Cetuximab Conjugated with Octreotide and Entrapped Calcium Alginate-beads for Targeting Somatostatin Receptors.

There is a need to formulate oral cetuximab (CTX) for targeting colorectal cancer, which is reported to express somatostatin receptors (SSTRs). Therefore, coating CTX with a somatostatin analogue such as octreotide (OCT) is beneficial. Alginate was used to coat CTX to facilitate delivery to the gastrointestinal tract (GIT). This study aimed to deliver CTX conjugated with OCT in the form of microparticles as a GIT-targeted SSTR therapy. Both CTX and OCT were conjugated using a solvent evaporation method and the conjugated CTX-OCT was then loaded onto Ca-alginate-beads (CTX-OCT-Alg), which were characterized for drug interactions using differential scanning calorimetry (DSC), and Fourier transform infrared spectra (FTIR). Moreover, the morphology of formulated beads was examined using a scanning electron microscope (SEM). The drug content and release profile were studied using UV spectroscopy. Finally, in vitro cytotoxicity of all compounds was evaluated. The results showed homogenous conjugated CTX-OCT with a diameter of 0.4 mm. DSC showed a delay in the OCT peak that appeared after 200 °C due to small polymer interaction that shifted the OCT peak. Moreover, FTIR showed no prominent interaction. SEM showed clear empty cavities in the plain Ca-alginate-beads, while CTX-OCT-Alg showed occupied beads without cavities. CTX-OCT-Alg had a negligible release in 0.1 N HCl, while the CTX-OCT was completely released after 300 min in phosphate buffer pH 7.4. All formulations showed good antiproliferative activity compared with free drugs. The formulated CTX-OCT-Alg are a promising platform for targeting colorectal cancer through GIT

Distinctive Left-Sided Distribution of Adrenergic-Derived Cells in the Adult Mouse Heart

Adrenaline and noradrenaline are produced within the heart from neuronal and non-neuronal sources. These adrenergic hormones have profound effects on cardiovascular development and function, yet relatively little information is available about the specific tissue distribution of adrenergic cells within the adult heart. The purpose of the present study was to define the anatomical localization of cells derived from an adrenergic lineage within the adult heart. To accomplish this, we performed genetic fate-mapping experiments where mice with the cre-recombinase (Cre) gene inserted into the phenylethanolamine-n-methyltransferase (Pnmt) locus were cross-mated with homozygous Rosa26 reporter (R26R) mice. Because Pnmt serves as a marker gene for adrenergic cells, offspring from these matings express the β-galactosidase (βGAL) reporter gene in cells of an adrenergic lineage. βGAL expression was found throughout the adult mouse heart, but was predominantly (89%) located in the left atrium (LA) and ventricle (LV) (p<0.001 compared to RA and RV), where many of these cells appeared to have cardiomyocyte-like morphological and structural characteristics. The staining pattern in the LA was diffuse, but the LV free wall displayed intermittent non-random staining that extended from the apex to the base of the heart, including heavy staining of the anterior papillary muscle along its perimeter. Three-dimensional computer-aided reconstruction of XGAL+ staining revealed distribution throughout the LA and LV, with specific finger-like projections apparent near the mid and apical regions of the LV free wall. These data indicate that adrenergic-derived cells display distinctive left-sided distribution patterns in the adult mouse heart

Transtubular Transoral Approach for Irreducible Ventral Craniovertebral Junction Compressive Pathologies: Surgical Technique and Outcome

Introduction: To investigate the use of a tubular retractor to provide access to the craniovertebral junction (CVJ) sparing the soft palate with the aim of reducing complications associated with traditional transoral approach but yet allowing adequate decompression of the CVJ. Materials and methods: Twelve consecutive patients with severe myelopathy (JOA-score less than 11) from ventral CVJ compression were operated between 2014-2020 using a tubular retractor assisted transoral decompression. Results: All patients improved neurologically statistically (p=0.02). There were no posterior pharynx wound infections or rhinolalia. There was one case with incomplete removal of the lateral wall of odontoid and one incidental durotomy. Conclusions: A Tubular retractor provides adequate access for decompression of the ventral compression of CVJ. As the tubular retractor pushed away the uvula, soft palate and pillars of the tonsils as it docked on the posterior pharyngeal wall, the traditional complications associated with traditional transoral procedures is completely avoided

