Lebanony, Hila Benjamin, Shlomit Gilad, Harvey Pass, Daisuke Nonaka, Jingyao Zhong, Yael Spector, Nitzan Rosenfeld, Ayelet Chajut, Dalia Cohen, Ranit Aharonov, Mahesh Mansukhani
Journal: Clinical Cancer Research (2008)

A42   Recent advances in developing targeted therapies for lung cancer require greater accuracy in the sub-classification of NSCLC. Therapies such as VEGF inhibitors can be a source of high risk for adverse response in cases of squamous cell carcinoma. Variability and the lack of specific, standardized assays is an impediment to adequately identify patients for such treatments. MicroRNAs are a family of small non-coding RNAs that have a wide impact on gene expression. MicroRNAs are highly tissue-specific, involved in tumorigenesis and well-preserved in various clinical samples including archival FFPE samples, making them promising biomarkers for molecular diagnostics. We applied high-throughput profiling to identify microRNA biomarkers for the differentiatial diagnosis of squamous from non-squamous lung carcinoma, and used microarrays to measure microRNA expression levels in over 100 adenocarcinoma and squamous NSCLC samples. A single microRNA was identified and further validated by qRT-PCR as a highly specific marker for squamous cell lung carcinoma. Based on this finding, a microRNA-based qRT-PCR diagnostic assay that measures expression of this microRNA was developed with dozens of additional NSCLC FFPE samples. The assay was tested and validated on an independent blinded cohort of more than 70 NSCLC FFPE samples, reaching accuracy greater than 90% in identification of squamous cell lung carcinomas. The microRNA-based assay we describe is the first standardized diagnostic assay that can provide highly accurate sub-classification of NSCLC cases.
Stimulating arteriogenesis but not atherosclerosis: IFN-α/β receptor subunit 1 as a novel therapeutic target: Figure 1
Authors: Clément Cochain, Alma Zernecke
Journal: Cardiovascular Research (2015)

This editorial refers to ‘MAb therapy against the IFN-α/β receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden’ by P.F.A. Teunissen et al ., pp. 255–266. 

In ischaemic diseases such as myocardial infarction (MI), restoration of sufficient blood supply to ischaemic areas through arteriogenesis is critical for preservation of tissue integrity and function.1 Although ischaemia activates natural mechanisms promoting arteriogenesis, these are often insufficient to alleviate the consequences of ischaemia in patients, prompting the need for novel therapeutic strategies.1 One significant hurdle, however, is that several pro-arteriogenic mechanisms and therapeutic approaches also promote atherosclerotic plaque development.1,2 Teunissen et al. 3 now show that targeting the IFN-α/β receptor subunit 1 (IFNAR1) stimulates functional perfusion of ischaemic tissue while only minimally affecting atherosclerosis.

Arteriogenic and atherosclerotic processes often engage similar mechanisms. For example, limb ischaemia induces the mobilization of Ly6Chigh monocytes to the bloodstream, which then infiltrate ischaemic tissue to promote blood flow recovery in mice,4 but also constitutes the main …
Mortality Patterns Among U.S. Veterans by Occupation. I. Cancer
Authors: A Blair, J Walrath, E Rogot
Journal: JNCI Journal of the National Cancer Institute (1985)

The mortality experience of a nation-wide cohort of 293,958 veterans was analyzed by occupation and industry to generate hypotheses in occupational cancer. Results are presented on 107,563 deaths occurring between 1954 and 1970. Information on usual employment (occupation and industry) and smoking habits was available from questionnaires completed in 1954 and 1957. Complete enumeration of these results by occupation and industry is available as special National Cancer Institute monographs from the author (A. B.). This report presents the mortality experience for selected occupations. Excesses of lung cancer among shipyard workers, truck drivers, and plumbers are consistent with previous reports. Elevated risks for stomach cancer among carpenters and machinists may reflect exposure to dusts, abrasives, and cutting oils.
Precursor control of neurotransmitter synthesis.
Authors: R J Wurtman, F Hefti, E Melamed
Journal: Pharmacological Reviews (1980)

