tbuckley/cabot-search huggingface dataset:
Systemic Therapy of Spontaneous Prostate Cancer in Transgenic Mice with Oncolytic Herpes Simplex Viruses
Authors: Susan Varghese, Samuel D. Rabkin, G. Petur Nielsen, Usha MacGarvey, Renbin Liu, Robert L. Martuza
Journal: Cancer Research (2007)

Abstract Oncolytic viruses are an innovative therapeutic strategy for cancer, wherein viral replication and cytotoxicity are selective for tumor cells. Here we show the efficacy of systemically administered oncolytic viruses for the treatment of spontaneously arising tumors, specifically the use of oncolytic herpes simplex viruses (HSV) administered i.v. to treat spontaneously developing primary and metastatic prostate cancer in the transgenic TRAMP mouse, which recapitulates human prostate cancer progression. Four administrations of systemically delivered NV1023 virus, an HSV-1/HSV-2 oncolytic recombinant, to TRAMP mice at 12 or 18 weeks of age (presence of prostate adenocarcinoma or metastatic disease, respectively) inhibited primary tumor growth and metastases to lymph nodes. Expression of interleukin 12 (IL-12) from NV1042 virus, a derivative of NV1023, was additionally effective, significantly reducing the frequency of development of prostate cancer and lung metastases, even when the mice were treated after the onset of metastasis at 18 weeks of age. NV1042-infected cells, as detected by 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside staining for Lac Z expressed by the virus, were present in prostate tumors 1 week after the final virus injection and viral DNA was detected at 2 weeks after final virus injection by real-time PCR in primary and metastatic tumors but not in liver or blood. No toxicity was observed in any of the treated mice. The efficacy of the IL-12–expressing NV1042 virus in this aggressive prostate cancer model using a clinically relevant treatment paradigm merits its consideration for clinical studies. [Cancer Res 2007;67(19):9371–9]
Telomere Attrition and Decreased Fetuin-A Levels Indicate Accelerated Biological Aging and Are Implicated in the Pathogenesis of Colorectal Cancer
Authors: Fraser Maxwell, Liane M. McGlynn, Hannah C. Muir, Dinesh Talwar, Michaela Benzeval, Tony Robertson, Campbell S. Roxburgh, Donald C. McMillan, Paul G. Horgan, Paul G. Shiels
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Increasing chronological age is a risk factor for many types of cancer including colorectal. An understanding of the biology of aging and factors which regulate it may provide insight into cancer pathogenesis. The role of telomere biology in both the cancer and aging process could prove useful in this regard. Experimental Design: Using quantitative PCR, we determined telomere length in the peripheral blood leukocytes of 64 colorectal cancer (CRC) patients and 1,348 controls. We also measured telomere length in 32 colorectal tumor samples and matched normal tissue. We aimed to assess whether telomere lengths were reflected in circulating mediators of inflammation and redox control factors, including fetuin-A, a circulating modulator of calcium homeostasis. Results: CRC patients had shorter telomeres [adjusted mean ratio of relative telomere repeat copy number to single-copy gene number (RelT/S) = 0.61] compared with chronologically older controls (mean age = 75, adjusted mean RelT/S = 0.70; ANCOVA, P = 0.004). Telomere length in tumor tissue [median = 0.43, interquartile range (IQR) = 0.40] was significantly shorter than adjacent normal tissue (median = 0.65, IQR = 0.28; P = 0.004). Patients with low fetuin-A levels were shown to have significantly shorter telomeres (P = 0.041). Patients with rectal tumors had significantly higher levels of fetuin-A than those with colonic tumors (P = 0.045). Conclusions: We have observed that patients with CRC display clear evidence of telomere attrition compared with controls. This is congruent with accelerated biological aging in the pathogenesis of CRC. An imbalance in redox control mechanisms and calcium homeostasis may be a contributing factor to telomere dynamics in our patients. Furthermore, fetuin-A levels can be used to distinguish between colon and rectal cancers. Clin Cancer Res; 17(17); 5573–81. ©2011 AACR.
Targeting XRCC1 Deficiency in Breast Cancer for Personalized Therapy
Authors: Rebeka Sultana, Tarek Abdel-Fatah, Rachel Abbotts, Claire Hawkes, Nada Albarakati, Claire Seedhouse, Graham Ball, Stephen Chan, Emad A. Rakha, Ian O. Ellis, Srinivasan Madhusudan
Journal: Cancer Research (2012)

