tbuckley/cabot-search huggingface dataset:
Allergen-induced Synthesis of F<sub>2</sub>-Isoprostanes in Atopic Asthmatics
Authors: RYSZARD DWORSKI, JOHN J. MURRAY, L. JACKSONROBERTS, JOHN A. OATES, JASON D. MORROW, LAURA FISHER, JAMES R. SHELLER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

It is thought that reactive oxygen species (ROS) participate in the inflammation which characterizes asthma, but the evidence supporting this contention is incomplete. F2-isoprostanes (F2-IsoPs) are arachidonate products formed on membrane phospholipids by the action of ROS and thereby represent a quantitative measure of oxidant stress in vivo. Using a mass spectrometric assay we measured urinary release of F2-IsoPs in 11 patients with mild atopic asthma after inhaled allergen challenge. The excretion of F2-IsoPs increased at 2 h after allergen (1.5 ± 0.2 versus 2.6 ± 0.3 ng/mg creatinine) and remained significantly elevated in all urine collections for the 8-h period of the study (analysis of variance [ANOVA]). The measured compounds were of noncyclooxygenase origin because neither aspirin nor indomethacin given before challenge suppressed them. Urinary F2-IsoPs remained unchanged after inhaled methacholine challenge. In nine atopic asthmatics, F2-IsoPs were quantified in bronchoalveolar lavage fluid (BALF) at baseline values and in a separate segment 24 h after allergen instillation. F2-IsoPs were elevated late in the BALF (0.9 ± 0.2 versus 11.4 ± 3.0 pg /ml, baseline versus allergen, respectively, p = 0.007). The increase was inhibited by pretreatment of the subjects with inhaled corticosteroids. These findings provide a new evidence for a role for ROS and lipid peroxidation in allergen-induced airway inflammation. Dworski R, Murray JJ, Roberts LJ, II, Oates JA, Morrow JD, Fisher L, Sheller JR. Allergen-induced sythesis of F2-isoprostanes in atopic asthmatics: evidence for oxident stress.
Alternatives to conventional ileostomy
Authors: J Alexander-Williams
Journal: Gut (1986)

be interpreted with caution as all have been designed as open and non-randomised trials, giving evidence of rather small and partially insignificant decreases of fat excretion in the stools.Furthermore we would also draw attention to our observation, that cimeditine might have a de- trimental effect on lung function in cystic fibrosis patients.3Because we observed a significant increase of airway resistance caused by cimetidine therapy we would state, that H2 blocking therapy in cystic fibrosis patients should be used with great caution.
Inactivation of SAG/RBX2 E3 ubiquitin ligase suppresses KrasG12D-driven lung tumorigenesis
Authors: Hua Li, Mingjia Tan, Lijun Jia, Dongping Wei, Yongchao Zhao, Guoan Chen, Jie Xu, Lili Zhao, Dafydd Thomas, David G. Beer, Yi Sun
Journal: Journal of Clinical Investigation (2014)

Cullin-RING ligases (CRLs) are a family of E3 ubiquitin ligase complexes that rely on either RING-box 1 (RBX1) or sensitive to apoptosis gene (SAG), also known as RBX2, for activity. RBX1 and SAG are both overexpressed in human lung cancer; however, their contribution to patient survival and lung tumorigenesis is unknown. Here, we report that overexpression of SAG, but not RBX1, correlates with poor patient prognosis and more advanced disease. We found that SAG is overexpressed in murine KrasG12D-driven lung tumors and that Sag deletion suppressed lung tumorigenesis and extended murine life span. Using cultured lung cancer cells, we showed that SAG knockdown suppressed growth and survival, inactivated both NF-κB and mTOR pathways, and resulted in accumulation of tumor suppressor substrates, including p21, p27, NOXA, and BIM. Importantly, growth suppression by SAG knockdown was partially rescued by simultaneous knockdown of p21 or the mTOR inhibitor DEPTOR. Treatment with MLN4924, a small molecule inhibitor of CRL E3s, also inhibited the formation of KrasG12D-induced lung tumors through a similar mechanism involving inactivation of NF-κB and mTOR and accumulation of tumor suppressor substrates. Together, our results demonstrate that Sag is a Kras-cooperating oncogene that promotes lung tumorigenesis and suggest that targeting SAG-CRL E3 ligases may be an effective therapeutic approach for Kras-driven lung cancers.
Neuromuscular Control of the Oropharynx and Esophagus in Health and Disease
Authors: J. L. Conklin, J. Christensen
Journal: Annual Review of Medicine (1994)

