tbuckley/cabot-search huggingface dataset:
Multi‐Responsive “Turn‐On” Nanocarriers for Efficient Site‐Specific Gene Delivery In Vitro and In Vivo
Authors: Yiyan He, Jie Zhou, Shengnan Ma, Yu Nie, Dong Yue, Qian Jiang, Aisha Roshan Mohamed Wali, James Zhenggui Tang, Zhongwei Gu
Journal: Advanced Healthcare Materials (2016)

Systemic gene delivery is a complicated and multistep process that confronts numerous biological barriers. It remains a formidable challenge to exploit a single gene carrier with multiple features to combat all obstacles collectively. Herein, a multi‐responsive “turn‐on” polyelectrolyte complex (DNA/OEI‐SS x /HA‐SS‐COOH, DSS) delivery system is demonstrated with a sequential self‐assembly of disulfide‐conjugated oligoethylenimine (OEI‐SS x ) and disulfide bond‐modified hyaluronic acid envelope (HA‐SS‐COOH) that can combat multiple biological barriers collectively when administered intravenously. DSS is designed to effectively accumulate at the tumor tissue and to be internalized into tumor cells by recognizing CD44. The multi‐responsive “turn‐on” DSS can respond to the alterations of hyaluronidases and glutathione at both the tumor site and at the intracellular milieu. Sequential degradation and detachment of the HA‐SS‐COOH envelope followed by the dissociation of the OEI‐SSx/DNA inner core contributes to the activation of the endosomal escape and gene release functions, thus greatly enhancing nuclear gene delivery. A systematic investigation of DSS has revealed that the tumor accumulation ability, internalization, and endosome escape of the DSS nanocarriers, DNA unpacking and nuclear transportation are all remarkably improved by the multi‐responsive “turn‐on” design resulting in highly efficient gene transfection in vitro and in vivo.
At the cross-point of connexins, calcium, and ATP: blocking hemichannels inhibits vasoconstriction of rat small mesenteric arteries
Authors: Mélissa Bol, Nan Wang, Marijke De Bock, Benjamin Wacquier, Elke Decrock, Ashish Gadicherla, Kelly Decaluwé, Bert Vanheel, Harold Victor Maria van Rijen, Dmitri Vadim Krysko, Geert Bultynck, Geneviève Dupont, Johan Van de Voorde, Luc Leybaert
Journal: Cardiovascular Research (2016)

Connexins form gap-junctions (GJs) that directly connect cells, thereby coordinating vascular cell function and controlling vessel diameter and blood flow. GJs are composed of two hemichannels contributed by each of the connecting cells. Hemichannels also exist as non-junctional channels that, when open, lead to the entry/loss of ions and the escape of ATP. Here we investigated cross-talk between hemichannels and Ca2+/purinergic signalling in controlling blood vessel contraction. We hypothesized that hemichannel Ca2+ entry and ATP release contributes to smooth muscle cell (SMC) Ca2+ dynamics, thereby influencing vessel contractility. We applied several peptide modulators of hemichannel function and inhibitors of Ca2+ and ATP signalling to investigate their influence on SMC Ca2+ dynamics and vessel contractility.Confocal Ca2+ imaging studies on small mesenteric arteries (SMAs) from rat demonstrated that norepinephrine-induced SMC Ca2+ oscillations were inhibited by blocking IP3 receptors with xestospongin-C and by interfering with hemichannel function, most notably by the specific Cx43 hemichannel blocking peptide TAT-L2 and by TAT-CT9 that promotes Cx43 hemichannel opening. Evidence for hemichannel involvement in SMC function was supported by the fact that TAT-CT9 significantly increased SMC resting cytoplasmic Ca2+ concentration, indicating it facilitated Ca2+ entry, and by the observation that norepinephrine-triggered vessel ATP release was blocked by TAT-L2. Myograph tension measurements on isolated SMAs showed significant inhibition of norepinephrine-triggered contractility by the ATP receptor antagonist suramin, but the strongest effect was observed with TAT-L2 that gave ∼80% inhibition at 37 °C. TAT-L2 inhibition of vessel contraction was significantly reduced in conditional Cx43 knockout animals, indicating the effect was Cx43 hemichannel-dependent. Computational modelling suggested these results could be explained by the opening of a single hemichannel per SMC.These results indicate that Cx43 hemichannels contribute to SMC Ca2+ dynamics and contractility, by facilitating Ca2+ entry, ATP release, and purinergic signalling.
Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: A phase II study of the Belgian Group of Digestive Oncology.
Authors: I. Borbath, A. Ceratti, C. Verslype, A. Demols, T. Delaunoit, A. Deleporte, S. Laurent, P. Vergauwe, E. Van Cutsem, J. Van Laethem
Journal: Journal of Clinical Oncology (2011)

