tbuckley/cabot-search huggingface dataset:
Activity of the Hypoxia-Activated Prodrug, TH-302, in Preclinical Human Acute Myeloid Leukemia Models
Authors: Scott Portwood, Deepika Lal, Yung-Chun Hsu, Rodrigo Vargas, Megan K. Johnson, Meir Wetzler, Charles P. Hart, Eunice S. Wang
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth. Experimental Design: We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models. Results: We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models. Conclusions: Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. Clin Cancer Res; 19(23); 6506–19. ©2013 AACR.
Gene-expression signature of vascular invasion in hepatocellular carcinoma
Authors: Beatriz Mínguez, Yujin Hoshida, Augusto Villanueva, Sara Toffanin, Laia Cabellos, Swan Thung, John Mandeli, Daniela Sia, Craig April, Jian-Bing Fan, Anja Lachenmayer, Radoslav Savic, Sasan Roayaie, Vincenzo Mazzaferro, Jordi Bruix, Myron Schwartz, Scott L. Friedman, Josep M. Llovet
Journal: Journal of Hepatology (2011)
Comparison of Ivor-Lewis vs Sweet Esophagectomy for Esophageal Squamous Cell Carcinoma
Authors: Bin Li, Jiaqing Xiang, Yawei Zhang, Hecheng Li, Jie Zhang, Yihua Sun, Hong Hu, Longsheng Miao, Longfei Ma, Xiaoyang Luo, Sufeng Chen, Ting Ye, Yiliang Zhang, Yang Zhang, Haiquan Chen
Journal: JAMA Surgery (2015)

Sweet esophagectomy is performed widely in China, while the Ivor-Lewis procedure, with potential benefit of an extended lymphadenectomy, is limitedly conducted owing to concern for a higher risk for morbidity. Thus, the role of the Ivor-Lewis procedure for thoracic esophageal cancer needs further investigation.To determine whether Ivor-Lewis esophagectomy is associated with increased postoperative complications compared with the Sweet procedure.A randomized clinical trial was conducted from May 2010 to July 2012 at Fudan University Shanghai Cancer Center, Shanghai, China, of 300 patients with resectable squamous cell carcinoma in the middle and lower third of the thoracic esophagus. Intent-to-treat analysis was performed.Patients were randomly assigned to receive either the Ivor-Lewis (n = 150) or Sweet (n = 150) esophagectomy.The primary outcome of this clinical trial was operative morbidity (any surgical or nonsurgical complications). Secondary outcomes included oncologic efficacy (number of lymph nodes resected and positive lymph nodes), postoperative mortality (30-day and in-hospital mortality), and patient discharge.Resection without macroscopical residual (R0/R1) was achieved in 149 of 150 patients in each group. Although there was no significant difference between the 2 groups regarding the incidence of each single complication, a significantly higher morbidity rate was found in the Sweet group (62 of 150 [41.3%]) than in the Ivor-Lewis group (45 of 150 [30%]) (P = .04). More patients in the Sweet group (8 of 150 [5.3%]) received reoperations than in the Ivor-Lewis group (1 of 150 [0.7%]) (P = .04). The median hospital stay was 18 days in the Sweet group vs 16 days in the Ivor-Lewis group (P = .002). Postoperative mortality rates in the Ivor-Lewis (1 of 150) and Sweet (3 of 150) groups were 0.7% and 2.0%, respectively (P = .25). More lymph nodes were removed during Ivor-Lewis esophagectomy than during the Sweet procedure (22 vs 18, P < .001).Early results of this study demonstrate that the Ivor-Lewis procedure can be performed with lower rates of postoperative complications and more lymph node retrieval. Ivor-Lewis and Sweet esophagectomies are both safe procedures with low operative mortalities.clinicaltrials.gov Identifier:NCT01047111.
Applicability of laser scanning cytometry to study paediatric alveolar macrophages
Authors: H.J. Bunn, G. Woltmann, J. Grigg
Journal: European Respiratory Journal (2002)