The oropharynx and esophagus convey swallowed materials from the mouth to the stomach and protect the airways from aspiration. These functions are subserved by complex neuromuscular interactions that coordinate the timing of the peristaltic contractions of the swallowing organs. The oropharynx and upper esophagus are composed of striated muscle, whereas the distal esophagus is composed of smooth muscle. The central nervous system completely controls peristalsis in the striated muscle organs. In the distal esophagus, neuromuscular mechanisms intrinsic to the esophagus control peristalsis. Diseases of the striated muscle, of the smooth muscle, or of the nervous system can lead to a derangement of peristalsis and disrupt the propulsion of swallowed materials to the stomach.
On the Road to Combinations of Targeted Therapies: PPM1H Phosphatase as a Suppressor of Trastuzumab Resistance
Authors: Nicola Aceto, Mohamed Bentires-Alj
Journal: Cancer Discovery (2011)

Abstract Lee-Hoeflich and colleagues use RNA interference screening to identify the serine/threonine phosphatase PPM1H as an inhibitor of trastuzumab resistance in vitro. This finding extends the molecular portrait of trastuzumab-resistant cells and provides a rationale when searching for potential therapeutic targets among regulators of PPM1H and/or its substrates. Cancer Discovery; 1(4): 285–6. ©2011 AACR. Commentary on Lee-Hoeflich et al., p. 326.
Audit of chest drains for pleural effusions in a tertiary care centre
Authors: R. Naseer, P.K. Plant, M.E.J. Callister
Journal: European Respiratory Journal (2011)

Background: Pleural effusion is a common clinical problem with malignant effusions likely to become an increasing burden. Recent guidelines recommend chest drains (ICDs) for effusions are performed under USS guidance, written consent is obtained & only in emergencies should ICDs be placed out of working hours. Over the last 24 months we have introduced a structured ultrasound training programme for respiratory trainees & a chest drain course for juniors.

Method: We audited ICDs for effusions in June & July 2010 in a tertiary centre.

Results: There were 32 ICD'S inserted in 28 patients (pts) with a mean age of 71. 62.5% Female, 37.5% Male. 56% Right & 44% Left sided. 32% had known malignant effusion. Of the 68% with an undiagnosed effusion 53% had known malignancy & 33% had an end diagnosis of malignancy. 36% were placed out of working hours. Only 2 patients were pleurodesed.

View this table:

Summary of results





Conclusion: Respiratory education helped achieve adherence to guidelines for patients managed by respiratory medicine, however a large number of ICD'S are inserted by radiology and a significant number are being managed by Oncology. Therefore effective management of pleural effusions requires close liaison with & education of other specialities with local pleural guidelines formulated through consultation with radiology and oncology.
Inhaled Nitric Oxide Modifies Left Ventricular Diastolic Stress in the Presence of Vasoactive Agents in Heart Failure
Authors: Shunsuke Natori, Naoyuki Hasebe, Yin-Tie Jin, Tomoyuki Matsusaka, Akira Ido, Hironobu Matsuhashi, Tadashi Ihara, Kenjiro Kikuchi
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Nitric oxide (NO) inhalation therapy has been widely used in several diseases with pulmonary hypertension. However, application of NO inhalation therapy remains controversial in heart failure. Cardiovascular effects of inhaled NO (iNO) were evaluated in dogs before and after induction of heart failure with and without infusion of vasoactive agents. iNO did not affect the baseline left ventricular (LV) function or the response to isoproterenol in control conditions or heart failure induced by procainamide. Pulmonary vascular resistance was significantly decreased by iNO in heart failure with infusion of vasoactive agents. Unexpectedly, LV end-diastolic pressure was significantly elevated by iNO in heart failure in the presence of infusion of vasoactive agents independent of their types; either the vasodilating agents of acetylcholine and nitroglycerin or the vasoconstricting agents of norepinephrine and angiotensin-II. The end-diastolic LV dimension and wall stress were also significantly increased by iNO, however, those at end systole were not affected. These results suggested that NO inhalation therapy reduced pulmonary vascular resistance, whereas in the presence of additional stress of vasoactive agents, it increased LV preload and end-diastolic wall stress in heart failure.
Are Corticosteroids Effective in All Patients With Cancer-Related Pain?
Authors: James F. Cleary
Journal: Journal of Clinical Oncology (2014)

