tbuckley/cabot-search huggingface dataset:
TIMP-4 Is Regulated by Vascular Injury in Rats
Authors: Clare M. Dollery, Jean R. McEwan, Mingsheng Wang, Qingxiang Amy Sang, Yiliang E. Liu, Y. Eric Shi
Journal: Circulation Research (1999)

The role of basement membrane-degrading matrix metalloproteinases (MMPs) in enabling vascular smooth muscle cell migration after vascular injury has been established in several animal models. In contrast, the role of their native inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), has remained unproven despite frequent coregulation of MMPs and TIMPs in other disease states. We have investigated the time course of expression and localization of TIMP-4 in rat carotid arteries 6 hours, 24 hours, 3 days, 7 days, and 14 days after balloon injury by in situ hybridization, immunohistochemistry, and Western blot analysis. TIMP-4 protein was present in the adventitia of injured carotid arteries from 24 hours after injury. At 7 and 14 days after injury, widespread immunostaining for TIMP-4 was observed throughout the neointima, media, and adventitia of injured arteries. Western blot analysis confirmed the quantitative increase in TIMP-4 protein at 7 and 14 days. In situ hybridization detected increased expression of TIMP-4 as early as 24 hours after injury and a marked induction in neointimal cells 7 days after injury. We then studied the effect of TIMP-4 protein on the migration of smooth muscle cells through a matrix-coated membrane in vitro and demonstrated a 53% reduction in invasion of rat vascular smooth muscle cells. These data and the temporal relationship between the upregulation of TIMP-4, its accumulation, and the onset of collagen deposition suggest an important role for TIMP-4 in the proteolytic balance of the vasculature controlling both smooth muscle migration and collagen accumulation in the injured arterial wall.
Re: Neurocognitive Functioning in Adult Survivors of Childhood Noncentral Nervous System Cancers
Authors: A. M. Morelli, S. Ravera, I. Panfoli
Journal: JNCI Journal of the National Cancer Institute (2011)

