tbuckley/cabot-search huggingface dataset:
Mechanism of Pneumocystis carinii attachment to cultured rat alveolar macrophages.
Authors: S T Pottratz, W J Martin
Journal: Journal of Clinical Investigation (1990)

Pneumocystis carinii (PC) pneumonia begins as an intra-alveolar process resulting in injury to the alveolar epithelium with subsequent invasion of the lung interstitium. The clearance of PC organisms from the alveolar space is a critical function of alveolar macrophages (AM), the resident alveolar phagocytic cells. In this study the mechanism of PC attachment to AM was determined using 51Cr-labeled organisms, with PC attachment reaching a maximum of 18.9 +/- 2.5% after 4 h. Attachment was significantly decreased by preincubation of the AM with a monoclonal anti-fibronectin antibody directed against the cell attachment site of fibronectin (from 17.8 +/- 2.2% to 8.3 +/- 1.0%, P less than 0.01), or by addition of the fibronectin cell binding site analogue Arg-Gly-Asp-Ser (RGDS) (from 18.1 +/- 2.3% to 2.9 +/- 0.8%, P less than 0.01). An anti-fibronectin monoclonal antibody directed against the heparin binding domain of fibronectin had no effect on PC attachment. Addition of the specific calcium ion chelating agent EGTA to the culture media similarly decreased attachment from 16.9 +/- 2.0% to 5.1 +/- 1.1% (P less than 0.01). Fibronectin-mediated attachment of PC to AM did not result in phagocytosis of the organisms by the AM as determined by chemiluminescence measurements. Therefore, the data indicate that PC attachment to AM is a calcium-dependent process mediated by the cell binding domain of fibronectin which does not trigger a phagocytic response by the AM.
Retinal and Gingival Hemorrhaging and Chronic Hyperglycemia
Authors: Philippe P. Hujoel, Marni Stott-Miller
Journal: Diabetes Care (2010)

OBJECTIVE To assess the hypothesis that retinopathies are indicative of systemic microvascular injury. RESEARCH DESIGN AND METHODS The only U.S. national survey assessing microvascular hemorrhaging at two distinct anatomical sites was the National Health and Nutrition Examination Survey (1988–1994). The systemic microvascular injury hypothesis was assessed by modeling the association of retinal and gingival hemorrhaging and the factors that explain this association. RESULTS Individuals in whom one or more in five gingival sites was hemorrhaging had a 57% increased odds for retinal hemorrhaging (95% CI: 1.26–1.94). This association between retinal and gingival hemorrhaging was 51% explained by A1C concentrations. Retinal and gingival hemorrhaging exhibited the signature J-shaped prevalence patterns when plotted as a function of A1C concentrations. CONCLUSIONS Gingival hemorrhaging reflected on retinal hemorrhaging, and both shared chronic hyperglycemia as an explanatory marker. These epidemiological findings support the hypothesis that retinopathies are reflective of systemic microvascular injury.
PCI-24781 Induces Caspase and Reactive Oxygen Species–Dependent Apoptosis Through NF-κB Mechanisms and Is Synergistic with Bortezomib in Lymphoma Cells
Authors: Savita Bhalla, Sriram Balasubramanian, Kevin David, Mint Sirisawad, Joseph Buggy, Lauren Mauro, Sheila Prachand, Richard Miller, Leo I. Gordon, Andrew M. Evens
Journal: Clinical Cancer Research (2009)

We investigated the cytotoxicity and mechanisms of cell death of the broad-spectrum histone deacetylase (HDAC) inhibitor PCI-24781, alone and combined with bortezomib in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines and primary lymphoproliferative (CLL/SLL) cells.Apoptosis, mitochondrial membrane potential, cell cycle analysis, and reactive oxygen species (ROS) were measured by flow cytometry, whereas caspase activation was determined by Western blot. Nuclear factor kappaB (NF-kappaB)-related mRNAs were quantified by reverse transcription-PCR, NF-kappaB-related proteins by Western blotting, and NF-kappaB DNA-binding activity by electromobility shift assay. Finally, gene expression profiling was analyzed.PCI-24781 induced concentration-dependent apoptosis that was associated with prominent G(0)/G(1) arrest, decreased S-phase, increased p21 protein, and increased ROS in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Dose-dependent apoptosis with PCI-24781 was also seen among primary CLL/SLL cells. PCI-24781-induced apoptosis was shown to be ROS- and caspase-dependent. Combined PCI-24781/bortezomib treatment resulted in strong synergistic apoptosis in all non-Hodgkin lymphoma lines (combination indices, 0.19-0.6) and was additive in Hodgkin lymphoma and primary CLL/SLL cells. Further, PCI-24781/bortezomib resulted in increased caspase cleavage, mitochondrial depolarization, and histone acetylation compared with either agent alone. Gene expression profiling showed that PCI-24781 alone significantly down-regulated several antioxidant genes, proteasome components, and NF-kappaB pathway genes, effects that were enhanced further with bortezomib. Reverse transcription-PCR confirmed down-regulation of NF-kappaB1 (p105), c-Myc, and IkappaB-kinase subunits, where NF-kappaB DNA binding activity was decreased.We show that PCI-24781 results in increased ROS and NF-kappaB inhibition, leading to caspase-dependent apoptosis. We also show that bortezomib is synergistic with PCI-24781. This combination or PCI-24781 alone has potential therapeutic value in lymphoma.
Long-term human hematopoiesis in the SCID-hu mouse.
Authors: R Namikawa, K N Weilbaecher, H Kaneshima, E J Yee, J M McCune
Journal: The Journal of Experimental Medicine (1990)

