Early- and late-onset pancreatic adenocarcinoma: A population-based comparative study

BackgroundPancreatic cancer is projected to become the second leading cause of cancer related death in the US. We aim to investigate the demographics, clinical outcomes and survival outcomes of patients diagnosed with early-onset (<40 years) and late-onset (>40 years) pancreatic adenocarcinoma (PAC).MethodsData on PAC between 1975 and 2016 were extracted from the Surveillance, Epidemiology, and End Results Registry.ResultsWithin the study period, 136,100 patients were identified which included 1181 patients with early-onset PAC and 134,919 patients with late-onset PAC. Both cohorts tend to present with distant metastasis (70.3% vs 57.9%). Both groups also showed an exponential rise in incidence (early-onset 3.69% annual change vs late-onset 6.25% annual change). When stratified by anatomical location, there was a trend of increasing cancer in the head of the pancreas for patients <40 years (3.63% annual change). While late PAC showed increasing cancer in all anatomical locations, the largest increase was observed in the tail of the pancreas (8.62% annual change). Overall, there was a mild difference in survival for early- and late-onset PAC (7 months vs 6 months, respectively, log rank p = 0.004). Both age groups showed the worse prognosis when cancer occurred in the tail of the pancreas (6 months vs 4 months, respectively). On cox proportion analysis, patients with late-onset PAC had twice the risk of mortality compared to early-onset PAC (HR 2.06, CI: 1.788–2.370, P = 0.001).ConclusionsOur study showed that both early- and late-onset PAC are increasing and while prognosis remains poor. Tumor anatomy showed a growing incidence of early-onset PAC in the head of the pancreas while late-onset PAC showed a rising incidence in the body and tail of the pancreas.     

When the Blood Pressure Misleads You: A Diagnostic Conundrum in an Unusual Case of Coarctation

A 4-month-old previously healthy baby was found to be in congestive heart failure with LV dysfunction and a right aortic arch with severe coarctation, undetectable by blood pressure measurements. A cardiac CT and central blood pressure led to the diagnosis of a unique anatomic variant of aortic coarctation. Once diagnosed the patient underwent surgery with an uncomplicated recovery.     

Human cytomegalovirus-specific immunity following haemopoietic stem cell transplantation

The herpesvirus Human Cytomegalovirus (HCMV) is an important opportunistic infection in recipients of allogeneic haemopoietic stem cell transplants, in whom HCMV-specific CD8+ and CD4+ T-cell responses are impaired. The nature of the HCMV-specific T-cell response in healthy virus carriers has been characterised in detail. High frequencies of circulating CD8+ T-cells that recognise defined viral peptides are maintained for years, and include individual CD8+ clones that have undergone extensive clonal expansion and phenotypic diversification in vivo. Following stem cell transplantation, the kinetics of HCMV-specific CD8+ T-cell reconstitution in the recipient are related to the presence or absence of antigen-experienced CD8+ T-cells transferred via the allograft, and to the presence of the virus in the recipient. We discuss recent progress in our understanding of HCMV-specific immunity in healthy virus carriers and in recipients after alloSCT.     

Carotid intima-media thickness in children with Kawasaki disease

Kawasaki disease (KD) is an acute medium vessel vasculitis seen in children. The most significant long-term complication is related to coronary artery abnormalities. Use of intravenous immunoglobulins, however, has led to significant reduction in incidence of coronary aneurysms. What is more alarming is the fact that higher risk of cardiovascular disease is seen in even those children who do not have coronary artery aneurysms during subacute phase. Various factors like abnormal lipid profiles, abnormal vessel wall reactivity and endothelial dysfunction have been implicated for this. Carotid intima-media thickness (cIMT) has been used as a surrogate marker for atherosclerosis. This study was planned to evaluate cIMT in children with KD. Twenty-seven children with diagnosis of KD at least 1 year prior to enrolment were evaluated for cIMT at enrolment and then after 3 months. Fasting lipid profile was done for all patients. Mean cIMT was significantly higher in children with KD compared to controls. In lipid profiles, undesirable HDL-C and triglyceride levels were seen in 2 and 3 children, respectively. Undesirable and borderline LDL-C levels were seen in 1 and 2 patients, respectively. Undesirable and borderline total cholesterol levels were seen in 1 and 3 patients, respectively. Higher cIMTs were seen in our cohort of KD patients. Proatherogenic abnormalities in lipid profile were seen in a few patients. Both abnormalities may predict a higher risk of atherosclerosis in future. The results of this study need to be replicated on a larger study sample and over longer follow-up periods.     

Conjugation of Emtansine Onto Trastuzumab Promotes Aggregation of the Antibody–Drug Conjugate by Reducing Repulsive Electrostatic Interactions and Increasing Hydrophobic Interactions

The impact of drug conjugation on intra- and intermolecular interactions of trastuzumab (TmAb) was determined by comparing the conformational and colloidal stabilities of TmAb and trastuzumab emtansine (T-DM1). In low ionic strength formulations, drug conjugation to native lysine residues of TmAb significantly reduced the repulsive electrostatic interactions between T-DM1 molecules. When these electrostatic interactions were screened in solutions with high ionic strength, intermolecular interactions between T-DM1 molecules were found to be more attractive than those between TmAb molecules. Drug conjugation lowered the colloidal stability of T-DM1 compared to TmAb, making T-DM1 more susceptible to agitation-induced aggregation. The presence of polysorbate-20 in the formulations inhibited aggregation of TmAb and T-DM1 induced by the hydrophobic air-water interface. Furthermore, the effect of increased hydrophobic interactions between T-DM1 molecules was studied by monitoring aggregation in TmAb and T-DM1 solutions that were incubated at 4°C, 25°C, and 50°C. Conjugating DM1 to TmAb increased the hydrophobicity of the molecule, and faster aggregation of T-DM1 at 50°C could be attributed to a temperature-dependent increase in hydrophobic interactions between T-DM1 molecules.     

Novel analogs of sulfasalazine as system xc− antiporter inhibitors: Insights from the molecular modeling studies

System x_c⁻ (Sx_c⁻), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sx_c⁻. However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood–brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure–activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sx_c⁻ antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sx_c⁻ inhibitory activity following in vitro Sx_c⁻ inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.     

Integration of Modern Molecular Tools with Geological Processes to Reveal Species Phylogeny,Biogeographical Niche Prediction,and Bio-Evolution

Nature is integrated, being simultaneously controlled by different natural aspects. Genetics, bioinformatics, biostatistics and geology are four diverse and broad scientific disciplines. But we believe that these can offer important insights into species distribution and evolution, if integrated. This perspective is grounded on a case study of the family Salvadoraceae, where species distribution and phylogeny show high correlation with the geological records. The results obtained from published and ongoing research indicate that we are pointing toward better visualizing the overlapping boundaries of these specific disciplines, which will be able to more accurately answer key evolutionary questions. We highlight: (1) the combined application of bedrock-soil geological data and bioinformatics to resolve evolutionary questions regarding species eco-distribution, niche prediction and bio-evolution; and (2) signifies the importance of relaxing boundaries between the disciplines to come to a better conclusion on species diversity and distribution-driven controls. Overall, we express and briefly explain our hypothesis to integrate modern analytical tools, viz., statistical correlation of geological data via. geo-statistics (Geo), and spatiotemporal biostatistics via. geo-informatics (Geo), with gene-based paleontological shreds of evidence, and sequence-based bioinformatics, to devise a practical analysis tool, namely “Geo² gene-bioinformatics”. We invoke the development of algorithms through computational-based programs that can provide useful correlations to understand evolutionary systematics and phylogeny, species distribution, and niche prediction.