EGFR-Targeted Cationic Polymeric Mixed Micelles for Codelivery of Gemcitabine and miR-205 for Treating Advanced Pancreatic Cancer.

Gemcitabine (GEM), a first-line chemotherapy for pancreatic cancer undergoes rapid metabolism and develops chemoresistance after repeated administration. We previously demonstrated that the combination of GEM and miR-205 provides an effective therapeutic strategy to sensitize GEM-resistant pancreatic cancer cells. Since epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer cells, in this study, we aimed to deliver mixed micelles containing GEM and miR-205 decorated with EGFR-targeting cetuximab (C225) monoclonal antibody for targeted therapy. Cetuximab C225 was conjugated to malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (C225-PEG-PCD) to prepare mixed micelles with mPEG-b-PCC-g-GEM-g-DC-g-TEPA for targeted codelivery of GEM and miR-205. This mixed micelle formulation showed a significant enhancement in EGFR-mediated cellular uptake in GEM-resistant MIA PaCa-2R cells. Further, an enhanced tumor accumulation of C225-micelles conjugated with near-infrared fluorescent Cy7.5 dye and Dy677-labeled miR-205 in orthotopic pancreatic tumor bearing NSG mice was evident after systemic administration. In addition, inhibition of tumor growth was also observed with increased apoptosis and reduced EMT after treatment with C225-micelles containing GEM and miR-205. Therefore, we believe that the targeted delivery of GEM and miR-205 in combination could be a novel strategy for treating advanced pancreatic cancer.

Mutations in ANTXR1 cause GAPO syndrome.

The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. We studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262C>T [p.Arg88*] and c.505C>T [p.Arg169*]) or splicing mutations (c.1435-12A>G [p.Gly479Phefs*119]) in ANTXR1, which encodes anthrax toxin receptor 1. The nonsense mutations predictably trigger nonsense-mediated mRNA decay, resulting in the loss of ANTXR1. The transcript with the splicing mutation theoretically encodes a truncated ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C terminus. GAPO syndrome's major phenotypic features, which include dental abnormalities and the accumulation of extracellular matrix, recapitulate those found in Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix regulation. Thus, we propose that mutations affecting ANTXR1 function are responsible for this disease's characteristic generalized defect in extracellular-matrix homeostasis.

The use of mandibular nerve block in unilateral mandibular fracture to evaluate the mouth opening for assessment of airway.

Background: Facial area is one of the most frequently injured area of the body, accounting for 23-97% of all facial fractures. Treatments under general anesthesia as those for maxillofacial fractures or infections is a highly complicated and a major challenging task in trismus associated patients. The main culprit in trismus is the increase muscle tone of masticatory muscles which are supplied via the mandibular nerve, blocking which could help increase the mouth opening thus, changing the whole of airway management. Material and Method: A prospective study was done on 50 patients of ASA grade I-II with unilateral mandibular fracture with trismus posted for maxillofacial surgery. Mandibular nerve block was given via extraoral approach with 5 ml of 0.5% bupivacaine using peripheral nerve stimulator to determine the difference in Pre block and Post block mouth opening and the VAS score at 2, 5, 10, 15, 20, 25, and 30 minutes. Results: The Interincisor distance measured Pre block was 1.20 ± 0.32 mm and was significantly increased after 5 mins onwards from the block (P < 0.005). The VAS score determined Pre block was 5.14 ± 1.37 which significantly decreased just 2 minutes after the application of block (P < 0.005). Conclusion: Mandibular nerve block decreases the pain and will aid in the decision making by an anesthetist regarding airway management as it helps in increasing the inter incisor distance significantly. Moreover, given the feasibility and effectiveness of the block it could be included in standard of care protocol for mandibular fracture patients.

Proniosomes: the effective and efficient drug-carrier system.

Niosomes, liposomes and proniosomes are the most abundantly used vesicular systems for the transdermal delivery of drugs. Proniosomes are nonhydrated niosomes, which, upon hydration, form niosomes. Various researches have proved the advantages of proniosomes over the other conventional dosage forms currently available in the market. Proniosomes overcome physical stability problems involved with other vesicular systems such as leaking, fusion and aggregation. The stability and shelf life of proniosomes especially have been found to be much better and prolonged in comparison to other vesicular systems such as liposomes. The present review has been written in an effort to bring yet another viewpoint from a different angle and curated to compile the latest updates in this highly attractive delivery system from today's research point.

Melanotic neuroectodermal tumor of infancy: 2 decades of clinical experience with 18 patients.

PURPOSE: The purpose of this article is to report our experience in the management of 18 patients with melanotic neuroectodermal tumor of infancy involving the maxillary alveolus. PATIENTS AND METHODS: All patients presented with hard nontender swelling involving the upper alveolus with facial deformity. Analysis included hematocrit, coagulation profile, serum creatinine, and screening for vanillyl mandelic acid and catecholamines. Imaging studies included x-ray of the maxilla and chest, ultrasound of the abdomen, computed tomography scan (1990 to 1999), and magnetic resonance imaging (after 1999). All surgeries were performed using endotracheal anesthesia, and complete gross excision of the tumor was achieved with coverage of the defect with mucoperiosteal flaps. All specimens were subjected to histopathology and immunohistochemistry. RESULTS: The expansion of the alveolus produced by the tumor improved in 4 to 6 months. Subsequent dentition was affected by the removal of involved tooth buds during the operation. All the patients are in regular follow-up (maximum 206 months) and there has been no local recurrence or distant metastasis. Mean follow-up time was 130.8 months (95% confidence interval, 168.8-210.6). Overall survival at 17 years was 85.6%. Median survival could not be established due to statistically insignificant sample size, while mean survival time was 189.7 months (95% confidence interval, 103.7-157.8). CONCLUSIONS: In the absence of metastatic disease, melanotic neuroectodermal tumors of infancy can be successfully managed by local excision.