XRCC1 is a key component of DNA base excision repair, single strand break repair, and backup nonhomologous end-joining pathway. XRCC1 (X-ray repair cross-complementing gene 1) deficiency promotes genomic instability, increases cancer risk, and may have clinical application in breast cancer. We investigated XRCC1 expression in early breast cancers (n = 1,297) and validated in an independent cohort of estrogen receptor (ER)-α-negative breast cancers (n = 281). Preclinically, we evaluated XRCC1-deficient and -proficient Chinese hamster and human cancer cells for synthetic lethality application using double-strand break (DSB) repair inhibitors [KU55933 (ataxia telangectasia-mutated; ATM inhibitor) and NU7441 (DNA-PKcs inhibitor)]. In breast cancer, loss of XRCC1 (16%) was associated with high grade (P < 0.0001), loss of hormone receptors (P < 0.0001), triple-negative (P < 0.0001), and basal-like phenotypes (P = 0.001). Loss of XRCC1 was associated with a two-fold increase in risk of death (P < 0.0001) and independently with poor outcome (P < 0.0001). Preclinically, KU55933 [2-(4-Morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one] and NU7441 [8-(4-Dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one] were synthetically lethal in XRCC1-deficient compared with proficient cells as evidenced by hypersensitivity to DSB repair inhibitors, accumulation of DNA DSBs, G2-M cell-cycle arrest, and induction of apoptosis. This is the first study to show that XRCC1 deficiency in breast cancer results in an aggressive phenotype and that XRCC1 deficiency could also be exploited for a novel synthetic lethality application using DSB repair inhibitors. Cancer Res; 73(5); 1621-34. ©2012 AACR.
30 Days: Minimum Wage
Authors: Trevor Jackson
Journal: BMJ (2005)

More4, 27 October at 9 pm Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img>![Graphic][4]</img> R emember Morgan Spurlock, the US documentary maker who in the award winning film Super Size Me ate only McDonald's fast food for a month (see BMJ 2004;328: 1266)? Now Spurlock has swapped McDonalds for Mcjobs, in a bid to find out what it is like to live for 30 days on the US minimum wage—$5.15 (£2.90; €4.30) an hour. “Millions of Americans do full time jobs and still live below the poverty line,” he says. Can he and his fiancée, Alex, a vegan chef, hack it? To make things realistic, the pair freeze their … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif
Acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus
Authors: Ricard Farré, Fernando Fornari, Kathleen Blondeau, Michael Vieth, Rita De Vos, Raf Bisschops, Veerle Mertens, Ans Pauwels, Jan Tack, Daniel Sifrim
Journal: Gut (2009)

Background Oesophageal mucosa dilated intercellular spaces (DIS) may be important for symptom perception in non-erosive reflux disease (NERD). Patients with NERD might have DIS even in the proximal oesophagus. We aimed to assess the effect of oesophageal perfusions with acid and weakly acidic solutions on ‘exposed’ and ‘non-exposed’ oesophageal mucosa and its relationship to symptoms in healthy subjects. Methods 14 healthy volunteers underwent upper gastrointestinal endoscopy with biopsies at 3 and 13 cm proximal to the oesophagogastric junction (OGJ). In following sessions, subjects received 30 min perfusions with neutral, weakly acidic, acidic and acidic-bile acid solutions at 5 cm above the EGJ (separated 4 weeks). Biopsies were taken 20 min after perfusions. Electron microscopy was used to measure DIS. Subjects scored heartburn during perfusions using a visual analogue scale. Results (1) Oesophageal perfusion with acid solutions, with or without bile acids, provoked DIS in the ‘exposed’ oesophageal mucosa; (2) oesophageal perfusion with weakly acidic solutions provoked identical changes to those observed after perfusion with acid solutions; (3) distal oesophageal perfusions not only provoked changes in the ‘exposed’ but also in the more proximal ‘non-exposed’ mucosa; and (4) in spite of the presence of perfusion-induced DIS, most healthy subjects did not perceive heartburn during the experiments. Conclusions The human oesophageal mucosa is very sensitive to continuous exposure with acidic and weakly acidic solutions. In spite of the presence of intraluminal acid and DIS, healthy subjects did not experience heartburn, suggesting that NERD patients should have other critical factors underlying their symptoms.
Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection
Authors: Yaseen M. Arabi, Ahmed A. Arifi, Hanan H. Balkhy, Hani Najm, Abdulaziz S. Aldawood, Alaa Ghabashi, Hassan Hawa, Adel Alothman, Abdulaziz Khaldi, Basel Al Raiy
Journal: Annals of Internal Medicine (2014)

