tbuckley/cabot-search huggingface dataset:
Combining Adoptive Cellular and Immunocytokine Therapies to Improve Treatment of B-Lineage Malignancy
Authors: Harjeet Singh, Lisa Marie Serrano, Timothy Pfeiffer, Simon Olivares, George McNamara, David D. Smith, Zaid Al-Kadhimi, Stephen J. Forman, Stephen D. Gillies, Michael C. Jensen, David Colcher, Andrew Raubitschek, Laurence J.N. Cooper
Journal: Cancer Research (2007)

Abstract Currently, the lineage-specific cell-surface molecules CD19 and CD20 present on many B-cell malignancies are targets for both antibody- and cell-based therapies. Coupling these two treatment modalities is predicted to improve the antitumor effect, particularly for tumors resistant to single-agent biotherapies. This can be shown using an immunocytokine, composed of a CD20-specific monoclonal antibody fused to biologically active interleukin 2 (IL-2), combined with ex vivo expanded human umbilical cord blood–derived CD8+ T cells, that have been genetically modified to be CD19 specific, for adoptive transfer after allogeneic hematopoietic stem-cell transplantation. We show that a benefit of targeted delivery of recombinant IL-2 by the immunocytokine to the CD19+CD20+ tumor microenvironment is improved in vivo persistence of the CD19-specific T cells, and this results in an augmented cell-mediated antitumor effect. Phase I trials are under way using anti-CD20-IL-2 immunocytokine and CD19-specific T cells as monotherapies, and our results warrant clinical trials using combination of these two immunotherapies. [Cancer Res 2007;67(6):2872–80]
A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans
Authors: Anna C Need, Dalia Kasperavičiūtė, Elizabeth T Cirulli, David B Goldstein
Journal: Genome biology (2009)

It was recently shown that the genetic distinction between self-identified Ashkenazi Jewish and non-Jewish individuals is a prominent component of genome-wide patterns of genetic variation in European Americans. No study however has yet assessed how accurately self-identified (Ashkenazi) Jewish ancestry can be inferred from genomic information, nor whether the degree of Jewish ancestry can be inferred among individuals with fewer than four Jewish grandparents.Using a principal components analysis, we found that the individuals with full Jewish ancestry formed a clearly distinct cluster from those individuals with no Jewish ancestry. Using the position on the first principal component axis, every single individual with self-reported full Jewish ancestry had a higher score than any individual with no Jewish ancestry.Here we show that within Americans of European ancestry there is a perfect genetic corollary of Jewish ancestry which, in principle, would permit near perfect genetic inference of Ashkenazi Jewish ancestry. In fact, even subjects with a single Jewish grandparent can be statistically distinguished from those without Jewish ancestry. We also found that subjects with Jewish ancestry were slightly more heterozygous than the subjects with no Jewish ancestry, suggesting that the genetic distinction between Jews and non-Jews may be more attributable to a Near-Eastern origin for Jewish populations than to population bottlenecks.
Analysis of conditional heterozygous STXBP1 mutations in human neurons
Authors: Christopher Patzke, Yan Han, Jason Covy, Fei Yi, Stephan Maxeiner, Marius Wernig, Thomas C. Südhof
Journal: Journal of Clinical Investigation (2015)

Heterozygous mutations in the syntaxin-binding protein 1 (STXBP1) gene, which encodes Munc18-1, a core component of the presynaptic membrane-fusion machinery, cause infantile early epileptic encephalopathy (Ohtahara syndrome), but it is unclear how a partial loss of Munc18-1 produces this severe clinical presentation. Here, we generated human ES cells designed to conditionally express heterozygous and homozygous STXBP1 loss-of-function mutations and studied isogenic WT and STXBP1-mutant human neurons derived from these conditionally mutant ES cells. We demonstrated that heterozygous STXBP1 mutations lower the levels of Munc18-1 protein and its binding partner, the t-SNARE-protein Syntaxin-1, by approximately 30% and decrease spontaneous and evoked neurotransmitter release by nearly 50%. Thus, our results confirm that using engineered human embryonic stem (ES) cells is a viable approach to studying disease-associated mutations in human neurons on a controlled genetic background, demonstrate that partial STXBP1 loss of function robustly impairs neurotransmitter release in human neurons, and suggest that heterozygous STXBP1 mutations cause early epileptic encephalopathy specifically through a presynaptic impairment.
Analysis of the absolute risks in coeliac disease indicates the importance of the prevention of osteoporosis * Author's reply
Authors: J R F Walters, J West
Journal: Gut (2007)

In their article reviewing recent advances in coeliac disease ( Gut 2006; 55 :1037–46), the authors discuss the impact of clinically diagnosed coeliac disease, including the two most recognised complications of osteoporotic fracture and malignancy. Their analysis correctly concludes that there is now reasonably precise information of the actual risks to patients of osteoporosis, lymphoma and other malignancies, but they describe the overall risk of fractures as being “at most moderate”. They miss, however, the opportunity to compare the absolute risks of these complications, which suggest in fact that osteoporosis prevention should remain the principal concern of long-term care in this condition.