Chemosensitization and inhibition of pancreatic cancer stem cell proliferation by overexpression of microRNA-205.

Treatment of pancreatic cancer with gemcitabine (GEM) is limited due to its rapid plasma metabolism and development of chemoresistance. MicroRNA (miRNA) regulates cancer stem cell (CSC) maintenance and induces chemoresistance in cancer cells. In this study, we observed differential downregulation of miR-205 (miR-205-5p) in human pancreatic cancer tissues and cells. Compared to GEM-sensitive MIA PaCa-2 cells, miR-205 was highly downregulated in GEM-resistant MIA PaCa-2R cells. Lentivirus-mediated overexpression of miR-205 inhibits MIA PaCa-2R cell proliferation after GEM-treatment. Further investigation confirmed that miR-205 alone significantly reduces the proliferation of CSCs and tumor growth in mouse models. However, miR-205 in combination with GEM was more efficient in reducing the proliferation of CSCs and 3D spheroids. Moreover, miR-205 overexpressing MIA PaCa-2R cells induced orthotopic tumor growth was significantly inhibited after intravenous administration of GEM-conjugated methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-gemcitabine-graft-dodecanol (mPEG-b-PCC-g-GEM-g-DC) (mPEG-b-PCC-g-GEM-g-DC) polymeric micelles. Also, a reduction in CSCs, EMT and chemoresistance markers was observed in miR-205 overexpressing MIA PaCa-2R cells. Immunohistochemical analysis of orthotopic tumors showed a decrease in drug resistance protein caveolin-1 and cell proliferation marker Ki-67 in combination treatment. Overall, our findings suggest that miR-205 resensitizes GEM-resistant pancreatic cancer cells to GEM and acts as a tumor suppressor miRNA.

Host-derived tumor endothelial marker 8 promotes the growth of melanoma.

Tumor endothelial marker 8 (TEM8) was initially identified as a gene overexpressed in the vasculature of human tumors and was subsequently identified as an anthrax toxin receptor. To assess the functional role of TEM8, we disrupted the TEM8 gene in mice by targeted homologous recombination. TEM8(-/-) mice were viable and reached adulthood without defects in physiologic angiogenesis. However, histopathologic analysis revealed an excess of extracellular matrix in several tissues, including the ovaries, uterus, skin, and periodontal ligament of the incisors, the latter resulting in dental dysplasia. When challenged with B16 melanoma, tumor growth was delayed in TEM8(-/-) mice, whereas the growth of other tumors, such as Lewis lung carcinoma, was unaltered. These studies show that host-derived TEM8 promotes the growth of certain tumors and suggest that TEM8 antagonists may have utility in the development of new anticancer therapies.

Conservative management of necrotizing fascitis in children.

BACKGROUND: Necrotizing fascitis (NF) is a severe infection of the subcutaneous tissue and fascia affecting children and adults. Conventional management includes resuscitation, aggressive debridement of necrotic tissue, and sometimes, additional measures such as hyperbaric oxygen and immunoglobulin therapy. This paper reports conservative management of 18 patients with NF with minimal morbidity and mortality. MATERIAL AND METHODS: Patients with NF admitted to our department between January 2000 and February 2004 were included in the study (N = 18). In all cases, the presentation was rapidly progressing cellulitis progressing to cutaneous gangrene between 6 and 18 hours. The patients were managed by aggressive fluid resuscitation, analgesia, broad-spectrum antibiotics, and dressing with liberal quantities of povidone iodine ointment. After separation of the gangrenous skin margins from the surrounding healthy tissue between 24 and 72 hours, dead skin and fascia were removed with forceps on the ward, the wound washed with liberal quantities of water, and the ointment dressing reapplied. This procedure was repeated until all the dead tissue had been removed. Once the wound was granulating, dressings were changed at increasing intervals until healing took place by secondary intention. RESULTS: The patients were aged between 5 days and 11 years. In all, NF began as a small boil progressing to a rapidly spreading cellulitis. None of the patients was operated during the acute stage of the infection. Blackening of the skin and separation of the edges occurred within 8-72 hours, the dead tissue was allowed to separate from the granulating base and could be removed at the bedside with minimal blood loss. Blood transfusion was required only in 2 patients where hemoglobin was < 9 gm/dL. Of the 18 patients, 6 grew group A streptococci and staphylococci in a polymicrobial wound culture, whereas the other 12 had polymicrobial flora without streptococci. The clinical course and outcomes were similar in both types of wounds. There was 1 death in the study group, and 1 patient required skin grafting. All other survivors had healing by secondary intention without disability. The period for complete epithelization varied between 3 and 8 weeks. Patients were discharged home when 70% of the wound had healed. There was extensive scarring in 3 children with NF involving the back. The other children had minimal or no scarring. None of the patients had any restriction in the movement of limbs or joints. These findings were compared with 16 retrospective patients of NF treated before January 2000 by the conventional approach of aggressive early debridement, the results of the conservative approach were superior with shorter hospital stay, lower number of blood transfusions, earlier appearance of granulation tissue, and shorter duration of complete healing. CONCLUSIONS: We conclude that the conservative management of NF offers advantages in morbidity without compromising the outcome. In our hospital setup, conservative treatment was less expensive and easily carried out. We would therefore advocate conservative management for the treatment of this condition.