Coimplantation of small fragments of human fetal thymus and fetal liver into immunodeficient SCID mice resulted in the formation of a unique structure (Thy/Liv). Thereafter, the SCID-hu mice showed reproducible and long-term reconstitution of human hematopoietic activity. For periods lasting 5-11 mo after transplantation, active T lymphopoiesis was observed inside the grafts and cells that were negative for T cell markers were found to have colony-forming units for granulocyte/macrophage (CFU-GM) and erythroid burst-forming unit (BFU-E) activity in the methylcellulose colony assay. In addition, structures similar to normal human bone marrow were observed inside the Thy/Liv grafts, consisting of blast cells, mature and immature forms of myelomonocytic cells, and megakaryocytes. These data indicate long-term maintenance, in vivo, of human progenitor cells for the T lymphoid, myelomonocytic, erythroid, and megakaryocytic lineages. The role of the implanted fetal liver fragments was analyzed using HLA-mismatched Thy/Liv implants. The HLA type of the liver donor was found on T cells and macrophages in the graft. In addition, cells grown in the methylcellulose colony assay and cells in a bone marrow-like structure, the "thymic isle," expressed the HLA type of the liver donor. Thus, the Thy/Liv implants provided a microenvironment in which to follow human hematopoietic progenitor cells for multiple lineages. The formation of the Thy/Liv structures also results in a continuous source of human T cells in the peripheral circulation of the SCID-hu mouse. Though present for 5-11 mo, these cells did not engage in a xenograft (graft-versus-host) reaction. This animal model, the first in which multilineage human hematopoietic activity is maintained for long periods of time, should be useful for the analysis of human hematopoiesis in vivo.
Institutional Clinical Trial Accrual Volume and Survival of Patients With Head and Neck Cancer
Authors: Evan J. Wuthrick, Qiang Zhang, Mitchell Machtay, David I. Rosenthal, Phuc Felix Nguyen-Tan, André Fortin, Craig L. Silverman, Adam Raben, Harold E. Kim, Eric M. Horwitz, Nancy E. Read, Jonathan Harris, Qian Wu, Quynh-Thu Le, Maura L. Gillison
Journal: Journal of Clinical Oncology (2014)

