tbuckley/cabot-search huggingface dataset:
Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma
Authors: Marta Garnelo, Alex Tan, Zhisheng Her, Joe Yeong, Chun Jye Lim, Jinmiao Chen, Kiat Hon Lim, Achim Weber, Pierce Chow, Alexander Chung, London Lucien PJ Ooi, Han Chong Toh, Mathias Heikenwalder, Irene O L Ng, Alessandra Nardin, Qingfeng Chen, Jean-Pierre Abastado, Valerie Chew
Journal: Gut (2015)

<h3>Objective</h3> The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis. <h3>Design</h3> Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of <i>CD19, CD8A, IFNG</i> was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study. <h3>Results</h3> Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells. <h3>Conclusions</h3> The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.
Therapeutic targeting of autophagy in neurodegenerative and infectious diseases
Authors: David C. Rubinsztein, Carla F. Bento, Vojo Deretic
Journal: The Journal of Experimental Medicine (2015)

Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation. Although autophagy may impact many facets of human biology and disease, in this review we focus on the ability of autophagy to protect against certain neurodegenerative and infectious diseases. Autophagy enhances the clearance of toxic, cytoplasmic, aggregate-prone proteins and infectious agents. The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation. Autophagic control of inflammation is one area where autophagy may have similar benefits for both infectious and neurodegenerative diseases beyond direct removal of the pathogenic agents. Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating.
Effect of Angiostatin 4.5 on endometrial adenocarcinoma
Authors: Luciano A. Guerreiro Lucas, Christopher A. Mitchell, Paul Barber, Keyi Jiang, Gerald A. Soff, Gillian M. Tozer
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

3025 

Tumors depend on the formation of a functioning microvascular network in order to grow and metastasise. The anti-angiogenic agent Angiostatin4.5 (AS4.5) is the naturally occurring isoform of Angiostatin in human plasma. AS4.5 is a distinct compound from the highly publicised Angiostatin owned at the time by Entremed. AS4.5 is a 55kD protein comprising kringles 1 to 4 plus 85% of kringle 5 of plasminogen. In vitro , AS4.5 induces endothelial cell (EC) apoptosis, inhibits EC proliferation and migration but has no direct effect on a range of tumor cell types. In vivo administration of AS4.5 results in inhibited tumor growth, presumably as a result of changes to the tumor vasculature. In this in vivo study we have investigated the effects of AS4.5 on the developing tumor vasculature. Dorsal skin-fold window chambers were surgically implanted in SCID mice under Hypnorm/midazolam anaesthesia. A small (≈1 mm) tumor fragment of human endometrial adenocarcinoma (EA) was transplanted into the chamber. Mice were treated with AS4.5 2mg/kg/day s.c. for 10 consecutive days starting 24hr after surgery (day 1). Controls received saline only. Control n = 3, AS4.5 treated n = 3. Shortly before intravital imaging, each mouse was injected i.v. with fluorescently (DiI) labelled erythrocytes. Video and still images were captured on days 1 to 11 at a range of objective magnifications (2.5x-20x) using both transmitted and fluorescent light. Vascular morphometry was analysed using in-house developed computer software. EA tumors treated with AS4.5 grew significantly slower than controls (by day 11, they were 156±13% and 282±46% of their initial area, respectively). Vascularization commenced on day 3 in controls and on day 4 in treated tumors. On days 6 to 8, treated tumors had fewer small calibre capillaries (length < 80 μm; diameter < 12 μm) and, on days 7 and 8, greater interstitial distance (average distance of a tumor cell from the nearest vessel; day 7, treated: 83±29; control: 20±3, day 8, treated: 43±6; control: 19±3 μm). Also during that period erythrocyte velocity was lower in treated tumors in comparison to controls (day 8, treated: 221±23; control: 384±31, day 9, treated: 210±14; control: 337±29 μm/min). However, when tumors were fully vascularized, treated tumors appeared more efficiently vascularized, in terms of both number of small calibre vessels and erythrocyte velocity, then the equivalent sized controls on an earlier day. Here we show that administration of AS4.5 to developing tumors slows the vascularization process, as manifested by a reduced rate of development of small calibre vessels, higher interstitial distance and lower erythrocyte velocity. These effects are sufficient to produce substantial tumor growth inhibition. The possibility that blood flow of treated tumours, once fully vascularised, is higher than in untreated tumours requires further investigation.
The Presence Of Residual Disease After Induction and/Or Consolidation Therapy Based On Wilms’ Tumor 1 (WT1) Expression Is a Strong Prognostic Factor For Relapse and Survival In AML
Authors: Carolina Martínez-Laperche, Mi Kwon, Ana Carolina Franco-Villegas, Carmen Chillón, Nerea Castro, Sandra Dolz, Carlos Rodríguez-Medina, Eduardo Anguita, Nuria Perez, Miriam López-Parra, MI Prieto Conde, F Rámos Ortega, J Nicolás Rodriguez, Lourdes Hermosín, Jose Antonio García Marco, Maite Gómez Casares, Eva Barragan, M. González, Joaquín Martínez López, Jóse Luis Díez Martín, Ismael Buno
Journal: Blood (2013)
Effect of denosumab on prolonging bone-metastasis free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.
Authors: Fred Saad, Matthew Raymond Smith, Neal D. Shore, Stephane Oudard, Kurt Miller, Bertrand Tombal, Paul Sieber, Karim Fizazi, Peter Van Veldhuizen, Ronaldo Damião, Gavin M. Marx, Juan Morote, Zhishen Ye, Roger D. Dansey, Carsten Dietrich Goessl
Journal: Journal of Clinical Oncology (2012)