Laser scanning cytometry (LSC) generates quantitative information on immune receptor expression from cells cytocentrifuged onto a microscope slide. In children, the description of developmental changes in immune receptor expression on alveolar macrophages (AM) has been limited by the small number of cells recovered by bronchoalveolar lavage (BAL). The applicability of LSC to the study of AM from normal children was therefore assessed. AM were obtained by BAL of normal children following intubation prior to elective surgery. The ability of LSC to identify the cytoplasm of AM was assessed using either: 1) autofluorescence; 2) forward scatter; 3) nuclear staining with propidium iodide; or 4) a fluorescent-labelled monoclonal antibody to CD68, a pan-macrophage antigen. LSC could only reliably identify individual AM when stained with CD68. The sensitivity for detecting single whole AM using CD68 was 0.97 and the positive predictive value was 0.88, respectively, with excellent repeatability. In addition, a range of immunofluorescence parameters were generated for CD68. It is concluded that laser scanning cytometry is suited to the study of immune receptor expression from small numbers of paediatric alveolar macrophages, when CD68 is used for cell identification.
A review of the actions and control of intracellular pH in vascular smooth muscle
Authors: G Smith
Journal: Cardiovascular Research (1998)

Objective: This review is an account of the physiological issues involved in the effects of pH on vascular smooth muscle tone. The following criteria were considered when reviewing the literature: (i) the type of smooth muscle, i.e. either tonic or phasic, (ii) the source of the smooth muscle i.e. pulmonary, systemic, large artery, resistance artery, vein or cell line, (iii) the effects of changing intracellular or extracellular pH alone, (iv) the acute or chronic effects of altered pH (v) the influence of extracellular pH on intracellular pH and (vi) the influence of altered intracellular pH on basal or agonist induced tone. Studies of the effects of pH on the individual intracellular components of vascular tone, specifically sarcoplasmic reticulum and contractile proteins function are considered. Finally, the pH sensitivity of molecular components that contribute to smooth muscle cell tone are reviewed. Conclusions: There appear to be distinct differences in the response of large arteries and resistance arteries to altered intracellular pH which may be based on the different properties of the smooth muscle within the wall of each blood vessel. Similarly, systemic and pulmonary vessels may respond differently, but no systematic study exists to allow a more definitive conclusion. Factors controlling intracellular pH such as intracellular buffering power and sarcolemmal pH regulating mechanisms may differ across the vascular bed and may contribute to some of the differences observed in response to altered extracellular pH. Finally, few studies have examined the pH sensitivity the intracellular processes involved in basal tone and pharmaco-mechanical coupling in vascular smooth muscle. More information concerning these latter aspects of smooth muscle function is required to progress the understanding of the modulator action of pH on vascular tone.
Prospective study of dietary patterns and chronic obstructive pulmonary disease among US men
Authors: R. Varraso, T. T Fung, F. B Hu, W. Willett, C. A Camargo
Journal: Thorax (2007)

Hemorrhagic shock (HS) due to major trauma and surgery predisposes the host to the development of systemic inflammatory response syndrome (SIRS), including acute lung injury (ALI), through activating and exaggerating the innate immune response. IL-1β is a crucial proinflammatory cytokine that contributes to the development of SIRS and ALI. Lung endothelial cells (EC) are one important source of IL-1β, and the production of active IL-1β is controlled by the inflammasome. In this study, we addressed the mechanism underlying HS activation of the inflammasome in lung EC. We show that high mobility group box 1 acting through TLR4, and a synergistic collaboration with TLR2 and receptor for advanced glycation end products signaling, mediates HS-induced activation of EC NAD(P)H oxidase. In turn, reactive oxygen species derived from NAD(P)H oxidase promote the association of thioredoxin-interacting protein with the nucleotide-binding oligomerization domain-like receptor protein NLRP3 and subsequently induce inflammasome activation and IL-1β secretion from the EC. We also show that neutrophil-derived reactive oxygen species play a role in enhancing EC NAD(P)H oxidase activation and therefore an amplified inflammasome activation in response to HS. The present study explores a novel mechanism underlying HS activation of EC inflammasome and thus presents a potential therapeutic target for SIRS and ALI induced after HS.
High prevalence of antibody to hepatitis C virus in patients with hepatocellular carcinoma (HCC)
Authors: M. Colombo, G. Kuo, L. Choo, M. Houghton, M.A. Tommasini, M.G. Rumi, M.L. Dioguardi, M.F. Donato, E. Del Ninno
Journal: Journal of Hepatology (1989)
Genetic predisposition and environmental danger signals initiate chronic autoimmune hepatitis driven by CD4<sup>+</sup>T cells
Authors: Matthias Hardtke-Wolenski, Katja Fischer, Fatih Noyan, Jerome Schlue, Christine S. Falk, Maike Stahlhut, Norman Woller, Florian Kuehnel, Richard Taubert, Michael P. Manns, Elmar Jaeckel
Journal: Hepatology (2013)

