Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy

Gemcitabine is a chemotherapeutic that is widely used for the treatment of a variety of haematological malignancies and has become the standard chemotherapy for the treatment of advanced pancreatic cancer. Combinational gemcitabine regimes (e.g. with doxorubicin) are being tested in clinical trials to treat a variety of cancers, including colon cancer. The limited success of these trials has prompted us to pursue a better understanding of gemcitabine's mechanism of cell killing, which could dramatically improve the therapeutic potential of this agent. For comparison, we included gamma irradiation that triggers robust cell cycle arrest and Cr(VI), which is a highly toxic chemical that induces a robust p53-dependent apoptotic response. Gemcitabine induced a potent p53-dependent apoptosis that correlated with the accumulation of pro-apoptotic proteins such as PUMA and Bax. This is accompanied by a drastic reduction in p2l and 14-3-3 sigma protein levels, thereby significantly sensitizing the cells to apoptosis. In vitro and in vivo studies demonstrated that gemcitabine required PUMA transcription to instigate an apoptotic programme. This was in contrast to Cr(VI)-induced apoptosis that required Bax and was independent of transcription. An examination of clinical colon and pancreatic cancer tissues shows higher p53, p21, 14-3-3 sigma and Bax expression compared with matched normal tissues, yet there is a near absence of PUMA protein. This may explain why gemcitabine shows only limited efficacy in the treatment of these cancers. Our results raise the possibility that targeting the Bax-dependent cell death pathway, rather than the PUMA pathway, could result in significantly improved patient outcome and prognosis for these cancers.Fundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BPD/84634/2012]; European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Canadian Institute of Health Researchinfo:eu-repo/semantics/publishedVersio

Serum CA 19-9 as a Marker of Resectability and Survival in Patients with Potentially Resectable Pancreatic Cancer Treated with Neoadjuvant Chemoradiation

Purpose The role of carbohydrate antigen (CA) 19-9 in the evaluation of patients with resectable pancreatic cancer treated with neoadjuvant therapy prior to planned surgical resection is unknown. We evaluated CA 19-9 as a marker of therapeutic response, completion of therapy, and survival in patients enrolled on two recently reported clinical trials. Patients and Methods We analyzed patients with radiographically resectable adenocarcinoma of the head/uncinate process treated on two phase II trials of neoadjuvant chemoradiation. Patients without evidence of disease progression following chemoradiation underwent pancreaticoduodenectomy (PD). CA 19-9 was evaluated in patients with a normal bilirubin level. Results We enrolled 174 patients, and 119 (68%) completed all therapy including PD. Pretreatment CA 19-9 <37 U/ml had a positive predictive value (PPV) for completing PD of 86% but a negative predictive value (NPV) of 33%. Among patients without evidence of disease at last follow-up, the highest pretreatment CA 19-9 was 1,125 U/ml. Restaging CA 19-9 <61 U/ml had a PPV of 93% and a NPV of 28% for completing PD among resectable patients. The area under the receiver-operating characteristics curve of pretreatment and restaging CA 19-9 levels for completing PD was 0.59 and 0.74, respectively. We identified no association between change in CA 19-9 and histopathologic response (P = 0.74). Conclusions Although the PPV of CA 19-9 for completing neoadjuvant therapy and undergoing PD was high, its clinical utility was compromised by a low NPV. Decision-making for patients with resectable PC should remain based on clinical assessment and radiographic staging.PublishedN/

Bioavailable Trace Metals in Neurological Diseases

Medical treatment in Wilson’s disease includes chelators (d-penicillamine and trientine) or zinc salts that have to be maintain all the lifelong. This pharmacological treatment is categorised into two phases; the first being a de-coppering phase and the second a maintenance one. The best therapeutic approach remains controversial, as only a few non-controlled trials have compared these treatments. During the initial phase, progressive increase of chelators’ doses adjusted to exchangeable copper and urinary copper might help to avoid neurological deterioration. Liver transplantation is indicated in acute fulminant liver failure and decompensated cirrhosis; in cases of neurologic deterioration, it must be individually discussed. During the maintenance phase, the most important challenge is to obtain a good adherence to lifelong medical therapy. Neurodegenerative diseases that lead to a mislocalisation of iron can be caused by a culmination of localised overload (pro-oxidant siderosis) and localised deficiency (metabolic distress). A new therapeutic concept with conservative iron chelation rescues iron-overloaded neurons by scavenging labile iron and, by delivering this chelated metal to endogenous apo-transferrin, allows iron redistribution to avoid systemic loss of iron

New Insights into Alzheimer's Disease Progression: A Combined TMS and Structural MRI Study

BACKGROUND: Combination of structural and functional data of the human brain can provide detailed information of neurodegenerative diseases and the influence of the disease on various local cortical areas. METHODOLOGY AND PRINCIPAL FINDINGS: To examine the relationship between structure and function of the brain the cortical thickness based on structural magnetic resonance images and motor cortex excitability assessed with transcranial magnetic stimulation were correlated in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients as well as in age-matched healthy controls. Motor cortex excitability correlated negatively with cortical thickness on the sensorimotor cortex, the precuneus and the cuneus but the strength of the correlation varied between the study groups. On the sensorimotor cortex the correlation was significant only in MCI subjects. On the precuneus and cuneus the correlation was significant both in AD and MCI subjects. In healthy controls the motor cortex excitability did not correlate with the cortical thickness. CONCLUSIONS: In healthy subjects the motor cortex excitability is not dependent on the cortical thickness, whereas in neurodegenerative diseases the cortical thinning is related to weaker cortical excitability, especially on the precuneus and cuneus. However, in AD subjects there seems to be a protective mechanism of hyperexcitability on the sensorimotor cortex counteracting the prominent loss of cortical volume since the motor cortex excitability did not correlate with the cortical thickness. Such protective mechanism was not found on the precuneus or cuneus nor in the MCI subjects. Therefore, our results indicate that the progression of the disease proceeds with different dynamics in the structure and function of neuronal circuits from normal conditions via MCI to AD

Device Evolution and New Concepts to Preserve Renal Artery Patency in Challenging Infrarenal Aortic Necks

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Transducer-based evaluation of tremor

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer‐based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet‐based measures, vocal acoustic analysis, and several other transducer‐based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet‐based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer‐based measures requires careful attention to their limitations and validity in a particular clinical or research setting