Studies performed during the past decade have shown that the rates at which certain neurons produce and release their neurotransmitters can be affected by precursor availability, and thus by the changes in plasma composition that occur after ingestion of the precursors in purified form or as constituents of foods. Thus, tryptophan administration or a plasma ratio of tryptophan to other large neutral amino acids, thereby raising brain tryptophan levels, increasing the substrate saturation of tryptophan hydroxylase, and accelerating the synthesis and release of serotonin. Tyrosine administration or a high-protein meal similarly elevates brain tyrosine and can accelerate catecholamine synthesis in the CNS and sympathoadrenal cells, while the consumption of lecithin or choline increases brain choline levels and neuronal acetylcholine synthesis. The physiologic and biochemical mechanisms that must exist in order for nutrient consumption to affect neurotransmitte synthesis have been characterized and include: 1) the lack of significant feedback control of plasma levels of the precursor; 2) the lack of a real "bloodbrain barrier" for the precursor, i.e. the ability of the plasma level of the precursor to control its influx into, or efflux from, the CNS; 3) the existence of a low-affinity (and thus unsaturated) transport system mediating the flux of the precursor between blood and brain; 4) low-affinity kinetics for the enzyme that initiates the conversion of the precursor to the transmitter; and, 5) the lack of end-product inhibition of the enzyme, in vivo, by its ultimate product, the neurotransmitter. The extent to which neurotransmitter synthesis in any particular aminergic neuron happens to be affected by changes in the availability of its precursor probably varies directly with the neuron's firing frequency. This relationship allows precursor administration to produce selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons potentially capable of utilizing the precursor for this purpose. It also allows the investigator to predict when administering the precursor might be useful for amplifying a physiologic process, or for treating a pathologic state. (for example, tyrosine administration raises blood pressure in hypotensive rats, lowers it in hypertensive animals, and has little effect on blood pressure in normotensive animals; the elevation in blood pressure probably reflects enhanced catecholamine release from sympathoadrenal cells, while the reduction in hypertensive animals probably results from increased catecholamine release within the brain-stem.) Such predictions are now being tested clinically in many institution. Available evidence suggests that lecithin or cholie administration can diminish the frequency of abnormal movements in patients with tardive dyskinesia...
Stomach Cancer Among Japanese in Hawaii&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: William Haenszel, Minoru Kurihara, Mitsuo Segi, Richard K. C. Lee
Journal: JNCI Journal of the National Cancer Institute (1972)

Study of 220 Japanese stomach cancer patients and 440 hospital controls in Hawaii revealed that migrants (Issei) from prefectures with the highest stomach cancer risks in Japan continued to display an excess risk in Hawaii, but this effect did not persist among their Nisei offspring. Lower risks were suggested for Nisei, but not Issei adhering to Western-style diets. These nativity distinctions are consistent with other studies suggesting that early exposures are critical. Associations of stomach cancer with consumption of specific foods were noted. Elevated risks were described for Issei and Nisei users of pickled vegetables and dried/salted fish, the most frequent consumers having the highest risks. Since similar associations did not appear for raw fish and unprocessed vegetables, suspicion is directed to methods of preparation. Low risks were suggested for several Western vegetables, many of which are eaten raw. The associations for uncooked vegetables appeared independent of those found for pickled vegetables; both persisted after control for other facets of vegetable consumption. Associations for tobacco, liquor, coffee, and milk were observed only in the Issei population. Points of consistency between the Hawaii findings and those assembled in Japan are cited. Experimental evidence bearing on the epidemiologic data for processed fish and vegetables is mentioned.—J Natl Cancer Inst 49: 969–988, 1972.
Effect of 7,12-Dimethylbenz[&lt;italic&gt;a&lt;/italic&gt;]anthracerie on Non-Neoplasfic and Neoplastic Rodent Cells in Culture
Authors: Virginia J. Evans, Floyd M. Price, Harold A. Kerr, Hector Montes de Oca
Journal: JNCI Journal of the National Cancer Institute (1970)

The resistance or susceptibility to the toxic effect of 7,12-dimethylbenz[a]anthracene (DMBA) in neoplastic and non-neoplastic, long-term, paired rodent lines in vitro appeared useful as a reliable, rapid, supplementary assay to determine tentatively the non-neoplastic state of the cell lines examined. No cytotoxicity was initially found in freshly explanted mouse embryo cells in the horse serum or fetal calf serum systems when surely they were not malignant. In long-term culture, in our system, sensitivity without exception was related to the non-neoplastic state. Data from such cells, usually obtained only after prolonged latent periods in appropriate hosts, are mandatory to confirm conclusively whether these cells can produce tumors. Limitations of the use of the assay with DMBA are recognized. Theories are proposed to account for the response of both freshly explanted and long-term cultures of rodent cells to DMBA.
Friend Erythroleukemia Virus Complex: Role of Viral Components in Modifying Erythroid Differentiation in Mice&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: B Fagg, W Ostertag
Journal: JNCI Journal of the National Cancer Institute (1982)