The relative and absolute risks of fractures were well described in an important population-based cohort of patients with 4732 disease, using data from the UK General Practice Research Database between 1987 and 2002, by West et al 1 These authors also published data on the risks of malignancy in the same cohort of patients with disease over the same period.2 Data from these two papers have been extracted and combined in table 1.

View this table:

 Table 1  
 Reported numbers, hazard ratios and rates for fractures, malignancy and lymphoproliferative disorders in a cohort of patients with coeliac disease1,2



The hazard ratios for fractures are between 1.3 (for any fracture) and 1.9 (hip fracture at any age). The ratios for …
Factors Predictive of Distant Metastases in Patients With Breast Cancer Who Have a Pathologic Complete Response After Neoadjuvant Chemotherapy
Authors: Ana M. Gonzalez-Angulo, Sean E. McGuire, Thomas A. Buchholz, Susan L. Tucker, Henry M. Kuerer, Roman Rouzier, Shu-Wan Kau, Eugene H. Huang, Paolo Morandi, Alberto Ocana, Massimo Cristofanilli, Vicente Valero, Aman U. Buzdar, Gabriel N. Hortobagyi
Journal: Journal of Clinical Oncology (2005)

To identify clinicopathological factors predictive of distant metastasis in patients who had a pathologic complete response (pCR) after neoadjuvant chemotherapy (NC).Retrospective review of 226 patients at our institution identified as having a pCR was performed. Clinical stage at diagnosis was I (2%), II (36%), IIIA (27%), IIIB (23%), and IIIC (12%). Eleven percent of all patients were inflammatory breast cancers (IBC). Ninety-five percent received anthracycline-based chemotherapy; 42% also received taxane-based therapy. The relationship of distant metastasis with clinicopathologic factors was evaluated, and Cox regression analysis was performed to identify independent predictors of development of distant metastasis.Median follow-up was 63 months. There were 31 distant metastases. Ten-year distant metastasis-free rate was 82%. Multivariate Cox regression analysis using combined stage revealed that clinical stages IIIB, IIIC, and IBC (hazard ratio [HR], 4.24; 95% CI, 1.96 to 9.18; P < .0001), identification of < or = 10 lymph nodes (HR, 2.94; 95% CI, 1.40 to 6.15; P = .004), and premenopausal status (HR, 3.08; 95% CI, 1.25 to 7.59; P = .015) predicted for distant metastasis. Freedom from distant metastasis at 10 years was 97% for no factors, 88% for one factor, 77% for two factors, and 31% for three factors (P < .0001).A small percentage of breast cancer patients with pCR experience recurrence. We identified factors that independently predicted for distant metastasis development. Our data suggest that premenopausal patients with advanced local disease and suboptimal axillary node evaluation may be candidates for clinical trials to determine whether more aggressive or investigational adjuvant therapy will be of benefit.
Inflammatory ultrasound features show independent associations with progression of structural damage after over 2 years of follow-up in patients with hand osteoarthritis
Authors: Marion C Kortekaas, Wing-Yee Kwok, Monique Reijnierse, Margreet Kloppenburg
Journal: Annals of the Rheumatic Diseases (2014)