Neutron Electric Dipole Moment Constraint on Scale of Minimal Left-Right Symmetric Model

Using an effective theory approach, we calculate the neutron electric dipole moment (nEDM) in the minimal left-right symmetric model with both explicit and spontaneous CP violations. We integrate out heavy particles to obtain flavor-neutral CP-violating effective Lagrangian. We run the Wilson coefficients from the electroweak scale to the hadronic scale using one-loop renormalization group equations. Using the state-of-the-art hadronic matrix elements, we obtain the nEDM as a function of right-handed W-boson mass and CP-violating parameters. We use the current limit on nEDM combined with the kaon-decay parameter $\epsilon$ to provide the most stringent constraint yet on the left-right symmetric scale $M_{W_R} > (10 \pm 3)$ TeV.Comment: 20 pages and 8 figure

Very low prevalence of epidermal growth factor receptor (EGFR) protein expression and gene amplification in Saudi breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Breast cancers which demonstrate EGFR protein expression, gene amplification and/or gene mutations may benefit therapeutically from tyrosine kinase inhibitors. In Western studies, EGFR protein expression has been demonstrated in 7-36% of breast cancer patients, while gene amplification has been found in around 6% of cases and mutations were either absent or extremely rare. Studies addressing EGFR protein expression and gene amplification in Saudi breast cancer patients are extremely scanty and the results reported have been mostly non-conclusive. Herein we report the prevalence of EGFR protein expression and gene amplification in a cohort of Saudi breast cancer patients.</p> <p>Findings</p> <p>We noticed a remarkably low incidence of EGFR protein expression (1.3%) while analyzing the spectrum of molecular subtypes of breast cancer in a Saudi population by immunohistochemistry. Also, <it>EGFR </it>gene amplification could not be demonstrated in any of 231 cases studied using silver enhanced <it>in situ </it>hybridization.</p> <p>Conclusions</p> <p>The extremely low incidence of EGFR protein expression and gene amplification in Saudi breast cancer patients as compared to Western populations is most probably ethnically related as supported by our previous finding in the same cohort of a spectrum of molecular breast cancer types that is unique to the Saudi population and in stark contrast with Western and other regionally based studies. Further support to this view is provided by earlier studies from Saudi Arabia that have similarly shown variability in molecular breast cancer subtype distribution between Saudi and Caucasian populations as well as a predominance of the high-grade pathway in breast cancer development in Middle East women. More studies on EGFR in breast cancer are needed from different regions of Saudi Arabia before our assumption can be confirmed, however.</p

Readmission Rates of Patients Discharged against Medical Advice: A Matched Cohort Study

OBJECTIVE: We compared the readmission rates and the pattern of readmission among patients discharged against medical advice (AMA) to control patients discharged with approval over a one-year follow-up period. METHODS: A retrospective matched-cohort study of 656 patients(328 were discharged AMA) who were followed for one year after their initial hospitalization at an urban university-affiliated teaching hospital in Vancouver, Canada that serves a population with high prevalence of addiction and psychiatric disorders. Multivariate conditional logistic regression was used to examine the independent association of discharge AMA on 14-day related diagnosis hospital readmission. We fit a multivariate conditional negative binomial regression model to examine the readmission frequency ratio between the AMA and non-AMA group. PRINCIPAL FINDINGS: AMA patients were more likely to be homeless (32.3% vs. 11%) and have co-morbid conditions such as psychiatric illnesses, injection drug use, HIV, hepatitis C and previous gastrointestinal bleeding. Patients discharged AMA were more likely to be readmitted: 25.6% vs. 3.4%, p<0.001 by day 14. The AMA group were more likely to be readmitted within 14 days with a related diagnosis than the non-AMA group (Adjusted Odds Ratio 12.0; 95% Confidence Interval [CI]: 3.7-38.9). Patients who left AMA were more likely to be readmitted multiple times at one year compared to the non-AMA group (adjusted frequency ratio 1.6; 95% CI: 1.3-2.0). There was also higher all-cause in-hospital mortality during the 12-month follow-up in the AMA group compared to non-AMA group (6.7% vs. 2.4%, p = 0.01). CONCLUSIONS: Patients discharged AMA were more likely to be homeless and have multiple co-morbid conditions. At one year follow-up, the AMA group had higher readmission rates, were predisposed to multiple readmissions and had a higher in-hospital mortality. Interventions to reduce discharges AMA in high-risk groups need to be developed and tested

