Oxygen and glucose distribution after intracorneal lens implantation.

PURPOSE: Insertion of an implant in the cornea to achieve corneal multifocality has been suggested as a solution for presbyopia. However, unresolved issues related to nutrient transport need to be resolved. Our aim was to find the best lens position and influence lens transport properties in order to optimize nutrient supply to corneal cells. METHOD: An axisymmetric corneal model was built to simulate the nutrient transport in the cornea. Oxygen and glucose concentrations were calculated for normal cornea and intracorneal lens wearing conditions. The simulation considers the different tissue layers (epithelium, stroma, and endothelium) as well as layer and solute concentration dependent consumption. RESULTS: The minimum oxygen tension in the cornea was found to be higher when the lens was placed at 3/4 of the corneal thickness. Moreover, in this position, the influence of the inlay diffusivity was smaller than at more anterior or posterior placements. The diffusivity of the inlay affects the way nutrients will be transported through the cornea. The threshold where glucose may diffuse through or around the implant was found to be 1/100th of the stromal diffusivity. CONCLUSIONS: Computational methods are especially attractive to study nutrient transport in the cornea due to the difficulties associated with in vivo or in vitro measurements. The exact parameters that dictate the corneal metabolism are not known. However, the combined analysis of oxygen and glucose distribution is valuable in order to predict the complex physiological changes that arise under intracorneal lens implantation.     

Combining targeted therapies

Therapeutics in oncology are rapidly changing, with the advent of the so-called “targeted drugs.” A clear example is trastuzumab, an anti-HER2 monoclonal antibody, and its role in the treatment of breast cancer. Trastuzumab was followed by other monoclonal antibodies like cetuximab (anti-EGFR) and bevacizumab (anti-VEFG) and by tyrosine kinase inhibitors such as imatinib, gefitinib (anti-EGFR) and others. The complex biology of the cancer cell leads us to search combination strategies to act simultaneously in different points of signals transduction pathways to enhance the anticancer effect. Here we review various clinical trials and also experimental data exploring these new drugs in combination. Combination with chemotherapy is beyond the scope of this review. For this review, we have selected the following agents: cetuximab, trastuzumab, bevacizumab, panitumumab, imatinib, erlotinib, gefitinib, sorafenib, sunitinib, and lapatinib.     

STI-571 (Gleevec) potentiates the effect of cisplatin in inhibiting the proliferation of head and neck squamous cell carcinoma in vitro

OBJECTIVE: The objective of this study was to determine whether STI-571 (Gleevec; imatinib mesylate) could sensitize established head and neck squamous cell carcinoma (HNSCC) cell lines to the effects of cisplatin. METHODS: Western blot analysis and immunofluorescence were used to examine the expression of the tyrosine kinases that are known targets of Gleevec, including c-kit, c-Abl, and platelet-derived growth factor receptor, on the cell lines, and immunohistochemistry was performed to determine the expression of these kinases in human HNSCC tissue. Once these targets were confirmed, clonogenic cell survival assays were performed to determine the effect STI-571 had on growth and proliferation when used in combination with cisplatin compared with STI-571 alone or cisplatin alone. Cells were incubated with a range of doses of STI-571 24 hours before the addition of cisplatin. Flow cytometry analysis was performed to determine cell-cycle distribution and to measure apoptosis caused by the various treatments. An annexin V assay was also used to further measure apoptosis. RESULTS: Our results indicate that STI-571 potentiates the effect of cisplatin and leads to a significant decrease in cell proliferation and colony formation compared with cisplatin alone in a dose-dependent fashion. Surprisingly, there was a slight decrease in the level of apoptosis when Gleevec was used in combination with cisplatin compared with cisplatin alone. Gleevec alone resulted in a slight increase in G1 phase of the cell cycle, whereas cisplatin alone resulted in a G2 arrest. The addition of Gleevec to cisplatin resulted in an enhanced S/G2 phase accumulation. Although we did not demonstrate an increase in cisplatin-induced cell death, we postulate that the increased S/G2 arrest resulting from the DNA damage in the presence of Gleevec results in decreased proliferation of HNSCC, resulting in a net decrease in colony formation. CONCLUSIONS: The small molecule inhibitor Gleevec, which targets specific tyrosine kinases that are expressed in HNSCC, can significantly potentiate the antiproliferative effects of cisplatin. Because Gleevec alone has minimal side effects, treatment with the combination treatment of cisplatin and Gleevec may result in increased efficacy of cisplatin in treating this cancer. Additional studies are warranted, keeping in mind that drug combinations may result in unexpected toxicities that are not frequently seen with either drug alone.     