To study the development of inflammatory features and it's relation to structural damage over a 2.3-year period in patients with hand osteoarthritis (HOA).Synovial thickening, effusion and power Doppler signal (PDS) in distal interphalangeal (DIP), proximal interphalangeal (PIP), 1st carpometacarpal (CMC) metacarpal phalangeal (MCP) and 1st interphalangeal (IP) joints were assessed using ultrasonography in 56 consecutive HOA patients (mean age 61.2 years, 85.7% female) fulfilling American College of Rheumatology (ACR) classification criteria, at baseline and follow-up. Radiographic progression of osteophytes and joint space narrowing (JSN) was scored using the OARSI atlas. With generalised estimating equations (GEE), OR with 95% CIs were calculated for the associations between inflammatory ultrasound features and radiographic progression taking in account patient effect, age, gender, Body Mass Index, baseline osteophytes and JSN scores, and other inflammatory ultrasound features.Of 1680 joints, 8.4%, 8.7%, and 19.8% had synovial thickening, PDS or effusion at baseline, respectively. 7.1% and 5.7% of joints had progression of osteophytes and JSN, respectively. Independent associations were found between synovial thickening, effusion and PDS (grade 2-3 vs 0), and progression of osteophytes (OR (95% CI): 2.6 (1.02 to 6.5), 3.5 (1.7 to 7.4) and 5.7 (1.5 to 21.1)) and of JSN (OR (95% CI): 3.4 (1.3 to 8.4), 3.3 (1.5 to 7.6) and 3.1 (1.01 to 9.2)). Persistent inflammatory features at baseline and follow-up showed stronger associations with radiographic progression than fluctuating inflammatory features in comparison with no inflammatory features.Inflammatory features, especially when persistently present, are independently associated with radiological progression in HOA after 2.3 years, indicating a role of inflammation in the aetiology of structural damage in HOA.
Noninvasive Positive-Pressure Ventilation for Postextubation Respiratory Distress
Authors: Sean P Keenan, Caroline Powers, David G McCormack, Gary Block
Journal: JAMA (2002)

ContextNoninvasive positive-pressure ventilation (NPPV) has been demonstrated to be effective in preventing the need for endotracheal intubation in some patients who present with acute respiratory failure. It is also used for patients who develop acute respiratory distress after extubation, but there are no randomized controlled trials that address its effectiveness in this population.ObjectiveTo determine the effectiveness of NPPV compared with standard medical therapy in preventing the need for endotracheal reintubation in high-risk patients who develop respiratory distress during the first 48 hours after extubation.DesignRandomized, controlled, unblinded study with concealed allocation conducted between August 1, 1996 and October 31, 1999.SettingAn intensive care unit (ICU) in an academic, tertiary care hospital in Ontario.PatientsEighty-one patients with a history of cardiac or respiratory disease or who initially required ventilatory support for more than 2 days and who developed respiratory distress within 48 hours of extubation.InterventionsPatients were randomly assigned to receive standard medical therapy alone (supplemental oxygen to maintain oxygen saturation by pulse oximetry ≥95%; n = 42) or NPPV by face mask plus standard medical therapy (n = 39).Main Outcome MeasuresRates of reintubation, duration of mechanical ventilation, lengths of ICU and hospital stay, and hospital mortality.ResultsComparing the NPPV group with the standard-therapy group, there was no difference in the rate of reintubation (72% vs 69%; relative risk, 1.04; 95% confidence interval, 0.78-1.38) or hospital mortality (31% for both groups; relative risk, 0.99; 95% confidence interval, 0.52-1.91). Similarly, no difference was found in duration of mechanical ventilation or length of ICU or hospital stay.ConclusionsThe addition of NPPV to standard medical therapy does not improve outcome in heterogeneous groups of patients who develop respiratory distress during the first 48 hours after extubation.
Clinical features and course of type A and type B vitiligo
Authors: M. KOGA, T. TANGO
Journal: British Journal of Dermatology (1988)

Four hundred and eighty one cases of vitiligo (acquired idiopathic depigmentation) were studied clinically. They were divided into two types, type B, in which depigmented patches are confined to a definite dermatome in the same manner as herpes zoster, and type A, which included all cases of vitiligo not classified as type B. The ratio of type A:type B was approximately 3:I. Onset of type A vitiligo could occur at any age, whereas type B generally affected the young. The activity of type B vitiligo usually ceased after one year, following rapid spread over the particular dermatomal area. However, in type A vitiligo new depigmented patches continued to appear throughout the patients' lives. Association with halo naevus and Köbner's phenomenon were observed exclusively in type A. Association with diseases with a proven or suggested allergic or immunological aetiology was more often found in type A. These findings support our hypothesis that type A and type B vitiligo have a different pathogenesis and that autoimmune mechanisms play a role only in type A.
Mitochondria-dependent and -independent Regulation of Granzyme B–induced Apoptosis
Authors: Glen MacDonald, Lianfa Shi, Christine Vande Velde, Judy Lieberman, Arnold H. Greenberg
Journal: The Journal of Experimental Medicine (1999)