245 Background: Cholangiocarcinomas (CCK) are uncommon tumors with an increasing incidence and a poor prognosis. Epidermal growth factor receptor (EGFR) expression and activation in CCK have been demonstrated. Methods: We conducted a multicenter phase II trial combining cetuximab (Ctx), an anti-EGFR chimerized IgG1 monoclonal antibody, to gemcitabine (Gem). Patients with either locally advanced (LA) or metastatic (M) CCK (excluding gallbladder) were included; no prior systemic therapy was allowed. Ctx was administrated at the initial dose of 400 mg/m 2 and further injections at 250 mg/m 2 every 7 days, and Gem was administrated at 1000 mg/m 2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the progression-free survival (PFS) rate at 6 months. A Simon 2-stage design was used. We hypothesized that Gem/Ctx would improve 6 month-PFS rate from 20% to 40%. We needed 3 patients with PFS ≥ 6 months from the first 13 to further include a total of 43 patients. Results: Forty-four patients with advanced CCK (41% LA/59%M) were enrolled from 09/2008 to 01/2010. Median age was 61.5 years (range 40-86) and baseline ECOG PS was 0 for 68% and 1 for 32% of the patients. Forty-three percent of the patients had prior surgery. Forty-six percent of the patients were free from progression at 6 months. Median PFS was 5.8 months (95% CI, 4.4-7.4 m) and median overall survival was 11.6 months (95% CI, 8.7-14.6 m). Nine patients (20.9%) had partial response with a median duration of 5 months (range 2-10 m). Disease control rate (PR + SD &gt; 8 weeks) was 81.4%. The most common grades 3/4 related-toxicities were haematological abnormalities (47.7%), skin rash (13.6%) and fatigue (11.3%). Due to toxicity, 6 patients discontinued study treatment; 14 and 3 patients had a Gem and Ctx dose reduction respectively. Among the nine responders, 8 experienced a skin rash of at least grade 2, suggesting a relationship between skin toxicity and efficacy. Conclusions: Our study met its endpoint, i.e., a PFS rate of 46% at 6 months, suggesting that Gem-Ctx combination had promising activity with a manageable toxicity profile in advanced CCK. Adding Ctx to the new standard of care Gem-cisplatin deserves further investigations in CCK. [Table: see text]
Future jobs of FDA’s haematology-oncology reviewers
Authors: Jeffrey Bien, Vinay Prasad
Journal: BMJ (2016)

Medical reviewers at the US Food and Drug Administration are vital to effective regulation, interpreting whether a drug’s harm-benefit balance is favourable. When regulators leave government, some work or consult for the industries they regulated.1 2 Although this “revolving door” has been criticised,1 2 it has not been studied. We sought to measure how often it occurs at the FDA.

