Erlotinib in the treatment of advanced pancreatic cancer

Single agent gemcitabine has been the mainstay of therapy for advanced pancreatic cancer over the past decade. Multiple trials of newer chemotherapeutic agents both alone and in combination have yielded disappointing results, spurring the ongoing search for new agents and combinations in this aggressive malignancy. Inhibitors of the epidermal growth factor receptor (EGFR) have shown promising activity in multiple solid tumors types, and preclinical data support a role for EGFR inhibition in pancreatic cancer. A recent phase III study by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) demonstrated a significant survival benefit with the addition of the EGFR tyrosine kinase inhibitor, erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer, becoming the first phase III study to demonstrate a survival benefit of combination therapy as well as targeted therapy in this disease. This article reviews the evidence supporting EGFR inhibition and the use of erlotinib in advanced pancreatic cancer as well as future implications of targeted therapy in this challenging malignancy

Spectroscopic signatures of tetralayer graphene polytypes

Tetralayer graphene has recently become a new addition to the family of few-layer graphene with versatile electronic properties. This material can be realised in three distinctive stacking configurations, for which we determine spectroscopic signatures in angle-resolved photoemission spectroscopy (ARPES), dynamical optical conductivity, and Raman spectra of inter-band excitations. The reported library of spectral features of tetralayer graphenes can be used for the non-invasive identification of the stacking order realised in a particular film.Comment: Pages 11, figures

Probing the DNA kink structure induced by the hyperthermophilic chromosomal protein Sac7d

Sac7d, a small, abundant, sequence-general DNA-binding protein from the hyperthermophilic archaeon Sulfolobus acidocaldarius, causes a single-step sharp kink in DNA (∼60°) via the intercalation of both Val26 and Met29. These two amino acids were systematically changed in size to probe their effects on DNA kinking. Eight crystal structures of five Sac7d mutant–DNA complexes have been analyzed. The DNA-binding pattern of the V26A and M29A single mutants is similar to that of the wild-type, whereas the V26A/M29A protein binds DNA without side chain intercalation, resulting in a smaller overall bending (∼50°). The M29F mutant inserts the Phe29 side chain orthogonally to the C2pG3 step without stacking with base pairs, inducing a sharp kink (∼80°). In the V26F/M29F-GCGATCGC complex, Phe26 intercalates deeply into DNA bases by stacking with the G3 base, whereas Phe29 is stacked on the G15 deoxyribose, in a way similar to those used by the TATA box-binding proteins. All mutants have reduced DNA-stabilizing ability, as indicated by their lower T(m) values. The DNA kink patterns caused by different combinations of hydrophobic side chains may be relevant in understanding the manner by which other minor groove-binding proteins interact with DNA

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

Lessons learnedThe addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.BackgroundThis randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.MethodsPatients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).ResultsOne hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen.ConclusionAddition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup

Kaon differential flow in relativistic heavy-ion collisions

Using a relativistic transport model, we study the azimuthal momentum asymmetry of kaons with fixed transverse momentum, i.e., the differential flow, in heavy-ion collisions at beam momentum of 6 GeV/c per nucleon, available from the Alternating Gradient Synchrotron (AGS) at the Brookhaven National Laboratory (BNL). We find that in the absence of kaon potential the kaon differential flow is positive and increases with transverse momentum as that of nucleons. The repulsive kaon potential as predicted by theoretical models, however, reduces the kaon differetnial flow, changing it to negative for kaons with low momenta. Cancellation between the negative differential flow at low mementa and the positive one at high momenta is then responsible for the experimentally observed nearly vanishing in-plane transverse flow of kaons in heavy ion experiments.Comment: Phys. Rev. C in pres

Outcome Evaluation of a Short-Term Hospitalization and Community Support Program for People Who Abuse Ketamine

Ketamine is a popular recreational drug among young people in Hong Kong. Long-term abuse of ketamine can lead to acute urological and medical issues, which often require immediate care at emergency rooms. Many patients require short-term hospitalization for medical management. This opens a brief time window, within which mental health professionals could engage young people who abuses ketamine in psychosocial, functional, and lifestyle interventions. The Crisis Accommodation Program (CAP) is a short-term hospitalization and community support program that addresses the health care needs of young people who abuse ketamine. During short-term hospitalization, the patient participates in a range of cognitive and psychosocial assessments, motivational interviewing, emotions management, and lifestyle re-design interventions. Upon discharge, social work professionals of non-government agencies continue to work with the patients on their action plans in the community. This evaluation study uses a quasi-experimental non-equivalent group design, in which the outcomes of the treatment group (n = 84) are compared with a comparison group (n = 34) who have a history of ketamine abuse but who have not joined the treatment program. The results confirm that the treatment group showed significant increases in motivation for treatment, reduction in drug use, improvement in cognitive screening tests, healthy lifestyle scores, and self-efficacy in avoidance of drugs over 13 weeks. When compared with the comparison group, the treatment group had significant decreases in anxiety and treatment needs and had moved from pre-contemplation to the contemplation or preparation stage. However, there were no significant changes in outcome measures covering lifestyle or self-efficacy in drug avoidance. Overall, the CAP is effective in reducing drug use, anxiety, and helping patients to move from pre-contemplation to the contemplation or preparation stage of change. The study results suggest that health care professionals can successfully engage young people who abuse ketamine to participate in a package of psychosocial interventions, motivational interviewing, and lifestyle re-design during their hospital stay for management of urological problems. The CAP also highlights the importance of collaboration between hospitals and community social services in the management of addiction