National Comprehensive Cancer Network guidelines recommend patients with head and neck cancer (HNC) receive treatment at centers with expertise, but whether provider experience affects survival is unknown.The effect of institutional experience on overall survival (OS) in patients with stage III or IV HNC was investigated within a randomized trial of the Radiation Therapy Oncology Group (RTOG 0129), which compared cisplatin concurrent with standard versus accelerated fractionation radiotherapy. As a surrogate for experience, institutions were classified as historically low- (HLACs) or high-accruing centers (HHACs) based on accrual to 21 RTOG HNC trials (1997 to 2002). The effect of accrual volume on OS was estimated by Cox proportional hazards models.Median RTOG accrual (1997 to 2002) at HLACs was four versus 65 patients at HHACs. Analysis included 471 patients in RTOG 0129 (2002 to 2005) with known human papillomavirus and smoking status. Patients at HLACs versus HHACs had better performance status (0: 62% v 52%; P = .04) and lower T stage (T4: 26.5% v 35.3%; P = .002) but were otherwise similar. Radiotherapy protocol deviations were higher at HLACs versus HHACs (18% v 6%; P < .001). When compared with HHACs, patients at HLACs had worse OS (5 years: 51.0% v 69.1%; P = .002). Treatment at HLACs was associated with increased death risk of 91% (hazard ratio [HR], 1.91; 95% CI, 1.37 to 2.65) after adjustment for prognostic factors and 72% (HR, 1.72; 95% CI, 1.23 to 2.40) after radiotherapy compliance adjustment.OS is worse for patients with HNC treated at HLACs versus HHACs to cooperative group trials after accounting for radiotherapy protocol deviations. Institutional experience substantially influences survival in locally advanced HNC.
Replication of association of IL1 gene complex members with ankylosing spondylitis in Taiwanese Chinese
Authors: C-T Chou
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To test the association of interleukin 1 (IL1) gene family members with ankylosing spondylitis (AS), previously reported in Europid subjects, in an ethnically remote population. <b>Methods:</b> 200 Taiwanese Chinese AS patients and 200 ethnically matched healthy controls were genotyped for five single nucleotide polymorphisms (SNPs) and the IL1RN.VNTR, markers previously associated with AS. Allele, genotype, and haplotype frequencies were compared between cases and controls. <b>Results:</b> Association of alleles and genotypes of the markers IL1F10.3, IL1RN.4, and IL1RN.VNTR was observed with AS (p&lt;0.05). Haplotypes of pairs of these markers and of the markers IL1RN.6/1 and IL1RN.6/2 were also significantly associated with AS. The strongest associations observed were with the marker IL1RN.4, and with the two-marker haplotype IL1RN.4–IL1RN.VNTR (both p = 0.004). Strong linkage disequilibrium was observed between all marker pairs except those involving IL1B-511 (D′ 0.4 to 0.9, p&lt;0.01). <b>Conclusions:</b> The IL1 gene cluster is associated with AS in Taiwanese Chinese. This finding provides strong statistical support that the previously observed association of this gene cluster with AS is a true positive finding. These authors contributed equally to the study.
Small GTPase R-Ras Regulates Integrity and Functionality of Tumor Blood Vessels
Authors: Junko Sawada, Takeo Urakami, Fangfei Li, Akane Urakami, Weiquan Zhu, Minoru Fukuda, Dean Y. Li, Erkki Ruoslahti, Masanobu Komatsu
Journal: Cancer Cell (2012)
High IgA rheumatoid factor levels are associated with poor clinical response to tumour necrosis factor inhibitors in rheumatoid arthritis
Authors: F. Bobbio-Pallavicini, R. Caporali, C. Alpini, S. Avalle, O. M Epis, C. Klersy, C. Montecucco
Journal: Annals of the Rheumatic Diseases (2006)

To investigate whether rheumatoid factor isotypes and anti-cyclic citrullinated peptide (anti-CCP) antibodies are related to clinical response in patients with rheumatoid arthritis treated with tumour necrosis factor alpha (TNFalpha) inhibitors.The study was carried out on 132 patients with advanced rheumatoid arthritis refractory to disease-modifying antirheumatic drugs. Patients were treated with infliximab (n = 63), etanercept (n = 35) or adalimumab (n = 34). All patients completed 1 year of follow-up, and 126 were evaluable for clinical response according to the disease activity score (DAS) criteria. IgM, IgA and IgG rheumatoid factors and anti-CCP antibodies were assessed by ELISA both before anti-TNFalpha treatment and 1 year later.The DAS response was reached in 66% of evaluable patients (61% infliximab, 65% etanercept and 76% adalimumab; p = 0.354). A significant reduction in the rheumatoid factor level was reported by all treatment groups after 1 year. The frequency of positive tests for the different antibodies did not differ between responders and non-responders at baseline; however, significantly higher IgA rheumatoid factor levels were reported by the non-responder group (130.4 U/ml (interquartile range 13.8-276.7) v 24.8 U/ml (10.2-90.8); p = 0.003). A significant decrease (p<0.001) in the levels of all rheumatoid factor isotypes in the responder group was reported after 1 year of treatment, whereas anti-CCP antibody levels were not significantly affected.According to the clinical response, anti-TNFalpha agents seem to reduce IgM, IgG and IgA rheumatoid factor levels. More interestingly, high pretreatment levels of IgA rheumatoid factor are associated with a poor clinical response to TNFalpha inhibitors.
Improving Care for Depression in Patients With Comorbid Substance Misuse
Authors: Katherine E Watkins, Susan M Paddock, Lily Zhang, Kenneth B Wells
Journal: American Journal of Psychiatry (2006)