Kadan-Lottick et al. (1) recently published an article in the Journal on the analysis of neurocognitive functioning in adult survi- vors of childhood noncentral nervous system cancers, in which they concluded that there is a statistically significant higher percentage of neurocognitive functioning impairment among these adult survivors than among their siblings. They found that radiation therapy and also chemotherapy (mostly with methotrexate, which hinders DNA synthesis) of noncentral nervous system cancers are associated with delayed impairment in task efficiency (1). Albini et al. (2) showed in the Journal that cancer chemotherapeutic agents (eg, 5-fluoro- uracil, capecitabine, and cytarabine) also cause cardiotoxicity, an increasingly rele- vant toxic side effect of this therapy. A stronger association among patients in these cells, the number of mitochondria remained constant. These results establish a link between myelin sheath construction and mitochondrial proliferation because oligodendrocytes produce myelin in the central nervous system. In fact, mitochon- drial DNA, which has a higher turnover than nuclear DNA, is more likely to be sensitive to antimetabolites that inhibit DNA synthesis than nuclear DNA. Therefore, cells with high mitochondrial turnover, such as oligodendrocytes (5), are more likely to be sensitive to antimetabo- lites that inhibit DNA synthesis. We have reported (7) that extramito- chondrial oxidative production of ATP takes place in isolated myelin vesicles, indi- cating that myelin production may be asso- ciated with extramitochondrial oxidative phosphorylation. Such a mechanism could reconcile the high energy demand of the brain with the scarcity of mitochondria in brain tissue (7). In light of our recent report (7), it is tempting to hypothesize that the fate of mitochondria in oligodendrocytes is to be delivered to the site of sheath formation so that they can fuse with the myelin sheath. Although this process remains to be docu- mented, it is in keeping with our increasing knowledge about mitochondrial dynamics and with the trophic role that has been at- tributed to myelin. Because oligodendro- cytes have an elevated mitochondrial turnover and because the myelin sheath apparently contains components of oxida- tive phosphorylation, future investigations should examine the hypotheses that the cognitive impairment after cancer therapy with antimetabolites is a delayed conse- quence of defective myelin sheath produc- tion and that impairment of oxidative phosphorylation, which is essential for chemical energy production, is the ultimate cause of demyelination.
Colorectal Papillomavirus Infection in Patients with Colorectal Cancer
Authors: Sohrab Bodaghi, Koji Yamanegi, Shu-Yuan Xiao, Maria Da Costa, Joel M. Palefsky, Zhi-Ming Zheng
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Infection with human papillomaviruses (HPV) is associated with the development of cervical cancer, but whether HPVs have a role in colorectal cancer remains controversial. Experimental Designs: To determine the relationship between HPV and colorectal cancer, we did a retrospective, controlled study using tumor and tumor-adjacent colorectal tissues dissected from patients with colorectal cancer, as well as colorectal tissues from control individuals with no cancer. The samples were processed in a blinded fashion for nested PCR and in situ PCR detection of HPV DNAs. The PCR products were gel-purified and sequenced for HPV genotyping. Results: We found that colorectal tissues from 28 of 55 (51%) patients with colorectal cancer were positive for HPV DNA. Colorectal tissues from all 10 control individuals were negative for HPV DNA (P = 0.0034). Of the 107 usable (GAPDH+) samples collected as paired colorectal tissues (tumor and tumor-adjacent tissues) from the patients, 38 (36%) had HPV16 (n = 31), HPV18 (n = 5), or HPV45 (n = 2), with HPV DNA in both tumor and tumor-adjacent tissues of 10 paired samples, 13 in only the tumor, and 5 in only tumor-adjacent tissues. In situ PCR detection of the tumor tissues confirmed the presence of HPV DNA in tumor cells. Conclusion: Our results suggest that colorectal HPV infection is common in patients with colorectal cancer, albeit at a low DNA copy number, with HPV16 being the most prevalent type. HPV infection may play a role in colorectal carcinogenesis.
Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC
Authors: S.-H. I. Ou, P.A. Jänne, C.H. Bartlett, Y. Tang, D.-W. Kim, G.A. Otterson, L. Crinò, P. Selaru, D.P. Cohen, J.W. Clark, G.J. Riely
Journal: Annals of Oncology (2014)
Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study
Authors: Lene Sofie Granfeldt Østgård, Bruno C. Medeiros, Henrik Sengeløv, Mette Nørgaard, Mette Klarskov Andersen, Inge Høgh Dufva, Lone Smidstrup Friis, Eigil Kjeldsen, Claus Werenberg Marcher, Birgitte Preiss, Marianne Severinsen, Jan Maxwell Nørgaard
Journal: Journal of Clinical Oncology (2015)

Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age.In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs.Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61).Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.
Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype
Authors: Antony Cougnoux, Guillaume Dalmasso, Ruben Martinez, Emmanuel Buc, Julien Delmas, Lucie Gibold, Pierre Sauvanet, Claude Darcha, Pierre Déchelotte, Mathilde Bonnet, Denis Pezet, Harald Wodrich, Arlette Darfeuille-Michaud, Richard Bonnet
Journal: Gut (2014)

