Pathway databases and tools for their exploitation: benefits, current limitations and challenges

In past years, comprehensive representations of cell signalling pathways have been developed by manual curation from literature, which requires huge effort and would benefit from information stored in databases and from automatic retrieval and integration methods. Once a reconstruction of the network of interactions is achieved, analysis of its structural features and its dynamic behaviour can take place. Mathematical modelling techniques are used to simulate the complex behaviour of cell signalling networks, which ultimately sheds light on the mechanisms leading to complex diseases or helps in the identification of drug targets. A variety of databases containing information on cell signalling pathways have been developed in conjunction with methodologies to access and analyse the data. In principle, the scenario is prepared to make the most of this information for the analysis of the dynamics of signalling pathways. However, are the knowledge repositories of signalling pathways ready to realize the systems biology promise? In this article we aim to initiate this discussion and to provide some insights on this issue.

Fluorescence-activated cell sorting and cloning of bona fide CD8+ CTL with reversible MHC-peptide and antibody Fab' conjugates.

The isolation of subsets of Ag-specific T cells for in vitro and in vivo studies by FACS is compromised by the fact that the soluble MHC-peptide complexes and Abs used for staining, especially when combined, induce unwanted T cell activation and eventually apoptosis. This is especially a problem for CD8+ CTL, which are susceptible to activation-dependent cell death. In this study, we show that reversible MHC-peptide complexes (tetramers) can be prepared by conjugating MHC-peptide monomers with desthiobiotin (DTB; also called dethiobiotin) and multimerization by reaction with fluorescent streptavidin. While in the cold these reagents are stable and allow good staining, they rapidly dissociate in monomers at elevated temperatures, especially in the presence of free biotin. FACS cloning of Melan-A (MART-1)-specific CTL from a melanoma-infiltrated lymph node with reversible HLA-A2 Melan-A26-35 multimers yielded over two times more clones than when using the conventional biotin-containing multimers. CTL clones obtained by means of reversible multimers killed Melan-A-positive tumor cells more efficiently as compared with clones obtained with the stable multimers. Among the CTL obtained with the reversible multimers, but much less among those obtained with the stable multimers, a high proportion of clones exhibited high functional and physical avidity and died upon incubation with soluble MHC-peptide complexes. Finally, we show that Fab' of an anti-CD8 Ab can be converted in reversible DTB streptavidin conjugates the same way. These DTB reagents efficiently and reversibly stained murine and human CTL without affecting their viability.

Transcranial direct current stimulation for the treatment of focal hand dystonia.

The treatment of writer's cramp, a task-specific focal hand dystonia, needs new approaches. A deficiency of inhibition in the motor cortex might cause writer's cramp. Transcranial direct current stimulation modulates cortical excitability and may provide a therapeutic alternative. In this randomized, double-blind, sham-controlled study, we investigated the efficacy of cathodal stimulation of the contralateral motor cortex in 3 sessions in 1 week. Assessment over a 2-week period included clinical scales, subjective ratings, kinematic handwriting analysis, and neurophysiological evaluation. Twelve patients with unilateral dystonic writer's cramp were investigated; 6 received transcranial direct current and 6 sham stimulation. Cathodal transcranial direct current stimulation had no favorable effects on clinical scales and failed to restore normal handwriting kinematics and cortical inhibition. Subjective worsening remained unexplained, leading to premature study termination. Repeated sessions of cathodal transcranial direct current stimulation of the motor cortex yielded no favorable results supporting a therapeutic potential in writer's cramp.

Pharmacotherapeutic management of locally advanced prostate cancer: current status.

Locally advanced prostate cancer (LAPC) is a heterogeneous entity usually embracing T3-4 and/or pelvic lymph-node-positive disease in the absence of established metastases. Outcomes for LAPC with single therapies have traditionally been poor, leading to the investigation of adjuvant therapies. Prostate cancer is a hormonally sensitive tumour, which usually responds to pharmacological manipulation of the androgen receptor or its testosterone-related ligands. As such, androgen deprivation therapy (ADT) has become an important adjuvant strategy for the treatment of LAPC, particularly for patients managed primarily with radiotherapy. Such results have generally not been replicated in surgical patients. With increased use of ADT has come improved awareness of the numerous toxicities associated with long-term use of these agents, as well as the development of strategies for minimizing ADT exposure and actively managing adverse effects. Several trials are exploring agents to enhance radiation cell sensitivity as well as the application of adjuvant docetaxel, an agent with proven efficacy in the metastatic, castrate-resistant setting. The recent work showing activity of cabazitaxel, sipuleucel-T and abiraterone for castrate-resistant disease in the post-docetaxel setting will see these agents investigated in conjunction with definitive surgery and radiotherapy.

