tbuckley/cabot-search huggingface dataset:
Tau missorting and spastin-induced microtubule disruption in neurodegeneration: Alzheimer Disease and Hereditary Spastic Paraplegia
Authors: Hans Zempel, Eva-Maria Mandelkow
Journal: Molecular Neurodegeneration (2015)

In Alzheimer Disease (AD), the mechanistic connection of the two major pathological hallmarks, namely deposition of Amyloid-beta (Aβ) in the form of extracellular plaques, and the pathological changes of the intracellular protein Tau (such as phosphorylation, missorting, aggregation), is not well understood. Genetic evidence from AD and Down Syndrome (Trisomy 21), and animal models thereof, suggests that aberrant production of Aβ is upstream of Tau aggregation, but also points to Tau as a critical effector in the pathological process. Yet, the cascade of events leading from increased levels of Aβ to Tau-dependent toxicity remains a matter of debate. Using primary neurons exposed to oligomeric forms of Aβ, we have found that Tau becomes mislocalized (missorted) into the somatodendritic compartment. Missorting of Tau correlates with loss of microtubules and downstream consequences such as loss of mature spines, loss of synaptic activity, and mislocalization of mitochondria. In this cascade, missorting of Tau induces mislocalization of TTLL6 (Tubulin-Tyrosine-Ligase-Like 6) into the dendrites. TTLL6 induces polyglutamylation of microtubules, which acts as a trigger for spastin mediated severing of dendritic microtubules. Loss of microtubules makes cells unable to maintain transport of mitochondria, which in turn results in synaptic dysfunction and loss of mature spines. These pathological changes are absent in TauKO derived primary neurons. Thus, Tau mediated mislocalization of TTLL6 and spastin activation reveals a pathological gain of function for Tau and spastin in this cellular model system of AD. In contrast, in hereditary spastic paraplegia (HSP) caused by mutations of the gene encoding spastin (spg4 alias SPAST), spastin function in terms of microtubule severing is decreased at least for the gene product of the mutated allele, resulting in overstable microtubules in disease model systems. Whether total spastin severing activity or microtubule stability in human disease is also affected is not yet clear. No human disease has been associated so far with the long-chain polyglutamylation enzyme TTLL6, or the other TTLLs (1,5,11) possibly involved. Here we review the findings supporting a role for Tau, spastin and TTLL6 in AD and other tauopathies, HSP and neurodegeneration, and summarize possible therapeutic approaches for AD and HSP.
Preoperative therapy for esophageal cancer: a randomized comparison of chemotherapy versus radiation therapy.
Authors: D P Kelsen, B Minsky, M Smith, J Beitler, D Niedzwiecki, D Chapman, M Bains, M Burt, R Heelan, B Hilaris
Journal: Journal of Clinical Oncology (1990)

Ninety-six patients with operable epidermoid cancer of the esophagus were entered into a phase III, random assignment study designed to compare the efficacy of two preoperative approaches (chemotherapy [CT] or radiation therapy [RT]). Major study end points were objective response rates, surgical outcome, and recurrence pattern. Patients were randomly assigned to receive either two cycles of cisplatin, vindesine, and bleomycin or 55 Gy of radiation before a planned surgical procedure. Postoperative crossover therapy (radiation to those receiving preoperative CT and vice versa) was given to patients with T3Nany or unresectable tumors. Objective response rates of the primary tumor to preoperative therapy were similar (RT 64%, CT 55%), as were operability rates (RT 77%, CT 75%), resection rates (RT 65%, CT 58%), and operative mortality (RT 13.5%, CT 11.1%). Significantly higher doses of CT could be administered when CT was given as initial therapy, rather than after RT/surgery. Local failure or persistence occurred in 33% of operable patients. The median survival for all patients was 11 months; 20% remain alive without disease (median follow-up, 34 months). Because of the crossover design, it was not possible to analyze survival according to the preoperative therapy arm alone. This study suggests that since CT is as effective in treating local tumor as RT, but can also potentially treat systemic disease, investigational programs using CT before surgery as part of initial treatment for localized esophageal cancer should continue. However, if a significant impact on overall survival is to be achieved, more effective chemotherapy regimens or schedules need to be identified. Outside of carefully designed clinical trials, surgery alone or radiation alone remain standard therapy.
Choosing a Health Insurance Plan
Authors: Saurabh Bhargava, George Loewenstein
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Plasticity of adult endothelium: how frequent and to what extent?
Authors: Jeremy D. Pearson
Journal: Cardiovascular Research (2015)

This editorial refers to ‘Endothelial-to-mesenchymal transition contributes to fibro-proliferative vascular disease and is modulated by fluid shear stress’ by J.-R. Moonen et al. , doi:10.1093/cvr/cvv175. 