Inhibition of Monkeypox virus replication by RNA interference

The Orthopoxvirus genus of Poxviridae family is comprised of several human pathogens, including cowpox (CPXV), Vaccinia (VACV), monkeypox (MPV) and Variola (VARV) viruses. Species of this virus genus cause human diseases with various severities and outcome ranging from mild conditions to death in fulminating cases. Currently, vaccination is the only protective measure against infection with these viruses and no licensed antiviral drug therapy is available. In this study, we investigated the potential of RNA interference pathway (RNAi) as a therapeutic approach for orthopox virus infections using MPV as a model. Based on genome-wide expression studies and bioinformatic analysis, we selected 12 viral genes and targeted them by small interference RNA (siRNA). Forty-eight siRNA constructs were developed and evaluated in vitro for their ability to inhibit viral replication. Two genes, each targeted with four different siRNA constructs in one pool, were limiting to viral replication. Seven siRNA constructs from these two pools, targeting either an essential gene for viral replication (A6R) or an important gene in viral entry (E8L), inhibited viral replication in cell culture by 65-95% with no apparent cytotoxicity. Further analysis with wild-type and recombinant MPV expressing green fluorescence protein demonstrated that one of these constructs, siA6-a, was the most potent and inhibited viral replication for up to 7 days at a concentration of 10 nM. These results emphasis the essential role of A6R gene in viral replication, and demonstrate the potential of RNAi as a therapeutic approach for developing oligonucleotide-based drug therapy for MPV and other orthopox viruses

An enigmatic hypoplastic defect of the maxillary lateral incisor in recent and fossil orangutans from Sumatra (Pongo abelii) and Borneo (Pongo pygmaeus)

Developmental dental pathologies provide insight into health of primates during ontogeny, and are particularly useful for elucidating the environment in which extant and extinct primates matured. Our aim is to evaluate whether the prevalence of an unusual dental defect on the mesiolabial enamel of the upper lateral incisor, thought to reflect dental crowding during maturation, is lesser in female orangutans, with their smaller teeth, than in males; and in Sumatran orangutans, from more optimal developmental habitats, than in those from Borneo. Our sample includes 49 Pongo pygmaeus (87 teeth), 21 P. abelii (38 teeth), Late Pleistocene paleo-orangutans from Sumatra and Vietnam (67 teeth), Late Miocene catarrhines Lufengpithecus lufengensis (2 teeth), and Anapithecus hernyaki (7 teeth). Methods include micro-CT scans, radiography, and dental metrics of anterior teeth. We observed fenestration between incisor crypts and marked crowding of unerupted crowns, which could allow tooth-to-tooth contact. Tooth size does not differ significantly in animals with or without the defect, implicating undergrowth of the jaw as the proximate cause of dental crowding and defect presence. Male orangutans from both islands show more defects than do females. The defect is significantly more common in Bornean orangutans (71 %) compared to Sumatran (29 %). Prevalence among fossil forms falls between these extremes, except that all five individual Anapithecus show one or both incisors with the defect. We conclude that maxillary lateral incisor defect is a common developmental pathology of apes that is minimized in optimal habitats and that such evidence can be used to infer habitat quality in extant and fossil apes