4510 Background: Denosumab, an anti-RANK-ligand monoclonal antibody, has been shown to prolong BMFS by a median 4.2 months and with a 15% risk reduction vs. placebo in men with non-metastatic CRPC and baseline PSA value ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤10.0 months. To determine the efficacy of denosumab in men at greatest risk for bone metastases, we evaluated BMFS in a subset of men with PSADT ≤6 months (previously reported in Smith MR, et al: J Clin Oncol. 23:2918-2925, 2005). Methods: 1,432 men with non-metastatic CRPC (baseline medians: PSA: 12.3 ng/mL, PSADT: 5.1 months, ADT duration: 47.1 months) were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or placebo. The first patient enrolled February 2006; primary analysis cut-off was July 2010, when &gt;660 men had developed bone metastasis or died. The primary endpoint was BMFS (time to first bone metastasis or death from any cause). BMFS results are presented for men with baseline PSADT ≤6 months. Results: Median BMFS in the placebo group of men with PSADT ≤6 months was 6.5 months shorter than for the placebo group in the full population (18.7 months vs. 25.2 months), indicating that these men are at particularly high risk. In this group of men with PSADT ≤6 months, denosumab prolonged BMFS by a median of 7.2 months and with a 23% reduction in risk compared with placebo (Table). Conclusions: Patients with shortened PSADT are at higher risk of developing bone metastasis and denosumab is markedly effective at prolonging BMFS in this subset of patients. [Table: see text]
Heterogeneity of cytotoxic T cell infiltration in breast and colorectal cancer
Authors: James Ziai, Houston Gilbert, Oded Foreman, Jeffrey Eastham-Anderson, Felix Chu, Mahrukh Huseni, Jeong M Kim
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The prognostic value of intra-tumoral cytotoxic T cells has been demonstrated in multiple tumor types. However, immune infiltrate heterogeneity can lead to potentially significant misrepresentations of marker prevalence in routine histological sections. We examined step sections
Immune response correlation with progression-free survival in glioblastoma following dendritic cell immunotherapy (ICT-107).
Authors: S. Phuphanich, J. Rudnick, M. Mazer, H. Q. Wang, N. Serrano, J. Richardson, C. Wheeler, M. Singh, K. Black, J. Yu
Journal: Journal of Clinical Oncology (2010)

