tbuckley/cabot-search huggingface dataset:
Consequences of Range Contractions and Range Shifts on Molecular Diversity
Authors: Miguel Arenas, Nicolas Ray, Mathias Currat, Laurent Excoffier
Journal: Molecular Biology and Evolution (2011)

Due to past and current climatic changes, range contractions and range shifts are essential stages in the history of a species. However, unlike range expansions, the molecular consequences of these processes have been little investigated. In order to fill this gap, we simulated patterns of molecular diversity within and between populations for various types of range contractions and range shifts. We show that range contractions tend to decrease genetic diversity as compared with population with stable ranges but quite counterintuitively fast range contractions preserve higher levels of diversity and induce lower levels of genetic differentiation among refuge areas than slow contractions. Contrastingly, fast range shifts lead to lower levels of diversity than slow range shifts. At odds with our expectations, we find that species actively migrating toward refuge areas can only preserve higher levels of diversity in refugia if the contraction is rapid. Under slow range contraction or slow range shift, active migration toward refugia lead to a larger loss of diversity as compared with scenarios with isotropic migration and may thus not be a good evolutionary strategy. These results suggest that the levels of diversity preserved after a climate change both within and between refuge areas will not only depend on the dispersal abilities of a species but also on the speed of the change. It also implies that a given episode of climatic change will impact differently species with different generation times.
GROUP TREATMENT OF CONDITIONALLY DISCHARGED PATIENTS IN A MENTAL HEALTH CLINIC
Authors: SAMUEL P. SHATTAN, LUAN DCAMP, EMI FUJII, G. G. FROSS, ROBERT J. WOLFF
Journal: American Journal of Psychiatry (1966)

Current literature has explored the possibilities of the use of the group approach to the treatment of state hospital patients who have been discharged to a mental health clinic for outpatient care. This paper deals with a method employed by a psychiatric team in the management of such patients. The rationale for the use of the group approach took a number of factors into account: 1) It is felt by some that a one-to-one relationship is particularly threatening for more severely ill patients. The group approach reduces the intensity of this relationship. 2) Some patients with ego weakness tend to acquire strength by identification with the group. 3) Patients in our groups are seen for a longer period of time than would normally be allotted to them during the brief, stereotyped, drug renewal interviews that usually constitute patient aftercare. 4) The group interaction offers a more variegated sampling of behavior on which to base clinical appraisals. 5) Seeing patients in groups is felt to be more efficient than seeing the same number of patients individually. A psychiatric team used an approach employing an initial orientation meeting for an experimental sample of 45 conditionally discharged patients and their relatives, followed by monthly group treatment sessions for the patients. This experimental sample was compared with a control sample of 45 patients who did not receive group treatment, seen during the same time period and matched for age, sex, race, marital status and diagnosis. The results of our study were obtained by comparing these two groups of patients for the following variables: return to hospital, significant at .05 level; receiving of absolute discharge, significant at .01 level; number of clinic contacts, significant at .01 level; mean number of months out of hospital, trend; chronicity, trend; employment after a year, not significant; receipt of medication, not significant. We feel, therefore, that the findings of this study show that the group approach bears wider application in improving outpatient programs for an ever-increasing population of ex-hospital patients.
Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia
Authors: Wolfgang R. Sperr, John-Hendrik Jordan, Mehrdad Baghestanian, Hans-Peter Kiener, Puchit Samorapoompichit, Hans Semper, Alexander Hauswirth, Gerit-Holger Schernthaner, Andreas Chott, Susanne Natter, Dietrich Kraft, Rudolf Valenta, Lawrence B. Schwartz, Klaus Geissler, Klaus Lechner, Peter Valent
Journal: Blood (2001)
The Future of Cancer Therapy: Selecting Patients Likely to Respond to PD1/L1 Blockade
Authors: Antoni Ribas, Paul C. Tumeh
Journal: Clinical Cancer Research (2014)

It is conceivable that, in the near future, an assay that defines the likelihood of a patient with advanced cancer to respond to immunotherapy based on PD1/L1 blockade will be the initial decision point to select the treatment of patients with any cancer type.
A multicenter randomized, open-label, proof-of-concept, phase II trial comparing gemcitabine with and without IMM-101 in advanced pancreatic cancer.
Authors: Angus George Dalgleish
Journal: Journal of Clinical Oncology (2015)