The authors investigated whether quality improvement programs for depression would be effective among substance misusers and whether there would be a differential program-by-comorbidity effect.A group-level randomized controlled trial (Partners in Care) compared two quality improvement programs for depression with usual care. Consecutive patients (N=27,332) from six managed care organizations in five states were screened, and 1,356 were enrolled: 443 received usual care while the rest entered a quality improvement program involving either medication (N=424) or therapy (N=489). Multiple logistic regression was used to test hypotheses and compute standardized predictions of the adjusted rates of depression and use of psychotherapy and antidepressants.Under usual care conditions, depressed patients with substance misuse had an increased probability of ongoing depression despite higher rates of overall appropriate treatment. Among clients with comorbid substance misuse, the quality improvement programs were associated with improved depression outcomes at 12 months and increased antidepressant use at 6 months. Among clients with no substance misuse, the quality improvement programs improved depression outcomes at 6 months and were associated with increased treatment utilization.Co-occurring substance misuse is associated with depression and with increased risk for poorer depression treatment outcomes under usual care conditions. Quality improvement programs can significantly reduce the likelihood of probable depressive disorders in depressed patients with and without comorbid substance misuse. No consistent evidence was found for a differential program-by-comorbidity effect except for a suggestion of greater increase in psychotherapy among individuals with no substance misuse.
SULFUR AMINO ACID METABOLISM: Pathways for Production and Removal of Homocysteine and Cysteine
Authors: Martha H. Stipanuk
Journal: Annual Review of Nutrition (2004)

▪ Abstract Tissue concentrations of both homocysteine (Hcy) and cysteine (Cys) are maintained at low levels by regulated production and efficient removal of these thiols. The regulation of the metabolism of methionine and Cys is discussed from the standpoint of maintaining low levels of Hcy and Cys while, at the same time, ensuring an adequate supply of these thiols for their essential functions. S-Adenosylmethionine coordinately regulates the flux through remethylation and transsulfuration, and glycine N-methyltransferase regulates flux through transmethylation and hence the S-adenosylmethionine/S-adenosylhomocysteine ratio. Cystathionine β-synthase activity is also regulated in response to the redox environment, and transcription of the gene is hormonally regulated in response to fuel supply (insulin, glucagon, and glucocorticoids). The H 2 S-producing capacity of cystathionine γ-lyase may be regulated in response to nitric oxide. Cys is substrate for a variety of anabolic and catabolic enzymes. Its concentration is regulated primarily by hepatic Cys dioxygenase; the level of Cys dioxygenase is upregulated in a Cys-responsive manner via a decrease in the rate of polyubiquitination and, hence, degradation by the 26S proteasome.
NPY's mixed messages
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

A stress hormone sends mixed signals to immune cells, according to a study on page 1527. Wheway and colleagues show that neuropeptide Y (NPY) activates antigen-presenting cells (APCs) but shuts off T cells. If correctly sequenced, these activities would both turn on and then limit certain immune responses.NPY is an abundant neuropeptide that is released from sympathetic nerve endings. In the brain, NPY regulates physiological and emotional processes, including metabolism, heart rate, and depression. NPY is also produced by activated immune cells and has been shown to dampen cytokine production by macrophages and inhibit the killer activity of natural killer cells.






Figure 

Neuropeptide Y (NPY) stimulates cytokine production from antigen-presenting cells, but inhibits it from T cells.




The effects of NPY on T cells, however, have been controversial. Treatment with NPY ameliorates autoimmune disease in a mouse model of multiple sclerosis, suggesting a suppressive effect on the disease-inducing T helper (Th)-1 cells. But mice lacking the major lymphoid receptor for NPY (Y1) were protected from colitis, another Th1-driven autoimmune disease, suggesting that NPY signaling normally activates Th1 cells.

The study by Wheway and colleagues helps clear up these conflicting reports. They show that NPY indeed inhibits Th1 responses, as T cells from Y1-deficient mice produced more interferon (IFN)-γ than wild-type cells when stimulated in vitro. When transferred, Y1-deficient T cells were hyperactive and triggered more severe colitis in recipient mice than did wild-type T cells.

However, the receptor-deficient mice themselves were resistant to T cell–mediated colitis when treated with an intestinal irritant. The defect was traced to APCs, which could not be activated in the absence of NPY signaling. APCs from the Y1-deficient mice failed to produce the Th1-promoting cytokines interleukin-12 and TNF and could not activate naive T cells. These mice were thus protected because the T cell response never got started.

