tbuckley/cabot-search huggingface dataset:
Response-Guided Neoadjuvant Chemotherapy for Breast Cancer
Authors: Gunter von Minckwitz, Jens Uwe Blohmer, Serban Dan Costa, Carsten Denkert, Holger Eidtmann, Wolfgang Eiermann, Bernd Gerber, Claus Hanusch, Jörn Hilfrich, Jens Huober, Christian Jackisch, Manfred Kaufmann, Sherko Kümmel, Stefan Paepke, Andreas Schneeweiss, Michael Untch, Dirk Michael Zahm, Keyur Mehta, Sibylle Loibl
Journal: Journal of Clinical Oncology (2013)

We investigated disease-free survival (DFS) and overall survival (OS) after response-guided neoadjuvant chemotherapy in patients with early breast cancer.We treated 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) and randomly assigned early responders to four (n = 704) or six (n = 686) additional TAC cycles, and early nonresponders to four cycles of TAC (n = 321) or vinorelbine and capecitabine (NX; n = 301) before surgery.DFS was longer in early responders receiving TAC × 8 than in those receiving TAC × 6 (hazard ratio [HR], 0.78; 95% CI, 0.62 to 0.97; P = .026), and in early nonresponders receiving TAC-NX than in those receiving TAC × 6 (HR, 0.59; 95% CI, 0.49 to 0.82; P = .001). Exploratory analysis showed that DFS after response-guided chemotherapy (TAC × 8 or TAC-NX) was significantly longer (HR, 0.71; 95% CI, 0.60 to 0.85; P < .003), as was OS (HR, 0.79; 95% CI, 0.63 to 0.99; P = .048), than on conventional chemotherapy (TAC × 6). DFS was longer after response-guided chemotherapy in all hormone receptor-positive tumors (luminal A HR = 0.55, luminal B [human epidermal growth factor receptor 2 (HER2) negative] HR = 0.40, and luminal B [HER2 positive] HR = 0.56), but not in hormone receptor-negative tumors (HER2 positive [nonluminal] HR = 1.01 and triple negative HR = 0.87). Pathologic complete response did not predict these survival effects. pCR predicted an improved DFS in triple-negative (HR = 6.67), HER2-positive (nonluminal; HR 5.24), or luminal B (HER2-negative) tumors (HR = 3.74).This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor-positive tumors. If confirmed, the response-guided approach could provide a clinically meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer.
Ethics of predictive testing for Huntington's chorea: the need for more information.
Authors: D I Craufurd, R Harris
Journal: BMJ (1986)

The finding of a genetically linked polymorphic DNA marker has made possible a predictive test for Huntington's chorea. This DNA probe has so far been used only for research and has technical limitations, but some workers now wish to apply it to clinical predictions. Those identified by the probe as being probable carriers of the Huntington's chorea gene would be exposed to uncertain psychological risks and social pressures. Ethical guidelines should be established, but these require greater knowledge of the potential benefits and hazards of this powerful new procedure. Controlled clinical trials are urgently needed.
Dehydroepiandrosterone sulphate reduces chronic hypoxic pulmonary hypertension in rats
Authors: V. Hampl, J. Bíbová, V. Povýšilová, J. Herget
Journal: European Respiratory Journal (2003)