<h3>Background</h3> <i>Escherichia coli</i> strains harbouring the <i>pks</i> island (<i>pks</i>+ <i>E. coli</i>) are often seen in human colorectal tumours and have a carcinogenic effect independent of inflammation in an AOM/IL-10<sup>−/−</sup> (azoxymethane/interleukin) mouse model. <h3>Objective</h3> To investigate the mechanism sustaining <i>pks</i>+ <i>E. coli</i>-induced carcinogenesis. <h3>Method</h3> Underlying cell processes were investigated <i>in vitro</i> and <i>in vivo</i> (xenograft model) using intestinal epithelial cells infected by <i>pks</i>+ <i>E. coli</i> or by an isogenic mutant defective for <i>pks</i> (<i>pks</i>− <i>E. coli</i>). The results were supported by data obtained from an AOM/DSS (azoxymethane/dextran sodium sulphate) colon cancer mouse model and from human colon cancer biopsy specimens colonised by <i>pks</i>+ <i>E. coli</i> or <i>pks− E. coli</i>. <h3>Results</h3> Colibactin-producing <i>E. coli</i> enhanced tumour growth in both xenograft and AOM/DSS models. Growth was sustained by cellular senescence (a direct consequence of small ubiquitin-like modifier (SUMO)-conjugated p53 accumulation), which was accompanied by the production of hepatocyte growth factor (HGF). The underlying mechanisms involve microRNA-20a-5p, which targets SENP1, a key protein regulating p53 deSUMOylation. These results are consistent with the expression of SENP1, microRNA-20a-5p, HGF and phosphorylation of HGF receptor found in human and mouse colon cancers colonised by <i>pks</i>+ <i>E. coli</i>. <h3>Conclusion</h3> These data reveal a new paradigm for carcinogenesis, in which colibactin-induced senescence has an important role.
Lymph node ratio as a prognostic factor in elderly patients with pathological N1 non-small cell lung cancer
Authors: J. P. Wisnivesky, J. Arciniega, G. Mhango, J. Mandeli, E. A. Halm
Journal: Thorax (2010)

<h3>Background</h3> Lymph node (LN) metastasis is an important predictor of survival for patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of the extent of LN involvement among patients with N1 disease remains unknown. A study was undertaken to evaluate whether involvement of a higher number of N1 LNs is associated with worse survival independent of known prognostic factors. <h3>Methods</h3> Using the Surveillance, Epidemiology and End Results-Medicare database, 1682 resected patients with N1 NSCLC diagnosed between 1992 and 2005 were identified. As the number of positive LNs is confounded by the total number of LNs sampled, the cases were classified into three groups according to the ratio of positive to total number of LNs removed (LN ratio (LNR)): ≤0.15, 0.16–0.5 and &gt;0.5. Lung cancer-specific and overall survival was compared between these groups using Kaplan–Meier curves. Stratified and Cox regression analyses were used to evaluate the relationship between the LNR and survival after adjusting for potential confounders. <h3>Results</h3> Lung cancer-specific and overall survival was lower among patients with a high LNR (p&lt;0.0001 for both comparisons). Median lung cancer-specific survival was 47 months, 37 months and 21 months for patients in the ≤0.15, 0.16–0.5 and &gt;0.5 LNR groups, respectively. In stratified and adjusted analyses, a higher LNR was also associated with worse lung cancer-specific and overall survival. <h3>Conclusions</h3> The extent of LN involvement provides independent prognostic information in patients with N1 NSCLC. This information may be used to identify patients at high risk of recurrence who may benefit from aggressive postoperative therapy.
The Address Delivered in the Section of Pathology
Authors: J. H. Jackson
Journal: BMJ (1882)

Subsequent recent investigations have confirmed the author's views regarding the existence of this bacterium.He has now observed it in all the phases through which a bacterial organism may be traced, and will shortly be able to publish an account of methods by which it can be more readily observed.-August,2882.THE DEATH-RATE OF BILSTON last year was the most satisfactory on record.The average death-rate of the place thirty years ago was from 31 to 32 per IOOO; last year, thanks to sanitary improvement and the efforts of the medical oficer of health, it was reduced to I6.I per IOOO, which must be regarded as very satisfactory for a Black County town.Onl1y 31 deaths, moreover, out of the 38 I recorded were due to in- fectious diese, a result which may, or may not, be due to Bilston being "one of the best drained towns in the country."i
Activation of Kupffer cells and caspase-3 involved in rat hepatocyte apoptosis induced by endotoxin
Authors: Eisaku Hamada, Toshirou Nishida, Yasuo Uchiyama, Jun-ichi Nakamura, Kyoko Isahara, Hiromu Kazuo, Tai-Ping Huang, Takashi Momoi, Toshinori Ito, Hikaru Matsuda
Journal: Journal of Hepatology (1999)
Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production
Authors: Krisztián Németh, Asada Leelahavanichkul, Peter S T Yuen, Balázs Mayer, Alissa Parmelee, Kent Doi, Pamela G Robey, Kantima Leelahavanichkul, Beverly H Koller, Jared M Brown, Xuzhen Hu, Ivett Jelinek, Robert A Star, Éva Mezey
Journal: Nature Medicine (2008)
Geriatric Factors Predict Chemotherapy Feasibility: Ancillary Results of FFCD 2001-02 Phase III Study in First-Line Chemotherapy for Metastatic Colorectal Cancer in Elderly Patients
Authors: Thomas Aparicio, Jean-Louis Jouve, Laurent Teillet, Dany Gargot, Fabien Subtil, Valérie Le Brun-Ly, Jacques Cretin, Christophe Locher, Olivier Bouché, Gilles Breysacher, Jacky Charneau, Jean-François Seitz, Mohamed Gasmi, Laetitia Stefani, Mohamed Ramdani, Thierry Lecomte, Emmanuel Mitry
Journal: Journal of Clinical Oncology (2013)