How is a T cell response ever mounted if the same signal that turns on the APC turns off the T cell? The authors suspect that it comes down to timing. The expression of the Y1 receptor on T cells might be induced only after activation, thus providing a negative feedback loop that keeps activated T cells from running amok. The authors now plan to study NPY-induced signaling in different cell types to determine how the same molecule tells some cells to go and others to stop.
Improving the detection rate of early gastric cancer requires more than open access gastroscopy: a five year study
Authors: Z Suvakovic, M G Bramble, R Jones, C Wilson, N Idle, J Ryott
Journal: Gut (1997)

Background/aims —To explore the reasons why patients with gastric cancer continue to present with advanced disease despite open access gastroscopy. Patients —All patients diagnosed with gastric cancer between 1 August 1989 and 31 July 1994. Methods —A retrospective study of the presentation of gastric cancer in South Tees; patients were diagnosed at open access gastroscopy or referred through conventional channels. Primary care records of 81 patients dying between 1991 and 1995 were analysed for previous symptoms, investigations, and antisecretory drug therapy. Findings were compared with 200 age and sex matched controls. Results —The overall incidence of earlier stage gastric cancer remains low at 13%. Diagnostic delay occurs in both primary and secondary care due to a high incidence of previous dyspepsia and investigation. One in six patients had been previously investigated in the three years prior to diagnosis, the majority of whom were on antisecretory drugs. Conclusions —Early gastric cancer remains rare in South Tees health district. Advantages of open access gastroscopy appear to be compromised by delayed referral to hospital and failure of endoscopists to recognise the early disease; either they are unaware of its appearance or prior treatment with an H 2 receptor antagonist masks the disease by allowing mucosal healing.
Barttin Activates ClC-K Channel Function by Modulating Gating
Authors: Martin Fischer, Audrey G.H. Janssen, Christoph Fahlke
Journal: Journal of the American Society of Nephrology (2010)

Barttin is an accessory subunit that modifies protein stability, subcellular distribution, and voltage-dependent gating of ClC-K chloride channels expressed in renal and inner ear epithelia. ClC-K channels are double-barreled channels with two identical protopores that may be opened by individual or common gating processes. Using heterologous expression in mammalian cells and patch-clamp recordings, we studied the effects of barttin on gating of rat ClC-K1 and human ClC-Ka. In the absence of barttin, rClC-K1 channels displayed two gating processes with distinct kinetics and voltage dependence. A fast gating process, activated by membrane hyperpolarization, opens and closes individual rClC-K1 protopores. In addition, slow common gating steps, stimulated by membrane depolarization, act on both protopores together. Coexpression of barttin results in voltage-independent open probabilities of the common gate, causing increased channel activity at physiologic potentials. In contrast to rClC-K1, human ClC-Ka is functional only when coexpressed with barttin. Single-channel recordings of hClC-Ka/barttin show double-barreled channels with fast protopore gating without apparent cooperative gating steps. These findings demonstrate that barttin stimulates chloride flux through ClC-K channels by modifying cooperative gating of the double-barreled channels and highlight a physiologic role for gating of epithelial ClC chloride channels.
Phase I Study of Abagovomab in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Authors: Birgit C. Schultes, L. Mary Smith, Christopher F. Nicodemus
Journal: Clinical Cancer Research (2007)

To the Editor: In their article, Sabbatini et al. ([1][1]) describe the phase I data of abagovomab, a murine anti-idiotype antibody to the CA125-specific monoclonal antibody OC125. In their Introduction, they compare abagovomab's mechanism of action to oregovomab's, a murine Ab1 antibody to CA125.
Disruption of T Cell Homeostasis in Mice Expressing a T Cell–Specific Dominant Negative Transforming Growth Factor β II Receptor
Authors: Philip J. Lucas, Seong-Jin Kim, Spencer J. Melby, Ronald E. Gress
Journal: The Journal of Experimental Medicine (2000)

The immune system, despite its complexity, is maintained at a relative steady state. Mechanisms involved in maintaining lymphocyte homeostasis are poorly understood; however, recent availability of transgenic (Tg) and knockout mouse models with altered balance of lymphocyte cell populations suggest that cytokines play a major role in maintaining lymphocyte homeostasis. We show here that transforming growth factor (TGF)-β plays a critical role in maintaining CD8+ T cell homeostasis in a Tg mouse model that specifically overexpresses a dominant negative TGF-β II receptor (DNRII) on T cells. DNRII T cell Tg mice develop a CD8+ T cell lymphoproliferative disorder resulting in the massive expansion of the lymphoid organs. These CD8+ T cells are phenotypically “naive” except for the upregulation of the cell surface molecule CD44, a molecule usually associated with memory T cells. Despite their dominance in the peripheral lymphoid organs, CD8+ T cells appear to develop normally in the thymus, suggesting that TGF-β exerts its homeostatic control in the peripheral immune system.