Autoimmune hepatitis (AIH) is defined as a chronic liver disease with loss of tolerance against liver tissue eventually leading to cirrhosis if left untreated. 80%-90% of patients can be treated with a life-long immunosuppression. Unfortunately, there are strong drug-related side effects and steroid-refractory patients. Therefore, there is a need for a model system to investigate the complex immunopathogenesis of this chronic disease and subsequently to develop new therapeutic interventions. We developed a new model of experimental murine AIH (emAIH) by a self-limited adenoviral infection with the hepatic autoantigen formiminotransferase cyclodeaminase (FTCD). After an initial transient hepatitis there was a chronic evolving AIH, finally leading to portal and lobular fibrosis. We could show that the genetic predisposition provided by the NOD background was essential for creating a fertile field for the development of liver-specific autoimmunity. However, a strong environmental trigger was additionally necessary to initiate the disease. Besides the break of humoral tolerance, T-cell tolerance against hepatic self-antigens was also broken and CD4+ T cells were identified as essential drivers of the disease. As the disease was successfully treated with prednisolone and budesonide, the model will be helpful to develop and test new therapeutic interventions. Conclusion : We developed a new murine AIH model closely resembling AIH in patients that explains the mechanisms of AIH pathophysiology. In addition, emAIH provides options to test therapeutic alternatives for patients not achieving remission, with reduced side effects of chronic nonspecific immunosuppression. (Hepatology 2013;58:718–728)
Racial and Ethnic Disparities in the Receipt of Cancer Treatment
Authors: V. L. Shavers
Journal: JNCI Journal of the National Cancer Institute (2002)