Classification of current anticancer immunotherapies.

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

Thromboangiitis obliterans: a rare cause of a reversible Raynaud's phenomenon.

A 25-year-old woman with progressive Raynaud's phenomenon and digital necrosis is presented. Systemic sclerosis and other connective tissue disorders as well as atherosclerosis and arterial emboli were excluded with appropriate laboratory examinations. Arteriography revealed multiple palmar and digital occlusions with corkscrew-shaped vessels. Based on these characteristic arteriographic and clinical findings, the diagnosis of thromboangiitis obliterans was finally retained. With intravenous perfusion of the prostacyclin analogue iloprost (2 ng/kg/min, 6 h daily during 21 days), a complete healing of Raynaud's phenomenon and of the digital necrosis was observed. There was no recurrence during the 1-year follow-up. This observation demonstrates that thromboangiitis obliterans is a potential reversible cause of severe Raynaud's phenomenon in young women even in the absence of lower limb involvement. Early recognition is important to avoid irreversible complications such as loss of digits.

Current Population Reports Series P-26, Federal-State cooperative program for population estimates, July 1974

T his report presents population estimates for July 1, 1972 and provisional estimates for July 1, 1973, for counties and metropolitan areas prepared under the auspices of the Federal State Cooperative Program for Local Population Estimates. The objective of this program. is the development and publication of State - prepared estimates of the population of counties using uniform procedures largely standardized for data input and methodology. The methods used have been mutually agreed upon by the individual States and the Bureau of the Census on the basis of a test of methods against the 1970 census. For a more detailed description of the program.

Current Population Reports Series P-26, Federal-State cooperative program for population estimates, September 1975

This report presents population estimates for July 1, 1973 and provisional estimates for July 1, for counties and metropolitan areas prepared under the auspices of the Federal State Cooperative Program for Local Population Estimates. The objective of this program. is the development and publication of State - prepared estimates of the population of counties using uniform procedures largely standardized for data input and methodology. The methods used have been mutually agreed upon by the individual States and the Bureau of the Census on the basis of a test of methods against the 1970 census. For a more detailed description of the program.

Frontshear and backshear instabilities of the mean longshore current

An analytical model based on Bowen and Holman [1989] is used to prove the existence of instabilities due to the presence of a second extremum of the background vorticity at the front side of the longshore current. The growth rate of the so-called frontshear waves depends primarily upon the frontshear but also upon the backshear and the maximum and the width of the current. Depending on the values of these parameters, either the frontshear or the backshear instabilities may dominate. Both types of waves have a cross-shore extension of the order of the width of the current, but the frontshear modes are localized closer to the coast than are the backshear modes. Moreover, under certain conditions both unstable waves have similar growth rates with close wave numbers and angular frequencies, leading to the possibility of having modulated shear waves in the alongshore direction. Numerical analysis performed on realistic current profiles confirm the behavior anticipated by the analytical model. The theory has been applied to a current profile fitted to data measured during the 1980 Nearshore Sediment Transport Studies experiment at Leadbetter Beach that has an extremum of background vorticity at the front side of the current. In this case and in agreement with field observations, the model predicts instability, whereas the theory based only on backshear instability fai led to do so.

Cytotoxic T-cell and NK-cell Lymphomas: Current Questions and Controversies.

The cytotoxic T-cell and natural killer (NK)-cell lymphomas and related disorders are important but relatively rare lymphoid neoplasms that frequently are a challenge for practicing pathologists. This selective review, based on a meeting of the International Lymphoma Study Group, briefly reviews T-cell and NK-cell development and addresses questions related to the importance of precise cell lineage (αβ-type T cell, γδ T cell, or NK cell), the implications of Epstein-Barr virus infection, the significance of anatomic location including nodal disease, and the question of further categorization of enteropathy-associated T-cell lymphomas. Finally, developments subsequent to the 2008 World Health Organization Classification, including the recognition of indolent NK-cell and T-cell disorders of the gastrointestinal tract are presented.