336 Background: Immunotherapy is becoming established as an effective way of treating cancer. Immodulon Therapeutics is developing IMM-101, a heat-killed whole cell preparation of Mycobacterium obuense (NCTC 13365), which modulates systemic immune responses, as an adjunctive immunotherapy for pancreatic cancer. Methods: Patients with advanced pancreatic cancer and a WHO score of 0-2 were assigned randomly to receive IMM-101 (0.1 mL intradermal injection of 10 mg/mL) plus Gemcitabine (Gem) (1000 mg/m 2 for 3 consecutive weeks out of 4) or Gem alone. Per protocol, this could be continued to a 12-cycle maximum. The primary efficacy endpoint was overall survival (OS). Safety, tolerability and progression free survival (PFS) were also assessed. Results: A total of 110 patients were randomized, 75 to receive IMM-101 plus Gem and 35 Gem alone (ITT population). The PP population consisted of 63 and 35 patients, respectively. Conclusions were similar; here we report results of the PP analysis. Median OS was increased significantly by 29% to 7.2 months in the IMM-101 plus Gem group compared to 5.6 months in the Gem group (p=0.022; HR 0.60, 95% CI 0.38-0.94). Median PFS was increased significantly by 83% to 4.4 months in the IMM-101 plus Gem group compared to 2.4 months in the Gem group (p=0.003; HR 0.51, 95% CI 0.32-0.81). In the pre-defined sub-group of patients with metastatic disease (n=82), median OS was increased significantly by 70% to 7.5 months in the IMM-101 plus Gem group (n=54) compared to 4.4 months in the Gem group (n=28) (p=0.002; HR 0.46, 95% CI 0.28-0.76). A highly significant 91% increase in median PFS from 2.3 months in the Gem group to 4.4 months in the IMM-101 plus Gem group was observed (p&lt;0.001; HR 0.40, 95% CI 0.24-0.66). IMM-101 was well tolerated. The only adverse events of NCI CTC ≥Grade 3 occurring more frequently in the IMM-101 group (absolute difference in frequency between the groups &gt;5%) were asthenia 10.8% and abdominal pain 8.1% (both 2.9% in the Gem group). Conclusion: Clinically meaningful increases in OS and PFS were demonstrated with IMM-101. No additional burden of adverse events above those relating to chemotherapy or the underlying disease was observed. Clinical trial information: NCT01303172.
Development of the Novel Biologically Targeted Anticancer Agent Gefitinib
Authors: Michael Wolf, Helen Swaisland, Steven Averbuch
Journal: Clinical Cancer Research (2004)

Abstract The emergence of novel, biologically targeted anticancer agents such as gefitinib (‘Iressa’, ZD1839) has raised the question of how the dose for later-stage clinical development and clinical use is best determined. For cytotoxic drugs, because toxic effects and antitumor activity often fall within the same dose range and are dose dependent, the clinically used dose will depend on the therapeutic window. Therefore, the maximum tolerated dose identified in Phase I trials is typically used to determine the dose level for Phase II and III trials. However, because biologically targeted agents are expected to provide clinical benefits that are not predicted by surrogate end points of toxicity to normal replicating tissue, new Phase I trials have been designed to determine the optimum biological dose for use in further studies. A large, multifaceted Phase I program was designed to evaluate the pharmacokinetics, safety, efficacy, and targeted biological activity of a once-daily oral dose of gefitinib. The maximum tolerated dose was ≥700 mg/day, although doses as low as 150 mg/day provided (a) plasma concentrations sufficient for pharmacological activity, (b) evidence of targeted biological effect, and (c) antitumor activity. From these observations, two large Phase II trials (‘Iressa’ Dose Evuluation in Advanced Lung Cancer 1 and 2) evaluated 250- and 500-mg/day doses of gefitinib in patients with advanced non-small cell lung cancer (NSCLC). As predicted from the Phase I trials, doses &amp;gt;250 mg/day provided no additional efficacy benefit, whereas adverse effects increased in a dose-dependent manner. Consequently, the recommended dose of gefitinib in NSCLC is 250 mg/day. The early clinical trial development of gefitinib provides a model for the development of novel, noncytotoxic anticancer agents.
P59 Why do we often fail to meet the gold standard for the diagnosis of active tuberculosis?
Authors: S. Huq, M. Haris, M. Gautam, P. D. O. Davies
Journal: Thorax (2010)