Pathogenesis of pulmonary hypertension includes vascular smooth muscle cell membrane depolarisation and consequent calcium influx. Usually, calcium-gated potassium channels are activated under such conditions and repolarise the membrane. However, in pulmonary hypertension they are downregulated. The authors hypothesised that pharmacological augmentation of these channels would reduce pulmonary hypertension. Dehydroepiandrosterone sulphate (DHEA‐S, 0.1 mg·mL −1 ), a recently characterised activator of calcium-gated potassium channels, was given to rats in drinking water. Pulmonary arterial blood pressure, increased by 4 weeks of hypoxia (from 15±0.2 to 29.4±2.5 mmHg), was selectively attenuated in rats treated with DHEA‐S for the whole duration of the hypoxic exposure (23.9±0.9 mmHg) and in rats given DHEA‐S only after pulmonary hypertension had fully developed (last 2 weeks of hypoxia; 24.4±1.4 mmHg). Pulmonary vascular remodelling and right ventricular hypertrophy associated with pulmonary hypertension were also reduced by DHEA‐S. Cardiac index and systemic arterial blood pressure did not differ among the groups. The authors conclude that treatment with an activator of calcium-gated potassium channels, dehydroepiandrosterone sulphate, known to be well tolerated by humans, reduces hypoxic pulmonary hypertension in rats.
Cancer Cells Cue the p53 Response of Cancer-Associated Fibroblasts to Cisplatin
Authors: Jens O. Schmid, Meng Dong, Silke Haubeiss, Godehard Friedel, Sabine Bode, Andreas Grabner, German Ott, Thomas E. Mürdter, Moshe Oren, Walter E. Aulitzky, Heiko van der Kuip
Journal: Cancer Research (2012)

Current understanding of the p53 response is based mainly upon in vitro studies of homogeneous cell populations. However, there is little information on whether the same principles operate within heterogeneous tumor tissues that are comprised of cancer cells and other cell types, including cancer-associated fibroblasts (CAF). Using ex-vivo tissue cultures, we investigated p53 status and responses to cisplatin in tumor cells and CAFs from tissue specimens isolated from 32 lung cancer patients. By comparing cultivated tissue slices with the corresponding tumor tissues fixed immediately after surgery, we found that morphology, proliferation, and p53 staining pattern were preserved during cultivation. Unexpectedly, when CAFs were analyzed, p53 accumulation and induction of p21 was observed only in tumors with constitutively low p53 protein and accumulation upon cisplatin treatment. In contrast, in tumors with no p53 accumulation in cancer cells there was also no p53 accumulation or p21 induction in adjacent CAFs. Furthermore, induction of cisplatin-induced apoptosis in CAFs was selectively observed in tumors characterized by a parallel induction of cancer cell death. Our findings reveal an interdependence of the p53 response in cancer cells and adjacent CAFs within tumor tissues, arguing that cancer cells control the response of their microenvironment to DNA damage.
REHABILITATION OF TENDINOPATHY: WHERE TO FROM HERE?
Authors: J L Cook
Journal: British Journal of Sports Medicine (2013)

The exercise or loading approaches to treatment of tendinopathy have been at the forefront of treatment options for the last 30 years. Prior to that, the predominance of the inflammatory model prescribed that rest, ice and anti-inflammatory medication was the only suitable approach. This approach was overwhelmingly unsuccessful; failure to recover and recurrence were common. In the 70′s Curwin and Stanish reported that eccentric loading was beneficial for tendinopathy, and although this received some notice in the clinical world, the Alfredson paper in 1995 resulted in an explosion of interest in eccentric load for tendinopathy. Since then much research has confirmed the benefits of eccentric exercise, however the reasons for its effectiveness have not been elucidated. The effectiveness appears to be specific to rehabilitation of active people; eccentric exercise in season, and in the inactive population was less successful. The specificity of eccentric-only exercise has also been questioned- although eccentric clearly has to be part of the programme, it has been shown to be effective when combined with concentric exercise and with quite high loads. Is there more progress to be made in the area of exercise-based rehabilitation? If the continuum model is correct, then consideration of loading in different stages is essential, remembering that the eccentric programme was shown to be most effective in chronic degenerative tendinopathy. Reactive tendinopathy is likely to require different loading regimes, as will the common clinical presentation of reactive on degenerative tendinopathy. Power and energy storage loads have not been considered in research, although clinically they are a critical part of rehabilitation. Research in these areas is likely to be complex and require multi-centre trials; it may be up to the people at this conference to prioritise this research as a group.
t-tubules and sarcoplasmic reticulum function in cardiac ventricular myocytes
Authors: C. Orchard, F. Brette
Journal: Cardiovascular Research (2007)

