tbuckley/cabot-search huggingface dataset:
Abstract 1713: PDK1 and hexokinase 2 are downstream effectors of PTEN loss and regulate response to targeted therapies in multiple tumor types
Authors: Evangelos Pazarentzos, Trever G. Bivona
Journal: Cancer Research (2014)

Abstract Recent advances in molecular profiling of many human tumor types has enabled the development and clinical use of molecularly-targeted therapies in patients. Many tumors exhibit inactivation of PTEN which is predicted to sensitize tumor cells to PI3 kinase or AKT inhibitor therapy. However, clinical responses to PI3 kinase or AKT inhibitors are variable and not curative. Furthermore, these responses in patients do not correlate uniformly with PTEN inactivation. Therefore, we investigated whether PTEN inactivation could lead to dependence on signaling pathways and components that function independently of PI3K or AKT and that could serve as novel therapeutic targets in PTEN deficient tumors. Using multiple human tumor models including lung adenocarcinoma, lung squamous, renal cell carcinoma, and prostate adenocarcinoma that express or lack PTEN and Gene Set Enrichment Analysis, we identified alterations in numerous metabolic regulatory genes in response to PTEN inactivation, including hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1). We found that in PTEN-deficient tumor cells HK2 is upregulated and selectively localizes to the mitochondria, where it enhances glycolytic flux and inhibits apoptosis. Furthermore, we found that PDK1 is also upregulated upon PTEN inactivation and suppresses oxidative phosphorylation, upregulating glycolysis and the production of lactate. Thus, we uncovered a novel role for HK2 and PDK1 in the metabolic reprogramming that occurs as a consequence of PTEN inactivation in tumor cells. Furthermore, we found that overexpression of either HK2 or PDK1 confers resistance to targeted therapies against PI3K and other oncogenic drivers more broadly. Conversely, genetic or pharmacological suppression of HK2 or PDK1 enhances response to targeted therapy in multiple tumor cell types. Together, our data identify HK2 and PDK1 as novel molecular biomarkers and promising therapeutic targets in multiple PTEN deficient tumor types. Citation Format: Evangelos Pazarentzos, Trever G. Bivona. PDK1 and hexokinase 2 are downstream effectors of PTEN loss and regulate response to targeted therapies in multiple tumor types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1713. doi:10.1158/1538-7445.AM2014-1713
Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies.
Authors: B Uziely, S Jeffers, R Isacson, K Kutsch, D Wei-Tsao, Z Yehoshua, E Libson, F M Muggia, A Gabizon
Journal: Journal of Clinical Oncology (1995)

PURPOSE The purpose of our studies was to define the maximal-tolerated dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menlo Park, CA), a doxorubicin formulation of polyethyleneglycol-coated liposomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I setting. PATIENTS AND METHODS Two separate phase I studies were conducted following the initial human pharmacokinetic testing at one of the sites (Hadassah). The starting dose of 20 mg/m2 at the University of Southern California was just below the dose without toxicity in the pharmacokinetic study. At Hadassah, the phase I starting dose was just above their earlier safe single doses, 60 mg/m2. Both studies involved cohorts of at least three patients and redosing every 3 to 4 weeks. To determine the recommended dose for phase II trials, an additional level of 50 mg/m2 every 3 weeks was explored, and the level of 60 mg/m2 every 4 weeks was expanded. RESULTS A total of 56 patients receiving 281 courses of DOX-SL was accrued and evaluated for toxicity. Hand-foot (H-F) syndrome and stomatitis are the two main dose-limiting factors of DOX-SL. Stomatitis was dose-limiting for high single doses of DOX-SL greater than 70 mg/m2. Skin toxicity manifested primarily as H-F syndrome was dose-limiting for repetitive dosing, but acceptable at either 50 mg/m2 every 3 weeks or 60 mg/m2 every 4 weeks. Attenuation of acute subjective symptoms and lack of alopecia were generally observed. Patients with carcinomas of the breast, ovary, prostate, and head and neck were among those showing objective antitumor responses or improvement based, in part, on blood levels of tumor markers. CONCLUSION The toxicity profile of DOX-SL differs prominently from that of the free drug administered by bolus or rapid infusion and with some differences, resembles that of prolonged continuous infusion. This finding, as well as the antitumor activity observed, supports wide phase II testing of DOX-SL in solid tumors.
Nontuberculous mycobacteria – Isolation in respiratory specimens and its clinical relevance
Authors: Sergio Campainha, Rosario Braga, Isabel Valente, Aurora Carvalho, Raquel Duarte
Journal: European Respiratory Journal (2011)