Since September 2012, 170 confirmed infections with Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization, including 72 deaths. Data on critically ill patients with MERS-CoV infection are limited.To describe the critical illness associated with MERS-CoV.Case series.3 intensive care units (ICUs) at 2 tertiary care hospitals in Saudi Arabia.12 patients with confirmed or probable MERS-CoV infection.Presenting symptoms, comorbid conditions, pulmonary and extrapulmonary manifestations, measures of severity of illness and organ failure, ICU course, and outcome are described, as are the results of surveillance of health care workers (HCWs) and patients with potential exposure.Between December 2012 and August 2013, 114 patients were tested for suspected MERS-CoV; of these, 11 ICU patients (10%) met the definition of confirmed or probable cases. Three of these patients were part of a health care-associated cluster that also included 3 HCWs. One HCW became critically ill and was the 12th patient in this case series. Median Acute Physiology and Chronic Health Evaluation II score was 28 (range, 16 to 36). All 12 patients had underlying comorbid conditions and presented with acute severe hypoxemic respiratory failure. Most patients (92%) had extrapulmonary manifestations, including shock, acute kidney injury, and thrombocytopenia. Five (42%) were alive at day 90. Of the 520 exposed HCWs, only 4 (1%) were positive.The sample size was small.MERS-CoV causes severe acute hypoxemic respiratory failure and considerable extrapulmonary organ dysfunction and is associated with high mortality. Community-acquired and health care-associated MERS-CoV infection occurs in patients with chronic comorbid conditions. The health care-associated cluster suggests that human-to-human transmission does occur with unprotected exposure.None.
Intraobserver and interobserver variation in the histopathological assessment of liver allograft rejection
Authors: Jake A. Demetris, Steven H. Belle, John Hart, Klaus Lewin, Jurgen Ludwig, Dale C. Snover, Weldon G. Tillery, Katherine Detre
Journal: Hepatology (1991)

A study to determine the reproducibility of histopathological findings and diagnoses of rejection was carried out on a series of 42 liver allograft needle biopsy specimens by five pathologists practicing at four liver transplant centers. Pathologists from each of the four centers read each slide independently on two different occasions and were asked to assess 12 histopathological features and render a diagnosis. For all histological variables, the intrarater agreement was higher than the interrater agreement. Moderate to excellent agreement occurred among the pathologists about all histological variables thought to be important in establishing the diagnosis of acute rejection (i.e., portal tract inflammation, subendothelial inflammation and bile duct damage). Other variables such as lobular disarray, bile duct proliferation and particularly arteritis, however, were only fairly or poorly reproducible. Surprisingly, the diagnosis of acute rejection was more reproducible than the individual histopathological findings that were thought to be the basis for the diagnosis. The agreement for the diagnosis of chronic rejection, however, varied according to observer. We noted that relatively inexperienced observers within this group had some difficulties agreeing with more experienced observers in establishing a diagnosis of chronic rejection. These findings demonstrate that the histopathological diagnosis of acute cellular liver allograft rejection is highly reproducible within a group of experienced pathologists and that this diagnosis can be pooled in a common data base with confidence. (Hepatology 1991;14:751-755).
Applications and Limitations of Hemapheresis
Authors: Arthur J. Silvergleid
Journal: Annual Review of Medicine (1983)

Hemapheresis is the selective collection of any blood component. With the use of automated equipment, hemapheresis has become practical both for procuring specific components for transfusion and for removing specific components considered pathogenic factors in clinical disease. This review considers all aspects of hemapheresis, including its role in blood component procurement and its potential therapeutic applications. Attention is focused on the clinical indications for the use of apheresis-harvested components, and on the rationale for the effectiveness of therapeutic cytapheresis and plasma exchange.
Lung transfer factor and KCO at cardiac frequency 100 beats/min as a guide to impaired function of lung parenchyma.
Authors: S S Chu, J E Cotes
Journal: Thorax (1984)