In most healthy blood vessels, average endothelial cell turnover is very low, with cell lifespan estimates of up to many years—hardly indicative of a cell type that might be expected to undergo substantial proliferative and phenotypic changes in response to external stimuli. This contrasts with the relatively rapid and continuous turnover of many epithelial cell linings, with replacement by generation from local progenitor cells, such as in the skin or gut. However, this perspective needs to be balanced by our knowledge of significant and rapid alterations in endothelial cell behaviour in the control of vascular homeostasis, for example in response to altered shear stress or to pro-inflammatory mediators. And, indeed, there are also clear examples of the ability of adult endothelium to chronically adapt its phenotype. One of these is the generation of so-called high endothelial venules at sites of chronic inflammation, where the thickened endothelial cells are specialized to enhance lymphocyte trafficking and the phenotype …
BCIRG 006: Docetaxel and trastuzumab-based regimens improve DFS and OS over AC-T in node positive and high risk node negative HER2 positive early breast cancer patients: Quality of life (QOL) at 36 months follow-up
Authors: N. J. Robert, W. Eiermann, T. Pienkowski, J. Crown, M. Martin, M. Pawlicki, A. Chan, V. Bee, D. Slamon, H. Au
Journal: Journal of Clinical Oncology (2007)

19647 Background: The primary objective of the BCIRG 006 trial was to determine if the use of trastuzumab in early high-risk HER2-positive breast cancer significantly improved clinical outcomes. A secondary objective was to evaluate the QOL of patients receiving the 2 treatments. Methods: The BCIRG 006 trial compared adjuvant standard AC (doxorubicin/cyclophosphamide x 4 cycles) followed by docetaxel x 4 [AC-T] or 2 trastuzumab-containing regimens, AC followed by T with trastuzumab x 1 year [AC-TH] or TCarbo x 6 with trastuzumab x 1 year [TCH] in patients with node positive or high-risk node negative HER2-positive early breast cancer (n=3222). Results: The 2nd planned interim analysis, median follow-up at 36 months, showed that both AC-TH and TCH significantly improved the DFS and OS over the control (relative reduction risk of relapse 39% (P&lt;0.0001) and 33% (P=0.0003) respectively, for AC-TH and TCH vs control). Relative reduction in the risk of death was 41% (P=0.0041) and 34% (P =0.017) respectively, for AC-TH and TCH vs control. Congestive heart failure occurred in 0.4% of patients in AC-T and TCH vs 1.9% of patients in AC-TH. Global safety profile was acceptable in all 3 arms and more favourable in TCH than AC-TH. QOL, a secondary endpoint of this trial, was assessed using the EORTC QLQC-30, BR-23, and EQ5D. We will present the primary QOL endpoints comparing Physical Function, Global Health Status, Future Perspectives, and Systemic Treatment Effects change scores from baseline to mid-chemotherapy, end of chemotherapy, and 12 months follow-up (with a 10% change considered clinically important). The proportion of patients with improved/stable/worsened QOL scores will be compared with chi-square tests. Other QOL exploratory analyses will be presented. [Table: see text]
Abstract 14583: Value of High Sensitivity Troponin Assays in Non Selected Patients With Chest Pain Admitted to Emergency Department
Authors: Luigi M Biasucci, Gina Biasillo, Roberta Della Bona, Milena Leo, Massimo Gustapane, Ilaria Dato, Giulia Pignataro, Niccolo Gentiloni Silveri, Mario Plebani, Martina Zaninotto, Monica Mion, Filippo Crea
Journal: Circulation (2010)

Early diagnosis of acute coronary syndrome (ACS) and the proper management of chest pain pts still represents a clinical challenge in the emergency department (ED). International guidelines recomme...
Echocardiographic findings and the search for a gold standard in patients with arrhythmogenic right ventricular dysplasia**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Melvin M. Scheinman, Michael H. Crawford
Journal: Journal of the American College of Cardiology (2005)
Influence of thiozolidinediones (TZD) exposure on the progression of oral leukoplakia (L) and erythroplakia (E) to the development of head and neck cancer (HNC).
Authors: A. Kunthur, E. Siegel, R. Govindarajan
Journal: Journal of Clinical Oncology (2010)