<h3>Introduction</h3> Although laboratory culture of <i>Mycobacterium tuberculosis</i> (M TB) remains the gold standard for the diagnosis of active tuberculosis (TB), only 66% of pulmonary and 46% of extra-pulmonary cases of TB in the UK are culture confirmed.1 The Health Protection Agency9s Strategic Plan aims for at least 70% of pulmonary TB cases to be confirmed by positive culture. The aim of this study was to identify the reasons for not obtaining culture confirmation in a cohort of active TB patients. <h3>Methods</h3> A retrospective study of all patients with active tuberculosis in a TB centre between January and December 2009. <h3>Results</h3> 69 patients (46 male) with a mean age of 42 years (range 3–83) were diagnosed. 36 (52%) had pulmonary TB with or without extra-pulmonary disease and 33 (48%) had extra-pulmonary TB only. 29 (81%) cases of pulmonary TB were culture positive and 4 (11%) had no growth on culture. 3 (8%) cases had no sample obtained. These were all children aged 3–5 years who had a positive Mantoux test, evidence of TB on chest radiograph and a history of close contact. 17 (52%) cases of extra-pulmonary TB were culture positive. 10 (30%) had samples taken but no growth on culture. 2 (6%) had samples obtained but not sent for culture while 4 (12%) had no sample obtained. <h3>Conclusion</h3> The commonest reason for not obtaining culture confirmation was a negative growth (20%). Failure to obtain a microbiological sample (10%) and failure to send the collected sample for mycobacterial culture (3%) were the other reasons. A positive culture of M TB is important because it not only confirms the diagnosis but also provides the drug susceptibility profile of the organism. Our finding that the largest proportion of cases not confirmed by positive culture was due to no growth from a specimen suggests that the current microbiological methods for growing M TB may be inadequate and further research is needed to increase the diagnostic yield. Secondly, there is a need to educate those sending samples, including surgeons and radiologists performing biopsies, so that specimens are sent correctly.
Induction of HLA-DP4–Restricted Anti-Survivin Th1 and Th2 Responses Using an Artificial Antigen-Presenting Cell
Authors: Makito Tanaka, Marcus O. Butler, Sascha Ansén, Osamu Imataki, Alla Berezovskaya, Lee M. Nadler, Naoto Hirano
Journal: Clinical Cancer Research (2011)

In previous cancer vaccine clinical trials targeting survivin, induction of specific CD8(+) T-cell responses did not consistently lead to clinical responses. Considering the critical role of CD4(+) T-cell help in generating antitumor immunity, integration of anti-survivin CD4(+) T-cell responses may enhance the efficacy of anti-survivin cancer immunotherapy. Human leukocyte antigen (HLA)-DP4 is emerging as an attractive MHC target allele of CD4(+) T cell-mediated immunotherapy, because it is one of the most frequent HLA alleles in many ethnic groups. In this article, we aimed to elucidate DP4-restricted CD4(+) T-cell responses against survivin in cancer patients.We generated a human cell-based artificial antigen-presenting cell (aAPC) expressing HLA-DP4, CD80, and CD83 and induced DP4-restricted antigen-specific CD4(+) T cells. The number, phenotype, effector function, and in vitro longevity of generated CD4(+) T cells were determined.We first determined previously unknown DP4-restricted CD4(+) T-cell epitopes derived from cytomegalovirus pp65, to which sustained Th1-biased recall responses were induced in vitro by using DP4-aAPC. In contrast, DP4-aAPC induced in vitro both Th1 and Th2 long-lived anti-survivin CD4(+) T cells from cancer patients. Both survivin-specific Th1 and Th2 cells were able to recognize survivin-expressing tumors in a DP4-restricted manner. Neither survivin-specific interleukin 10 secreting Tr1 cells nor Th17 cells were induced by DP4-aAPC.DP4-restricted anti-survivin Th1 and Th2 immunity with sufficient functional avidity can be induced from cancer patients. The development of strategies to concurrently induce both CD4(+) and CD8(+) T-cell responses against survivin is warranted for optimal anti-survivin cancer immunotherapy.
Human biomonitoring of arsenic and antimony in case of an elevated geogenic exposure.
Authors: T W Gebel, R H Suchenwirth, C Bolten, H H Dunkelberg
Journal: Environmental Health Perspectives (1998)