Using the set of FDA haematology-oncology drug approvals listed on its …
Phase II study of carboplatin and paclitaxel in elderly women with newly diagnosed ovarian, peritoneal, or fallopian tube cancer
Authors: R. T. Penson, A. B. Kornblith, J. Lee, M. Roche, T. Atkinson, C. D. Gibson, N. S. Horowitz, K. J. Krag, C. N. Krasner, U. A. Matulonis
Journal: Journal of Clinical Oncology (2008)

5590 Background: More than 50% of cases of ovarian cancer occur in the older patient population (>65), the only group with an increasing incidence. The elderly with ovarian cancer are thought to have a worse prognosis with possible causative factors being more aggressive biology, inability to tolerate aggressive debulking surgery and chemotherapy, and comorbidities. Carboplatin and paclitaxel remains the standard of care for newly diagnosed patients with suboptimally debulked epithelial ovarian cancer. Methods: The primary objective was to determine the completion rate of six cycles of carboplatin/paclitaxel in an elderly population, and evaluate clinical parameters that predict completion of treatment including VES-13 score, Charlson co-morbidity index, nutritional status, and pharmacokinetics of paclitaxel. Eligibility: Age 70 or older. Treatment: carboplatin AUC 5 IV and paclitaxel 175 mg/m2 IV over three hours, q21 days. Results: 12 patients were enrolled with a median age 82 (75–86), with ECOG performance score 0(n=2), 1(n=8), and 2(n=2). The study was formally audited when 3 of the patients died on study, and the study was closed. One 84-yo died of toxicity complicating PD after #1 with a combination of progression and toxicity with nausea and vomiting leading to dehydration and ARF, an 82-yo died suddenly #6 day 5 in CR, and a 75-yo died of aspiration after vomiting during #2. Grade 3/4 toxicity included cognitive disturbance, constipation, enteritis, fatigue (2), febrile neutropenia (2), obstipation, hypoxia, infection, and vomiting. Only 3 patients were able to complete treatment, one with cognitive impairment and only 2 without dose delays or reductions. Conclusions: Standard chemotherapy in vulnerable populations can be associated with unacceptable excess toxicity. Reported series with positive outcomes in geriatric populations likely reflect significant selection bias. Careful consideration should be given to initial treatment with reduced doses (Carboplatin AUC 4 and paclitaxel 135 mg/m2) and escalation as tolerated. No significant financial relationships to disclose.
Oxidative stress and ageing
Authors: M.A. Birch-Machin, A. Bowman
Journal: British Journal of Dermatology (2016)

Oxidative stress is the resultant damage due to redox imbalances (increase in destructive free radicals [reactive oxygen species (ROS)] and reduction in antioxidant protection/pathways) and is linked to ageing in many tissues including skin. In ageing skin there are bioenergetic differences between keratinocytes and fibroblasts which provide a potential ageing biomarker. The differences in skin bioenergy are part of the mitochondrial theory of ageing which remains one of the most widely accepted ageing theories describing subsequent increasing free radical generation. Mitochondria are the major source of cellular oxidative stress and form part of the vicious cycle theory of ageing. External and internal sources of oxidative stress include UVR/IR, pollution (environment), lifestyle (exercise and diet), alcohol and smoking all of which may potentially impact on skin although many exogenous actives and endogenous antioxidant defence systems have been described to help abrogate the increased stress. This also links to differences in skin cell types in terms of the UVR action spectrum for nuclear and mitochondrial DNA damage (the latter a previously described UVR biomarker in skin). Recent work associates bioenergy production and oxidative stress with pigment production thereby providing another additional potential avenue for targeted anti‐ageing intervention in skin. This new data supporting the detrimental effects of the numerous wavelengths of UVR may aid in the development of cosmetic/sunscreen design to reduce the effects of photoageing. Recently, complex II of the mitochondrial electron transport chain appears to be more important than previously thought in the generation of free radicals (suggested predominantly by non‐human studies). We investigated the relationship between complex II and ageing using human skin as a model tissue. The rate of complex II activity per unit of mitochondria was determined in fibroblasts and keratinocytes cultured from skin covering a wide age range. Complex II activity significantly decreased with age in fibroblasts (P =0·015), but not in keratinocytes. This was associated with a significant decline in transcript expression (P =0·008 and P =0·001) and protein levels (P =0·0006 and P =0·005) of the SDHA and SDHB catalytic subunits of complex II respectively. In addition there was a significant decrease in complex II activity with age (P =0·029) that was specific to senescent skin cells, our study being the first to investigate these differences with senescence and skin age. There was no decrease in complex IV activity with increasing age, suggesting possible locality to complex II. Our study provides a future potential biomarker for monitoring the progression of skin ageing.
The who and what of imaging in sarcoma and correlation with survival.
Authors: Vadim S Koshkin, Vanessa Bolejack, Lawrence H. Schwartz, Binsheng Zhao, Rashmi Chugh, Richard L. Wahl, Denise K. Reinke, Lee J. Helman, Shreyaskumar Patel, Scott Schuetze, Laurence H. Baker
Journal: Journal of Clinical Oncology (2015)

