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.     

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large‐scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.     

Vesicouterine fistulae: our experience of 17 cases and literature review

Aim

A retrospective study of vesicouterine fistulae managed from 1996 to 2011 analyzed the incidence, symptomatology, diagnosis, and surgical outcome.

Patients & methods

During the study period, 17 patients were managed, of whom 14 underwent abdominal repair and three underwent vaginal repair. Mean patient age was 31.1 years and mean follow-up 7.3 years.

Results

Vesicouterine fistulae resulted following cesarean section in 13 patients and vaginal delivery in four. Eleven patients presented with urinary leakage via the vagina and seven with menouria. All patients had successful outcomes irrespective of treatment approach. The uterus was conserved in ten patients, of whom seven had completed their childbearing. The remaining three conceived spontaneously and underwent elective cesarean section.

Conclusion

The majority of vesicouterine fistulae occur following cesarean section, and it is feasible to achieve 100 % successful repair. Though the majority require abdominal repair, a few selected cases can be successfully repaired vaginally.     

Enhanced therapeutic effect of multiple injections of HSV-TK + GCV gene therapy in combination with ionizing radiation in a mouse mammary tumor model.

PURPOSE: Standard therapies for breast cancer lack tumor specificity and have significant risk for recurrence and toxicities. Herpes simplex virus-thymidine kinase (HSV-tk) gene therapy combined with radiation therapy (XRT) may be effective because of complementary mechanisms and distinct toxicity profiles. HSV-tk gene therapy followed by systemic administration of ganciclovir (GCV) enhances radiation-induced DNA damage by generating high local concentrations of phosphorylated nucleotide analogs that increase radiation-induced DNA breaks and interfere with DNA repair mechanisms. In addition, radiation-induced membrane damage enhances the "bystander effect" by facilitating transfer of nucleotide analogs to neighboring nontransduced cells and by promoting local and systemic immune responses. This study assesses the effect of single and multiple courses of HSV-tk gene therapy in combination with ionizing radiation in a mouse mammary cancer model. METHODS AND MATERIALS: Mouse mammary TM40D tumors transplanted s.c. in syngeneic immunocompetent BALB-c mice were treated with either adenoviral-mediated HSV-tk gene therapy or local radiation or the combination of gene and radiation therapy. A vector consisting of a replication-deficient (E1-deleted) adenovirus type 5 was injected intratumorally to administer the HSV-tk gene, and GCV was initiated 24 h later for a total of 6 days. Radiation was given as a single dose of 5 Gy 48 h after the HSV-tk injection. A metastatic model was developed by tail vein injection of TM40D cells on the same day that the s.c. tumors were established. Systemic antitumor effect was evaluated by counting the number of lung nodules after treating only the primary tumors with gene therapy, radiation, or the combination of gene and radiation therapy. To assess the therapeutic efficacy of multiple courses of this combinatorial approach, one, two, and three courses of HSV-tk + GCV gene therapy, in combination with radiation, were compared to HSV-tk or XRT alone and to sham-treated animals. (Treatments were repeated at 7-day intervals from the HSV-tk injection.) RESULTS: Both single-therapy modalities reduced tumor growth by 11% compared to controls, while the combined therapy resulted in a decrease of 29%. Median survival was 36 days in the combined therapy group, compared to 33 days in the monotherapy groups and 26 days in the control group. In the metastatic model, the number of lung nodules was reduced by 59.5% after HSV-tk gene therapy, whereas radiotherapy had no effect on metastatic growth. Combined therapy led to an additional 66.7% reduction in lung colonization. Compared to controls, local tumor growth was maximally suppressed by three courses of combined therapy (51.5%), followed by two courses of combined therapy (37.2%), and three sessions of XRT alone (35.6%). Median survival was also significantly prolonged to 58 days with the three courses of combined therapy, followed by two courses, to 45 days. All other treatment groups demonstrated median survival times between 26 and 35 days, while controls had a median survival of 24 days. CONCLUSIONS: These results indicate that multiple courses of HSV-tk therapy in combination with radiation improve the therapeutic efficacy of this approach and may provide therapeutic implications for the treatment of human breast cancer and other solid tumors.     

Fatty acyl amide derivatives of doxorubicin: synthesis and in vitro anticancer activities

Doxorubicin is extensively used in anticancer therapy. Doxorubicin is highly hydrophilic, has short half-life, and its use is associated with severe side effects at high doses. Fatty acyl amide derivatives of doxorubicin were synthesized with the expectation to improve the lipophilicity and anticancer activity of the drug. The lipophilicity was enhanced with the increase in chain length of fatty acyl moiety. Conjugation of 4′-amino group with fatty acids through an amide bond reduced the anticancer activity in leukemia, breast, ovarian, and colon cancer cell lines, suggesting that the presence of free amino group is required for anticancer activity of doxorubicin. Dodecanoyl-doxorubicin derivative was consistently the most effective among the synthesized derivatives and inhibited the proliferation of colon (HT-29) and ovarian (SK-OV-3) cancer cells by 64% and 58%, respectively, at a concentration of 1 μM after 96 h incubation.     