Disc degeneration: current surgical options.

Chronic low back pain attributed to lumbar disc degeneration poses a serious challenge to physicians. Surgery may be indicated in selected cases following failure of appropriate conservative treatment. For decades, the only surgical option has been spinal fusion, but its results have been inconsistent. Some prospective trials show superiority over usual conservative measures while others fail to demonstrate its advantages. In an effort to improve results of fusion and to decrease the incidence of adjacent segment degeneration, total disc replacement techniques have been introduced and studied extensively. Short-term results have shown superiority over some fusion techniques. Mid-term results however tend to show that this approach yields results equivalent to those of spinal fusion. Nucleus replacement has gained some popularity initially, but evidence on its efficacy is scarce. Dynamic stabilisation, a technique involving less rigid implants than in spinal fusion and performed without the need for bone grafting, represents another surgical option. Evidence again is lacking on its superiority over other surgical strategies and conservative measures. Insertion of interspinous devices posteriorly, aiming at redistributing loads and relieving pain, has been used as an adjunct to disc removal surgery for disc herniation. To date however, there is no clear evidence on their efficacy. Minimally invasive intradiscal thermocoagulation techniques have also been tried, but evidence of their effectiveness is questioned. Surgery using novel biological solutions may be the future of discogenic pain treatment. Collaboration between clinicians and basic scientists in this multidisciplinary field will undoubtedly shape the future of treating symptomatic disc degeneration.

Oculopalatal tremor: current concepts and new observations.

PURPOSE OF REVIEW: Oculopalatal tremor (OPT) is an acquired disorder resulting from the interruption of a specific brainstem circuitry, the dentato-rubro-olivary pathway or Guillain-Mollaret triangle. The recent literature on OPT and olivary hypertrophy was reviewed with specific interest regarding causes, diagnostic procedures, physiopathology and therapies. RECENT FINDINGS: OPT is associated with inferior olivary hypertrophy, and recent findings have provided a better understanding of its intimate mechanisms. A dual-mechanism model, combining an oscillator (inferior olive) and a modulator/amplifier (cerebellum), best explains the development of OPT. Electrotonic coupling and specific Ca channels contribute to oscillations of inferior olivary nucleus neurons in OPT. Improvement of visual symptoms can be achieved with oral gabapentin or memantine. SUMMARY: Both the neuronal circuitry and the physiopathology of OPT are now better understood. This opens up an era of specific therapy for this rare cause of disabling oscillopsia.

Is tumour size an underestimated feature in the current TNM system for malignancies of the pancreatic head?

BACKGROUND: As the long-term survival of pancreatic head malignancies remains dismal, efforts have been made for a better patient selection and a tailored treatment. Tumour size could also be used for patient stratification. METHODS: One hundred and fourteen patients underwent a pancreaticoduodenectomy for pancreatic adenocarcinoma, peri-ampullary and biliary cancer stratified according to: ≤20 mm, 21-34 mm, 35-45 mm and >45 mm tumour size. RESULTS: Patients with tumour sizes of ≤20 mm had a N1 rate of 41% and a R1/2 rate of 7%. The median survival was 3.4 years. N1 and R1/2 rates increased to 84% and 31% for tumour sizes of 21-34 mm (P = 0.0002 for N, P = 0.02 for R). The median survival decreased to 1.6 years (P = 0.0003). A further increase in tumour size of 35-45 mm revealed a further increase of N1 and R1/2 rates of 93% (P < 0.0001) and 33%, respectively. The median survival was 1.2 years (P = 0.004). Tumour sizes >45 mm were related to a further decreased median survival of 1.1 years (P = 0.2), whereas N1 and R1/2 rates were 87% and 20%, respectively. DISCUSSION: Tumour size is an important feature of pancreatic head malignancies. A tumour diameter of 20 mm seems to be the cut-off above which an increased rate of incomplete resections and metastatic lymph nodes must be encountered and the median survival is reduced.