10511 Background: Response and progression are surrogates for survival that inform clinical decisions. Comparison of anatomic and functional imaging modalities in a large prospective clinical trial can suggest the optimal method of selecting patients who benefit from further therapy. Methods: 115 patients with metastatic, chemo-refractory Ewing’s Sarcoma were treated with R1507, a human monoclonal antibody directed at IGF-1 receptor, as part of SARC011 study (J Clin Onc vol 29). Each pt had anatomic imaging with CT or MR at baseline and 6-week intervals and FDG-PET at baseline and on day 9. Anatomic imaging results were reported by each of the 31 sarcoma centers using WHO criteria. An expert central radiology group performed an independent review and volumetric analysis on 76 pts. Using log-rank analysis we defined the optimal volume cut points for progression and response at 6 wk imaging which correlated with OS, and compared this model to previously established criteria including WHO (both central and local), RECIST and PERCIST. Results: Volume increase of 175% for prior lesions at 6 wks was the optimal cutoff for decreased OS (p < 0.001) and thus progression. Optimal cutoff for response was a 45% volume decrease. OS of patients with PD at 6 wks was significantly reduced compared to non-progressors based on Volume (R2 = 0.17) as well as other criteria: RECIST (R2= 0.17), WHO_Central (R2= 0.16), WHO_Local (R2= 0.14). Patients with PMD by PERCIST on day 9 had reduced OS vs. non-progressors (p = 0.001). Progression type impacted survival, as pts with new lesions and enlarging prior lesions had decreased OS compared to pts with either variable alone. Conclusions: In a large clinical trial we identified pts with decreased OS based on multiple anatomic imaging criteria at week 6 and functional imaging by PERCIST as early as day 9. A new model using volumetric analysis with cutoffs different from those extrapolated from RECIST or WHO was introduced, and its utility should be assessed in a prospective clinical trial. Clinical trial information: NCT00642941. Non-Progressors Progressors Response Stable Disease Progressive Disease p-value (PD vs. non-PD) N Median OS (days) N Median OS N Median OS RECIST 16 204 26 152 34 91 <.001 VOLUME 19 204 30 149 27 84 <.001 WHO 14 204 25 154 37 91 <.001 LocalWHO 17 166 21 162 38 97 .002
The proteome pattern cGvHD_MS14 allows early and accurate prediction of chronic GvHD after allogeneic stem cell transplantation
Authors: E M Weissinger, C Human, J Metzger, L Hambach, D Wolf, H T Greinix, A M Dickinson, W Mullen, D Jonigk, Z Kuzmina, H Kreipe, P Schweier, O Böhm, I Türüchanow, D Ihlenburg-Schwarz, J Raad, A Durban, M Schiemann, C Könecke, H Diedrich, E Holler, G Beutel, J Krauter, A Ganser, M Stadler
Journal: Leukemia (2016)
Loss of TET2 Function in Myelodysplastic Syndrome Results in Intragenic Hypermethylation and Alterations in mRNA Splicing
Authors: Allegra M Lord, Kendell Clement, Rebekka K. Schneider, McConkey Marie, Michelle C. Chen, Ross L. Levine, Ann Mullally, Naomi Galili, Abdullah Mahmood Ali, Azra Raza, Rafael Bejar, Alexander Meissner, Benjamin L. Ebert
Journal: Blood (2014)
Pharmacogenomics in a trial of gemcitabine/axitinib compared with gemcitabine/placebo in advanced pancreatic cancer
Authors: A. K Loomis, G. J Brock, J Williams, F Gao, R. Y. T Fan, A Ricart, D Richel, J Bennouna, G Springett, J Maurel, D Lambrechts, Eric Van Cutsem
Journal: Annals of Oncology (2010)
Meta analysis of recent phase III adjuvant chemotherapy trials in resected rectal cancer.
Authors: Saba Imtiaz, Jamal M Zekri, Rawan Al - Saadi, Haneen Al-Omar
Journal: Journal of Clinical Oncology (2015)

