Oncolytic virotherapy for pancreatic ductal adenocarcinoma: A glimmer of hope after years of disappointment?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and highly lethal malignancies. Existing therapeutic interventions have so far been unsuccessful in improving prognosis, and survival remains very poor. Oncolytic virotherapy represents a promising, yet not fully explored, alternative strategy for the treatment of PDAC. Oncolytic viruses (OVs) infect, replicate within and lyse tumor cells specifically and stimulate antitumor immune responses. Multiple challenges have hampered the efficacy of oncolytic virotherapy for PDAC, the most significant being the desmoplastic and immunosuppressive pancreatic tumor microenvironment (TME). The TME limits the access of therapeutic drugs and the infiltration of effector T cells and natural killer (NK) cells into the tumor mass. Additionally, cancer cells promote the secretion of immunosuppressive factors and develop mechanisms to evade the host immune system. Because of their oncolytic and immune-stimulating properties, OVs are the ideal candidates for counteracting the pancreatic immunosuppressive TME and for designing combination therapies that can be clinically exploited in clinical trials that seek to improve the prognosis of PDAC.     

Organoid model: A new hope for pancreatic cancer treatment?

Pancreatic cancer is a rapidly progressing disease with a poor prognosis. We still have many questions about the pathogenesis, early diagnosis and precise treatment of this disease. Organoids, a rapidly emerging technology, can simulate the characteristics of pancreatic tumors. Using the organoid model of pancreatic cancer, we can study and explore the characteristics of pancreatic cancer, thereby effectively guiding clinical practice and improving patient prognosis. This review introduces the development of organoids, comparisons of organoids with other preclinical models and the status of organoids in basic research and clinical applications for pancreatic cancer.     

What hope for African primate diversity?

Available empirical evidence suggests that many primate populations are increasingly threatened by anthropogenic actions and we present evidence to indicate that Africa is a continent of particular concern in terms of global primate conservation. We review the causes and consequences of decline in primate diversity in Africa and argue that the major causes of decline fall into four interrelated categories: deforestation, bushmeat harvest, disease and climate change. We go on to evaluate the rarity and distribution of species to identify those species that may be particularly vulnerable to threats and examine whether these species share any characteristic traits. Two factors are identified that suggest that our current evaluation of extinction risk may be overly optimistic; evidence suggests that the value of existing forest fragments may have been credited with greater conservation value in supporting primate populations than they actually have and it is clear that the extinction debt from historical deforestation has not being adequately considered. We use this evaluation to suggest what future actions will be advantageous to advance primate conservation in Africa and evaluate some very positive conservation gains that are currently occurring.     

Can mosquitoes be bitten? A new hope for anti-malarial drug design

The crystal structure of PfPK5, a cyclin-dependent kinase from Plasmodium falciparum, is the first CDK structure determined from a nonhuman source and represents a potential new target for anti-malarial drug development.     

Probabilistic sampling of protein conformations: New hope for brute force?

Protein structure prediction from sequence alone by "brute force" random methods is a computationally expensive problem. Estimates have suggested that it could take all the computers in the world longer than the age of the universe to compute the structure of a single 200-residue protein. Here we investigate the use of a faster version of our FOLDTRAJ probabilistic all-atom protein-structure-sampling algorithm. We have improved the method so that it is now over twenty times faster than originally reported, and capable of rapidly sampling conformational space without lattices. It uses geometrical constraints and a Leonard-Jones type potential for self-avoidance. We have also implemented a novel method to add secondary structure-prediction information to make protein-like amounts of secondary structure in sampled structures. In a set of 100,000 probabilistic conformers of 1VII, 1ENH, and 1PMC generated, the structures with smallest Calpha RMSD from native are 3.95, 5.12, and 5.95A, respectively. Expanding this test to a set of 17 distinct protein folds, we find that all-helical structures are "hit" by brute force more frequently than beta or mixed structures. For small helical proteins or very small non-helical ones, this approach should have a "hit" close enough to detect with a good scoring function in a pool of several million conformers. By fitting the distribution of RMSDs from the native state of each of the 17 sets of conformers to the extreme value distribution, we are able to estimate the size of conformational space for each. With a 0.5A RMSD cutoff, the number of conformers is roughly 2N where N is the number of residues in the protein. This is smaller than previous estimates, indicating an average of only two possible conformations per residue when sterics are accounted for. Our method reduces the effective number of conformations available at each residue by probabilistic bias, without requiring any particular discretization of residue conformational space, and is the fastest method of its kind. With computer speeds doubling every 18 months and parallel and distributed computing becoming more practical, the brute force approach to protein structure prediction may yet have some hope in the near future.     