Although the existence of t-tubules in mammalian cardiac ventricular myocytes has been recognized for a long time, it now appears that their structure and function are more complex than previously believed. Recent work has provided evidence that many of the key proteins underlying excitation–contraction coupling are located predominantly at the t-tubules. L-type Ca2+ current (ICa) flowing across the t-tubule membrane provides a rapidly inactivating Ca2+ influx that triggers Ca2+ release from the sarcoplasmic reticulum (SR), thereby allowing rapid and synchronous Ca2+ release throughout the cell; ICa at the t-tubules also appears to be more sensitive than that at the surface membrane to regulation by beta-adrenergic stimulation and intracellular Ca2+. In contrast, although its density is lower, ICa flowing across the surface membrane inactivates slowly, and thus may help load the SR with Ca2+. There is also increasing evidence that many of the mechanisms that remove Ca2+ from the cytoplasm are located predominantly at the t-tubules, which therefore play an important role in determining cellular, and hence SR, Ca2+ content. Thus, the t-tubules appear to play a central role in the increase and subsequent decrease of Ca2+ during the systolic Ca2+ transient. Remodelling of the t-tubules has been reported in cardiac pathologies, and may play a role in the altered cellular, and hence cardiac, function observed in such conditions.
Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis
Authors: Johannan F. Brandse, Ron A. Mathôt, Desiree van der Kleij, Theo Rispens, Yaël Ashruf, Jeroen M. Jansen, Svend Rietdijk, Mark Löwenberg, Cyriel Y. Ponsioen, Sharat Singh, Gijs R. van den Brink, Geert R. D’Haens
Journal: Clinical Gastroenterology and Hepatology (2015)
Doppler ultrasound identifies increased resistive indices in SSc
Authors: N Bregenzer
Journal: Annals of the Rheumatic Diseases (2003)

heumatoid arthritis (RA) is a chronic inflammatory disease which is characterised mainly by synovial inflammation and joint destruction, as well as extraarticular manifestations. 1 Cytokines have a central role in the pathogenesis of this synovial inflammation.Tumour necrosis factor a (TNFa) is one of the dominant cytokines.Many studies have shown that TNFa is present in biologically significant amounts in RA synovial tissue and fluids, and the amount seems to parallel the extent of inflammation and bone erosion. 2 3 Persistent inflamed monarthritis in patients with RA is difficult to treat.Usually it is treated with local patches, intraarticular injections of steroids, or even with chemical, radioactive, or surgical synovectomy. 4 The introduction of anti-TNFa treatments, especially the infusion of infliximab, 5 prompted us to investigate the effectiveness and safety of intra-articular injection of infliximab in patients with RA and resistant monarthritis.
Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation
Authors: Jing Li, Kyungho Kim, Eunsil Hahm, Robert Molokie, Nissim Hay, Victor R. Gordeuk, Xiaoping Du, Jaehyung Cho
Journal: Journal of Clinical Investigation (2014)

Interactions between platelets, leukocytes, and activated endothelial cells are important during microvascular occlusion; however, the regulatory mechanisms of these heterotypic cell-cell interactions remain unclear. Here, using intravital microscopy to evaluate mice lacking specific isoforms of the serine/threonine kinase AKT and bone marrow chimeras, we found that hematopoietic cell-associated AKT2 is important for neutrophil adhesion and crawling and neutrophil-platelet interactions on activated endothelial cells during TNF-α-induced venular inflammation. Studies with an AKT2-specific inhibitor and cells isolated from WT and Akt KO mice revealed that platelet- and neutrophil-associated AKT2 regulates heterotypic neutrophil-platelet aggregation under shear conditions. In particular, neutrophil AKT2 was critical for membrane translocation of αMβ2 integrin, β2-talin1 interaction, and intracellular Ca2+ mobilization. We found that the basal phosphorylation levels of AKT isoforms were markedly increased in neutrophils and platelets isolated from patients with sickle cell disease (SCD), an inherited hematological disorder associated with vascular inflammation and occlusion. AKT2 inhibition reduced heterotypic aggregation of neutrophils and platelets isolated from SCD patients and diminished neutrophil adhesion and neutrophil-platelet aggregation in SCD mice, thereby improving blood flow rates. Our results provide evidence that neutrophil AKT2 regulates αMβ2 integrin function and suggest that AKT2 is important for neutrophil recruitment and neutrophil-platelet interactions under thromboinflammatory conditions such as SCD.
Oral l-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1
Authors: Kevin Garofalo, Anke Penno, Brian P. Schmidt, Ho-Joon Lee, Matthew P. Frosch, Arnold von Eckardstein, Robert H. Brown, Thorsten Hornemann, Florian S. Eichler
Journal: Journal of Clinical Investigation (2011)

Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate l-serine to the alternative substrate l-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% l-serine–enriched diet reduced dSL levels. l-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% l-alanine–enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, l-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder.
Immunologic responsiveness of the C3H/HeJ mouse: differential ability of butanol-extracted lipopolysaccharide (LPS) to evoke LPS-mediated effects.
Authors: M G Goodman, D E Parks, W O Weigle
Journal: The Journal of Experimental Medicine (1978)

The lipopolysaccharide (LPS)-protein complex extracted from the cell wall of Escherichia coli K235 by the butanol-water technique has been shown to evoke a mitogenic response in bone marrow-derived (B) lymphocytes from the C3H/HeJ mouse strain. These mice are resistant to the effects of LPS extracted with phenol. Therefore, the ability of butanol-extracted LPS to modulate a spectrum of C3H/HeJ B-cell functions was investigated. Both butanol-extracted (LPS-B) and phenol-extracted (LPS-P) LPS preparations activated responder C3H/St spleen cell cultures to polyclonal antibody production, while only LPS-B activated C3H/HeJ spleen cells. Both LPS-P and LPS-B acted as adjuvants when injected after aggregated human gamma globulin (HGG) in C3H/St mice, but neither preparation was effective as a adjuvant in C3H/HeJ mice. LPS-P injected with deaggregated HGG (tolerogen) into LPS-sensitive mice has been shown previously to inhibit the induction of tolerance HGG. In the present studies, it was shown that LPS-B, but not LPs-p, was able to inhibit tolerance induction to HGG in the C3H/HeJ, whereas both preparations were effective in the C3H/St. LPS has also been shown to bypass tolerant T cells in LPS-sensitive mice late in tolerance to HGG at a time when B cells are responsive. However, in the C3H/HeJ, neither LPS-B nor LPS-P was capable of this function. The responsiveness of these B cells to HGG was demonstrated in transfer experiments. Thus, in the C3H/HeJ, LPS-B stimulates mitogenesis, polyclonal B-cell activation, and inhibition of tolerance induction, but cannot act as an effective adjuvant or as a bypass mechanism to activate B cells in the presence of tolerant T cells. The explanation for this pattern of responses may be attributable to yet another cellular defect in the C3H/HeJ mouse.
Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel
Authors: Marc Schmidt, Badrinarayanan Raghavan, Verena Müller, Thomas Vogl, György Fejer, Sandrine Tchaptchet, Simone Keck, Christoph Kalis, Peter J Nielsen, Chris Galanos, Johannes Roth, Arne Skerra, Stefan F Martin, Marina A Freudenberg, Matthias Goebeler
Journal: Nature Immunology (2010)
HISTOPATHOLOGICAL EFFECTS IN MICE OF HETEROLOGOUS ANTILYMPHOCYTE SERUM
Authors: Robert N. Taub, Eugene M. Lance
Journal: The Journal of Experimental Medicine (1968)

The effects of heterologous rabbit anti-mouse lymphocyte antiserum on the morphology of lymphoid and other tissues was investigated in CBA mice. The lymphoid tissues exhibited characteristic changes specific for ALS treatment, which were an invariable accompaniment to its immunosuppressive effects. These consisted of peripheral lymphopenia occurring at some time during a course of ALS treatment and persistent depletion of small lymphocytes in lymph node paracortical areas and splenic follicular periarteriolar zones. The thymic histology was generally well preserved. It is suggested that the relevant lesions reflect a rapid depletion of the pool of recirculating lymphocytes, possibly by a primary cytotoxic effect exerted on cells peripheral to lymphoid tissue. Other histologic features attendant to the administration of ALS were accounted for as consequences of immunization of ALS recipients to rabbit serum constituents or by the deleterious effects of antibodies directed against tissues other than lymphoid cells.
The Antithrombotic Effects of Statins
Authors: A. Phillip Owens, Nigel Mackman
Journal: Annual Review of Medicine (2014)