The present study was carried out to determine which component of the polycythemic strain of Friend erythroleukemia virus (FV-P)--Friend helper virus [Friend murine leukemia virus (F-MuLV)] of the replication-defective spleen focus-forming virus (SFFV)--is responsible for inducing erythropoietin-independent erythropoiesis and expansion of the erythroid compartment in infected mice. F-MuLV and SFFV were cloned in SC1 cells to give a cell line 643/22N, which released only F-MuLV and SC204, a nonproducer cell line carrying SFFV. On superinfection with specific helper viruses, SC204 yielded further cell lines, which released SFFV in conjunction with 1) Friend, 2) Moloney, or 3) Gross helper viruses. With the use of an in vitro colony formation assay to monitor erythropoiesis in the bone marrow of inbred DBA/2J mice infected with any of the virus preparations containing SFFV plus helper virus, the erythroid precursor cell population was found to become erythropoietin-independent and amplified; adult mice infected with any of the helper viruses alone did not develop any symptoms of Friend disease. Thus the biologic activity of the FV-P complex was unaffected by replacement of the F-MuLV with an unrelated helper virus (Moloney or Gross). These results indicated that the SFFV component of FV-P is responsible for modifying erythroid differentiation in adult mice.
Abstract 4071: Heart Failure Patients in Rural Areas have Better Event-Free Survival than Those Living in Urban Areas
Authors: Jia-Rong Wu, Terry A Lennie, Marla J De Jong, Misook L Chung, Mary Kay Rayens, Barbara Riegel, Debra K Moser
Journal: Circulation (2008)

Evidence of health disparities between urban and rural populations usually favors those in urban areas. Unknown is the impact of rurality on heart failure (HF) outcomes. The purpose of this study w...
Renal papillary necrosis--a sixteen-year clinical experience.
Authors: M D Griffin, E J Bergstralhn, T S Larson
Journal: Journal of the American Society of Nephrology (1995)

This study sought to characterize patients with renal papillary necrosis seen at one tertiary referral center by reviewing medical records of patients with a confirmed diagnosis between January 1, 1976 and September 1, 1992. One hundred sixty-five cases were identified. The mean age at diagnosis was 57 yr (SD 15). The female-to-male ratio was 1.1:1.0. Ninety-two percent of patients were white. Seventy-seven percent of cases were unsuspected before diagnosis, and 16% were diagnosed at autopsy. The most common associated conditions were urinary tract infection, analgesic abuse, urinary tract obstruction, diabetes mellitus, and sickle cell disease. There was considerable overlap in the presence of these conditions, with two or more identified in 36% of patients. In addition, 11% of patients had none of these well-recognized risks. Other diagnoses in this group included lupus nephritis, Wegener's granulomatosis, and renal artery stenosis. A decline in case numbers of approximately 50% was demonstrated over the last 10 yr studied. This period was associated with a 57% reduction in the number of excretory urograms carried out, suggesting that changes in diagnostic imaging preference may have contributed. Vital status and renal outcome data after diagnosis were obtained in 93% of cases. Of those diagnosed while living, survival was lowest among diabetic patients. Ten-year survival for nondiabetics was not significantly different from the expected survival of an age- and sex-matched cohort. The overall risk for requiring renal replacement therapy after the diagnosis of renal papillary necrosis in surviving patients was low (7% of 136 patients at risk).(ABSTRACT TRUNCATED AT 250 WORDS)
shRNA suppresses of IL-13 production in vitro
Authors: Igor Shilovskiy, Oxana Dmitrieva, Alexander Babakhin, Musa Khaitov
Journal: European Respiratory Journal (2013)