A bill of health for biometrics?

Few industries have such a need to promote privacy, fight fraud and cut costs at so many different levels as the healthcare market. Yet despite readily available biometric solutions on offer to combat these issues, Btt reveals this potentially lucrative sector is not yet yielding returns.     

New hope for dedicated genetically engineered bioenergy feedstocks?

The unique regulatory requirements and costs of genetic engineering (GE) are likely to inhibit commercialization of dedicated bioenergy crops due to the relatively small current market. Two recent regulatory approvals for GE plants, however, may signal a shift in policy and an opening of a door to a streamlined federal regulatory pathway for commercialization for non‐food plants. The change, however, may shift regulatory battles from the federal to the state and local level, as each state has independent authority to regulate plants under respective noxious weed/plant protection statutes. This previously dormant state regulatory power could result in even more complex barriers to commercialization of GE bioenergy crops‐‐replacing the regulatory delays embedded in the federal system with regulatory chaos at the state and local level.     

Diabetic cardiomyopathy? An echocardiographic study of young diabetics.

An echocardiographic study was carried out on 23 young diabetics, 19 of whom had retinopathy. Their diastolic function was analysed by comparing the timing and pattern of mitral valve opening with the pattern of left ventricular wall movement. Only six patients had all their values within the normal range. Fourteen patients had abnormalities similar to those seen in patients with cardiomyopathy; the close time relation between mitral valve movement and wall movement was lost and mitral valve opening delayed in eight patients. Three other patients had considerable outward wall movement before mitral valve opening, which is characteristic of ischaemic heart disease. Although these studies provide no definite evidence of a cause, the abnormalities found may reflect a subclinical diabetic cardiomyopathy due to small-vessel disease.     

Irradiation-induced angiosarcoma and anti-angiogenic therapy: A therapeutic hope?

Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin. They can be sporadic or caused by therapeutic radiation, hence secondary breast angiosarcomas are an important subgroup of patients. Assessing the molecular biology of angiosarcomas and identify specific targets for treatment is challenging. There is currently great interest in the role of angiogenesis and of angiogenic factors associated with tumor pathogenesis and as targets for treatment of angiosarcomas. A primary cell line derived from a skin fragment of a irradiation-induced angiosarcoma patient was obtained and utilized to evaluate cell biomarkers CD31, CD34, HIF-1alpha and VEGFRs expression by immunocytochemistry and immunofluorescence, drugs cytotoxicity by cell counting and VEGF release by ELISA immunoassay. In addition to previous biomarkers, FVIII and VEGF were also evaluated on tumor specimens by immunohistochemistry to further confirm the diagnosis. We targeted the VEGF–VEGFR-2 axis of tumor angiogenesis with two different class of vascular targeted drugs; caprelsa, the VEGFR-2/EGFR/RET inhibitor and bevacizumab the anti-VEGF monoclonal antibody. We found the same biomarkers expression either in tumor specimens and in the cell line derived from tumor. In vitro experiments demonstrated that angiogenesis plays a pivotal role in the progression of this tumor as cells displayed high level of VEGFR-2, HIF-1 alpha strongly accumulated into the nucleus and the pro-angiogenic factor VEGF was released by cells in culture medium. The evaluation of caprelsa and bevacizumab cytotoxicity demonstrated that both drugs were effective in inhibiting tumor proliferation. Due to these results, we started to treat the patient with pazopanib, which was the unique tyrosine kinase inhibitor available in Italy through a compassionate supply program, obtaining a long lasting partial response. Our data suggest that the study of the primary cell line could help physicians in choosing a therapeutic approach for patient that almost in vitro shows chances of success and that the anti-angiogenetic agents are a reliable therapeutic opportunity for angiosarcomas patients.     