Background: Nontuberculous mycobacteria (NTM) isolation have been increasingly described, particularly in developed countries. Few studies in Portugal characterize and report its clinical relevance.  Aim: Characterize NTM isolated from respiratory samples between 2007-2010 at our center.  Methods: Retrospective analysis of patients followed in our hospital with NTM isolation in at least one respiratory specimen.  Results: NTM were isolated in 108 samples, 68 patients; mean age: 53,5±17,0 years; 60,3% male. Fourteen (20,6%) had HIV, eight with AIDS.  Prior respiratory disease was present in 63,2% of patients, most frequently bronchiectasis (14;32,5%), tuberculosis sequelae (11;25,6%) and COPD (7;16,3%).  Eleven species were isolated, mostly M. avium complex (MAC), including M. avium and M. intracellular (27; 39,7%) and M. gordonae (23,33,8%).  We identified 22 (32,4%) cases of disease; 12 (54,5%) were female; 2 were HIV+. Seventeen (77,3%) had lung disease. One had multiple NTM disease (M. avium + M. genavense).  The agents related to disease were MAC (16;72,7%); M. kansasii (2;9,1%); M. xenopi and M. gordonae (both 2;9,1%). MAC was associated to disease (p=0.001; OR=3.2). A trend towards significance was observed between HIV infection and NTM disease (p=0.074; OR=2,8).  Discussion:M. gordonae was isolated in much higher frequency than that described in literature, possibly a geographical issue. Despite its little clinical significance when compared to MAC, it caused disease in 2 cases. NTM isolation didn9t relate to lung disease in 67,6% of cases. We found a statistically significant association between illness and MAC isolation. Further studies are needed to describe NTM and its clinical significance.
Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02.
Authors: N Wolmark, H Rockette, D L Wickerham, B Fisher, C Redmond, E R Fisher, M Potvin, R J Davies, J Jones, A Robidoux
Journal: Journal of Clinical Oncology (1990)

Between March 1984 and July 1988, 1,158 patients with Dukes' A, B, and C carcinoma of the colon were entered into National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-02. Patients were randomized to either no further treatment following curative resection or to postoperative fluorouracil (5-FU) and heparin administered via the portal vein. Therapy began on day of operation and consisted of constant infusion for 7 successive day. Average time on study was 41.8 months. A comparison between the two groups of patients indicated both an improvement in disease-free survival (74% v 64% at 4 years, overall P = .02) and a survival advantage (81% v 73% at 4 years, overall P = .07) in favor of the chemotherapy-treated group. When compared with the treated group, patients who received no further treatment had 1.26 times the risk of developing a treatment failure and 1.25 times the likelihood of dying after 4 years. Particularly significant was the failure to demonstrate an advantage from 5-FU in decreasing the incidence of hepatic metastases. The liver was the first site of treatment failure in 32.9% of 82 patients with documented recurrences in the control group and in 46.3% of 67 patients who received additional treatment. Therapy is administered via a regional route to affect the incidence of recurrence within the perfused anatomic boundary. Since, in this study, adjuvant portal-vein 5-FU infusion failed to reduce the incidence of hepatic metastases, it may be concluded that its use thus far is not justified. It may also be speculated that the disease-free survival and survival advantages (the latter of borderline significance) are a result of the systemic effects of 5-FU.
Sleep apnea in children with refaractory monosymptomatic nocturnal enuresis
Authors: Ashraf El-Mitwalli, Adel Salah Bediwy, Ashraf Ahmed Zaher, Abdel Baset Saleh
Journal: European Respiratory Journal (2013)

Background:  Children with nocturnal enuresis (NE) are believed to have deep sleep with high arousal threshold. Studies suggested that obstructive sleep apnoea-hypopnoea syndrome (OSAHS) and NE are common problems during childhood. We sought to asses the prevalence of OSAHS in children with refractory nocturnal enuresis and whether its severity is associated with the frequency of bedwetting.  MATERIALS AND METHODS : The study group comprised 43 children, aged 6-17 years, with refractory monosymptomatic NE and the control group 30 children, aged 5-17 years. All subjects underwent thorough neurological examination, single night polysomnography but only for patient group; a lumbosacral plain X-ray was done to exclude spina bifida.  RESULTS : The groups were well matched. Two subjects of the control group had mild OSAHS. The mean age of the patients was (10±3 years), thirty one were boys and sixty seven percent showed frequent NE (>3 days bedwetting/week). Patients with NE had significantly higher rates of OSAHS (P
Human Rhinovirus Presenting 4E10 Epitope of HIV-1 MPER Elicits Neutralizing Antibodies in Human ICAM-1 Transgenic Mice
Authors: Guohua Yi, Xiongying Tu, Preeti Bharaj, Hua Guo, Junli Zhang, Premlata Shankar, N Manjunath
Journal: Molecular Therapy (2015)