Elderly patients form a heterogeneous population. Evaluation of geriatric factors may help evaluate a patient's health status to better adapt treatment.Elderly patients with previously untreated metastatic colorectal cancer (mCRC) were randomly assigned to receive fluorouracil (FU) -based chemotherapy either alone or in combination with irinotecan (IRI) in the Fédération Francophone de Cancérologie Digestive (FFCD) 2001-02 study. Sites participating in the geriatric substudy completed geriatric screening tools to perform prognostic factor analyses for treatment safety during the first 4 months after treatment initiation.The geriatric score was calculated in 123 patients (44%). Median age was 80 years (range, 75 to 91 years). The Charlson comorbidity index was ≤ 1 in 75%, Mini-Mental State Examination (MMSE) score was ≤ 27/30 in 31%, and Instrumental Activities of Daily Living (IADL) showed impairment in 34% of the patients. Seventy-one patients (58%) had grade 3 to 4 toxicity, 41 (33%) had a dose-intensity reduction of more than 33%, and 54 (44%) had at least one unexpected hospitalization during the first 4 months after starting treatment. In multivariate analysis, significant predictive factors for grade 3-4 toxicity were IRI arm (odds ratio [OR], 5.03), MMSE ≤ 27/30 (OR, 3.84), and impaired IADL (OR, 4.67); for dose-intensity reduction of > 33%, the significant predictive factors were alkaline phosphates > 2 × upper limit of normal (OR, 4.16) and IRI arm (OR, 6.85); and for unexpected hospitalization, significant predictive factors were MMSE ≤ 27/30 (OR, 4.56) and Geriatric Depression Scale ≤ 2 (OR, 5.52).Geriatric factors (MMSE and IADL) are predictive of severe toxicity or unexpected hospitalization (MMSE) in a randomized prospective phase III study in mCRC. These results suggest that cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy.
Cost-effectiveness of surgery and its policy implications for global health: a systematic review and analysis
Authors: Tiffany E Chao, Ketan Sharma, Morgan Mandigo, Lars Hagander, Stephen C Resch, Thomas G Weiser, John G Meara
Journal: The Lancet Global Health (2014)