Part of the northern Palatinate region in Germany is characterized by elevated levels of arsenic and antimony in the soil due to the presence of ore sources and former mining activities. In a biomonitoring study, 218 residents were investigated for a putative increased intake of these elements. Seventy-six nonexposed subjects in a rural region in south lower Saxony were chosen as the reference group. Urine and scalp hair samples were obtained as surrogates to determine the internal exposures to arsenic and antimony. The analyses were performed using graphite furnace atomic absorption spectrometry except for arsenic in urine, which was determined by the hydride technique. This method does not detect organoarsenicals from seafood, which are not toxicologically relevant. In the northern Palatinate subjects, slightly elevated arsenic contents in urine and scalp hair (presumably not hazardous) could be correlated with an increased arsenic content in the soil. On the other hand, the results did not show a correlation between the antimony contents in the soil of the housing area and those in urine and hair. Except for antimony in scalp hair, age tended to be associated with internal exposures to arsenic and antimony in both study groups. Consumption of seafood had a slight impact on the level of urinary arsenic, which is indicative of the presence of low quantities of inorganic arsenicals and dimethylarsinic acid in seafood. The arsenic and antimony contents in scalp hair were positively correlated with the 24-hr arsenic excretion in urine. However, antimony in scalp hair was not correlated with seafood consumption as was arsenic in scalp hair and in urine. This indicated the existence of unidentified common pathways of exposure contributing to the alimentary body burden. Short time peaks in the 24-hr excretion of arsenic in urine, which could not be assigned to a high consumption of seafood, were detected for six study participants. This suggests that additional factors relevant in the exposure to arsenic are still unidentified.
Government must set up mechanism to save failing trusts
Authors: Adrian O'Dowd
Journal: BMJ (2005)

Pressure on NHS staff to maintain good care of patients will only get worse as the financial burdens on trusts grow, says a new report from the health policy think tank the King's Fund.

The report, published last week, warns that over the next few years a fifth of trusts are highly likely to have “large and persistent debts” that will put them at risk of failing.

These debts …
Chronic Burkholderia multivorans bronchial infection in a non-cystic fibrosis individual with mannose binding lectin deficiency
Authors: J L Whitehouse
Journal: Thorax (2005)

The case history is presented of a woman with multiple respiratory infections and mannose binding lectin (MBL) deficiency but no evidence of bronchiectasis who developed a chronic Burkholderia multivorans infection. Careful microbiological assessment is needed in patients with recurrent respiratory infection and the presence of B multivorans should trigger further immunological investigation including assessment of MBL status.
THE NEW HEALTH SOCIETY.
Authors: S.Henning Belfrage, Bruce Bruce-Porter, Harold Chapple, Ernest Clarke, IvoGeikie Cobb, Kenneth Goadby, L.Haden Guest, Alfred Jordan, W.Arbuthnot Lane, Nathan Mutch, HerbertJ. Paterson, CalebWilliams Saleeby, William Willcox, Leonard Williams
Journal: The Lancet (1926)
Acute Heart Failure Syndromes
Authors: Mihai Gheorghiade, Faiez Zannad, George Sopko, Liviu Klein, Ileana L. Piña, Marvin A. Konstam, Barry M. Massie, Edmond Roland, Shari Targum, Sean P. Collins, Gerasimos Filippatos, Luigi Tavazzi
Journal: Circulation (2005)
Discovery of Epigenetically Silenced Genes by Methylated DNA Immunoprecipitation in Colon Cancer Cells
Authors: Filipe V. Jacinto, Esteban Ballestar, Santiago Ropero, Manel Esteller
Journal: Cancer Research (2007)

Abstract CpG island promoter hypermethylation of tumor suppressor genes is a common hallmark of human cancer, and new large-scale epigenomic technologies might be useful in our attempts to define the complete DNA hypermethylome of tumor cells. Here, we report a functional search for hypermethylated CpG islands using the colorectal cancer cell line HCT-116, in which two major DNA methyltransferases, DNMT1 and DNMT3b, have been genetically disrupted (DKO cells). Using methylated DNA immunoprecipitation methodology in conjunction with promoter microarray analyses, we found that DKO cells experience a significant loss of hypermethylated CpG islands. Further characterization of these candidate sequences shows CpG island promoter hypermethylation and silencing of genes with potentially important roles in tumorigenesis, such as the Ras guanine nucleotide-releasing factor (RASGRF2), the apoptosis-associated basic helix-loop transcription factor (BHLHB9), and the homeobox gene (HOXD1). Hypermethylation of these genes occurs in premalignant lesions and accumulates during tumorigenesis. Thus, our results show the usefulness of DNMT genetic disruption strategies combined with methylated DNA immunoprecipitation in searching for unknown hypermethylated candidate genes in human cancer that might aid our understanding of the biology of the disease and be of potential translational use. [Cancer Res 2007;67(24):11481–6]
Molecular epidemiology of Salmonella enteritidis, an outbreak and sporadic cases studied by means of pulsed-field gel electrophoresis
Authors: Yasumoto Suzuki, Masamitsu Ishihara, Masakado Matsumoto, Shoichi Arakawa, Makoto Saito, Naohisa Ishikawa, Takashi Yokochi
Journal: Journal of Infection (1995)
Cartilage quality, overweight and osteoarthritis: a case for new behaviour?
Authors: Leif Dahlberg
Journal: Annals of the Rheumatic Diseases (2011)

Joint cartilage is indeed a metabolically active tissue. In this issue of Annals of the Rheumatic Diseases , the results of the study by Anandacoomarasamy et al 1 highlight two important issues of joint cartilage and osteoarthritis (OA): cartilage repair and OA progression. Unfortunately, many people equate cartilage repair with procedures that fill cartilage defects rather than replacing degraded molecules with newly synthesised molecules and consider that joint cartilage deterioration in OA is inevitable. In an elegantly designed study in obese subjects, the authors use MRI and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) to show that weight loss is associated with improvement in medial knee cartilage quality and quantity. In the light of OA mainly developing medially and considering that cartilage quality and OA risk are probably related, their results have significant preventive implications.

In the cartilage matrix, aggrecan is a highly negatively charged proteoglycan that is entrapped in a collagen fibrillar network through carboxylated or sulphated glycosaminoglycans (GAGs). GAGs can bind up to 50 times their weight in water resulting in a swelling pressure that is normally constrained by the tensile strength of the collagen network.1 This interaction is the key mechanism behind the viscoelastic properties of the articular cartilage, which provides joints with the necessary resistance to mechanical loading.2 3

The molecules in the cartilage matrix are continuously and balanced turned over. In joint disease, however, increased degradation versus biosynthesis finally results in the hallmark of OA, namely gradual cartilage loss and overt radiographic changes. The degradation and loss of GAGs is usually considered an early feature in developing OA. However, it is unclear to what extent GAG loss is relative or absolute: less GAG due to dilution by oedema or decreased biosynthesis versus degradation ratio. This may have implications in OA development since OA risk …
RORγt+Foxp3+ Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN
Authors: Malte A. Kluger, Matthias C. Meyer, Anna Nosko, Boeren Goerke, Michael Luig, Claudia Wegscheid, Gisa Tiegs, Rolf A. K. Stahl, Ulf Panzer, Oliver M. Steinmetz
Journal: Journal of the American Society of Nephrology (2015)

Cells expressing both the regulatory T cell (Treg)-inducing transcription factor Foxp3 and the Th17 transcription factor RORγt have been identified (biTregs). It is unclear whether RORγt(+)Foxp3(+) biTregs belong to the Th17-specific Treg17 cells, represent intermediates during Treg/Th17 transdifferentiation, or constitute a distinct cell lineage. Because the role of biTregs in inflammatory renal disease is also unknown, we studied these cells in the nephrotoxic nephritis (NTN) model of acute crescentic GN. Induction of NTN resulted in rapid renal and systemic expansion of biTregs. Notably, analyses of the biTreg expression profile revealed production of both anti-inflammatory (IL-10, IL-35) and proinflammatory (IL-17) cytokines. Additionally, biTregs expressed a signature of surface molecules and transcription factors distinct from those of Th17 cells and conventional Tregs (cTregs), and biTregs were identified in Treg17-deficient mice. Finally, fate reporter and cell transfer studies confirmed that biTregs are not Treg/Th17 transdifferentiating cells. Therapeutic transfer of biTregs suppressed the development of nephritis to an extent similar to that observed with transferred cTregs, but in vitro studies indicated different mechanisms of immunosuppression for biTregs and cTregs. Intriguingely, as predicted from their cytokine profile, endogenous biTregs displayed additional proinflammatory functions in NTN that were abrogated by cell-specific deletion of RORγt. In summary, we provide evidence that RORγt(+)Foxp3(+) biTregs are a novel and independent bifunctional regulatory T cell lineage distinct from cTregs, Treg17 cells, and Th17 cells. Furthermore, biTregs appear to contribute to crescentic GN and hence may be novel therapeutic targets.