Dibucaine in Ionic-Gradient Liposomes: Biophysical,Toxicological, and Activity Characterization

Administration of local anesthetics is one of the most effective pain control techniques for postoperative analgesia. However, anesthetic agents easily diffuse into the injection site, limiting the time of anesthesia. One approach to prolong analgesia is to entrap local anesthetic agents in nanostructured carriers (e.g., liposomes). Here, we report that using an ammonium sulphate gradient was the best strategy to improve the encapsulation (62.6%) of dibucaine (DBC) into liposomes. Light scattering and nanotracking analyses were used to characterize vesicle properties, such as, size, polydispersity, zeta potentials, and number. In vitro kinetic experiments revealed the sustained release of DBC (50% in 7 h) from the liposomes. In addition, in vitro (3T3 cells in culture) and in vivo (zebrafish) toxicity assays revealed that ionic-gradient liposomes were able to reduce DBC cyto/cardiotoxicity and morphological changes in zebrafish larvae. Moreover, the anesthesia time attained after infiltrative administration in mice was longer with encapsulated DBC (27 h) than that with free DBC (11 h), at 320 μM (0.012%), confirming it as a promising long-acting liposome formulation for parenteral drug administration of DBC.     

Duct-like diverticulum at the base of third ventricle tumors: a morphological signature diagnostic of papillary craniopharyngioma

This study describes and characterizes a narrow, hollow tubular structure, termed as duct-like diverticulum (DV), found specifically at the basal midline of papillary craniopharyngiomas (PCPs) located within the third ventricle (3V). The presence of this structure was systematically investigated on autopsy studies and magnetic resonance imaging (MRI) scans of 3536 craniopharyngioma (CP) cases published in the medical literature from 1911 to 2021, as well as in other twelve 3V tumor categories (n?=?1470 cases). A basal DV was observed in a total of 50 PCPs, including two of our own cases. This DV corresponds to a tubular-shaped recess invaginated at the midline bottom of the tumor, following the same angled trajectory as the pituitary stalk. It can be easily seen as a hypointense linear structure on T1- and T2-weighted MRI scans, with two main length types: long DVs (74%), which reach the tumor center, and short DVs (26%), which penetrate the tumor only a few millimeters. The DV sign identifies the papillary CP type with a specificity of 100% and a sensitivity of 33% in the overall CP population. This finding also serves to establish the strictly intra-3V location of the lesion with a 95% specificity and 42% sensitivity among papillary CPs. No similar basal DV was found in adamantinomatous CPs nor among other categories of strictly 3V tumors. Consequently, the presence of a diverticulum in a 3V tumor represents a morphological signature pathognomonic of the papillary type and a valuable sign to reliably define the strictly 3V topography.

     

The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma

BackgroundPleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM.MethodsWe analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA–drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up.ResultsWhile PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm² had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm² had a high risk of death (P=0.03) and a median survival time of 34 months.ConclusionsWe shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.     

Liver changes in patients with hyperthyroidism

We studied liver changes in the hepatic biopsies of five patients with hyperthyroidism. A characteristic histopathologic picture consisting of mild to moderate intrahepatocytic cholestasis, lobular inflammatory infiltrate with some eosinophils, and Kupffer cell hyperplasia was found in all cases. We discuss the specificity, clinicopathological correlations and the possible pathophysiology of these lesions.     

Measuring functional status of chronic coronary patients: Reliability, validity and responsiveness to clinical change of the reduced version of the Duke Activity Status Index (DASI)

AIMS: Health-related quality of life assessment may be useful forunderstanding the variability in functioning of patients witha similar level of clinical impairment. We assessed the reliability,validity and responsiveness to clinical change of a reducedversion of the Duke Activity Status Index (DASI) in chroniccoronary patients. METHODS AND RESULTS: The reduced version of the DASI, a measure of self-reportedfunctional capacity, was administered twice to two groups ofpatients: 46 stable coronary heart disease outpatients weretested and re-tested 2 weeks after their initial visit; and44 patients undergoing elective angioplasty for angina pectoriswere evaluated the day before and one month after the procedure.The Canadian Cardiovascular Society (CCS) functional grade wasassessed in all patients, and a treadmill exercise test wasperformed sequentially (before and after the procedure) in angioplastypatients. Cronbach's alpha reliability coefficients for reducedDASI scores were high (between 0·81 and 0·89).Correlations of the reduced DASI scores with CCS grade and exercisetest duration were moderately high (r= – 0·51 andr=0·45, respectively). Improvement after angioplastyas assessed by the reduced DASI scores was important (effectsize=0·75, P<0·001). CONCLUSION: The reduced DASI is reliable, valid and responsive to clinicalchanges. Health-related quality of life measures may be usefulin monitoring coronary patients.     

Engineering Th determinants for efficient priming of humoral and cytotoxic T cell responses

To engineer T(h) determinants (THd) to prime help for humoral or cytotoxic T cell responses, we modified ovalbumin [OVA(323-337)] and myoglobin [MYO(106-118)] eliciting T(h)1 and T(h)0 cytokine profiles respectively. Residues along the sequence of both THd were replaced with amino acids representative of different families. Replacements at positions P-1 and P5 pointing to the TCR in both THd afforded higher levels of IFN-gamma and IL-4 production. Peptides eliciting different proportions of IFN-gamma and IL-4 were co-immunized with a peptide hapten or a T cytotoxic determinant (TCd) respectively. OVA(323-337)- and MYO(106-118)-derived peptides afforded the best THd for the induction of cytotoxic T lymphocyte (CTL) and anti-hapten antibodies respectively. IFN-gamma and IL-4, primed by MYO(106-118)-derived peptides, correlated significantly with antibody production against the hapten (P < 0.05 for IFN-gamma and P < 0.05 for IL-4). Interestingly, two peptides derived from OVA(323-337), 323G and 327G, which induced the clearest T(h)2 cytokine profiles, were not the most efficient to prime cell help for the induction of anti-hapten antibodies. For CTL induction, OVA(323-337)-derived peptides, inducing a T(h)1-like profile, required a lower dose (5 nmol) than T(h)0 peptides (50 nmol). The dose of 50 nmol was detrimental for T(h)1-like peptides. Interestingly, IFN-gamma primed by the THd correlated significantly with that induced by the TCd (P < 0.01).     

The promise of gene therapy in gastrointestinal and liver diseases

Gene therapy consists of the transfer of genetic material to cells to achieve a therapeutic goal. In the field of gastroenterology and hepatology gene therapy has produced considerable expectation as a potential tool in the management of conditions that lack effective therapy including non-resectable neoplasms of the liver, pancreas and gastrointestinal tract, chronic viral hepatitis unresponsive to interferon therapy, liver cirrhosis, and inflammatory bowel disease.