Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.     

Genetic deregulation of the PIK3CA oncogene in oral cancer

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is one of the most commonly deregulated pathways in human cancers. PI3K comprises a catalytic (p110α) and regulatory subunit (p85), and p110α is encoded by the PIK3CA gene. Here, we summarize the known genetic alterations, including amplifications and mutations, of the PIK3CA oncogene in oral cancer. We discuss in detail PIK3CA mutations and their mutual exclusivity with pathway genes in addition to the incidence of PIK3CA mutations in relation to ethnicity. We describe the constitutive activation of PI3K signaling, oncogenicity, and the genetic deregulation of the PIK3CA gene and its association with oral cancer disease stage. We emphasize the importance of therapeutically targeting the genetically deregulated PIK3CA oncogene and its signaling. We also discuss the implications of targeting Akt and/or mTOR, which are the downstream effectors of PI3K that may possibly pave the way for molecular therapeutic targets for PIK3CA-driven oral carcinogenesis. Furthermore, this critical review provides a complete picture of the PIK3CA oncogene and its deregulation in oral cancer, which may facilitate early diagnosis and improve prognosis through personalized molecular targeted therapy in oral cancer.     

The Return of Actionable Variants Empirical (RAVE) Study,a Mayo Clinic Genomic Medicine Implementation Study: Design and Initial Results

Objectives

To identify clinically actionable genetic variants from targeted sequencing of 68 disease-related genes, estimate their penetrance, and assess the impact of disclosing results to participants and providers.

Adulticidal, repellent, and ovicidal properties of indigenous plant extracts against the malarial vector, Anopheles stephensi (Diptera: Culicidae)

Mosquito-borne diseases with an economic impact create loss in commercial and labor outputs, particularly in countries with tropical and subtropical climates. Mosquito control is facing a threat because of the emergence of resistance to synthetic insecticides. Extracts from plants may be alternative sources of mosquito control agents because they constitute a rich source of bioactive compounds that are biodegradable into nontoxic products and potentially suitable for use to control mosquitoes. Insecticides of botanical origin may serve as suitable alternative biocontrol techniques in the future. In view of the recently increased interest in developing plant origin insecticides as an alternative to chemical insecticide, this study was undertaken to assess the adulticidal, repellent, and ovicidal potential of the crude hexane, ethyl acetate, benzene, aqueous, and methanol solvent extracts from the medicinal plants Andrographis paniculata, Cassia occidentalis, and Euphorbia hirta against the medically important mosquito vector, Anopheles stephensi (Diptera: Culicidae).The adult mortality was observed after 24 h of exposure. All extracts showed moderate adulticide effects; however, the highest adult mortality was found in methanol extract of A. paniculata followed by C. occidentalis and E. hirta against the adults of A. stephensi with LC₅₀ and LC₉₀ values of 210.30, 225.91, and 263.91 ppm and 527.31, 586.36, and 621.91 ppm, respectively. The results of the repellent activity of hexane, ethyl acetate, benzene, aqueous, and methanol extract of A. paniculata, C. occidentalis, and E. hirta plants at three different concentrations of 1.0, 3.0, and 6.0 mg/cm² were applied on skin of forearm in man and exposed against adult female mosquitoes. In this observation, these three plant crude extracts gave protection against mosquito bites without any allergic reaction to the test person, and also, the repellent activity is dependent on the strength of the plant extracts. Mean percent hatchability of the ovicidal activity was observed 48 h post-treatment. The percent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. Mortality of 100 % with methanol extract of A. paniculata exerted at 150 ppm and aqueous, methanol extract of C. occidentalis and E. hirta were exerted at 300 ppm. These results suggest that the leaf extracts of A. paniculata, C. occidentalis, and E. hirta have the potential to be used as an ideal eco-friendly approach for the control of the A. stephensi. Further detailed research is needed to identify the active ingredient in the extracts and implement the effective mosquito management program.     

Ovicidal, repellent, adulticidal and field evaluations of plant extract against dengue, malaria and filarial vectors

Mosquitoes are insect vectors responsible for the transmission of parasitic and viral infections to millions of people worldwide, with substantial morbidity and mortality. Infections transmitted by mosquitoes include malaria, yellow fever, chikungunya, filariasis and other arboviruses. Insecticides of botanical origin may serve as suitable alternative biocontrol techniques in the future. The adulticidal activities of crude hexane, benzene, ethyl acetate, acetone and methanol leaf extracts of Acalypha alnifolia were assayed for their toxicity against three important vector mosquitoes, viz., Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus. The adult mortality was observed after 24 h of exposure. All extracts showed moderate adulticide effects; however, the highest adult mortality was found in methanol extract were observed. The LC₅₀ values of A. alnifolia leaf extracts against adulticidal activity of (hexane, benzene, ethyl acetate, acetone and methanol) A. aegypti, A. stephensi and C. quinquefasciatus were the following: A. aegypti values were 371.87, 342.97, 320.17, 300.86 and 279.75 ppm; A. stephensi values were 358.35, 336.64, 306.10, 293.01 and 274.76 ppm; C. quinquefasciatus values were 383.59, 354.13, 327.74, 314.33 and 291.71 ppm. The results of the repellent activity of hexane, benzene, ethyl acetate, acetone and methanol extract of A. alnifolia plant at three different concentrations of 1.0, 3.0, and 5.0 mg/cm² were applied on skin of forearm in man and exposed against adult female mosquitoes. In this observation, this plant crude extracts gave protection against mosquito bites without any allergic reaction to the test person, and also, the repellent activity is dependent on the strength of the plant extracts. Mean percent hatchability of the ovicidal activity was observed 48 h post-treatment. The percent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. Mortality of 100 % with methanol extract of A. alnifolia was exerted at 125 and 300 ppm. The larval density was decreased after the treatment of plant extracts at the breeding sites (water bodies system) of vector mosquitoes, and hence, these plant extracts are suitable alternatives of synthetic insecticides for mosquito vector management.These results suggest that the leaf solvent plant extracts have the potential to be used as an ideal eco-friendly approach for the control of mosquitoes. This study provides first report on the mosquito ovicidal, repellent and adulticidal activities of these plant extracts against mosquito vector species from India.     

Comparative Aesthetic Evaluation of Lip Reconstruction Using Abbe’s Flap in Secondary Cleft Lip Deformities: A Retrospective Study

AimTo objectively evaluate the surgical outcome of deformed cleft lip treated by Abbe’s flap using Digimizer image analysis software.MethodsFifteen Abbe’s flap (AF) reconstruction cases with satisfactory photographic records were acquired in Digimizer image analysis software. Anthropometric landmarks were marked on the lip. Bilateral lip lengths, height and width were measured preoperatively and postoperatively after AF reconstruction for comparison.ResultsIt was observed that by AF reconstruction, we could increase vermillion lip length and Cupid’s bow width, hence providing adequate bulk to the middle of the lip. In addition to it, in some cases we could achieve the acceptable anatomy of the centre of the Cupid’s bow with which it was sometimes disturbed during primary cheiloplasty. Lip length and lip height became proportionately equal bilaterally, leading to adequate lip symmetry in all cases.ConclusionComputer-assisted anthropometric analysis of photographs using Digimizer image analysis software (MedCalc Software, Belgium) demonstrates that AF lip reconstruction technique produces aesthetic lip consistently.