e14513 Background: Extrapolating from results in colon cancer, most practice guidelines recommend the use of adjuvant chemotherapy following surgery for patients with rectal cancer despite lack of supporting evidence. However, recently accumulating evidence refutes this practice. We conducted a systematic meta-analysis of published randomized phase III studies assessing this approach in the era of total meso-rectal excision (TME). Methods: Four trials fulfilled the inclusion criteria (EORTC-22921, PROCTOR-SCRIPT, I-CNR-RT and CHRONICLE). In total, 2195 patients with stage cT3-T4 and/or N+ rectal cancer undergone preoperative (chemo)radiotherapy followed by TME were randomized to adjuvant fluoropyrimidine based chemotherapy (n = 1100) or observation (n = 1095). Random effect meta-analysis of the literature (not individual patient data) was conducted using RevMan program. The outcomes of interest were 5 &10 year relapse free survival (RFS) and overall survival (OS). All 4 trials presented 5 year results while 10 years outcome was available in only some of them. Results: Patients’ median age ranged from 59-63 years. Sixty per cent of patients received pre-operative chemo-radiotherapy and 40% received preoperative radiotherapy alone. Fifty four per cent of patients completed the full course of adjuvant chemotherapy. Adjuvant chemotherapy significantly reduced risk of 5 years relapse [Hazard Ratio: 0.88 (95% CI: 0.79-0.97, P = 0.01)]. However, this statistical significance was lost at 10 years [Hazard Ratio: 0.87 (95% CI: 0.74-1.04, P = 0.13)]. There was no significant benefit of adjuvant chemotherapy on 5 and 10 year mortality [Hazard Ratio: 0.94 (95% CI: 0.83-1.07, P = 0.37)] and [Hazard Ratio: 0.92 (95% CI: 0.83-1.01, P = 0.09)] respectively. Conclusions: In the era of TME, adjuvant chemotherapy after (chemo)radiotherapy and surgery for patients with rectal cancer showed a small initial advantage in reducing relapse at 5 years. However, this was neither translated to OS nor to longer term benefit. These results do not support the current practice of adjuvant chemotherapy in this setting. New treatment strategies are required to improve outcome of these patients.
Valproate in Combination with Rituximab and CHOP As First Line Therapy in Diffuse Large B-Cell Lymphoma (VALFRID): Preliminary Results from a Phase I Trial with a Dose Expansion Cohort
Authors: Kristina Drott, Hans Hagberg, Thomas Relander, Cecilia Graffman, Johan Drott, Mats Jerkeman
Journal: Blood (2015)
Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease
Authors: Nadine Kuttkat, Antje Mohs, Kim Ohl, Guido Hooiveld, Thomas Longerich, Klaus Tenbrock, Francisco Javier Cubero, Christian Trautwein
Journal: Gut (2016)