Synthesis, anticancer activities, and cellular uptake studies of lipophilic derivatives of doxorubicin succinate

A number of lipophilic 14-substituted derivatives of doxorubicin were synthesized through conjugation of doxorubicin-14-hemisuccinate with different fatty amines or tetradecanol to enhance the lipophilicity, cellular uptake, and cellular retention for sustained anticancer activity. The conjugates inhibited the cell proliferation of human leukemia (CCRF-CEM, 69-76%), colon adenocarcinoma (HT-29, 60-77%), and breast adenocarcinoma (MDA-MB-361, 66-71%) cells at a concentration of 1 μM after 96-120 h of incubation. The N-tetradecylamido derivative of doxorubicin 14-succinate (10) exhibited consistently comparable antiproliferative activity to doxorubicin in a time-dependent manner (IC(50) = 77 nM in CCRF-CEM cells). Flow cytometry analysis showed a 3-fold more cellular uptake of 10 than doxorubicin in SK-OV-3 cells. Confocal microscopy revealed that the conjugate was distributed in cytoplasmic and perinuclear areas during the first 1 h of incubation and slowly relocalized in the nucleus after 24 h. The cellular hydrolysis study showed that 98% of compound 10 was hydrolyzed intracellularly within 48 h and released doxorubicin.     

Effect of gentamicin on proximal convoluted tubules of kidney in developing chicks

Aim: To study any teratogenic effect of gentamicin as a result of single-dose injection given therapeutically or accidentally. Materials and methods: The study was conducted on 60 fertilized eggs of white leghorn species in the Department of Anatomy, Pt BD Sharma PGIMS, Rohtak, Haryana. The eggs were incubated for 20 days and divided into treated (n = 30) and control (n = 30) groups. Eggs of treated and control groups were injected with 0.2 mg of gentamicin sulfate and ‘sterilized water for injection’, respectively, on the 4th day of incubation. On the 20th day, the chick embryos were extracted and then dissected to remove the kidneys. Results: No effect of gentamicin was found on either the mortality of chick embryos or the gross appearance of the newborn chicks and kidney as compared to the control group. The mean weight of both the right and left kidneys was found less in the treated group, though not statistically significant. On light microscopy, various changes in proximal convoluted tubules were noticed in both the groups which included cystic dilatation and cloudy swelling. Statistical analyses showed that these changes were significantly higher in both the kidneys of treated group in comparison to the control group. Conclusion: Gentamicin has a teratogenic effect on proximal convoluted tubules of kidney even if administered in a single dose during the development of an embryo.     

Theoretical and experimental studies of an oseltamivir–triazole-based thermoresponsive organogel

Low-molecular weight organic gelators have been of significant interest in recent years because of their interesting properties and potential applications in sensing technology, biomedicine and drug delivery. Herein, the synthesis, characterization and gelation properties of new oseltamivir conjugates are reported. The oseltamivir–triazole conjugate 1 was synthesized via a click-reaction in a 75% yield. The key features of this conjugate include the presence of amide, flexible ester linkages and a triazole scaffold linking a hydrophobic alkyl chain. The conjugate 1, possessing a long alkyl chain, showed gelation properties in various apolar organic solvents. This gelation behavior was not observed in the case of the deesterified conjugate 2; this indicated the necessity of the alkyl chain for gelation. The gelator 1 showed thermoreversible gelation properties in a range of linear alkane solvents (from n-pentane to n-dodecane). A scanning electron microscopic study suggests that the gelator 1 exists as cross-linked structures, which are self-aggregated in the range of submicrometers, as supported by extensive ¹H-NMR studies. The rheological parameters supported the occurrence of a soft gelation process, and the gel formed in n-decane was found to be stiffer than that formed in n-hexane. Computational studies suggested that the gelation behavior was indeed due to micelle formation and dependent on the lipophilicity of solvents.

Low-molecular weight organic gelators have been of significant interest in recent years because of their interesting properties and potential applications in sensing technology, biomedicine and drug delivery.     

Management of ureterovaginal fistulae: an audit

Introduction and hypothesis

A retrospective study was done from January 2008 to January 2011 to analyze the outcome of ureterovaginal fistula management in relation to intervention mode.

Patients and methods

Eighteen patients who developed ureterovaginal fistulae following gynecological and obstetric procedures were studied. Ureteroscopic stenting was attempted in 17 cases, and one patient electively underwent ureteral reimplantation.

Results

Ureteroscopic stenting was successfully accomplished in 13 of 17 patients; four patients underwent ureteral reimplantation, as stenting was not feasible. The success rate was 100 % at a mean follow-up of 24.6 months, irrespective of modality.

Conclusion

The majority of iatrogenic ureterovaginal fistulae can be successfully managed by ureteroscopic stenting. Our study also suggests that ureteroscopic stenting should be considered as the primary mode of intervention in all cases. Ureteral reimplantation is required and remains practicable when stenting turns out to be impossible.