Granzyme B (GraB) is required for the efficient activation of apoptosis by cytotoxic T lymphocytes and natural killer cells. We find that GraB and perforin induce severe mitochondrial perturbation as evidenced by the release of cytochrome c into the cytosol and suppression of transmembrane potential (Δψ). The earliest mitochondrial event was the release of cytochrome c, which occurred at the same time as caspase 3 processing and consistently before the activation of apoptosis. Granzyme K/perforin or perforin treatment, both of which kill target cells efficiently but are poor activators of apoptosis in short-term assays, did not induce rapid cytochrome c release. However, they suppressed Δψ and increased reactive oxygen species generation, indicating that mitochondrial dysfunction is also associated with this nonapoptotic cell death. Pretreatment with peptide caspase inhibitors zVAD-FMK or YVAD-CHO prevented GraB apoptosis and cytochrome c release, whereas DEVD-CHO blocked apoptosis but did not prevent cytochrome c release, indicating that caspases act both up- and downstream of mitochondria. Of additional interest, Δψ suppression mediated by GraK or GraB and perforin was not affected by zVAD-FMK and thus was caspase independent. Overexpression of Bcl-2 and Bcl-XL suppressed caspase activation, mitochondrial cytochrome c release, Δψ suppression, and apoptosis and cell death induced by GraB, GraK, or perforin. In an in vitro cell free system, GraB activates nuclear apoptosis in S-100 cytosol at high doses, however the addition of mitochondria amplified GraB activity over 15-fold. GraB- induced caspase 3 processing to p17 in S-100 cytosol was increased only threefold in the presence of mitochondria, suggesting that another caspase(s) participates in the mitochondrial amplification of GraB apoptosis. We conclude that GraB-induced apoptosis is highly amplified by mitochondria in a caspase-dependent manner but that GraB can also initiate caspase 3 processing and apoptosis in the absence of mitochondria.
Flicker Light–Induced Retinal Vasodilation in Diabetes and Diabetic Retinopathy
Authors: Thanh T. Nguyen, Ryo Kawasaki, Jie Jin Wang, Andreas J. Kreis, Jonathan Shaw, Walthard Vilser, Tien Y. Wong
Journal: Diabetes Care (2009)

OBJECTIVE Flicker light–induced retinal vasodilation may reflect endothelial function in the retinal circulation. We investigated flicker light–induced vasodilation in individuals with diabetes and diabetic retinopathy. RESEARCH DESIGN AND METHODS Participants consisted of 224 individuals with diabetes and 103 nondiabetic control subjects. Flicker light–induced retinal vasodilation (percentage increase over baseline diameter) was measured using the Dynamic Vessel Analyzer. Diabetic retinopathy was graded from retinal photographs. RESULTS Mean ± SD age was 56.5 ± 11.8 years for those with diabetes and 48.0 ± 16.3 years for control subjects. Mean arteriolar and venular dilation after flicker light stimulation were reduced in participants with diabetes compared with those in control subjects (1.43 ± 2.10 vs. 3.46 ± 2.36%, P &amp;lt; 0.001 for arteriolar and 2.83 ± 2.10 vs. 3.98 ± 1.84%, P &amp;lt; 0.001 for venular dilation). After adjustment for age, sex, diabetes duration, fasting glucose, cholesterol and triglyceride levels, current smoking status, systolic blood pressure, and use of antihypertensive and lipid-lowering medications, participants with reduced flicker light–induced vasodilation were more likely to have diabetes (odds ratio 19.7 [95% CI 6.5–59.1], P &amp;lt; 0.001 and 8.14 [3.1–21.4], P &amp;lt; 0.001, comparing lowest vs. highest tertile of arteriolar and venular dilation, respectively). Diabetic participants with reduced flicker light–induced vasodilation were more likely to have diabetic retinopathy (2.2 [1.2–4.0], P = 0.01 for arteriolar dilation and 2.5 [1.3–4.5], P = 0.004 for venular dilation). CONCLUSIONS Reduced retinal vasodilation after flicker light stimulation is independently associated with diabetes status and, in individuals with diabetes, with diabetic retinopathy. Our findings may therefore support endothelial dysfunction as a pathophysiological mechanism underlying diabetes and its microvascular manifestations.
Management of Effusive and Constrictive Pericardial Heart Disease
Authors: Brian D. Hoit
Journal: Circulation (2002)