2097 Background: Active immunotherapy offers the potential for high tumor-specific toxicity and sustained tumoricidal activity. We therefore have developed this protocol to exploit the most current knowledge of specific glioma-associated antigens and used these antigens to induce a potent T cell response. Methods: The goal of this study is to administer dendritic cells pulsed with tumor associated antigens (TAA) expressed on gliomas to therapeutically vaccinate patients. TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13R alpha, and AIM-3. In this phase I trial, sponsored by ImmunoCellular, HLA-A1 and/or HLA-A2 positive patients with newly diagnosed or recurrent brainstem glioma or glioblastoma were eligible. Mononuclear cells were isolated by leukapheresis, differentiated into dendritic cells in culture, pulsed with TAA peptides, and then administered intradermally three times at two week intervals. Results: Twenty-one patients with one screen failure, 16 males and 5 females, were enrolled between November 2006 and January 2010. There were 17 newly diagnosed supratentorial glioblastoma multiforme (GBM), 3 patients with recurrent GBM, and 1 brainstem glioma. Vaccination was followed by adjuvant chemotherapy. Immune response data on 17 glioblastoma patients showed 35% responders (> 1.5 fold increase IFN g production after vaccination = responsder by tetramer/FACS) with prolong survival in 6 responder and 11 nonresponder (114 and 87 wks: p = 0.046). Irrespective of immune responsiveness, 6 of 16 newly diagnosed GBM patients continue to show no signs of tumor recurrence, three of whom have gone more than two years with no disease progression (135-169 weeks). The median progression-free survival time in this group was 13.7 months and RT/TMZ regimen 6.9 months (EORTC/NCIC). Data on 20 patients and 57 courses of dendritic cell vaccines demonstrated zero grade 3/4 toxicities that were attributable to the vaccination. Conclusions: Survival and progression-free survival compare favorably to previously performed immunotherapy trials for glioblastoma. In addition, positive antitumor cytokine response correlated with longer progression-free survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImmunoCellular Therapeutics ImmunoCellular Therapeutics ImmunoCellular Therapeutics ImmunoCellular Therapeutics
Association of chronic kidney disease with abnormal cardiac mechanics and adverse outcomes in patients with heart failure and preserved ejection fraction
Authors: Erin D. Unger, Ruth F. Dubin, Rajat Deo, Vistasp Daruwalla, Julie L. Friedman, Crystal Medina, Lauren Beussink, Benjamin H. Freed, Sanjiv J. Shah
Journal: European Journal of Heart Failure (2015)
Death toll from swine flu in India exceeds 2500
Authors: Sophie Cousins
Journal: BMJ (2015)

More than 2500 people in India have died from H1N1 influenza this year, compared with 218 last year, the health ministry has said. In addition, more than 39 000 cases have been reported, compared with <1000 last year.

The western state of Maharashtra, which has had the highest number of cases and deaths across the country this year, is in the midst of its worst ever H1N1 outbreak, after the official death toll reached 674, with more than 7000 confirmed cases, local media have reported. The death toll in the state has surpassed the toll of the global H1N1 pandemic in 2009 and 2010, which reported 286 and 669 deaths respectively. …
Development and Application of a Lifestyle Score for Prevention of Lethal Prostate Cancer
Authors: S. A. Kenfield, J. L. Batista, J. L. Jahn, M. K. Downer, E. L. Van Blarigan, H. D. Sesso, E. L. Giovannucci, M. J. Stampfer, J. M. Chan
Journal: JNCI Journal of the National Cancer Institute (2015)

Several lifestyle factors have been associated with risk of lethal prostate cancer, but little is known about their combined effect. Our objective was to develop and apply a lifestyle score for prevention of lethal prostate cancer. We developed a lifestyle score among 42 701 men in the Health Professionals Follow-up Study (HPFS) followed from 1986 to 2010 and applied it among 20 324 men in the Physicians' Health Study (PHS) followed from 1982 to 2010. One point was given for each of: not currently smoking or quit 10 or more years ago, body mass index under 30kg/m 2 , high vigorous physical activity, high intake of tomatoes and fatty fish, and low intake of processed meat. Diet-only scores (range = 0–3) and total scores (range = 0–6) were calculated. We used multivariable Cox proportional hazards regression to estimate the risk of lethal prostate cancer, adjusting for potential risk factors of lethal prostate cancer. All statistical tests were two-sided. We observed 576 lethal prostate cancer events in HPFS and 337 in PHS. Men with 5–6 vs 0–1 points had a 68% decreased risk of lethal prostate cancer (hazard ratio [HR] = 0.32, 95% confidence interval [CI] = 0.19 to 0.52) in HPFS and a non-statistically significant 38% decreased risk (HR = 0.62, 95% CI = 0.30 to 1.26) in PHS. For dietary factors only, men with 3 vs 0 points had a 46% decreased risk (HR = 0.54, 95% CI = 0.30 to 0.96) in the HPFS and a non-statistically significant 30% decreased risk (HR = 0.70, 95% CI = 0.40 to 1.23) in PHS. Adhering to a healthy lifestyle, defined by not smoking, normal body weight, high physical activity, and a healthy diet, may lower risk of lethal prostate cancer.
The PARADIGM trial: A phase III study comparing sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer (LANHC).
Authors: Robert I. Haddad, Guilherme Rabinowits, Roy B. Tishler, Douglas Adkins, Fadlo Raja Khuri, Joseph Clark, Jochen H. Lorch, Sewanti Atul Limaye, Lori J. Wirth, Anne O'Neill, Sarah Riley, Marshall R. Posner
Journal: Journal of Clinical Oncology (2012)