Background:  Knockout mice studies revealed that IL-13 alone is sufficient to induce the most of allergic asthma (AA) manifestations independently from IL-4 or IL-5. These circumstances make IL-13 a promising therapeutic target using RNA interference phenomenon. Despite the simplicity of application of synthetic small interference RNA molecules the main disadvantage is their short term effect in comparison to short hairpin RNA (shRNA). In this study to silence of IL-13 several shRNAs variants were designed and tested in vitro.   Methods:  To develop the IL-13 expression system a full length BALB/c mouse il-13 gene was cloned into expression pUCHR-IRES-GFP vector and pUCHR-IRES-mIL13-GFP was derived. Seven variants of shRNAs against murine IL-13 were designed and cloned into pGIPZ expression vector. To test the designed shRNAs, 1*105 293T cells were co-transfected with 0.33 µg of pUCHR-IRES-mIL13-GFP and 1 µg of pGIPZ carrying designed shRNAs. shRNA targeting murine IL-4 was used as a negative control. Expression of IL-13 was detected by RT-PCR and ELISA 24 hours after co-transfection.   Results:  All variants of shRNAs reduced IL-13 expression in vitro, with different intensity. Three shRNA variants were most potent among all tested samples. The levels of mRNA suppression with these three variants estimated by RT-PCR were 88%, 85% and 78%, respectively. The levels of IL-13 secretion into the medium from transfected 293T cells were evaluated by ELISA and were decreased by 46%, 71% and 68%, respectively.   Conclusion:  Designed shRNAs which demonstrated high efficacy in IL-13 suppression in vitro may be a promising approach for in vivo studies in understanding the role of IL-13 in AA pathogenesis as well as for developing a novel AA treatment.
GROC (gemcitabine, rituximab, oxaliplatin combination) plus pegfilgrastim is less toxic and as active as DHAP and ESHAP for relapsed aggressive non-Hodgkin’s lymphoma (NHL)
Authors: F. Cabanillas, I. Liboy, E. Rodriguez-Monge, O. Pavia, N. Robles, N. Maldonado, E. Rivera, I. Torres, J. Perdomo, L. Acaba
Journal: Journal of Clinical Oncology (2008)

8530 Background: A more effective and less toxic salvage regimen for relapsed aggressive NHL is desirable for use prior to autologous stem cell transplant (ASCT). Gemcitabine (G) and Oxaliplatin (O) are active single agents in NHL and have modest myelosuppression. We hereby report the results of a trial designed to explore the GROC regimen based on G, O and Rituximab (R) administered every 14 days with Pegfilgrastim support. Methods: Doses were: R=375 mg/m2 on day 1, G=1,250 mg/M2 on day 2, O=100 mg/m2 on day 2 and Pegfilgrastim 6 mg day 3. Results: We have entered 37 pts all of whom are evaluable. Median age was 59, 12 were refractory to 1st line therapy, 14 had PR or PD as best response to preceding chemo regimen. Response rate to GROC: Overall= 81%, CR= 40.5%, PR=40.5%. At 2 yrs overall survival (OS) was 33% and PFS 29%. For pts who were not refractory to the preceding chemo regimen, the 2 yr PFS=49% and OS=52%. See table for comparison with other commonly used regimens. Despite the older age of patients receiving GROC, its toxicity appears to be lower and overall response rate is either similar or better. In 7/13 (54%) the response to GROC was better than to preceding regimen. Another intriguing finding is that in 16 cases, PFS was longer with GROC than with the preceding regimen. The most common non-hematologic toxicities were reversible transaminitis (grade 2 in 4, grade 3 in 3, grade 4 in 1), partially reversible neuropathy in 10 (grade 1–2 in 9, grade 3 in 1), and diarrhea in 3 (grade 4 in 1). We were able to deliver courses at a median interval of 14 days. Conclusions: 1- GROC is an effective dose dense salvage regimen even in pts with poor prognostic features such as older age than other regimens and refractoriness. 2- GROC appears as effective as DHAP, ESHAP and RICE but with considerably less hematologic and non- hematologic toxicity. 3- Because of its effectiveness and low toxicity profile, it deserves further evaluation as a first salvage option for relapsed aggressive NHL. Comparison of GROC vs other regimens Response and toxicity GROC (N=37) DHAP (N=63) ESHAP (N=85) RICE (N=34) Median Age 59 55 53 45 Overall Response Rate 81% 56% 58% 78% CR Rate 41% 31% 38% 53% Neutropenic fever 5% 52% 30% 24% Renal (creatinine twice baseline) 0 22% 22% n.a. Survival (3 yr) 33% 25% 32% 55%* * 25 were transplanted after RICE (all were eligible for ASCT) while only 4 after GROC due to either age or unavailability No significant financial relationships to disclose.