Excitation function of nucleon and pion elliptic flow in relativistic heavy-ion collisions

Within a relativistic transport (ART) model for heavy-ion collisions, we show that the recently observed characteristic change from out-of-plane to in-plane elliptic flow of protons in mid-central Au+Au collisions as the incident energy increases is consistent with the calculated results using a stiff nuclear equation of state (K=380 MeV). We have also studied the elliptic flow of pions and the transverse momentum dependence of both the nucleon and pion elliptic flow in order to gain further insight about the collision dynamics.Comment: 8 pages, 2 figure

The cyclic GMP modulators YC-1 and zaprinast reduce vessel remodeling through anti-proliferative and pro-apoptotic effects

Guanosine-specific cyclic nucleotide signaling is suggested to serve protective actions in the vasculature; however, the influence of selective pharmacologic modulation of cyclic guanosine monophosphate (GMP)-synthesizing soluble guanylate cyclase (sGC) or cyclic GMP-degrading phosphodiesterase (PDE) on vessel remodeling has not been thoroughly examined. In this study, rat carotid artery balloon injury was performed and the growth-modulating effects of the sGC stimulator YC-1 or the cGMP-dependent PDE-V inhibitor zaprinast were examined. YC-1 or zaprinast elevated vessel cyclic GMP content, reduced medial wall and neointimal cell proliferation, stimulated medial and neointimal cellular apoptosis, and markedly attenuated neointimal remodeling in comparable fashion. Interestingly, sGC inhibition by ODQ failed to noticeably alter neointimal growth, and concomitant zaprinast with YC-1 did not modify any parameter compared to individual treatments. These results provide novel in vivo evidence that YC-1 and zaprinast inhibit injury-induced vascular remodeling through anti-mitogenic and pro-apoptotic actions and may offer promising therapeutic approaches against vasoproliferative disorders. Originally published J Cardiovasc Pharmacol Ther, Vol. 14, No. 2, June 200

The CEEDER database of evidence reviews: An open-access evidence service for researchers and decision-makers

Evidence-informed decision-making aims to deliver effective actions informed by the best available evidence. Given the large quantity of primary literature, and time constraints faced by policy-makers and practitioners, well-conducted evidence reviews can provide a valuable resource to support decision-making. However, previous research suggests that some evidence reviews may not be sufficiently reliable to inform decisions in the environmental sector due to low standards of conduct and reporting. While some evidence reviews are of high reliability, there is currently no way for policy-makers and practitioners to quickly and easily find them among the many lower reliability ones. Alongside this lack of transparency, there is little incentive or support for review authors, editors and peer-reviewers to improve reliability. To address these issues, we introduce a new online, freely available and first-of-its-kind evidence service: the Collaboration for Environmental Evidence Database of Evidence Reviews (CEEDER: www.environmentalevidence.org/ceeder). CEEDER aims to transform communication of evidence review reliability to researchers, policy-makers and practitioners through independent assessment of key aspects of the conduct, reporting and data limitations of available evidence reviews claiming to assess environmental impacts or the effectiveness of interventions relevant to policy and practice. At the same time, CEEDER will provide support to improve the standards of future evidence reviews and support evidence translation and knowledge mobilisation to help inform environmental decision-making

Inducible and Reversible Clock Gene Expression in Brain Using the tTA System for the Study of Circadian Behavior

The mechanism of circadian oscillations in mammals is cell autonomous and is generated by a set of genes that form a transcriptional autoregulatory feedback loop. While these “clock genes” are well conserved among animals, their specific functions remain to be fully understood and their roles in central versus peripheral circadian oscillators remain to be defined. We utilized the in vivo inducible tetracycline-controlled transactivator (tTA) system to regulate Clock gene expression conditionally in a tissue-specific and temporally controlled manner. Through the use of Secretogranin II to drive tTA expression, suprachiasmatic nucleus– and brain-directed expression of a tetO::Clock(Δ19) dominant-negative transgene lengthened the period of circadian locomotor rhythms in mice, whereas overexpression of a tetO::Clock(wt) wild-type transgene shortened the period. Low doses (10 μg/ml) of doxycycline (Dox) in the drinking water efficiently inactivated the tTA protein to silence the tetO transgenes and caused the circadian periodicity to return to a wild-type state. Importantly, low, but not high, doses of Dox were completely reversible and led to a rapid reactivation of the tetO transgenes. The rapid time course of tTA-regulated transgene expression demonstrates that the CLOCK protein is an excellent indicator for the kinetics of Dox-dependent induction/repression in the brain. Interestingly, the daily readout of circadian period in this system provides a real-time readout of the tTA transactivation state in vivo. In summary, the tTA system can manipulate circadian clock gene expression in a tissue-specific, conditional, and reversible manner in the central nervous system. The specific methods developed here should have general applicability for the study of brain and behavior in the mouse