Water-soluble polymers for targeted drug delivery to human squamous carcinoma of head and neck

Human squamous cell carcinoma of the head and neck (SCCHN) is characterized by over expression of a tumor cell surface-specific receptor namely Hsp47/CBP2 that makes it a favorable candidate for targeted delivery of anticancer drugs. Several synthetic peptides have been identified as effective ligands for binding to CBP2. The purpose of this study is to investigate the potential of water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (Dox) conjugates containing a Hsp47/CBP2 binding peptide sequence, namely WHYPWFQNWAMA for targeted delivery to SCCHN. An HPMA copolymer containing Dox and CBP2 targeting peptide conjugated via lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer was synthesized by free radical precipitation copolymerization. A control polymer without targeting moiety was also synthesized. The conjugates were characterized for drug content, peptide content, molecular weight and molecular weight distribution. The uptake of polymeric conjugates by both drug resistant and drug sensitive SCCHN cells were determined in vitro by flow cytometry using FACS scan analysis. Cytotoxicity of the conjugates towards drug sensitive as well as multidrug resistant SCCHN cells were evaluated by a clonal survival assay and compared to free Dox. The cytotoxicity of the free peptide was similarly evaluated. The internalization and subcellular fate of the conjugates in drug sensitive SCCHN cells was monitored using confocal microscopy. The new targetable copolymer contained 0.16 mmole peptide/g polymer. Studies on drug sensitive SCCHN cells demonstrated lesser uptake of both targeted and non-targeted conjugates compared to free Dox suggesting a slower endocytic mechanism of uptake for the conjugates as opposed to rapid diffusion of free Dox. At higher Dox equivalent concentrations (>20 microM) the targeted conjugate showed significantly higher uptake (p < or = 0.028) than the non-targeted conjugate. The uptake of the targeted conjugate was inhibited in the presence of an anti Hsp47 antibody suggesting the involvement of active receptor mediated endocytosis in cell entry of the conjugate. Compared to free Dox, the targeted and non-targeted conjugates caused marginally lower inhibition (p < or = 0.01) of the drug sensitive SCCHN cells. In contrast, the same conjugates showed significantly higher uptake (p < or = 0.004) by drug resistant SCCHN cells and caused significantly higher inhibition (p < or = 0.02) of drug resistant SCCHN cells when compared to free Dox. Results suggest that the polymeric conjugates were able to overcome drug resistance. Confocal microscopy studies demonstrated the uptake of the polymeric conjugates, followed by internalization, intralysosomal localization and subsequent release of Dox. HPMA copolymer-Dox-peptide conjugates targeted to SCCHN cells were able to overcome drug resistance and increase efficacy in vitro. The results suggest that targetable polymeric conjugates have potential to improve systemic head and neck cancer chemotherapy by increasing tumor localization and reducing dose-limiting toxicity.     

Chronic mesenteric vascular insufficiency with gastric ulceration

Four middle-aged women presented with long histories of severe progressive weight loss and chronic abdominal pain. Endoscopically atypical gastric ulcers were identified in all; the ulcers were multiple and antral in location, with irregular shapes, sloping edges, and whitish sclerotic bases, and were surrounded by mottled and erythematous mucosa containing numerous superficial erosions. They did not heal with conservative therapy. All 4 patients were found to be suffering from chronic mesenteric vascular insufficiency. Balloon dilatation of the superior mesenteric artery in one and surgical revascularization in the others resulted in progressive clinical improvement and healing of the ulcers. The striking feature in these patients with mesenteric ischemia was the finding of gastric ulcers with a morphology different from the ordinary gastric ulcer, which healed only with revascularization. Future observation of similar lesions should suggest the possible diagnosis and expedite early treatment of mesenteric insufficiency in patients with this disorder.     

EEG and neuroimaging localization in partial epilepsy.

We have studied cortical localization provided by surface and sphenoidal electroencephalograms (EEGs) and that of computed tomography (CT), magnetic resonance imaging (MR) and single photon emission tomography (SPECT) in 58 patients with partial epilepsy. Each patient had EEG, MR and SPECT during a hospitalization period of 1-2 weeks. CT scans were obtained either during the same period or had been performed in the preceding year. EEG evaluation consisted of 3-5 days of continuous monitoring including video-telemetry and ambulatory recording as well as conventional EEGs with special electrode placements. Additionally 33 of 58 patients (55%) who were potential surgical candidates had sphenoidal recordings. All patients had an abnormal EEG which showed evidence of epileptic hyperexcitability. EEG abnormality was localized in 43 patients (74%). Neuroimaging studies were focally abnormal in 38 patients (66%); 12 CT (21%), 29 MR (50%) and 24 SPECT (41%). Thirty four of 43 patients with localized EEG had at least 1 focally abnormal neuroimaging study (79%), whereas 4 of 15 (27%) patients with non-localized EEG did so. Twenty-eight of 29 patients with focal MR (97%), 11 of 12 patients with focal CT (92%) and 20 of 24 patients with focal SPECT (83%) had a concordant focal EEG. EEG and neuroimaging localization agreed in all 15 patients in whom both MR and SPECT disclosed a concordant focal abnormality. This study demonstrates a significant (P less than 0.005) correlation between surface/sphenoid EEG and neuroimaging localization in partial epilepsy.     

Monitoring of motor evoked potentials with high intensity repetitive transcranial electrical stimulation during spinal surgery

Objective.Clinical utility of high voltage repetitive transcranial electrical stimulation (TES) was investigated in 46 patients undergoing spine surgery. Methods.During spinal surgery, motor evoked potentials (MEPs) were recorded from upper or lower limb muscles following high voltage repetitive TES of motor cortex under propofol and opioid/N₂O anesthesia. Results.The number of responses evoked by the double pulse stimulation was significantly higher than the single pulse stimulation. A similar finding was obtained when repetitive and single pulse stimulation was compared. Compound muscle action potentials (CMAPs) were recorded from upper and lower limbs in 4 patients with cervical spine myelopathy. The CMAP was absent on the affected side in 1 patient, which improved slightly after decompression. Radiculopathy was clinically present in 6 patients undergoing posterior lumbar decompression and fusion. No improvement of MEP was noted intraoperatively after spinal decompression and instrumentation. Conclusion.The findings suggest that intraoperative MEP monitoring is feasible method, however, its immediate prognostic value for adequacy of neuronal decompression and improvement requires further studies with larger patient population.     

The effect of isolated soy protein adjunctive with flaxseed oil on markers of inflammation,oxidative stress,acute phase proteins,and wound healing of burn patients; a randomized clinical trial

Introduction

The objective was to determine the effect of isolated soy protein (ISP) and flaxseed oil (FO) on inflammatory and oxidative stress indices, acute phase proteins, and wound healing of burn patients.

Androgen receptor in salivary gland carcinoma: A review of an old marker as a possible new target

The role of the androgen receptor (AR) as an immunomarker for diagnosis of salivary gland duct carcinoma (SDC) is well known. Other non‐squamous cell head and neck cancers (NSCC‐HN), including a small subset of salivary gland cancers (SGCs), can also express AR. With the increase in effective and powerful new generation of anti‐androgen agents and drugs administered orally, more targetable AR‐driven NSCC‐HN, such as subsets of SGCs, should be investigated for possible expression of AR. In this review, we focus on SGC subtypes, which could express AR and describe the main androgen deprivation therapy (ADT) strategies.