<h3>Objective</h3> Th17 cells are a subset of CD4<sup>+</sup> T-helper cells characterised by interleukin 17 (IL-17) production, a cytokine that plays a crucial role in inflammation-associated diseases. The cyclic AMP-responsive element modulator-α (CREMα) is a central mediator of T-cell pathogenesis, which contributes to increased IL-17 expression in patients with autoimmune disorders. Since an increased Th17 response is associated with a poor prognosis in patients with chronic liver injury, we investigated the relevance of Th17 cells for chronic liver disease (CLD) and hepatocarcinogenesis. <h3>Design</h3> Transgenic mice overexpressing CREMα were crossed with hepatocyte-specific Nemo knockout mice (Nemo<sup>Δhepa</sup>) to generate Nemo<sup>Δhepa</sup>/CREMα<sup>Tg</sup> mice. The impact of CREMα<sup>Tg</sup> on CLD progression was examined. Additionally, soft agar colony formation assays, in vitro studies, adoptive transfer of bone marrow-derived cells (BMDCs) and T cells, and gene arrays in T cells were performed. <h3>Results</h3> 8-week-old Nemo<sup>Δhepa</sup>/CREMα<sup>Tg</sup> mice presented significantly decreased transaminase levels, concomitant with reduced numbers of CD11b<sup>+</sup> dendritic cells and CD8<sup>+</sup> T cells. CREMα<sup>Tg</sup> overexpression in Nemo<sup>Δhepa</sup> mice was associated with significantly reduced hepatic fibrogenesis and carcinogenesis at 52 weeks. Interestingly, hepatic stellate cell-derived retinoic acid induced a regulatory T-cell (Treg) phenotype in CREMα<sup>Tg</sup> hepatic T cells. Moreover, simultaneous adoptive transfer of BMDCs and T cells from CREMα<sup>Tg</sup> into Nemo<sup>Δhepa</sup> mice ameliorated markers of liver injury and hepatitis. <h3>Conclusions</h3> Our results demonstrate that overexpression of CREMα in T cells changes the inflammatory milieu, attenuating initiation and progression of CLD. Unexpectedly, our study indicates that CREMα transgenic T cells shift chronic inflammation in Nemo<sup>Δhepa</sup> livers towards a protective Treg response.
First-line<i>Helicobacter pylori</i>eradication therapies in countries with high and low clarithromycin resistance: a systematic review and network meta-analysis
Authors: Yee Hui Yeo, Sz-Iuan Shiu, Hsiu J Ho, Biyao Zou, Jaw-Town Lin, Ming-Shiang Wu, Jyh-Ming Liou, Chun-Ying Wu
Journal: Gut (2016)

Objective To determine the optimal regimen of different first-line Helicobacter pylori eradication therapies according to the clarithromycin resistance rate. Design Electronic search for articles published between January 2005 and April 2016. Randomised, controlled trials that reported the effectiveness of first-line eradication therapies in treatment-naïve adults were included. Two independent reviewers performed articles screening and data extraction. Network and traditional meta-analyses were conducted using the random effect model. Subgroup analyses were performed to determine the ranking of regimens in countries with high (&gt;15%) and low (&lt;15%) clarithromycin resistance. Data including adverse events and therapeutic cure rate were also extracted and analysed. Results 117 trials (totally 32 852 patients) for 17 H. pylori eradication regimens were eligible for inclusion. Compared with 7-day clarithromycin-based triple therapy, sequential therapy (ST) for 14 days had the highest effectiveness (OR=3.74, 95% CrI 2.37 to 5.96). ST-14 (OR=6.53, 95% CrI 3.23 to 13.63) and hybrid therapy (HY) for 10 days or more (OR=2.85, 95% CrI 1.58 to 5.37) represented the most effective regimen in areas with high and low clarithromycin resistance, respectively. The effectiveness of standard triple therapy was below therapeutic eradication rate in most of the countries. Longer duration was associated with higher eradication rate, but with a higher risk of events that lead to discontinuation. Conclusions ST and HY appeared to be the most effective therapies in countries with high and low clarithromycin resistance, respectively. The clinical decision for optimal regimen can be supported by referring to the rank ordering of relative efficacies stratified by local eradication rates, antibiotic resistance and safety profile. Trial registration number CRD42015025445.