5501 Background: PARADIGM is a multicenter phase III study comparing TPF (docetaxel, cisplatin, and 5-fluorouracil)-based ST (Arm A) to upfront cisplatin CRT (Arm B) in patients (pts) with LAHNC. Pt accrual was terminated in 12/2008 due to slow enrollment with 145 of 300 planned analyzable patients accrued. Safety data was previously presented at the 2010 ASCO annual meeting showing no unusual pattern of toxicities in either arm. Here we present the survival results. Methods: Pts were randomized to receive arm A-ST (as induction chemotherapy (ICT) with TPF x 3) followed by CRT with either weekly carboplatin and once daily radiotherapy, or weekly docetaxel and accelerated boost radiotherapy based on adequate response to ICT; or arm B - accelerated boost CRT with bolus cisplatin x 2. The primary endpoint was survival. With original accrual target of 300 analyzable patients, this study was powered at 80% to detect an improvement in 3-year survival from 55% (arm B) to 70% (arm A). Results: A total of 145 previously untreated pts were enrolled (Arm A: 70; Arm B: 75), of whom 127 were male and 127 were Caucasian. Median age was 55; patients had PS of 0 (97) or 1 (48). Sites of disease were oropharynx: 80, larynx: 24, hypopharynx: 15, and oral cavity: 26. Disease stages were II (1 pt), III (20 pts) and IV (124 pts). After a median follow-up of 49 months, 41 pts have died (20 in arm A and 21 in arm B). Three-year survival was 73% (arm A) and 78% (arm B) (HR1.09; 95% CI 0.59 to 2.03 p=0.77). Three-year progression-free survival was 67% (arm A) and 73% (arm B) (HR 1.2; 95% CI 0.65 to 2.22; p=0.55). Patterns of failure will be presented at the meeting. Conclusions: Althoughthese results suggest no survival differences between CRT and ST for patients with LAHNC, the study was terminated before the planned accrual could be reached. HPV status for the oropharynx cases which represented the majority of patients was not available for stratification; and excellent survival was seen in both arms.
Adoptive cellular therapy using bone marrow-derived T cells for the treatment of childhood leukemia
Authors: Jill Gershan, Katie Palen, James Weber, Monica Thakar, Bryon Johnson
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts The survival for pediatric leukemia patients is approaching 90%, but there are patient subgroups that fare poorly including those with relapsed, or high-risk, acute lymphocytic and acute myeloid leukemia (ALL and AML, respectively). For these reasons, there is an unprecedented
Palonosetron vs ondansetron: Prevention of chemotherapy-induced nausea and vomiting in pediatric patients in a multicycle study.
Authors: Edita Kabickova, Antonio Wachtel, Elena Basharova, Tulla Spinelli, Pierre Nicolas, Gabor Kovacs
Journal: Journal of Clinical Oncology (2015)