Attempts at eliciting neutralizing antibodies against human immunodeficiency virus (HIV)-1 have generally failed. Computationally designed epitope-scaffold platforms allow transplantation of structural epitopes to scaffold proteins. Human rhinovirus (HRV) allows such engrafting of HIV-1 epitopes on the surface scaffold proteins. However, since HRV infects only humans and great apes, the efficacy of chimeric HRV-based live viral vaccines is difficult to assess in animal models. Here, we used human ICAM-1 transgenic (hICAM-1 Tg) mice that support productive HRV infection to assess the efficacy of chimeric HRV expressing the HIV-1 membrane proximal external region (MPER) epitope, 4E10. Intranasal immunization with chimeric HRV in transgenic mice effectively induced antibodies that recognized 4E10 peptide as well as HIV-1 Env trimer. Importantly, the immunized mouse sera were able to neutralize HIV strains including those belonging to clades B and C. Moreover, intranasal immunization could bypass pre-existing immunity to HRV. Thus, chimeric HRV appears to provide a viable vaccine vehicle for HIV-1 immunization in humans.
Prospects for the NHS in England in the next parliament
Authors: C. Ham
Journal: BMJ (2015)

Investment and reform should be at the heart of the new government’s programme

The newly elected Conservative government faces an immediate challenge in keeping the NHS solvent in 2015-16 and a more fundamental challenge of transforming care to better meet the needs of an ageing population. It must also continue to improve patient safety and the quality of care without accentuating financial pressures facing NHS providers.

These challenges have to be tackled in the context of an NHS already struggling to meet key targets for patient care let alone fulfil new commitments, such as seven day working. The additional funding made available in 2015-16 in the coalition government’s autumn statement is undoubtedly welcome, yet NHS providers are forecasting a deficit of almost £2bn (€2.8bn; $3bn) by the end of this year.1 2 Of equal concern is growing pressure on staff in a service where patient experience is strongly shaped by staff experience.3

Any government would face limits in finding new resources for the NHS when the public finances are constrained by the need to reduce the deficit. Failure …
Parental history of atopy modifies the effect of breast feeding on recurrent wheeze in infants
Authors: Patricia Garcia-Marcos, Rosa Pacheco-Gonzalez, Manuel Sanchez-Solis, Javier Mallol, Paul Brand, Dirceu Sole, Luis Garcia-Marcos
Journal: European Respiratory Journal (2013)

Aim: To know how family history of atopy modifies the protective effect of breast feeding (3+ months) (BF) on recurrent wheeze (3+ episodes) (RW) of infants during the 1st year of life.

Methods: EISL has been described previously (Thorax 2010;65:1004-9). Briefly, parents from 22 centres answered a validated questionnaire (Int Arch Allergy Immunol 2007;144:44-50) on wheezing and risk factors during the 1st year of life of their children. Using the random effect logit model, using centre as panel variable, four models were built according to the existence of 0, 1, 2 or 3 parental (father and/or mother) atopic diseases (asthma, rhinoconjunctivitis or eczema). RW was compared to no wheeze (OR; 95% CI), and all models included as covariates: gender, smoking in pregnancy, having a cold in the 1st three months of life, attending to a nursery school, infant eczema, n. of siblings and persons at home, mould stains in the household walls and mother’s study level.

Results: Of 35,049 infants, 19,811 had no wheeze and 6,161 had RW (8,962 had 1/2 episodes and 115 had no information available). Compared with male gender, which was a significant risk factor across all strata, BF tended to be increasingly more protective as family history was less atopic.