Transfer factor (TL) and KCO have been measured by the single breath carbon monoxide method in 39 patients with confirmed or suspected lung disease, mostly of occupational origin, and 37 healthy subjects. TL and KCO at an exercise cardiac frequency of 100 beats/min (TL100 and KCO100) and the slopes of the regression of exercise transfer factor and KCO on exercise cardiac frequency (delta TL/delta fC and delta KCO/delta fC) were obtained. The discriminatory performance of these indices in detecting defective gas transfer was compared with that of TL and KCO at rest (TLrest and KCOrest). The slope indices did not distinguish between healthy subjects and patients with emphysema or conditions of the lung parenchyma, including asbestosis. The slope indices also failed to distinguish between individuals with normal and abnormal gas transfer at rest. The indices TL100 and KCO100 contributed additional information not contained in the indices at rest and they merit further study.
Aminoglycoside antibiotics traffic to the Golgi complex in LLC-PK1 cells.
Authors: R Sandoval, J Leiser, B A Molitoris
Journal: Journal of the American Society of Nephrology (1998)

Aminoglycoside antibiotics are known to be internalized via endocytosis and have been associated with subcellular organelle dysfunction; however, the route of intracellular trafficking and their distribution remain largely unknown. To address these questions, a Texas Red conjugate of gentamicin (TRG) was synthesized for dual-labeling experiments with the endoplasmic reticulum, Golgi, and lysosomal markers DiOC6-3, C6-NBD-ceramide, and fluorescent dextrans, respectively. Confocal images were overlaid to determine areas of colocalization. Initial characterization studies of the fluorescent gentamicin analogue revealed that both internalization and accumulation were inhibited by excess unlabeled gentamicin. Furthermore, the fluorescent gentamicin label was colocalized with unlabeled gentamicin, using immunologic techniques. LLC-PK1 cells were exposed to the fluorescent gentamicin in media containing 1 mg/ml labeled gentamicin for 8 h and then either fixed or chased with gentamicin-free media for an additional 16 or 40 h (24 to 48 h total). Studies with fluorescent dextrans revealed rapid intracellular colocalization within the endosomal and lysosomal systems. Neither endoplasmic reticulum nor mitochondrial colocalization could be detected. However, Golgi colocalization was revealed using both confocal and electron microscopic techniques at 8 h of TRG incubation, and continued to be present for an additional 40 h. Protein synthetic rates were quantified and revealed decreased synthesis at the 24-h chase mark. These results suggest that TRG can serve as a fluorescent tracer for aminoglycoside trafficking within cells. The fluorescent marker remained associated with vesicular structures at all times and colocalized with the Golgi apparatus. It is postulated that this early association of gentamicin with the Golgi complex may be an avenue for delivery of aminoglycosides to other intracellular compartments.
Monitoring of minimal residual disease (MRD) is useful to predict prognosis of adult patients with Ph-negative ALL: results of a prospective study (ALL MRD2002 Study)
Authors: Koji Nagafuji, Toshihiro Miyamoto, Tetsuya Eto, Tomohiko Kamimura, Shuichi Taniguchi, Takashi Okamura, Eiichi Ohtsuka, Takashi Yoshida, Masakazu Higuchi, Goichi Yoshimoto, Tomoaki Fujisaki, Yasunobu Abe, Yasushi Takamatsu, Shouhei Yokota, Koichi Akashi, Mine Harada
Journal: Journal of Hematology & Oncology (2013)