Corticosteroids are commonly used in cancer medicine. Many chemotherapy regimens, especially those used in the treatment of hematologic malignancies, often include corticosteroids, sometimes athigh-doses.Oftentheimpactofthesuddencessationafter5daysof high-dose corticosteroids was the major adverse effect reported by patients. Even more recently, corticosteroids were included in the patients with cancer demonstrated that corticosteroids were used commonly; 50% of patients with cancer in the palliative care setting received corticosteroids. 5 The most common indications for starting corticosteroids in this survey were appetite loss (37%), fatigue (36%), and poor well-being (33%) while pain was an indication in 25%. A recentreportfromNewZealand 6 showedthatofalmost1,200patients receiving care from seven inpatient hospices, two thirds had received at least one course of corticosteroids during that care. The reasons for corticosteroids were a nonspecific indication (40%), neurologic symptoms (25.3%), and soft-tissue infiltration symptoms (14.4%). Detailed information was recorded for a sample of 260 patients with the agent of choice being dexamethasone with a median dose of 8 mg (dose range, 1 mg-40 mg). Corticosteroids were prescribed for a me- dian duration of 29 days per course. Abrupt stopping occurred in 72 (23.2%) cases; of these 35 (49%) had been on a course of corticoste- roids for more than 3 weeks. Corticosteroid-prescribing guidelines, including cessation titration, were only available in one hospice. Ad- verse effects were recorded in 82 (32%) but only 52% of the 260 had regular monitoring, thus suggesting that adverse events were in fact much more common than reported. But do corticosteroids make a difference? The study by Norwe- gian investigators in the article that accompanies this editorial 7 uses high level evidence from a randomized, double-blind, placebo- controlledtrial.Usingwell-validatedtools,theymeasuredtheeffectof methylprednisone (16 mg twice daily) on pain, fatigue, and appetite over a 1-week period. The study showed no difference in pain scores between the two groups when measured as absolute or percentage differences, and this negative finding was not changed by regression analysis. The study did find significant differences in appetite stimu- lation, fatigue, and overall satisfaction in favor of the corticoste- roid group.
The dynamic vasa vasorum
Authors: E RITMAN, A LERMAN
Journal: Cardiovascular Research (2007)

The function of vasa vasorum is both to deliver nutrients and oxygen to arterial and venous walls and to remove "waste" products, either produced by cells in the wall or introduced by diffusional transport through the endothelium of the artery or vein. Although the relationship between changes in vasa vasorum characteristics and the development of atheromatous plaques is well documented, the role of vasa vasorum, especially in terms of their appearance and disappearance in disease processes such as atherosclerosis, are still not clearly understood in terms of their being causative or merely reactive. However, even if their proliferation is merely reactive, these new microvessels may be a source of disease progression by virtue of endothelial impairment and as a pathway for monocytic cells to migrate to sites of early disease. As both these features are aspects of the vasa vasorum function, this Review focuses on the following issues: 1) acute modulation of vasa vasorum patency due to surrounding compressive forces within vessel wall and due to variable tone in the smooth muscle within proximal vasa vasorum and 2) chronic angiogenic responses due to local cytokine accumulations such as occur in the wall of arteries in the presence of hypertension, hypercholesterolemia, accumulation of lipids, extravasated blood products (e.g., red blood cells, macrophages, inflammatory products) which attract monocytes, and response of vasa vasorum to pharmacological stimuli.
Japonicone A Suppresses Growth of Burkitt Lymphoma Cells through Its Effect on NF-κB
Authors: Xiaoguang Li, Xinying Yang, Yanling Liu, Nuoxi Gong, Wenbo Yao, Peizhan Chen, Jiangjiang Qin, Huizi Jin, Jingquan Li, Ruiai Chu, Lei Shan, Ruiwen Zhang, Weidong Zhang, Hui Wang
Journal: Clinical Cancer Research (2013)