A silver bullet for the treatment of depression?

The search for a rapid-acting antidepressant has been a subject of intense research interest for several decades. The article by Lucas and colleagues in this issue of Neuron provides compelling evidence from preclinical animal models that drugs acting at the serotonin 5-HT(4) receptor could finally achieve this goal. However, caution is warranted, as results from animal studies are not always predictive of therapeutic actions in humans.     

Treatments for spinal cord injury: is there hope in neurosteroids?

In this review, we describe the current therapeutic strategies to find a cure for paralysis. We use the example of DHEA, a neurosteroid normally produced in the developing neural tube, to raise the hypothesis that such a class of molecules, capable of modulating proliferation of committed neural precursors, could serve as an environmental cue in the adult injured spinal cord to promote re-population of CNS lesion with endogenous dormant precursor cells. Such mechanism may be a part of the natural response to heal the injured CNS and promote recovery of function, suggesting that neurosteroid-treatment could be a promising and novel therapeutic avenue for SCI. We will review pertinent biological activities of DHEA supporting this hypothesis, demonstrate that such activities, dependent on an intact sonic-hedgehog pathway, are responsible for the motor and bladder functional recovery observed after DHEA-treatment in the adult injured spinal cord. We will also raise the current limitations to further development of DHEA- or other neurosteroid-treatments as drug candidates, including the urgent need to further document DHEA long-term safety in CNS indications.     

A new predictor for the onset of atrial fibrillation?

In this issue of the Netherlands Heart Journal, the results of a substudy of the PREVEND trial are published.1 This prospective registry of presumably healthy citizens of Groningen aims to establish the association between microalbuminuria and the emergence of renal and cardiovascular diseases.2 This general population based long-term study extends the series of previous large-scale epidemiological trials conducted in the Netherlands. We recall among them the 1970 Vlagtwedde study for epidemiological cardiology and ischaemic heart disease, the 1982 Zutphen study of diet and cardiovascular diseases, the 1997 Maastricht study of circulatory arrest and sudden death, the 1998 Amsterdam study of out-of-hospital cardiac arrest and the 1999 Rotterdam study of prolonged QT interval and mortality.     

A role for skin in Ca metabolism of frogs?

• 1.1. In the leopard frog, Rana pipiens, in vivo Ca loss occurs in similar amounts across the skin and the urine. No change was detected in Ca loss when frogs were injected with either calcitonin or parathyroid hormone. Large doses of 1,25-(OH)₂vitamin D₃ increased urinary Ca loss.
• 2.2. ⁴⁵Ca accumulation across the skin in vivo each day is equivalent to 0.04% of total body Ca or 14% of the total Ca in the extracellular fluids. This accumulation was enhanced by prior adaptation of the frogs to a low Ca pond water.
• 3.3. Unidirectional influx (from 0.2 mM Ca on pond side) was remarkably similar in vitro: 0.56 and in vivo: 0.65 nmol cm⁻² h⁻¹. Based on in vitro measurements, an active transport process does not appear to be involved in this transcutaneous Ca movement.
• 4.4. Substantial deposits of Ca equivalent to five times the total in other “soft” tissues and eleven times that in the total extracellular fluids are found in R. pipiens skin.
• 5.5. Although cutaneous Ca does “turnover” slowly as shown by exchange with external ⁴⁵Ca. the skin Ca concentration does not change with the environmental Ca concentration.
• 6.6. Possible role(s) of cutaneous Ca in frogs' overall Ca metabolism are discussed.