ase study: A 69-year-old white male was referred for transesophageal echocardiography (TEE) two days after urgent coronary artery bypass grafting.In the first 24 postoperative hours, pleural and pericardial drainage was nearly 3 L, during which time the blood pressure was supported with inotropic agents.The next day, chest tube drainage was minimal, a transthoracic echocardiogram was unremarkable, and the patient was extubated.Shortly thereafter, the patient became hypotensive and dyspneic.TEE revealed a large loculated effusion with linear adhesions and thrombus that compressed both atria, as well as a large pleural effusion.There was marked respiratory variation in Doppler velocities across the tricuspid and mitral valves.At thoracotomy, 1 L of blood was removed from the pericardial space, bleeding at the site of aortic cannulation was sutured, and the patient made an uneventful recovery.Treatment of effusive and constrictive pericardial disease is often simple and gratifying, but frustration and unforeseen challenges await the unwary clinician.The symptoms and signs of pericardial disease, at times unmistakable (as in the patient described above), may be overshadowed by extracardiac manifestations of a systemic disorder; at other times, they are insidious and conceal their true nature.Pericardial constriction mimics hepatic cirrhosis and myocardial failure and may be virtually indistinguishable from restrictive cardiomyopathy.Another important problem is the lack of placebo-controlled trials from which appropriate therapy may be selected and of guidelines that assist in important clinical decisions; as a result, the practitioner must rely heavily on clinical judgment.Finally, therapeutic options in most cases are limited to antiinflammatory agents, drainage of pericar-dial fluid, and pericardiectomy.However, despite general agreement on how these measures should be applied in patients with either very mild or severe disease, there is little consensus on the management of the large number of cases encountered with clinical manifestations between these two extremes.
Characteristics of wheeze during histamine-induced airways obstruction in children with asthma.
Authors: S Rietveld, E H Dooijes, L H Rijssenbeek-Nouwens, F Smit, P J Prins, A M Kolk, W A Everaerd
Journal: Thorax (1995)

An automated system has been developed for the detection of sound patterns suggestive of airways obstruction in long term recordings. The first step, presented here, was tracheal sound recording during histamine-induced airways obstruction.The tracheal sounds of 29 children aged 8-19 years with asthma were recorded during airways obstruction caused by histamine inhalation using a system for continuous respiratory telemetry and computer analysis. Sound patterns were analysed, classified, and related to airways obstruction measured by lung function tests based on the forced expiratory volume in one second (FEV1).Five sound patterns were identified, one dominant sensitive and four specific to a fall in FEV1 of > 20%. The presence of at least one of three specific sound patterns during unforced respiration predicted a fall in FEV1 of > 20% in 87.5% of the subjects. The inspiratory and expiratory sound patterns were almost equally informative of airways obstruction.Wheezes can be differentiated with more precision than is currently accepted. Tracheal sound patterns are sensitive and specific predictors of histamine-induced airways obstruction. These patterns are neither invariably nor proportionally related to the results of lung function testing. However, they can be used for detection of airways obstruction on the basis of their presence or absence.
Significance of abnormal autoantibodies in patients presenting with IPF
Authors: Sam J L Hayward, David Mcallister, Pauline Macfarlane, Phoebe Wright, Gareth Stewart, William Wallace, John Murchison, John Simpson, Nikhil Hirani
Journal: European Respiratory Journal (2012)

Introduction   A subset of patients with IPF present with abnormal auto-antibodies (AAs) without clinical features sufficient to diagnose connective tissue disease (CTD). CTD-associated ILD is generally associated with a better prognosis than IPF.   Aims   To study the prevalence and significance of abnormal AAs in IPF.   Methods   Consecutively presenting patients with suspected IPF between 1/1/02 and 31/12/10 were prospectively recruited to a database. All IPF diagnoses required exclusion of overt CTD and an HRCT appearance of UIP with ≥ 70% probability. Patients with HRCT scans with ≥ 95% probability of UIP, or a confirmatory surgical lung biopsy were defined as definite IPF. The remainder were defined as probable IPF. Abnormal AA profile was defined as the presence of at least one of: RhF ≥40, ANA ≥1/640 and/or positive specific ENA screen. Patients were followed-up until Dec 2011 (median [IQR] among survivors 45 [25-63] months). Of 233 patients recruited, 25 did not have AAs performed within 12 months of presentation and were excluded. Of the 208 patients reported, 95 had definite IPF.   Results   AAs were abnormal in 18% of patients. Definite v probable IPF, gender, age, smoking and baseline lung function were similar for normal and abnormal AA groups. Only 3 patients developed overt CTD and all had abnormal AAs. Median survival was lower in those with abnormal AAs (39 v 69 months; unadjusted HR 1.57 [0.97 to 2.53] p=0.07; adjusted for age, sex, baseline VC, smoking and definite/probable IPF, HR 1.69 [1.03 to 2.78] p=0.04).   Conclusions   Only 1% of all IPF patients developed overt CTD. Abnormal AA serology was associated with a poorer survival.