NF-κB, a transcriptional regulator of diverse genes involved in cell survival, proliferation, adhesion, and apoptosis, has been implicated in various malignancies. We discovered a potent natural NF-κB inhibitor, Japonicone A, from the traditional herb Inula japonica Thunb, evaluated its preclinical pharmacology and therapeutic activity, and investigated the underlying mechanisms of action for its antitumor activity.Various types of cancer and normal cells were exposed to Japonicone A for cytotoxicity screening, followed by determination of cell apoptosis and cell-cycle arrest. Western blotting, immunostaining, and gene reporter assay were used to analyze NF-κB activity. Two xenograft models were used for therapeutic efficacy evaluation.Japonicone A killed cancer cells but had low cytotoxicity to normal cells. Burkitt lymphoma cells were particularly sensitive. Japonicone A inhibited the growth and proliferation of Raji, BJAB, and NAMALWA lymphoma cells and resulted in G2-M phase arrest and apoptosis. Furthermore, exposure of cells to Japonicone A caused inactivation of the TNF-α-TAK1-IKK-NF-κB axis and inhibition of TNF-α-stimulated NF-κB activity and nuclear translocation, followed by downregulation of NF-κB target genes involved in cell apoptosis (Bcl-2, Bcl-xL, XIAP, TRAF2) and in the cell cycle and growth (cyclin D, c-Myc). Moreover, Japonicone A inhibited local growth and dissemination of cancer cells to multiple organs in vivo.Japonicone A exerts significant anticancer effects on Burkitt lymphoma cells in vitro and in vivo through targeting of the NF-κB signaling cascade. These results highlight the potential of Japonicone A as a chemotherapeutic agent and warrant its development as a therapy for lymphomas.
A Clinical Lecture ON HYPERPLASIA OF BREAST TISSUES (MAZOPLASIA -- "CHRONIC MASTITIS"): Delivered before the Nottingham Medico-Chirurgical Society
Authors: G. L. Cheatle
Journal: BMJ (1924)

THE complete difference in histological and biological characters that definitely distinguish acute from chronic inflammation makes it difficult to understand how the term P' inflammation " can be common to both processes, until one realizes that the terms were applied when the knowledge of pathological processes was based on more slender evidence than exists at the present time.I recognize the advantages of conservatism in dealing with established terms, yet for some years I have found it imnpossible in this instance to
Exosome Targeting of Tumor Antigens Expressed by Cancer Vaccines Can Improve Antigen Immunogenicity and Therapeutic Efficacy
Authors: Ryan B. Rountree, Stefanie J. Mandl, James M. Nachtwey, Katie Dalpozzo, Lisa Do, John R. Lombardo, Peter L. Schoonmaker, Kay Brinkmann, Ulrike Dirmeier, Reiner Laus, Alain Delcayre
Journal: Cancer Research (2011)

MVA-BN-PRO (BN ImmunoTherapeutics) is a candidate immunotherapy product for the treatment of prostate cancer. It encodes 2 tumor-associated antigens, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP), and is derived from the highly attenuated modified vaccinia Ankara (MVA) virus stock known as MVA-BN. Past work has shown that the immunogenicity of antigens can be improved by targeting their localization to exosomes, which are small, 50- to 100-nm diameter vesicles secreted by most cell types. Exosome targeting is achieved by fusing the antigen to the C1C2 domain of the lactadherin protein. To test whether exosome targeting would improve the immunogenicity of PSA and PAP, 2 additional versions of MVA-BN-PRO were produced, targeting either PSA (MVA-BN-PSA-C1C2) or PAP (MVA-BN-PAP-C1C2) to exosomes, while leaving the second transgene untargeted. Treatment of mice with MVA-BN-PAP-C1C2 led to a striking increase in the immune response against PAP. Anti-PAP antibody titers developed more rapidly and reached levels that were 10- to 100-fold higher than those for mice treated with MVA-BN-PRO. Furthermore, treatment with MVA-BN-PAP-C1C2 increased the frequency of PAP-specific T cells 5-fold compared with mice treated with MVA-BN-PRO. These improvements translated into a greater frequency of tumor rejection in a PAP-expressing solid tumor model. Likewise, treatment with MVA-BN-PSA-C1C2 increased the antigenicity of PSA compared with treatment with MVA-BN-PRO and resulted in a trend of improved antitumor efficacy in a PSA-expressing tumor model. These experiments confirm that targeting antigen localization to exosomes is a viable approach for improving the therapeutic potential of MVA-BN-PRO in humans.
Helicobacter pylori infection is probably the cause of chronic idiopathic neutropenia (CIN)-associated splenomegaly
Authors: Helen A. Papadaki, Charis Pontikoglou, Dimitris G. Eliopoulos, Katerina Pyrovolaki, Rania Spyridaki, George D. Eliopoulos
Journal: American Journal of Hematology (2006)