Antigen Presentation After Stroke

Stroke induces a local inflammatory reaction and a plethora of innate immune responses in the brain where antigen-presenting cells become prominent. However, to date, it is still unclear whether antigen presentation is relevant to the neuropathological and functional outcome of stroke. Stroke does not trigger overt autoimmune reactions, but neural antigens have been found in lymphoid tissues of patient with stroke and it is unknown whether they promote tolerance or immune reactions that under certain conditions might contribute to the functional worsening observed in some patients. Autoantibodies to neural molecules have also been reported in patients with stroke, but the subclass of antibodies is important for their function, and the contribution of such findings to stroke outcome is not yet clear. Notably, stroke induces immunodepression highlighted by a transient lymphopenia, lymphoid organ atrophy, and monocyte deactivation. While these effects might reduce the chances of autoreactivity, they increase the risk of infection in patients with stroke and most frequently in those with severe stroke. Therefore any potential brain protective effect of stroke-induced immunodepression by attenuating or preventing lymphocyte-mediated brain damage is confounded by stroke severity and an increased incidence of infections. Systemic inflammation due to a number of comorbidities that are frequent in patients with stroke is also associated to a poor outcome. Herein, we review some relevant findings regarding the identification of neural antigens in stroke and discuss their potential contribution to the functional outcome of stroke.     

Olfactory bulb proteome dynamics during the progression of sporadic Alzheimer's disease: identification of common and distinct olfactory targets across Alzheimer-related co-pathologies

Olfactory dysfunction is present in up to 90% of Alzheimer''s disease (AD) patients. Although deposition of hyperphosphorylated tau and β-amyloid substrates are present in olfactory areas, the molecular mechanisms associated with decreased smell function are not completely understood. We have applied mass spectrometry-based quantitative proteomics to probe additional molecular disturbances in postmortem olfactory bulbs (OB) dissected from AD cases respect to neurologically intact controls (n=20, mean age 82.1 years). Relative proteome abundance measurements have revealed protein interaction networks progressively disturbed across AD stages suggesting an early imbalance in splicing factors, subsequent interrupted cycling of neurotransmitters, alteration in toxic and protective mechanisms of β-amyloid, and finally, a mitochondrial dysfunction together with disturbance in neuron-neuron adhesion. We also present novel molecular findings in the OB in an autopsy cohort composed by Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), mixed dementia, and progressive supranuclear palsy (PSP) cases (n = 41, mean age 79.7 years). Olfactory mediators deregulated during the progression of AD such as Visinin-like protein 1, RUFY3 protein, and Copine 6 were also differentially modulated in the OB in LBD, FTLD, and mixed dementia. Only Dipeptidyl aminopeptidase-like protein 6 showed a specific down-regulation in AD. However, no differences were observed in the olfactory expression of this protein panel in PSP subjects. This study demonstrates an olfactory progressive proteome modulation in AD, unveiling cross-disease similarities and differences especially for specific proteins involved in dendritic and axonic distributions that occur in the OB during the neurodegenerative process.     

Susceptibility Vessel Sign in Deep Perforating Arteries in Patients with Recent Small Subcortical Infarcts