1565 Background: Oral L&E are precancerous conditions. TZDs, PPARγ ligands used to treat type II diabetes mellitus (DM) have been shown to have in vitro antineoplastic activity. Statistically significant reduction in the HNC cancer has been reported on exposure to TZD. TZD have been evaluated in clinical trials to treat leukoplakia. We conducted a retrospective cohort analysis to evaluate the efficacy of TZDs in preventing the development of HNC in subjects with oral L&E who are exposed to TZDs. Methods: L, E HNC, and DM were identified using ICD 9 codes from the VISN 16 patient data base serving 10 VA health care facilities from to 1996 to 2008. Anti-DM drug history was obtained from pharmacy data. The association between TZD exposure and the development of HNC was evaluated using multivariate Cox regression with age and tobacco use as baseline covariates, anti-DM drug exposures as time-dependent covariates, with stratification on race. Results: 2,363 subjects were identified as having L or E. 115 subjects developed HNC during a total follow-up of 10283 years. Median age, yrs. (quartiles) 59 (52–67); males 2,264 (96%); females 99 (4%); Caucasians 1,647 (70%), African American 450 (19%); others/unknown race 266 (11%). Tobacco users 1,238 (52%); DM subjects 732 (31%). HNC rate was 0.8% per year in TZD users versus 1.1%/year in nonusers (HR 0.79; p=0.4) (Table). Conclusions: TZD exposure did not influence the progression of L&E to HNC. TZD use may decrease the incidence of HNC with out preexisting L&E. Exposure summary and multivariate Cox-regression analysis results Treatment Exposure summary Adjusted HR3(95% confidence limits) p value N (%1) Years (%2) HNC No drug 1,784 (75%) 8,013 (78%) 100 1.00 (reference) - TZDs 131 (5%) 455 (4%) 4 0.81 (0.18–3.71) 0.79 Insulin 228 (9%) 751 (7%) 6 1.00 (0.41–2.41) 0.99 Metformin 394 (16%) 1,416 (14%) 10 0.60 (0.25–1.46) 0.26 Sulfonylureas 392 (16%) 1,624 (16%) 12 0.84 (0.41–1.69) 0.62 1 % of 2,363 subjects. 2 % of 10,283 years of follow-up. 3 Hazard ratio of each treatment adjusting for the presence of age, tobacco, and the other treatments. No significant financial relationships to disclose.
Abstract 18847: Secretoneurin Provides Independent Prognostic Information in Patients with Heart Failure and Cardiac Arrest, and has a Direct Inhibitory Effect on Diastolic Ca2+ Leak and Arrhythmogenic Ca2+ Waves via CaMKIId Inhibition
Authors: Anett Hellebø Ottesen, William Edward Louch, Cathrine Rein Carlson, Ole Jørgen Bjarnason Landsverk, Jouni Kurola, Rune Forstrøm Johansen, Morten Kåre Moe, Jan Magnus Aaronsen, Arne Didrik Høiseth, Hilde Jarstadmarken, Ståle Nygård, Magnar Bjørås, Ivar Sjaastad, Ville Pettilä, Mats Stridsberg, Torbjørn Omland, Geir Christensen, Helge Røsjø
Journal: Circulation (2014)

Background:  Secretoneurin (SN) levels are increased in patients with heart failure (HF), but whether SN provides prognostic information in cardiovascular disease (CVD) and influences cardiomyocyte function are not known.   Methods and Results:  Circulating SN was measured  2+ /calmodulin (CaM)-dependent protein kinase II δ (CaMKIIδ). SN attenuated CaMKIIδ activity, reduced CaMKIIδ-dependent ryanodine receptor (RyR) phosphorylation, lowered diastolic Ca 2+  leak at different concentrations, and increased sarcoplasmic reticulum Ca 2+  content. These results were also consistent with results from cardiomyocytes of HF animals, as SN reduced RyR leak in HF reflected by less Ca 2+  sparks and waves. SN also reduced basal and isoproterenol (ISO)-induced frequency and dimensions of Ca 2+  sparks and the development of arrhythmogenic Ca 2+  waves, attenuated ISO-induced CaMKIIδ autophosphorylation, and reduced CaMKIIδ-induced RyR phosphorylation in the presence of ISO.   Conclusions:  SN is a novel CV biomarker that provides independent prognostic information to established risk indices and reduces diastolic Ca 2+  leak and arrhythmogenic Ca 2+  waves via direct CaMKIIδ inhibition, which identifies high SN levels as a compensatory mechanism in the most severely ill patients.
Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer.
Authors: C Myers, M Cooper, C Stein, R LaRocca, M M Walther, G Weiss, P Choyke, N Dawson, S Steinberg, M M Uhrich
Journal: Journal of Clinical Oncology (1992)

Suramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy.Suramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2.In 17 patients with measurable soft tissue disease, three had complete disappearance of soft tissue disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). The remaining 21 patients had disease limited to bone, and only one of these experienced resolution of more than 50% of all lesions on bone scan. Of these 21 patients, pretreatment PSA decreased by 75% or more in eight (38%) and normalized in five (25%). Median time to progression for all patients was 26.3 weeks, and median survival was 42.3 weeks. Patients with bone involvement alone exhibited a better survival than patients with soft tissue involvement (P2 = .02). Survival was strongly correlated (P2 = .0001) with a decline in the pretreatment PSA of greater than or equal to 75% by the eighth week on therapy, with nearly an 85% survival at 1 year compared with a 20% survival for those whose pretreatment PSA did not decline by that amount.We conclude that suramin is an active agent in hormone-refractory prostate carcinoma.
Shape analysis of hypertrophic and hypertensive heart disease using MRI-based 3D surface models of left ventricular geometry
Authors: Siamak Ardekani, Saurabh Jain, Alianna Sanzi, Celia P. Corona-Villalobos, Theodore P. Abraham, M. Roselle Abraham, Stefan L. Zimmerman, Katherine C. Wu, Raimond L. Winslow, Michael I. Miller, Laurent Younes
Journal: Medical Image Analysis (2015)
A cutaneous presentation of a common condition
Authors: Adam Daunton, Gerald Langman, J M R Goulding
Journal: BMJ (2015)

A 25 year old woman was reviewed on the ward by the dermatology team for persistent, painful intertriginous skin erosions beneath both breasts and in both groins. She had been admitted over a month ago with cellulitis around the erosions, which initially responded to intravenous antibiotics but needed several repeat courses owing to recurrence.

Crohn’s disease had necessitated a total colectomy at age 18 years. She also had severe learning difficulties and behavioural problems.

She could not tolerate topical treatments. The only regular drugs at admission were mesalazine 1500 mg daily and clozapine. High dose oral corticosteroids before colectomy caused a marked transient psychosis and she had not received further systemic corticosteroids since.

She was obese with deep sloughy linear erosions demonstrating the “knife-cut” sign beneath the abdominal apron, in the inguinal creases, and under both breasts (fig 1⇓). She also had an eroded ulcer in her right labium majus.



Fig 1 Knife-cut ulcer in the right submammary fold



Multiple skin swabs were negative for bacterial, candidal, and herpes simplex virus (HSV) infections. Initial skin biopsy showed only non-specific scarring in the dermis, but a deeper one showed non-caseating granulomatous inflammation.



### 1. Which differential diagnoses must be excluded in this patient?

#### Short answer

Linear erosive HSV infection, cutaneous Crohn’s disease, bacterial and fungal infections.

#### Discussion

The term “knife-cut” sign was originally used to refer to the linear fissures commonly seen on colonoscopy in patients with Crohn’s disease. It was later used to describe the cutaneous linear erosive lesions seen in some patients with Crohn’s disease affecting the skin (termed metastatic Crohn’s disease).1 However, other disorders may also produce linear erosive fissures with a similar appearance. …
Procalcitonin and MR-proAdrenomedullin combined score in the diagnosis and prognosis of systemic and localized bacterial infections
Authors: Silvia Angeletti, Massimo Ciccozzi, Marta Fogolari, Silvia Spoto, Alessandra Lo Presti, Sebastiano Costantino, Giordano Dicuonzo
Journal: Journal of Infection (2015)
Fate of the Testis following Epididymitis: A Clinical and Ultrasound Study
Authors: K M Desai, J C Gingell, J M Haworth
Journal: Journal of the Royal Society of Medicine (1986)

