Genetic and chemical targeting of epithelial-restricted with serine box reduces EGF receptor and potentiates the efficacy of afatinib.

EGF receptor (EGFR) is elevated in more than 90% of head and neck squamous cell carcinoma (HNSCC). However, a majority of patients with HNSCC do not respond to anti-EGFR therapeutics. Insensitivity to EGFR inhibitors may be due to kinase-independent actions of EGFR and/or activation of Her2. Strategies to reduce EGFR and Her2 protein levels in concert may be an optimal approach to enhance the efficacy of current anti-EGFR molecules. In this study, knockdown of epithelial-restricted with serine box (ESX) decreased EGFR and Her2 promoter activity, expression, and levels. ESX was elevated in primary HNSCC tumors and associated with increased EGFR and Her2. Genetic ablation of ESX decreased EGFR and Her2 levels and enhanced the antiproliferative effects of EGFR/Her2 tyrosine kinase inhibitors (TKI), lapatinib and afatinib. Biphenyl isoxazolidine, a novel small-molecule ESX inhibitor, reduced EGFR and Her2 levels and potentiated the antiproliferative efficacy of afatinib. Single-agent biphenyl isoxazolidine retarded the in vivo tumorigenicity of CAL27 cells. Importantly, the combination of biphenyl isoxazolidine and afatinib was significantly superior in vivo and resulted in a 100% response rate with a 94% reduction in tumor volume. Targeting EGFR/Her2 levels with an ESX inhibitor and EGFR/Her2 kinase activity with a TKI simultaneously is a highly active therapeutic approach to manage HNSCC. Our work provides evidence to support the further development of ESX inhibitors as an adjuvant to enhance the response rate of patients with HNSCC to current anti-EGFR/Her2 therapeutics.

Comparison of safety and efficacy of papaya dressing with hydrogen peroxide solution on wound bed preparation in patients with wound gape.

OBJECTIVE: Indian papaya or Carica papaya is known to have de-sloughing and wound-healing properties due to the presence of protease enzymes. The present study was done to compare the efficacy and safety of papaya dressing with hydrogen peroxide solution for preparation of wound bed in patients of postoperative wound gape. MATERIALS AND METHODS: A randomized, open-labeled interventional study was carried out over a period of 8 months at a tertiary care hospital on post-caesarean section patients with wound gape. The efficacy parameters studied were duration of time required to induce development of healthy granulation tissue and total duration of hospitalization. Safety parameters studied were adverse effects reported by patients and development of hypersensitivity reaction. RESULTS: A total of 64 patients were enrolled, of which 32 patients received hydrogen peroxide dressing and 31 patients received papaya dressing (one patient withdrew after randomization). Time required to induce the development of healthy granulation tissue and total duration of hospitalization were 6.2±1.6 days vs 2.5±0.5 days and 19.2±5.8 days vs 12.92±4.6 days in papaya and hydrogen peroxide dressing groups, respectively. Both primary efficacy parameters were significantly shorter in papaya dressing group. The incidence of adverse effects like local irritation and itching were comparable in both groups and the difference was not statistically significant. CONCLUSION: Papaya dressing is more efficacious and equally safe as compared to hydrogen peroxide dressing when used for wound bed preparation in patients with postoperative wound gape.

Molecular parameters of head and neck cancer metastasis.

Metastasis remains a major cause of mortality in patients with head and neck squamous cell carcinoma (HNSCC). HNSCC patients with metastatic disease have extremely poor prognoses, with an average survival rate of less than a year. Metastasis is an intricate sequential process that requires a discrete population of tumor cells to possess the capacity to intravasate from the primary tumor into systemic circulation, survive in circulation, extravasate at a distant site, and proliferate in a foreign, hostile environment. Literature has accumulated to provide mechanistic insight into several signal transduction pathways, receptor tyrosine kinases (RTKs), signal transducer and activator of transcription 3 (Stat3), Rho GTPases, protein kinase Cε (PKCsε), and nuclear factor-κB (NF-κB), that are involved in mediating a metastatic tumor cell phenotype in HN-SCC. Herein we highlight accrued information regarding the key molecular parameters of HNSCC metastasis.

TOO MANY MOUTHS promotes cell fate progression in stomatal development of Arabidopsis stems.

Mutations in TOO MANY MOUTHS (TMM), which encodes a receptor-like protein, cause stomatal patterning defects in Arabidopsis leaves but eliminate stomatal formation in stems. Stomatal development in wild-type and tmm stems was analyzed to define TMM function. Epidermal cells in young tmm stems underwent many asymmetric divisions characteristic of entry into the stomatal pathway. The resulting precursor cells, meristemoids, appropriately expressed cell fate markers such as pTMM:GFP. However, instead of progressing developmentally by forming a guard mother cell, the meristemoids arrested, dedifferentiated, and enlarged. Thus asymmetric divisions are necessary but not sufficient for stomatal formation in stems, and TMM promotes the fate and developmental progression of early precursor cells. Comparable developmental and mature stomatal phenotypes were also found in tmm hypocotyls and in the proximal flower stalk. TMM is also a positive regulator of meristemoid division in leaves suggesting that TMM generally promotes meristemoid activity. Our results are consistent with a model in which TMM interacts with other proteins to modulate precursor cell fate and progression in an organ and domain-specific manner. Finally, the consistent presence of a small number of dedifferentiated meristemoids in mature wild-type stems suggests that precursor cell arrest is a normal feature of Arabidopsis stem development.

Expression of vitreoscilla hemoglobin improves growth and levels of extracellular enzyme in Yarrowia lipolytica.

Enhancement in oxygen uptake by high-cell-density cultivations has been achieved previously by expression of the bacterial hemoglobin gene from Vitreoscilla. The Vitreoscilla hemoglobin (VHb) gene was expressed in the yeast Yarrowia lipolytica to study the effect of expression in this commercially important yeast. The expression of VHb in this yeast was found to enhance growth, contrary to reported observations in wild-type Saccharomyces cerevisiae in which there was no significant growth enhancement. VHb-expressing Y. lipolytica exhibited higher specific growth rate, enhanced oxygen uptake rate, and higher respiratory activity. We report the beneficial effects of VHb expression on growth under microaerobic as well as under nonlimiting dissolved oxygen conditions. Earlier studies in Y. lipolytica have demonstrated inhibition of mycelia formation by respiratory inhibitors and poor nitrogen source, conditions poor for growth. VHb(+) Y. lipolytica cells were more efficient at forming mycelia, indicating better utilization of available oxygen as compared with the VHb(-) cells. Expression of VHb was also found to increase the levels of enzyme ribonuclease secreted into the medium, a property that may be beneficial for producing heterologous proteins in Y. lipolytica.