A disproportionate number of cancer deaths occur among racial/ethnic minorities, particularly African Americans, who have a 33% higher risk of dying of cancer than whites. Although differences in incidence and stage of disease at diagnosis may contribute to racial disparities in mortality, evidence of racial disparities in the receipt of treatment of other chronic diseases raises questions about the possible role of inequities in the receipt of cancer treatment. To evaluate racial/ethnic disparities in the receipt of cancer treatment, we examined the published literature that addressed access/use of specific cancer treatment procedures, trends in patterns of use, or survival studies. We found evidence of racial disparities in receipt of definitive primary therapy, conservative therapy, and adjuvant therapy. These treatment differences could not be completely explained by racial/ethnic variation in clinically relevant factors. In many studies, these treatment differences were associated with an adverse impact on the health outcomes of racial/ethnic minorities, including more frequent recurrence, shorter disease-free survival, and higher mortality. Reducing the influence of nonclinical factors on the receipt of cancer treatment may, therefore, provide an important means of reducing racial/ethnic disparities in health. New data resources and improved study methodology are needed to better identify and quantify the full spectrum of nonclinical factors that contribute to the higher cancer mortality among racial/ethnic minorities and to develop strategies to facilitate receipt of appropriate cancer care for all patients.
Neurological Abnormalities in Schizophrenic Patients and Their Siblings
Authors: Baher Ismail, Elizabeth Cantor-Graae, Thomas F. McNeil
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The aim of this study was to investigate the prevalence and type of neurological abnormalities in schizophrenic patients and their nonpsychotic siblings. METHOD: A comprehensive neurological assessment, including evaluation of both hard and soft signs, was performed for 60 schizophrenic patients, 21 siblings, and 75 normal comparison subjects. RESULTS: None of the comparison subjects scored higher than 6 on the neurological assessment scale, but a score of 7 or higher was given to 67% of patients and 19% of siblings. Both patients and siblings scored significantly higher than comparison subjects on total neurological abnormalities, hard signs, soft signs, primitive reflexes, integrative sensory functions, and motor functions. The most conspicuous abnormalities were motor coordination problems and involuntary movements in the patients and cranial nerve deviations and mirror movements in their siblings. Levels of neurological abnormality were positively correlated within patient-sibling pairs. The total battery and hard signs best discriminated patients from comparison subjects. CONCLUSIONS: High levels of neurological abnormality characterize both schizophrenic patients and their siblings. The constellation of abnormalities and absence of overt psychopathology in siblings may represent the mildest form of disturbance within the schizophrenia spectrum. Levels of neurological abnormality covary positively in patients and siblings within the same family, suggesting common genetic and/or environmental pathogenic factors. An extended assessment battery provides optimal discrimination of patients from normal subjects, and hard signs are more differentially associated with schizophrenia than are soft signs. The neurological abnormality has no consistent localizing profile, and nearly all functional domains are involved. (Am J Psychiatry 1998; 155:84–89)
From burns unit to boardroom
Authors: James Partridge
Journal: BMJ (2006)

“It'll never happen to me.” Burns? I had never given them a thought. Facial disfigurement? Never heard of it, except in war films. Frightening, though.

Born in the early 1950s, privately educated, emerging in late 1970 as an 18 year old with reasonable prospects, I was a carefree youth with high ambitions heading for a prestigious university. I took my looks for granted, traded on them, even saw them as the key to my future.

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My life changed in a split second of bad judgment. I failed to see a bend in the road, the Land Rover toppled over, there was skidding and sparks, and the petrol tank exploded. I thought I was just singed. Lily Lewis, a former nurse travelling in the car behind, knew better. Thirty five years later, I salute her; she saved me.

I had nearly 40% severe burns. My face was swollen to three times its normal size and my legs and left hand were particularly damaged. My sight, lungs, and other organs, however, had survived unharmed. The next three months were a blur of sedation, operations, and pain. My visitors didn't need to say I looked dreadful—I could see it in their eyes. Getting my face into focus in a mirror was the big problem, but it had to be done. Rightly, there were no mirrors anywhere, so three months after the accident I decided I had to choose the moment myself and make a conscious effort.

What a sight: nasty scars, oozing scabs, redness, distortion, eyes hooded, mouth gaping. Words like “tarnished,” “devalued,” “disfigured,” and “deformed” came to mind, words I had never used, let alone applied to myself. “Not as bad as I'd expected” were my first stoic words, but hardly believable. What were my chances? “You'll be better in a few …

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The TPI and FTA-ABS Tests in Treated Late Syphilis
Authors: William G. Atwood
Journal: JAMA (1968)