Allogeneic hematopoietic stem cell transplantation (HSCT) for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is much more intensive than multi-agent combined chemotherapy, although allogeneic HSCT is associated with increased morbidity and mortality when compared with such chemotherapy. Minimal residual disease (MRD) status has been proven to be a strong prognostic factor for adult patients with Ph-negative ALL. We investigated whether MRD status in adult patients with ALL is useful to decide clinical indications for allogeneic HSCT. We prospectively monitored MRD after induction and consolidation therapy in adult patients with Ph-negative ALL. Of 110 adult ALL patients enrolled between July 2002 and August 2008, 101 were eligible, including 59 Ph-negative patients. MRD status was assessed in 43 patients by the detection of major rearrangements in TCR and Ig and the presence of chimeric mRNA. Thirty-nine patients achieved CR1, and their probabilities of 3-year overall survival and disease-free survival (DFS) were 74% and 56%, respectively. Patients who were MRD-negative after induction therapy (n = 26) had a significantly better 3-year DFS compared with those who were MRD-positive (n = 13; 69% vs. 31%, p = 0.004). All of 3 patients who were MRD-positive following consolidation chemotherapy and did not undergo allogeneic HSCT, relapsed and died within 3 years after CR. These results indicate that MRD monitoring is useful for determining the clinical indications for allogeneic HSCT in the treatment of ALL in CR1.
Developmental regulation of thymocyte susceptibility to deletion by "self"-peptide.
Authors: L M Spain, L J Berg
Journal: The Journal of Experimental Medicine (1992)

The specificity of the T cell receptor (TCR) repertoire for foreign peptide bound to self-major histocompatibility complex (MHC) molecules is determined in large part by positive and negative selection processes in the thymus, yet the mechanisms of these selection events remain unknown. Using in vitro organ culture of thymi isolated from mice transgenic for a TCR-alpha/beta specific for cytochrome c peptide bound to I-Ek, we analyzed the developmental timing of negative selection (deletion). On the basis of the experiments described below, we conclude that all CD4+8+ thymocytes, and only CD4+8+ thymocytes, are susceptible to negative selection mediated by the cytochrome c peptide antigen. First, we found that deletion of thymocytes resulting from addition of the cytochrome c peptide to the thymic organ cultures can occur at the earliest stage of TCR, CD4, and CD8 coexpression. Second, we found that CD4+8+ thymocytes isolated from positively selecting or nonselecting MHC haplotypes were equally efficiently deleted in vitro, suggesting that positive selection is not a prerequisite for deletion. Third, we examined the effects of TCR/ligand avidity on the developmental timing of deletion by varying the concentration of cytochrome c peptide added to the organ cultures. We detected deletion only at the CD4+8+ stage: intermediate concentrations of peptide that resulted in partial deletion of CD4+8+ cells did not eliminate the appearance of mature CD4+8- cells. Finally, we found that CD4+8- thymocytes were resistant to deletion as well as activation by peptide antigen added to the intact organ cultures. Nevertheless, the CD4+8- thymocytes isolated from the peptide-treated organ cultures responded vigorously to peptide presented by spleen cells in vitro. Thus, the T cells were tolerant of (but not anergized by) self-antigen encountered in thymic organ culture. Together, these results indicate that thymocytes susceptible to negative selection are not developmentally distinct from those susceptible to positive selection, and further, that the thymic microenvironment plays a role in regulating the outcome of TCR/ligand interactions.
Gene expression regulation in the context of mouse interspecific mosaic genomes
Authors: David L'Hôte, Catherine Serres, Reiner A Veitia, Xavier Montagutelli, Ahmad Oulmouden, Daniel Vaiman
Journal: Genome biology (2008)

Abstract Background Accumulating evidence points to the mosaic nature of the mouse genome. However, little is known about the way the introgressed segments are regulated within the context of the recipient genetic background. To address this question, we have screened the testis transcriptome of interspecific recombinant congenic mouse strains (IRCSs) containing segments of Mus spretus origin at a homozygous state in a Mus musculus background. Results Most genes (75%) were not transcriptionally modified either in the IRCSs or in the parent M. spretus mice, compared to M. musculus . The expression levels of most of the remaining transcripts were 'dictated' by either M. musculus transcription factors (' trans -driven'; 20%), or M. spretus cis -acting elements (' cis -driven'; 4%). Finally, 1% of transcripts were dysregulated following a cis - trans mismatch. We observed a higher sequence divergence between M. spretus and M. musculus promoters of strongly dysregulated genes than in promoters of similarly expressed genes. Conclusion Our study indicates that it is possible to classify the molecular events leading to expressional alterations when a homozygous graft of foreign genome segments is made in an interspecific host genome. The inadequacy of transcription factors of this host genome to recognize the foreign targets was clearly the major path leading to dysregulation.