10077 Background: Palonosetron (PALO) has been shown to be non-inferior to ondansetron (OND) at preventing chemotherapy-induced nausea and vomiting (CINV) in adult patients (pts) receiving moderately/highly emetogenic chemotherapy (MEC/HEC). Methods: This phase III study evaluated the efficacy/safety of two PALO doses (10, 20 µg/kg) vs OND (3 × 150 µg/kg) in pediatric pts receiving up to 4 MEC/HEC cycles. For the primary objective statistical analysis was used to show non-inferiority for PALO (δ = -15%) vs OND from complete response rates (CR, no emesis/rescue medication) in the acute phase (0–24h after first MEC/HEC dose) of cycle 1. Secondary objectives included CR rate in the delayed (>24–120h) and overall (0–120h) phases and safety. Results: In 493 pts aged 64 days–16.9 years the CR rate was highest in the PALO 20 µg/kg group in all phases of cycles 1, 3 and 4 with statistical non-inferiority shown for this dose vs OND in the acute phase of cycle 1 (see table). In cycles 1–4 treatment-emergent adverse events (TEAEs) were fewer in the PALO 20 µg/kg group (69.3%, 64.4%, 55.9%, 48.4%) vs the PALO 10 µg/kg (80.2%, 76.2%, 72.1%, 75.0%) and OND (81.7%, 82.6%, 68.2%, 72.2%) groups. Drug-related TEAEs (cycles 1–2 only) were comparable although highest in the OND group (4.7%). TEAEs in cycles 3–4 plus all study withdrawals and fatal TEAEs were not considered drug-related. Laboratory and ECG evaluations, inclusive of the QT interval raised no concerns. Conclusions: In pediatric pts receiving up to 4 MEC/HEC cycles palonosetron 20 µg/kg was non-inferior to OND in the acute phase of cycle 1, numerically superior to OND across all cycles and presented no significant safety risks. Clinical trial information: NCT01442376. CR rate Phase, % PALO 10 µg/kg N PALO 20 µg/kg N OND 3 × 150 µg/kg N Cycle 1 Acute 97.5% CI* of ΔCR† P-value‡ 166 54.2 -16.4–7.6 0.0242 165 59.4 -11.7–12.4 0.0022 162 58.6 Delayed Overall 28.9 23.5 38.8 32.7 28.4 24.1 Cycle 2 Acute Delayed Overall 82 66.7 35.8 33.3 90 65.6 38.9 35.6 86 59.3 32.6 29.1 Cycle 3 Acute Delayed Overall 43 44.2 30.2 27.9 59 81.4 42.4 40.7 44 63.6 27.3 27.3 Cycle 4 Acute Delayed Overall 19 47.4 31.6 21.1 31 64.5 32.3 29.0 19 52.6 26.3 21.1 *Mantel-Haenszel; †ΔCR=CRPalonosetron-CROndansetron; ‡Non-inferiority confirmed if p < 0.0125.
James Seeds Naunton Briggs Ivy Eunice Bryant (nee Tanner) Richard Henry Lionel Cohen Neville Lionel Gilburn Frank Ogle Graham Rachel Charlotte Anne MacNaughtan Hawes Keith Emile Jolles Albert Vivian ("Bing") Stevens Sydney Alexander Swanson Robert Stuart ("Charles") Wells Hugh Wilson Colin Charles Wise
Authors: C J C Cox, J. Robinson, G. Ford, G. Godber, J R Gilburn, C M Graham, P R R Clarke, D. Harborne, J. Hodgson, R S Rowntree, T R Wilson, R J Hay, R H Bolton, T. Austin, P. Scott, R. Vaughan
Journal: BMJ (1998)

General practitioner Caerphilly (b Caerphilly 1927, in the family home that was the practice surgery until 1984; q Cambridge/ UCH 1951), died of carcinoma of the pancreas on 28 December 1997.He spent two years' National Service in Germany in the Royal Army Medical Corps, then entered general practice in partnership with his father.In 1983 he retired to Pembrokeshire because of severe osteoarthritis of his back, but led a full life, sailing with his wife to Ireland many times, and also around Ireland and to Gibraltar.
Local delivery of a carbohydrate analog for reducing arthritic inflammation and rebuilding cartilage
Authors: Chaekyu Kim, Ok Hee Jeon, Do Hun Kim, J. Jeremy Chae, Lucas Shores, Nicholas Bernstein, Rahul Bhattacharya, Jeannine M. Coburn, Kevin J. Yarema, Jennifer H. Elisseeff
Journal: Biomaterials (2015)
Novel antisense therapeutics delivery systems: In vitro and in vivo studies of liposomes targeted with anti-CD20 antibody
Authors: Justyna M. Meissner, Monika Toporkiewicz, Aleksander Czogalla, Lucyna Matusewicz, Kazimierz Kuliczkowski, Aleksander F. Sikorski
Journal: Journal of Controlled Release (2015)

Antisense gene therapy using molecules such as antisense oligodeoxynucleotides, siRNA or miRNA is a very promising strategy for the treatment of neoplastic diseases. It can be combined with other treatment strategies to enhance therapeutic effect. In acute leukemias, overexpression of the antiapoptotic gene BCL2 is observed in more than 70% of cases. Therefore, reduction of the Bcl-2 protein level could, in itself, prevent the development of cancer or could possibly help sensitize cancer cells to apoptosis inducers. The main objective of our work is to develop therapeutic liposome formulations characterized by high transfection efficiency, stability in the presence of serum, as well as specificity and toxicity for target (leukemic) cells. Each of our liposomal formulations consists of a core composed of antisense oligonucleotides complexed by either cationic lipid, DOTAP, or a synthetic polycation, polyethyleneimine, encapsulated within liposomes modified with polyethylenoglycol. In addition, the liposomal shells are enriched with covalently-bound antibodies recognizing a well characterized bio-marker, CD20, exposed on the surface of leukemia cells. The resulting immunoliposomes selectively and effectively reduced the expression of BCL2 in target cells. Model animal experiments carried out on mice-engrafted tumors expressing the specific marker showed high efficiency of the liposome formulations against specific tumor development. In conclusion, we show that lipid formulations based on a polyplex or lipoplex backbone additionally equipped with antibodies are promising non-viral vectors for specific oligonucleotide transfer into human tumor cells.