The progress of 33 men suffering from acute epididymitis, the majority of whom were treated as hospital inpatients, was prospectively monitored in order to determine the incidence of complications, and to assess the prognostic implications of clinical and scrotal ultrasound features found at initial presentation. Serious testicular complications resulting in frank infarction, suppurative necrosis and late atrophy developed in 39%. Three factors were shown to have significant discriminant value in predicting an adverse outcome: severe degree of inflammation with induration of the spermatic cord; the presence of a coexistent bacterial urinary infection; and a uniformly reduced testicular echo pattern on the affected side as visualized on ultrasound. A more aggressive approach in addition to medical measures appears to be indicated in these patients. The rationale of early surgical decompression by epididymotomy and spermatic fasciotomy is discussed. Scrotal ultrasound should be considered as a routine investigation in the management of epididymitis.
Telomerase Inhibitor Imetelstat in Essential Thrombocythemia and Myelofibrosis
Authors: Ayalew Tefferi
Journal: New England Journal of Medicine (2015)

To the Editor: Baerlocher et al. (Sept.3 issue) 1 report on telomere-targeted treatment with imetelstat in 18 patients with essential thrombocythemia.The drug was effective in controlling platelet levels in all patients, albeit often at the expense of hemoglobin and neutrophil levels.However, the other main treatment goals in essential thrombocythemia 2 -controlling symptoms and preventing both disease progression and thromboembolic complications -were definitely not achieved.Fatigue, diarrhea, and nausea were all reported by more than 70% of the patients.A total of 3 patients had progression to myelofibrosis, and 2 patients had a thromboembolic event.Thus, treatment with imetelstat does not seem to be promising in this relatively benign disease.Only 4 patients had received interferon before undergoing this experimental therapy.Pegylated interferon alfa-2 is effective in controlling thrombocytosis in most patients, and it is not associated with myelofibrotic transformation, leukemogenicity, or other adverse long-term events. 3Furthermore, interferon may induce a deep molecular remission (i.e., a very low JAK2 V617F mutation level) and normalization of bone marrow changes, effects that in some patients may be maintained years after treatment cessation. 3,4 In Denmark, interferon is suggested as first-line treatment in patients with essential thrombocythemia. 5
Preliminary Safety and Efficacy Data Of Daratumumab In Combination With Lenalidomide and Dexamethasone In Relapsed Or Refractory Multiple Myeloma
Authors: Tobias Arkenau, Henk Lokhorst, Peter Gimsing, DMSci, Jakub Krejcik, Charlotte Lemech, Monique C. Minnema, Ulrik Lassen, Andrew Cakana, Nikolai Constantin Brun, Linda Basse, Antonio Palumbo, Paul G. Richardson
Journal: Blood (2013)
Whole Exome Sequencing of Philadelphia-Negative (Ph-negative) Myeloproliferative Neoplasms (MPNs) and Myelodysplastic/Myeloproliferative Disorders (MDS/MPD)
Authors: Fabio P S Santos, Renato D Puga, Ricardo Helman, Welbert Oliveira Pereira, Tarcila S Datoguia, Bianca Lisboa, Mariana Miyagi, Evelyn HA da Mata, Rodrigo Santucci, Guilherme F Perini, Eizabeth Xisto Souto, Carolina Kassab, Leandro Padua, Patricia W Bollman, Rodolfo Soares, Marcia Higashi, Adriana Valente Fadel, Juliane Musacchio, Ana Fernandes Schriefer, Marco Aurelio Salvino, Danielle Leao Cordeiro De Farias, Leila Martins Perobelli, Paulo A. A. Silveira, Nydia Bacal, Joao Carlos Guerra, Alanna Mara P. S Bezerra, Denise da Cunha Pasqualin, Marinus M Lima, Erika MM Costa, Vinicius R. P. Mattos, Isabel C Bello, Michelli Silva Diniz, Sandra S Nakashima, Elvira Velloso, Nelson Hamerschlak, Paulo Vidal Campregher
Journal: Blood (2014)
Most are performed by radiologists
Authors: R J Davies, C S Ward
Journal: BMJ (1995)

Radiologists, who every year scan hundreds of livers of all shapes, positions, and sizes, are better placed than anyone else to comment on the inappropriateness of performing blind right intercostal punctures with large calibre needles.They are also, by training and experience, the most expert in placing biopsy needles of all kinds under imaging guidance and are probably just waiting to be asked.