View this table:

Associations (odds ratios) of breast feeding and gender with recurrent wheeze according to the number of parental allergic diseases





Conclusion: The protective effect of BF on RW during the 1st year of life varies according to the parental history of atopy.
Rituximab, gemcitabine and oxaliplatin (R-GEMOX): An effective regimen for relapsed and refractory B-cell lymphoma
Authors: T. El Gnaoui, J. Dupuis, K. Belhadj, A. Rahmouni, C. Copie-Bergman, I. Gaillard, M. Diviné, I. M. Tabah-Fisch, F. Reyes, C. Haioun
Journal: Journal of Clinical Oncology (2006)

7562 Background: High-dose therapy with autologous stem cell support (HDT) is an established treatment for chemosensitive relapse in lymphoma. However, not all patients are candidates for HDT because of age, comorbidities or previous HDT. In addition,effective and less toxic alternatives to classical Cisplatin/ARA-C-based salvage regimens are needed. Methods: Based on the clinical activity, tolerability of rituximab (R), gemcitabine (G) and oxaliplatin (Ox) and synergy between these drugs, the R-GEMOX regimen was designed with R (375mg/m 2 d 1), G (1,000 mg/m 2 d 2) and Ox (100 mg/m 2 d 2). Treatment was given every two weeks. Between January 2002 and June 2005, 46 patients with refractory/relapsing B-cell CD20+ lymphoma not eligible for HDT were enrolled in an unicenter pilot study whose primary objective was overall response rate (ORR) after 4 cycles (induction phase). Patients were planned to receive 8 cycles if at least PR was observed after 4 cycles. Median age was 64 years (range: 43–78) and histological subtypes were: diffuse large B-cell lymphoma (n = 33), follicular (n = 8) and mantle cell (n = 5). Prior treatments included anthracyclin in 45 patients, rituximab in 26 (56%) and HDT in 14 (30%). The median number of prior treatments was 2 (range: 1 to 5) and 13 patients (28%) had received at least 3 prior regimens. Results: 315 cycles were given. The dose administered was 100% of the intended dose for the three drugs in all patients but 8, for whom the dose of oxaliplatin was reduced due to neurotoxicity (n = 7) or preexisting renal insufficiency (n = 1). Eight patients progressed during the induction phase. After 4 cycles, responses were: 10 CR, 13 CRu and 15 PR resulting in an ORR of 83%. At the end of treatment, among the 38 responder-patients, 36 patients achieved CR (78% of the entire population), one patient remained in PR and one progressed. With a median follow-up of 27 months, the 2-year progression-free and overall survivals were 53% and 66%, respectively. NCIC grade 3–4 neutropenia and thrombocytopenia were reported in 48% and 22% of the cycles. A grade 4 infection was observed in only 3% of the cycles. There was no renal toxicity. Conclusions: The R-GEMOX regimen shows promising activity with an acceptable toxicity. It is currently evaluated in a multicentric phase II study. [Table: see text]
Psychological Impact of Body Recovery Duties
Authors: James Thompson
Journal: Journal of the Royal Society of Medicine (1993)

The psychological effects of body recovery duties were studied in two groups, 28 specialized police volunteers and 40 ambulance workers. The Impact of Events scale and the General Health Questionnaire were administered to both groups. The results showed that 20% of the ambulance workers and 3% of the policemen were in the moderate to severe category of psychological distress. In neither group did age, number of incidents attended or years in service correlate with distress. Possible causes of the difference between the two groups, such as the way they were managed, are discussed.
Severe Herpetic Keratitis. II. The Costs Associated with Penetrating Keratoplasty
Authors: M J Menage, C M P Claoué
Journal: Journal of the Royal Society of Medicine (1988)

We report a study on 100 patients with severe herpetic keratitis. Overall, one in three of the study group required a penetrating keratoplasty (PK). These patients required a mean of 18 days as an inpatient and 15 outpatient visits in the year the PK was performed; these figures fell to 1 inpatient day and 8 outpatient visits in the second year after surgery. The financial cost of such therapy is discussed.
Escalating dose of mitoxantrone with high-dose cyclophosphamide, carmustine, and etoposide in patients with refractory lymphoma undergoing autologous bone marrow transplantation.
Authors: M Attal, P Canal, D Schlaifer, E Chatelut, A Dezeuze, F Huguet, C Payen, J Pris, G Laurent
Journal: Journal of Clinical Oncology (1994)