The perception of surgery as expensive and complex might be a barrier to its widespread acceptance in global health efforts. We did a systematic review and analysis of cost-effectiveness studies that assess surgical interventions in low-income and middle-income countries to help quantify the potential value of surgery.We searched Medline for all relevant articles published between Jan 1, 1996 and Jan 31, 2013, and searched the reference lists of retrieved articles. We converted all results to 2012 US$. We extracted cost-effectiveness ratios (CERs) and appraised economic assessments for their methodological quality using the 10-point Drummond checklist.Of the 584 identified studies, 26 met full inclusion criteria. Together, these studies gave 121 independent CERs in seven categories of surgical interventions. The median CER of circumcision ($13·78 per disability-adjusted life year [DALY]) was similar to that of standard vaccinations ($12·96-25·93 per DALY) and bednets for malaria prevention ($6·48-22·04 per DALY). Median CERs of cleft lip or palate repair ($47·74 per DALY), general surgery ($82·32 per DALY), hydrocephalus surgery ($108·74 per DALY), and ophthalmic surgery ($136 per DALY) were similar to that of the BCG vaccine ($51·86-220·39 per DALY). Median CERs of caesarean sections ($315·12 per DALY) and orthopaedic surgery ($381·15 per DALY) are more favourable than those of medical treatment for ischaemic heart disease ($500·41-706·54 per DALY) and HIV treatment with multidrug antiretroviral therapy ($453·74-648·20 per DALY).Our findings suggest that many essential surgical interventions are cost-effective or very cost-effective in resource-poor countries. Quantification of the economic value of surgery provides a strong argument for the expansion of global surgery's role in the global health movement. However, economic value should not be the only argument for resource allocation--other organisational, ethical, and political arguments can also be made for its inclusion.
Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression
Authors: D. Jeffrey Newport, Linda L. Carpenter, William M. McDonald, James B. Potash, Mauricio Tohen, Charles B. Nemeroff
Journal: American Journal of Psychiatry (2015)

Objective: The authors conducted a systematic review and meta-analysis of ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression. Method: Searches of MEDLINE, PsycINFO, and other databases were conducted for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes were rates of treatment response and transient remission of symptoms. Secondary outcomes included change in depression symptom severity and the frequency and severity of dissociative and psychotomimetic effects. Results for each NMDA antagonist were combined in meta-analyses, reporting odds ratios for dichotomous outcomes and standardized mean differences for continuous outcomes. Results: Ketamine (seven trials encompassing 147 ketamine-treated participants) produced a rapid, yet transient, antidepressant effect, with odds ratios for response and transient remission of symptoms at 24 hours equaling 9.87 (4.37–22.29) and 14.47 (2.67–78.49), respectively, accompanied by brief psychotomimetic and dissociative effects. Ketamine augmentation of ECT (five trials encompassing 89 ketamine-treated participants) significantly reduced depressive symptoms following an initial treatment (Hedges’ g=0.933) but not at the conclusion of the ECT course. Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, d-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects. Conclusions: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.
Endogenous angiotensin II contributes to basal peripheral vascular tone in sodium deplete but not sodium replete man
Authors: David E Newby, Satoko Masumori, Neil R Johnston, Nicholas A Boon, David J Webb
Journal: Cardiovascular Research (1997)

Objective: Both endothelin-1 and nitric oxide make important contributions to the maintenance of basal peripheral arteriolar tone. However, the role of angiotensin II, a key hormone regulating cardiovascular and renal function, in the regulation of peripheral vascular tone has not been fully characterised. Methods: Using local intra-arterial administration of losartan, a selective angiotensin II type 1 (AT1) receptor antagonist, we examined the contribution of endogenous angiotensin II to the maintenance of basal and sympathetically stimulated vascular tone in the forearm of healthy man under conditions of sodium repletion and depletion. The effects of losartan on responses to exogenous angiotensin I, angiotensin II, bradykinin and noradrenaline were also determined. Results: Losartan, in keeping with its actions as a selective AT1 receptor antagonist, inhibited responses to angiotensin I and II, but had no effect on responses to bradykinin or noradrenaline. The dose of angiotensin II required to cause a 20% vasoconstriction was 40- and 250-fold greater with 30 and 300 μg/min of losartan, respectively. However, in sodium replete subjects, losartan alone caused no significant changes in basal forearm blood flow (95% confidence interval of −7.2 to +8.0%), forearm vascular resistance or sympathetically stimulated forearm vasoconstriction. Sodium depletion elevated plasma renin activity and angiotensin II concentrations (p≤0.002) after which acute local administration of losartan increased forearm blood flow in a dose dependent manner (maximum of 69±17%; p<0.001). Conclusions: Endogenous angiotensin II does not contribute to the acute local maintenance of basal peripheral vascular tone in healthy man except under conditions of renin-angiotensin system activation such as sodium depletion.