Hypercholesterolemia is considered the primary risk factor for cardiovascular disease. An estimated 200 million prescriptions are issued per year for statins to treat hypercholesterolemia. Importantly, statins have additional beneficial effects independent of their effects on lipids. Recent studies have shown that statins reduce thrombosis via multiple pathways, including inhibiting platelet activation and reducing the pathologic expression of the procoagulant protein tissue factor. Many of the antithrombotic effects of statins are attributed to inhibiting prenylation of RhoA and effects on other intracellular signaling molecules such as NF-κB and KLF2. These antithrombotic activities of statins likely contribute to the ability of statins to reduce the incidence of cardiovascular death.
Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial
Authors: Lars Køber, Poul Erik Bloch Thomsen, Mogens Møller, Christian Torp-Pedersen, Jan Carlsen, Erik Sandøe, Kenneth Egstrup, Erik Agner, Jørgen Videbæk, Bradley Marchant, A John Camm
Journal: The Lancet (2000)
Treatment continuation in patients receiving biological agents or conventional DMARD therapy
Authors: A Zink, J Listing, S Kary, P Ramlau, M Stoyanova-Scholz, K Babinsky, U von Hinueber, E Gromnica-Ihle, S Wassenberg, C Antoni, P Herzer, J Kekow, M Schneider, R Rau
Journal: Annals of the Rheumatic Diseases (2005)

To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug (DMARD) treatment after previous DMARD failure.Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study. Data were available for 511 patients treated with etanercept, 343 with infliximab, 70 with anakinra, and 599 controls. Propensity scores were used to select a subsample of patients from the control group who were likely to be treated with biological agents because of their disease severity, as well as comparable infliximab and etanercept cases.Treatment continuation after 12 months was similar for etanercept (68.6% (95% confidence interval, 62% to 75%)) and infliximab (65.4% (58% to 73%)) but lower for anakinra (59% (41% to 77%)). Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone. Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures. After adjustment for baseline differences, the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate.Treatment continuation of biological agents in clinical practice is less likely than in randomised clinical trials but more likely than in comparable controls treated with conventional DMARDs.
Relationship between phospholipase C activation and prostaglandin E2 and cyclic adenosine monophosphate production in rabbit tubular epithelial cells. Effects of angiotensin, bradykinin, and arginine vasopressin.
Authors: C Welsh, G Dubyak, J G Douglas
Journal: Journal of Clinical Investigation (1988)

By employing early-passaged rabbit kidney epithelial cells in tissue culture, we demonstrated that angiotensin II (AII) has unique mechanisms of signal transduction. First, unlike its action in other target tissues, micromolar concentrations of AII are required to induce small rises in cytosolic calcium, [Ca2+]i, an action which is not accompanied by the release of inositol phosphates (IP). In contrast, nanomolar bradykinin (BK) mobilizes [Ca2+]i through activation of phospholipase C and release of IP. Neither of these stimulated calcium responses exhibits pertussis toxin (PTx) sensitivity. Secondly, AII and BK at 10(-9) to 10(-7) M stimulate cAMP indirectly through PGE2 production in distal cells. AII- and BK-stimulated PGE2 release is PTx inhibitible, suggestive of the presence of a GTP binding protein mediating the response. By contrast, arginine vasopressin fails to elicit rises in [Ca2+]i but exerts its primary effect on cAMP production in distal cells via direct coupling to a stimulatory GTP binding protein, as evidenced by uncoupling with cholera toxin. Regulation of PGE2 synthesis appears to occur via phospholipase A2, not C, by all three peptides.