PURPOSE We conducted a dose-finding study of mitoxantrone (MITO) in combination with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) in refractory lymphoma undergoing autologous bone marrow transplantation (ABMT). The objective were to determine the following: (1) the maximum-tolerated dose of MITO, (2) the extramedullary toxicity of this regimen, (3) its antitumor activity, and (4) the pharmacokinetic characteristics of MITO at each dose level. PATIENTS AND METHODS Escalating doses of MITO (15 to 90 mg/m2, single bolus infusion on day -8) followed by CBV were administered to 20 patients (mean age, 38.5 years) with refractory lymphoma. MITO concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS No toxic death occurred. The maximum-tolerated dose appears to be 75 mg/m2. Two of five patients treated with 90 mg/m2 developed severe organ toxicity, versus zero of 15 treated with doses up to 75 mg/m2. Duration of neutropenia was longer for patients treated with 90 mg/m2 (31.7 days) than for patients treated with doses up to 75 mg/m2 (22.1 days) (P &lt; .05). A linear relationship was observed between administered dose of MITO and (1) plasma peak value, (2) area under the curve (AUC), and (3) plasma concentration on the day of marrow infusion (day 0). Hematologic toxicity was related to the terminal half-life (T1/2) of MITO, and day-0 plasma concentration. A high complete response (CR) rate was observed (60%), and eight of 11 (73%) patients treated with MITO &gt; or = 60 mg/m2 achieved a CR. CONCLUSION MITO (up to 75 mg/m2) and CBV can be administered with acceptable toxicity and a promising CR rate in this poor-risk population, justifying further phase II studies.
Late-breaking abstract: The effects of roxithromycin as anti-inflammatoy agent on clinical outcomes in patient with bronchiectasis: A double blinded randomized controlled study
Authors: Siwasak Juthong, Sarayuth Eiamsa-ard
Journal: European Respiratory Journal (2011)

Bronchiectasis is an inflammatory airway disease with vicious cycle of infection and inflammation. Macrolides have been reported for improve clinical outcomes, we study the effects of macrolide on clinical outcomes such as symptom scores and quality of life in patient with bronchiectasis   Material and methods:  Randomized double blinded placebo controlled trials of roxithromycin 300 mg or placebo once daily for 8 weeks in patient with bronchiectasis. Clinical examination, pulmonary function test, St George9s Respiratory Questionaire (SGRQ) and sputum culture for aerobic bacteria were done each visits.   Results:  20 bronchiectatic patients, mean age of 56 years, were participated in this study. Nine patients has randomized to roxithromicin 300 mg and 11 patients received placebo once daily. Roxithromycin was shown to improve symptoms scores (mean difference of symptom scores = -2.11, p=0.04) compare with placebo (mean difference of symptom scores = 0.00, p=0.50). Quality of life which assessed by SGRQ was significant improved in the intervention group (p=0.04), but not in placebo (p=0.73). Pulmonary function tests (FEV1, FVC and KCO) were not improved in both groups. No patient in intervention group reported any adverse effect.   Conclusion:  Once daily roxithromycin showed benefit on clinical outcomes as well as quality of life. Larger studies of the effects of macrolide in bronchiectasis treatment with longer follow-up times should be done.
HIV and HIV dementia
Authors: Dennis L. Kolson, Francisco González-Scarano
Journal: Journal of Clinical Investigation (2000)

Lentiviruses, a group of retroviruses that includes HIV-1, have been known to be neurovirulent since landmark studies by Sigurdsson and others, who showed that chronic lentiviral infections could take hold in the central nervous system (CNS; reviewed in ref. 1). Since their discovery, HIV-1 and, to a lesser extent, HIV-2 have been recognized as CNS pathogens that can cause a subcortical dementia (HIV-associated dementia; HAD) in a significant proportion of infected patients (2). In HAD, as distinct from conventional cortical dementias, memory impairment typically occurs either in association with or following other cognitive symptoms like inattention, apathy, and psychomotor slowing. Motor symptoms such as lack of coordination are also characteristic of this condition.

The neuropathological changes induced by HIV-1 infection of the CNS include pallor of the myelin sheaths, proliferation or prominence of astrocytes, and the formation of multinucleated giant cells (syncytia). Microglia and brain macrophages are the main cellular targets for HIV infection in the CNS, and syncytium formation is a signature finding for this infection, since it results from interactions between the viral glycoproteins gp120 and gp41 and the principal cellular HIV-1 receptors in microglia, CD4 and CCR5. The presence of multinucleated giant cells in the CNS is the most specific finding in HIV infection, and it is roughly correlated with the antemortem diagnosis of HAD (3).