Sixty-seven patients who had been diagnosed and treated 13 or more years ago for latent or late syphilis were retested with use of several serological tests for syphilis. At the time of original diagnosis, all patients had been reactive in cardiolipin reagin tests and in the Treponema pallidum immobilization (TPI) test. It was found that 73% of patients were still reactive in one or more cardiolipin reagin tests and that 90% had retained TPI reactivity. In the newer fluorescent treponemal antibody-absorption (FTA-ABS) test, 98% were reactive. These results indicate that the FTA-ABS test is more sensitive than the TPI test.<i>Neither the FTA nor the TPI test, as presently performed, may be used as an index of therapeutic response, since both tests show reactivity 13 or more years after persumably adequate treatment</i>.
Proteinase 3 Enhances Endothelial Monocyte Chemoattractant Protein-1 Production and Induces Increased Adhesion of Neutrophils to Endothelial Cells by Upregulating Intercellular Cell Adhesion Molecule-1
Authors: MIRIAM E. J. TAEKEMA-ROELVINK, CEES VAN KOOTEN, SANDRA VAN DER KOOIJ, EVERT HEEMSKERK, MOHAMED R. DAHA
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Wegener's granulomatosis is an autoimmune disease that is characterized by systemic vasculitis and granuloma formation. Early influx of polymorphonuclear neutrophils (PMN), followed at a later stage by mononuclear cells, contributes to the granulomatous inflammation. Previous studies have shown that proteinase 3 (PR3), the major autoantigen in Wegener's granulomatosis, specifically binds to endothelial cells and plays a possible role in activation of these cells by enhancing interleukin-8 production, thus providing a chemotactic and activating stimulus for PMN. The present study demonstrated that PR3 enhances the production of monocyte chemoattractant protein-1 (MCP-1) by human umbilical vein endothelial cells (HUVEC) in a dose- and time-dependent manner. The PR3-induced increase in MCP-1 production was demonstrated at both the protein and the mRNA levels and was chemotactic for monocytes. In addition, it was demonstrated that PR3 induces a dose- and time-dependent increase in the expression of intercellular adhesion molecule-1 (ICAM-1) as determined by fluorescence-activated cell sorter analysis. The PR3-induced increase in expression of ICAM-1 was also demonstrated at the mRNA level. PR3 induced a slight increase in vascular cell adhesion molecule-1 expression and had no effect on the expression of both P- and E-selectin. Incubation of HUVEC for 24 h in the presence of PR3 resulted in a significant increase in adhesion of PMN, which was reduced to baseline levels in the presence of blocking monoclonal antibody anti—ICAM-1 or anti-CD18 or a combination of both. Monocytes showed a slight but statistically not significant increase in adhesion. Incubation of HUVEC with PR3 for 4 h did not result in enhanced adhesion of either PMN or monocytes. It was hypothesized that PR3, which may be released locally at inflammatory sites after activation of cytokineprimed PMN, plays a role in endothelial cell activation by enhancing both interleukin-8 and MCP-1 production, thus providing a chemotactic and activating stimulus for both PMN and monocytes. In addition, PR3 may contribute to the ongoing inflammation by enhancing the adhesion of PMN to endothelial cells by upregulating ICAM-1 expression.
Accelerated Evolution after Gene Duplication: A Time-Dependent Process Affecting Just One Copy
Authors: Cinta Pegueroles, Steve Laurie, M. Mar Albà
Journal: Molecular Biology and Evolution (2013)

Gene duplication is widely regarded as a major mechanism modeling genome evolution and function. However, the mechanisms that drive the evolution of the two, initially redundant, gene copies are still ill defined. Many gene duplicates experience evolutionary rate acceleration, but the relative contribution of positive selection and random drift to the retention and subsequent evolution of gene duplicates, and for how long the molecular clock may be distorted by these processes, remains unclear. Focusing on rodent genes that duplicated before and after the mouse and rat split, we find significantly increased sequence divergence after duplication in only one of the copies, which in nearly all cases corresponds to the novel daughter copy, independent of the mechanism of duplication. We observe that the evolutionary rate of the accelerated copy, measured as the ratio of nonsynonymous to synonymous substitutions, is on average 5-fold higher in the period spanning 4–12 My after the duplication than it was before the duplication. This increase can be explained, at least in part, by the action of positive selection according to the results of the maximum likelihood-based branch-site test. Subsequently, the rate decelerates until purifying selection completely returns to preduplication levels. Reversion to the original rates has already been accomplished 40.5 My after the duplication event, corresponding to a genetic distance of about 0.28 synonymous substitutions per site. Differences in tissue gene expression patterns parallel those of substitution rates, reinforcing the role of neofunctionalization in explaining the evolution of young gene duplicates.