Splenic volume and Helicobacter pylori (H. pylori) infection were evaluated in 67 patients with chronic idiopathic neutropenia (CIN) and 39 healthy individuals. Using ultrasound, splenomegaly was found in 61.7% of H. pylori-infected subjects compared to only 8.7% noted in the group of H. pylori-non-infected individuals (P < 0.0001). Splenomegaly was also found in 47.8% of CIN patients compared to 12.8% in the group of non-CIN subjects (P = 0.0003). However, applying the two-way ANOVA test, a statistically significant effect on splenic volume was documented for "factor H. pylori " (F1(102) = 16.800, P < 0.0001) but not for "factor CIN" (F1(102) = 3.213, P = 0.0760), suggesting that CIN-associated splenomegaly is probably due to H. pylori infection.
EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury
Authors: Yujiro Kida, Nicholas Ieronimakis, Claudia Schrimpf, Morayma Reyes, Jeremy S. Duffield
Journal: Journal of the American Society of Nephrology (2013)

Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 ΔV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 ΔV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in three-dimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 ΔV primary kidney microvascular endothelial cells migrated and proliferated less than wild-type microvascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.
Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study
Authors: Ferran Morell, Ana Villar, María-Ángeles Montero, Xavier Muñoz, Thomas V Colby, Sudhakar Pipvath, María-Jesús Cruz, Ganesh Raghu
Journal: The Lancet Respiratory Medicine (2013)
Early T cell activation in the skin from patients with systemic sclerosis
Authors: A Kalogerou
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objectives:</b> To determine if T cells in skin lesions in systemic sclerosis (SSc) express the early activation antigen CD69 that participates in cell-cell interactions. <b>Methods:</b> Skin biopsy specimens from 17 patients with SSc were analysed by immunohistochemistry using the indirect peroxidase method and monoclonal antibodies for CD3 (T cell marker), CD69 (early T cell activation marker), and CD68 (macrophage marker). <b>Results:</b> Mononuclear cells, containing mostly T cells and macrophages, were increased in SSc skin lesions and were present in perivascular areas. CD69 was expressed in these mononuclear cells. There was no correlation between the number of CD3+, CD69+, or CD68+ cells and the Rodnan skin score or disease duration. <b>Conclusions:</b> The expression of early T cell activation antigen CD69 in skin lesions suggests that T cells may actively participate in cell-cell contact with fibroblasts to promote fibrosis.
Large Randomized Study of Thymosin α 1, Interferon Alfa, or Both in Combination With Dacarbazine in Patients With Metastatic Melanoma
Authors: Michele Maio, Andrzej Mackiewicz, Alessandro Testori, Uwe Trefzer, Virginia Ferraresi, Jacek Jassem, Claus Garbe, Thierry Lesimple, Bernard Guillot, Pere Gascon, Katalin Gilde, Roberto Camerini, Francesco Cognetti
Journal: Journal of Clinical Oncology (2010)

Thymosin alpha 1 (Talpha1) is an immunomodulatory polypeptide that enhances effector T-cell responses. In this large randomized study, we evaluated the efficacy and safety of combining Talpha1 with dacarbazine (DTIC) and interferon alfa (IFN-alpha) in patients with metastatic melanoma.Four hundred eighty-eight patients were randomly assigned to five treatment groups: DTIC+IFN-alpha+Talpha1 (1.6 mg); DTIC+IFN-alpha+Talpha1 (3.2 mg); DTIC+IFN-alpha+Talpha1 (6.4 mg); DTIC+Talpha1 (3.2 mg); DTIC+IFN-alpha (control group). The primary end point was best overall response at study end (12 months). Secondary end points included duration of response, overall survival (OS), and progression-free survival (PFS). Patients were observed for up to 24 months.Ten and 12 tumor responses were observed in the DTIC+IFN-alpha+Talpha1 (3.2 mg) and DTIC+Talpha1 (3.2 mg) groups, respectively, versus four in the control group, which was sufficient to reject the null hypothesis that P(0) < or = .05 (expected response rate of standard therapy) in these two arms. Duration of response ranged from 1.9 to 23.2 months in patients given Talpha1 and from 4.4 to 8.4 months in the control group. Median OS was 9.4 months in patients given Talpha1 versus 6.6 months in the control group (hazard ratio = 0.80; 9% CI, 0.63 to 1.02; P = .08). An increase in PFS was observed in patients given Talpha1 versus the control group (hazard ratio = 0.80; 95% CI, 0.63 to 1.01; P = .06). Addition of Talpha1 to DTIC and IFN-alpha did not lead to any additional toxicity.These results suggest Talpha1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent.