tbuckley/cabot-search huggingface dataset:
Cutting to the chase: How pathogenic mutations cause Alzheimer’s
Authors: Michael S. Wolfe
Journal: The Journal of Experimental Medicine (2015)

Development of pancreatic ductal adenocarcinoma (PDAC) is known to be driven by a persistent inflammatory state, as oncogenic mutations alone are not sufficient for tumorigenesis.Toll-like receptors (TLRs), the pillars of the innate immune system, are highly expressed in the tumor microenvironment and on circulating leukocytes in PDAC.Contrasting results have reported antitumorigenic effects or induction of intrapancreatic inflammation and tumor progression upon ligation of different members of this receptor family.TLR9 in particular is expressed in both tumor and tumor-related cells, and its activation has been shown to impair tumor cell proliferation, suggesting that TLR9 agonists might be useful as adjuvant therapy.In this issue, Zambirinis et al. further examined the specific role of TLR9 signaling in PDAC.Gain-and loss-of-function experiments in a mouse model of PDAC showed that TLR9 activation is oncogenic in PDAC.Interestingly, these effects are only partially explained by activation of TLR9 signaling in the tumor cells themselves.Unexpectedly, the authors found expression of TLR9 on pancreatic stellate cells (PSCs; myofibroblast-like cells in the pancreas) and showed that TLR9 activation in these cells results in the production of the CCL3 and CCL11 chemokines.They show for the first time that CCL11 can promote the proliferation of pancreatic cancer cells in a dose-dependent manner.Activation of TLR9 in PSCs also leads to the recruitment of tumor suppressive regulatory T cells (T regs) that, together with TLR9activated myeloid-derived suppressor cells (MDSCs), favor the generation of an immunosuppressive microenvironment.Perhaps one of the most important aspects of the crosstalk between tumor cells and their microenvironment is the inhibition of anticancer immune responses.This new study provides compelling evidence that, in addition to the adaptive immune system, specific molecules in the innate immune system, such as TLR9, can play crucial roles in cancer development.Importantly, the recent development of small molecule agonists and antagonists of TLRs may offer a new strategy to inhibit cancer growth.It will be interesting to determine how such manipulations may be combined with other strategies to activate antitumor T cells.Another exciting aspect of this work is the prominent role of PSCs, providing further support to the notion that desmoplasia from fibroblasts plays a critical role in the recruitment and (in)activation of immune infiltrates in pancreatic cancer.Unquestionably, the molecular complexity of tumor, stroma, and immune cells will continue to engage the efforts of pancreatic cancer researchers for many years to come.
PWE-344 Retrospective cohort study to examine the frequency of follow-up for patients with intermediate grade colorectal adenomas (ia study)
Authors: A Brenner, J Martin, K Wooldrage, I Kralj-Hans, K Pack, P Greliak, U Shah, E Dadswell, F Lucas, S Duffy, W Atkin
Journal: Gut (2015)

<h3>Introduction</h3> <h3>Background</h3> UK and USA surveillance guidelines recommend 3-yearly surveillance for intermediate and higher-risk groups, respectively. To date, no study has examined surveillance needs in this group, which comprises nearly half of patients with adenomas. <h3>Aims and objective(s)</h3> To identify the optimum frequency of surveillance and assess whether there is substantial heterogeneity in risk; to examine the risks of cancer and advanced adenomas (AA). <h3>Method</h3> <h3>Design and Setting</h3> Retrospective, multi-centre cohort study, involving a hospitals dataset drawn from 17 UK NHS hospitals (n = 11,944), and three pooled screening cohorts (n = 2,353). <h3>Subjects</h3> Patients with intermediate-grade adenoma (s) defined as having 3–4 small adenomas (&lt;10 mm), or 1–2 adenomas, at least one of which is large (≥10 mm). <h3>Primary outcomes</h3> AA and colorectal cancer (CRC) detected at the first and second follow-up visits, and CRC incidence after baseline and first follow-up. <h3>Results</h3> Among 4,608 patients with follow-up in the hospital dataset, an increase in interval length was associated with a significant increased odds of AA and CRC at the first follow-up (p &lt; 0.001). Of 1,635 patients attending a second follow-up, a significant association was also found between interval and odds of advanced neoplasia at the second follow-up (p = 0.026). Among 11,944 patients, 168 CRCs occurred during 81,442 person-years of observation time after baseline (206 per 100,000 pyrs, 95% CI 177–240). A single surveillance visit conferred a considerable reduction in risk of CRC after baseline (p = 0.0001). Other independent predictors of CRC were used to devise higher (HIR) and lower (LIR) intermediate risk subgroups, between which there was substantial heterogeneity in risk. A single surveillance exam lowered risk in the HIR subgroup (n = 9,265); however the benefit of surveillance in the LIR (n = 2,679) was unclear. 1,828 intermediate risk patients with at least one follow-up in the pooled screening cohorts were younger, on average, than the hospital cohort. No association was found between findings at follow-up and interval, however, there was evidence of the benefit of surveillance and the LIR and HIR subgroups derived from the hospital dataset were discriminant of CRC risk in the screening participants. <h3>Conclusion</h3> A surveillance interval of three to four years seems suitable for the majority of intermediate-risk patients. Surveillance lowers future risk of CRC in intermediate risk patients; however there was heterogeneity in risk and surveillance needs, which suggested that a single follow-up may suffice in certain intermediate-risk patients. <h3>Disclosure of interest</h3> None Declared.
PK/PD profiles of the CXCL8 decoy protein PA401 after intravenous and intratracheal administration in saline and LPS exposed mice
Authors: Tiziana Adage, Angelika Falsone, Robert Doornbos, Mike Bartley, Andreas Kungl
Journal: European Respiratory Journal (2012)

Neutrophils play a crucial role in acute and chronic lung diseases including ALI, COPD, CF and severe asthma, and their presence in the lung has been correlated to disease severity and progression. Among the mediators of neutrophil recruitment into the lung CXCL8 is considered the major player.

CXCL8 exerts its chemotactic activity by binding to glycosaminoglycan (GAG) co-receptors on inflamed cells, thus creating a solid-phase haptotactic gradient and being properly presented to GPC receptors CXCR1/2 on neutrophils.

We have engineered higher affinity for GAGs into human CXCL8 obtaining a protein-based competitor for the CXCL8/GAG interaction. By further knocking-out the GPCR domain, we have obtained a decoy protein (PA401) with potent anti-inflammatory characteristics.

PA401 has been tested in murine models of lung inflammation induced by lipopolysaccharide (LPS) showing strong dose-dependent neutrophil reduction in bronchoalveolar lavage fluid (BALF) after intravenous (IV) and subcutaneous (SC) administration.

In the present study we have compared PA401 activity after IV and intratracheal (IT) administration in the same model, using saline exposed mice as control. PA401 plasma levels were also measured to assess pharmacokinetic profiles.

PA401 has strongly reduced BALF neutrophils number after IV and IT administration (up to -76%). The blood cells increase due to LPS exposure was also partly normalized by IV, but not IT treatment, possibly due to the differences in plasma exposure.

PA401 is a new biopharmaceutical with a unique mode of action interfering with lung neutrophilic inflammation and with activity after systemic and local delivery to the lung.
Phase II trial of radiation therapy/temozolomide/bevacizumab followed by bevacizumab/everolimus in the first-line treatment of glioblastoma multiforme (GBM).
Authors: K. C. Shih, D. R. Spigel, H. A. Burris, R. H. Brown, G. C. Shepard, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2010)

2075 Background: Bevacizumab is effective in the treatment of patients (pts) with relapsed GBM. The mTOR inhibitors may also be active against GBM, due to the frequent activation of the PI3 kinase pathway. We evaluated first-line treatment with bevacizumab added to standard radiation therapy (RT)/temozolomide, followed by maintenance treatment with bevacizumab/everolimus. Methods: Pts with GBM were eligible at diagnosis or after resection. Additional entry criteria: ECOG PS 0 or 1; adequate organ function; no previous therapy; standard bevacizumab exclusions. All pts received RT (standard dosages/techniques), temozolomide (75 mg/m2 po daily), and bevacizumab (10 mg/kg IV q 2 weeks). 4 weeks after completion of RT, pts received bevacizumab (10 mg/kg IV q 2 weeks), and everolimus (10 mg po daily) until tumor progression or intolerable toxicity. Median PFS was the primary endpoint. Results: Between 2/09 and 10/09, 68 pts were enrolled; the first 56 are included in this analysis. The median age was 59 yrs; 44 pts (79%) had previous partial or complete surgical resection. 52 pts (93%) completed combined modality therapy and 1 pt remains on therapy; 3 pts were removed from treatment (death on study – 2, pt request – 1). 41 pts (73%) began bevacizumab/everolimus maintenance; 29 are continuing treatment, while 12 have been removed from therapy (pt request – 3, toxicity – 2, Intercurrent illness -3, disease progression – 2, unknown -2). Response rates are as follows (n = 56): CR 2%, PR 30%, SD 52%, PD 0%, unevaluable 11%, too early 5%. After a median follow up of 6.5 months, 49 pts remain progression-free and 49 pts (88%) are alive. Grade 3/4 toxicity during combined modality included thrombocytopenia (9%) and fatigue (5%). Grade 3/4 toxicity during bevacizumab/everolimus included fatigue (17%) and pneumonitis (7%). 3 pts had early deaths, possibly treatment-related (pulmonary embolus 1, MI 1, bowel perforation 1). Conclusions: First-line therapy for GBM incorporating bevacizumab and everolimus was well-tolerated by most pts. Early assessments of efficacy are encouraging. Updated information on PFS and OS for all 68 patients will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech
METRAZOL SHOCK TREATMENT
Authors: FREDRICK C. REDLICH
Journal: American Journal of Psychiatry (1939)

This report is concerned with a pharmacologic and metabolic study of metrazol convulsive therapy in human subjects. It was found that the level of serum calcium and potassium remained almost unchanged before and after convulsive seizures. The characteristic increase in blood sugar may be due to an increased output of adrenalin. Serum sodium chloride was also slightly increased. The blood sedimentation rate was retarded after convulsions, and is interpreted as reflecting an increase of serum albumin. This change is discussed in its relation to the theories of protein metabolism changes in epilepsy (Frisch 15), Central nervous system stimulants such as carbon dioxide and ephedrine decreased the minimal convulsive dose of metrazol. Adrenalin and pituitrin were less effective in this regard. Strychnine, caffeine and theophylline had no such effect. Hypnotic and narcotic drugs—phenobarbital, sodium barbital and rutonal—exhibited a marked antagonistic action to metrazol while this effect was less with paraldehyde and chloral hydrate. Sodium bromide also has no antagonistic action. All of these observations tend to corroborate the Pick-Molitor theory of the action of hypnotics. The dose of metrazol required to produce a convulsion during insulin hypoglycemic shock is much smaller which tends to show that unconsciousness in insulin shock is pharmacologically and neurologically different from the coma induced by hypnotics and narcotics. In the human subject the results obtained were similar to those found in animal experiments. Previous administration of thyroxin to rats caused a decrease in the minimal convulsive dose of metrazol. Metrazol convulsions in man are produced by an intense stimulation of the vegetative and motor centers of the brain stem.
Abstract #LB-280: Expression of early placenta insulin-like growth factor in breast cancer a prerequisite of metastasis forming disseminated tumor cells?
Authors: Burkhard Brandt, Dirk Kemming, Harriet Wikman, Domique Bellet, Mike Helms, Klaus Pantel
Journal: Cancer Research (2009)

EPIL is expressed physiologically in the so-called invasive phase of placenta development during first trimester of pregnancy. Differential gene expression analysis between breast cancer cell subclones (SKBR3) with and without transendothelial invasive revealed EPIL as an autocrine regulator of cell motility and proliferation. Such experimental data has been translated to a clinical setting by using a prognostic tissue microarray (p    Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-280.
T-cell ontogeny after autologous bone marrow transplantation: failure to synthesize interleukin-2 (IL-2) and lack of CD2- and CD3-mediated proliferation by both CD4- and CD8+ cells even in the presence of exogeneous IL-2
Authors: S Cayeux, S Meuer, A Pezzutto, M Korbling, R Haas, R Schulz, B Dorken
Journal: Blood (1989)
Growth Hormone Replacement Therapy in Children With Medulloblastoma: Use and Effect on Tumor Control
Authors: Roger J. Packer, James M. Boyett, Anna J. Janss, Theodora Stavrou, Larry Kun, Jeffrey Wisoff, Carolyn Russo, Russell Geyer, Peter Phillips, Mark Kieran, Mark Greenberg, Stewart Goldman, Douglas Hyder, Richard Heideman, Dana Jones-Wallace, Gilbert P. August, Sharon H. Smith, Thomas Moshang
Journal: Journal of Clinical Oncology (2001)

Progress has been made in the treatment of medulloblastoma, the most common childhood malignant brain tumor: However, many long-term survivors will have posttherapy growth hormone insufficiency with resultant linear growth retardation. Growth hormone replacement therapy (GHRT) may significantly improve growth, but there is often reluctance to initiate GHRT because of concerns of an increased likelihood of tumor relapse.This study retrospectively reviewed the use of GHRT for survivors of medulloblastoma in 11 neuro-oncology centers in North America who received initial treatment for disease between 1980 and 1993 to determine its impact on disease control. A Landmark analysis was used to evaluate the relative risk of relapse in surviving patients.Five hundred forty-five consecutive patients less than 15 years of age at diagnosis were identified. Six-year progression-free survival (mean +/- SD) was 40% +/- 5% in children less than 3 years of age at diagnosis compared with 59% +/- 3% for older patients. Older patients with total or near-total resections (P = .003) and localized disease at diagnosis (P < .0001) had the highest likelihood of survival. One hundred seventy patients (33% +/- 3% of the cohort) received GHRT. GHRT use varied widely among institutions, ranging from 5% to 73%. GHRT was begun a mean of 3.9 years after diagnosis, later in children younger than 3 years at diagnosis (5.4 years). By Landmark analyses, for those surviving 2, 3, and 5 years after diagnosis, there was no evidence that GHRT increased the rate of disease relapse.This large retrospective review demonstrates that GHRT is underutilized in survivors of medulloblastoma and is used relatively late in the course of the illness. GHRT is not associated with an increased likelihood of disease relapse.
Large-Bowel Cancer in Hawaiian Japanese2
Authors: William Haenszel, John W. Berg, Mitsuo Segi, Minoru Kurihara, Frances B. Locke
Journal: JNCI Journal of the National Cancer Institute (1973)

Study of 179 Japanese patients with bowel cancer and 357 hospital controls in Hawaii revealed excess risks for persons who regularly ate Western-style meals only. The similarity in findings for Issei and Nisei sharply contrasts with results previously reported for stomach cancer in Issei and Nisei, where the reduced risk among persons regularly eating Western-style meals only was limited to the second-generation Nisei. Bowel cancer was associated with consumption of specific foods. Bowel cancer patients ate meats, legumes, and starches more frequently, with the case-control disparity being less pronounced for individuals consuming starches than for those eating meat and legumes. Beef and string beans were the major contributors to the meat and legume effects. There seemed to be separate effects for beef, string beans, and starches, and the case-control contrasts were strengthened when various combinations of foods were considered. Points of consistency between the Hawaii study and other evidence were noted. The findings on beef had the most immediate relevance. These results may narrow the area of search for etiologic factors and thus assist in planning future research on the complex sequence of events leading to bowel cancer.
For t 2 DNA vaccine prevents<i>Forcipomyia taiwana</i>(biting midge) allergy in a mouse model
Authors: M.-F. Lee, P.-P. Song, T.-M. Lin, Y.-T. Chiu, Y.-H. Chen
Journal: Allergy (2015)

Forcipomyia taiwana (biting midge) is the most prevalent allergenic biting insect in Taiwan, and 60% of the exposed subjects develop allergic reactions. Subjects with insect allergy frequently limit their outdoor activities to avoid the annoyingly intense itchy allergic reactions, leading to significant worsening of their quality of life. Allergen-specific immunotherapy is the only known therapy that provides long-term host immune tolerance to the allergen, but is time-consuming and cumbersome. This study tested whether the For t 2 DNA vaccine can prevent allergic symptoms in For t 2-sensitized mice.Two consecutive shots of For t 2 DNA vaccine were given to mice with a 7-day interval before sensitization with recombinant For t 2 proteins, using the two-step sensitization protocol reported previously.The For t 2 DNA vaccine at 50 μg prevented the production of For t 2-specific IgE (P < 0.05), as well as midge allergen-challenge-induced scratch bouts, midge allergen-induced IL-13 and IL-4 production from splenocytes, and inflammatory cell infiltrations in the lesions 48 h after intradermal challenge.This study is the first to demonstrate that DNA vaccine encoding midge allergen is effective in preventing allergic skin inflammation induced by biting midge. Immunotherapy using For t 2 DNA vaccine can protect mice from being sensitized by midge allergen and may be a promising treatment for biting midge allergy in the future.
Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trial
Authors: Fergus Macbeth, Simon Noble, Jessica Evans, Sheikh Ahmed, David Cohen, Kerenza Hood, Dana Knoyle, Seamus Linnane, Mirella Longo, Barbara Moore, Penella J. Woll, Wiebke Appel, Jeanette Dickson, David Ferry, Caroline Brammer, Gareth Griffiths
Journal: Journal of Clinical Oncology (2015)

Purpose Venous thromboembolism (VTE) is common in cancer patients. Evidence has suggested that low molecular weight heparin (LMWH) might improve survival in patients with cancer by preventing both VTE and the progression of metastases. No trial in a single cancer type has been powered to demonstrate a clinically significant survival difference. The aim of this trial was to investigate this question in patients with lung cancer. Patients and Methods We conducted a multicenter, open-label, randomized trial to evaluate the addition of a primary prophylactic dose of LMWH for 24 weeks to standard treatment in patients with newly diagnosed lung cancer of any stage and histology. The primary outcome was 1-year survival. Secondary outcomes included metastasis-free survival, VTE-free survival, toxicity, and quality of life. Results For this trial, 2,202 patients were randomly assigned to the two treatment arms over 4 years. The trial did not reach its intended number of events for the primary analysis (2,047 deaths), and data were analyzed after 2,013 deaths after discussion with the independent data monitoring committee. There was no evidence of a difference in overall or metastasis-free survival between the two arms (hazard ratio [HR], 1.01; 95% CI, 0.93 to 1.10; P = .814; and HR, 0.99; 95% CI, 0.91 to 1.08; P = .864, respectively). There was a reduction in the risk of VTE from 9.7% to 5.5% (HR, 0.57; 95% CI, 0.42 to 0.79; P = .001) in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinically relevant nonmajor bleeding in the LMWH arm. Conclusion LMWH did not improve overall survival in the patients with lung cancer in this trial. A significant reduction in VTE is associated with an increase in clinically relevant nonmajor bleeding. Strategies to target those at greatest risk of VTE are warranted.
Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance to the anti-EGFR monoclonal antibody cetuximab
Authors: Yang Lu, Xinqun Li, Ke Liang, Rodney Luwor, Zahid Siddik, Gordon Mills, John Mendelsohn, Zhen Fan
Journal: Cancer Research (2007)

4082  Cetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody that has been approved for treatment of patients with metastatic colorectal cancer. Cancer cells can develop resistance to cetuximab treatment. To explore potential resistant mechanism by which colorectal cancer cells acquire after treatment with cetuximab, we investigated biochemical changes in signaling pathways of a cetuximab-resistant subline of DiFi colorectal cancer cells (DiFi5) that was developed by exposing the cells to sub-effective doses of cetuximab over an extended period of time. Compared with parental DiFi cells that express high levels of EGFR, and in which cetuximab induces apoptosis, the cetuximab-resistant DiFi5 showed markedly lower protein levels of the EGFR, an increased association of EGFR with Cbl, and an increase in ubiquitination of EGFR. DiFi5 cells also contained a markedly higher level of Src-Y416 phosphorylation both at baseline and upon EGF stimulation. Although EGFR levels were low, DiFi5 cells responded to EGF stimulation with robust phosphorylation of EGFR on Y845 and strong phosphorylation of Akt and MAPK comparable to parental DiFi cells. Inhibition of Src kinase activity with PP2 strongly inhibited EGF-induced phosphorylation of Akt in both DiFi and DiFi5 cells. PP2 treatment did not alter MAPK phosphorylation in DiFi cells and even led to an elevation of MAPK phosphorylation in DiFi5 cells both at baseline and upon EGF stimulation. Most importantly, inhibition of Src kinase activity with PP2 reverses the resistance of DiFi5 cells to cetuximab-induced apoptosis without affecting the levels of EGFR in the cells. In summary, our data show that colorectal cancer cells can develop acquired resistance to cetuximab via EGFR ubiquitination and proteasomal degradation as well as through Src kinase-mediated signaling as an alternative pathway for cell growth and survival. As inhibitors to the EGFR are in clinical use and Src inhibitors are in clinical trials, our results suggest a novel combinatorial therapy targeting either concurrently or sequentially the EGFR and Src for cancer treatment.