ObjectivesRecent small subcortical infarcts (RSSI) are considered an acute manifestation of cerebral small vessel disease. Paramagnetic signals in perforating arteries supplying RSSI may be detected on T2*-relaxation derived sequences on MRI and is defined as susceptibility vessel sign (SVS). We aimed to study the prevalence of SVS in patients with RSSI, and explore whether its identification is related to cerebral small vessel disease markers.Materials and MethodsWe selected patients with RSSI identified on MRI during admission from a single-center stroke registry. The main demographic and clinical features, including vascular risk factors, were collected. Radiological features of RSSI and cerebral small vessel disease [white matter hyperintensities in deep and periventricular regions, enlarged perivascular spaces, lacunae, microbleeds, and brain atrophy] were described using validated qualitative scores. The presence of SVS was assessed on T2*gradient-echo or other susceptibility-weighted imaging. We compared the clinical and radiological features of patients with or without SVS in uni- and multivariate models.ResultsOut of 210 patients with an RSSI on an MRI, 35 (17%) showed SVS. The proportion of SVS+ patients was similar in different susceptibility imaging modalities (p=.64). Risk factor profiles and clinical course were similar in SVS+ and SVS- patients. SVS+ patients had a higher grade of deep white matter hyperintensities and brain atrophy, more lacunae (p=.001, p=.034, p=.022, respectively), and a similar degree of the rest of radiological variables, compared to SVS- patients. In the multivariate analysis, the grade of deep white matter hyperintensities was the only independent factor associated with SVS [OR 3.1 (95% CI, 1.5-6.4)].ConclusionsSVS in patients with RSSI is uncommon and related to a higher grade of deep white matter hyperintensities. Pathophysiological mechanisms underlying the deposition of hemosiderin in the path of occluded perforating arteries are uncertain and might include endothelial dysfunction or embolic mechanisms.     

Emerging issues in acute ischemic stroke

In this update we review studies on a wide range of topics, from diagnostic aspects of acute stroke to the clinical implications of the complex interaction between the brain and the immune system. Recent randomized trials and observational studies have reinforced the effectiveness of intravenous thrombolysis with t-PA in patients that qualify for this treatment, including patients presenting with mild symptoms or on subtherapeutic oral anticoagulation. Despite all the negative studies on the endovascular treatment of acute stroke, the utility of newer mechanical thrombectomy devices in patients with stroke and large vessel occlusion is being assessed in ongoing clinical trials. In addition to the various revascularization therapies that have a limited time window, treatments aimed at protecting the neurovascular unit may be used in more patients if their efficacy is confirmed in humans, and experimental studies suggest that the modulation of specific aspects of the immune system may increase the likelihood of successful recovery after cerebral ischemia.     

Association between colorectal cancer susceptibility loci and survival time after diagnosis with colorectal cancer

Genome-wide association studies have identified 16 germline single-nucleotide polymorphisms (SNPs) that are associated with colorectal cancer (CRC) incidence. We examined the relationship between these SNPs and survival of 2611 individuals with CRC, enrolled in 5 cohort studies. We used Cox regression analysis to associate SNPs with overall and CRC-specific survival times. The minor allele in rs4939827 (SMAD7) was associated with reduced overall survival (hazard ratio, 1.16; 95% confidence interval, 1.06-1.27; P = .002) and disease-specific survival (hazard ratio, 1.17; 95% confidence interval, 1.05-1.30; P = .005). Other SNPs were not associated significantly with survival. Common germline variations might be prognostic factors for patients with CRC. A variant in SMAD7 could affect progression of CRC.     

High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma

Using high‐resolution genomic microarray analysis, a distinct genomic profile was defined in 114 samples from patients with splenic marginal zone lymphoma (SMZL). Deletion or uniparental disomy of chromosome 7q were detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%) mature B‐cell lymphomas (P < 0·00001). The presence of unmutated IGHV, genomic complexity, 17p13‐TP53 deletion and 8q‐MYC gain, but not 7q deletion, correlated with shorter overall survival of SMZL patients. Mapping studies narrowed down a commonly deleted region of 2·7 Mb in 7q32.1‐q32.2 spanning a region between the SND1 and COPG2 genes. High‐throughput sequencing analysis of the 7q32‐deleted segment did not identify biallelic deletions/insertions or clear pathogenic gene mutations, but detected six nucleotide changes in IRF5 (n = 2), TMEM209 (n = 2), CALU (n = 1) and ZC3HC1 (n = 1) not found in healthy individuals. Comparative expression analysis found a fourfold down‐regulation of IRF5 gene in lymphomas with 7q32 deletion versus non‐deleted tumours (P = 0·032). Ectopic expression of IRF5 in marginal‐zone lymphoma cells decreased proliferation and increased apoptosis in vitro, and impaired lymphoma development in vivo. These results show that cryptic deletions, insertions and/or point mutations inactivating genes within 7q32 are not common in SMZL, and suggest that IRF5 may be a haploinsufficient tumour suppressor in this lymphoma entity.