Hydrophilicity Matching – A Potential Prerequisite for the Formation of Protein-Protein Complexes in the Cell

A binding event between two proteins typically consists of a diffusional search of binding partners for one another, followed by a specific recognition of the compatible binding sites resulting in the formation of the complex. However, it is unclear how binding partners find each other in the context of the crowded, constantly fluctuating, and interaction-rich cellular environment. Here we examine the non-specific component of protein-protein interactions, which refers to those physicochemical properties of the binding partners that are independent of the exact details of their binding sites, but which can affect their localization or diffusional search for one another. We show that, for a large set of high-resolution experimental 3D structures of binary, transient protein complexes taken from the DOCKGROUND database, the binding partners display a surprising, statistically significant similarity in terms of their total hydration free energies normalized by a size-dependent variable. We hypothesize that colocalization of binding partners, even within individual cellular compartments such as the cytoplasm, may be influenced by their relative hydrophilicity, potentially in response to local hydrophilic gradients

Fruit bearing shoot characteristics of apricot and sweet cherry cultivars in Hungary

: Our study was carried out on 23 apricot and 9 sweet cherry cultivars in February 2005. Fruiting laterals were classified into four groups (0-10 cm, 10-20 cm, 20-40 cm and >40 cm) and then the density and setting of flower buds were evaluated and expressed as bud/cm. The flower bud density of four types of fruit bearing shoots and the changes in the frost resistance were studied. Shoots were collected from a young orchard in Gone (apricot), Siófok (sweet cherry) and Nagykutas (sweet cherry). There were significant differences among the cultivars in the density of flower buds. The number of flower buds/cm shoot length ranged between 0.91 and 2.20 in the average of the different fruit bearing shoot types on apricot. Based on the results, the bud density of shorter shoots is generally higher on apricot, but this is not valid for all cultivars. For cvs. Magyarkajszi and Ceglédi bíborkajszi, the highest flower bud density was detected on shoots of medium length (10-40 cm). There were fivefold and almost twofold (1.85) differences in bud density among cultivars on shoots shorter than 10 cm length and longer than 40 cm length, respectively. The ratio of the bud densities of the different types of shoots also ranged between wide boundaries. For cvs. Bayoto, Toyesi and Toyiba this ratio was 2.5-3.5, while for cv. Magyarkajszi it was 1.3. In the average of fruit bearing shoots on sweet cherry, cv. Bigarreau Burlat (1.10 bud/cm) and cv. Germersdorfi 45 (0.61 bud/cm) had the largest and the lowest flower bud density, respectively. Among the fruit bearing shoots, the largest flower bud density was in the group of 0-10 cm fruiting laterals. Among cultivars, cv. Bigarreau Burlat had the largest bud density. In the groups of n- i 0 cm, 10-20 cm, 20-30 cm and 30-40 cm fruiting laterals, the lowest flower bud density was for cv. Linda, cv. Germersdorfi 45, cv. Ferrovia and cv. Sunburst, respectively. On cvs. Van and Bigarreau Burlat, large numbers of double-set flower buds were observed on the fruit bearing shoots longer than 20 cm. Fruit setting differed on the different types of fruit bearing shoots, with the lowest value measured on above 40 cm shoots. The highest fruit setting was observed on cv. Katalin, while the lowest value was measured on cv. Germersdorfi 3

Supplementary Material for: Reimbursement in the context of precision oncology approaches in metastatic breast cancer: challenges and experiences

Background: Precision oncology programs using Next Generation Sequencing (NGS) to detect predictive biomarkers are extending therapeutic options for patients with metastatic breast cancer (mBC). Regularly, based on the recommendations in the interdisciplinary molecular tumor board (iMTB), an inclusion in a clinical trial is not possible. In this case, the German health-insurance system allows for the application of reimbursement for an off-label drug use. Here we describe the current challenges and our experience with reimbursement of molecular therapies in mBC. Methods: A total of 100 applications for reimbursement of off-label therapies recommended by an iMTB were filed for patients with mBC, of which 89 were evaluable for this analysis. The approval rate was correlated with the molecular level of evidence of the respective therapy according to the NCT and ESCAT classification as well as with pretreatment therapy lines. Findings: Overall, 53.9% (48/89) of reimbursement applications were approved. Applications for therapies based on level of evidence m1 (NCT classification), tier I and II (ESCAT classification) had a significantly and clinically relevant increased chance of reimbursement, while a greater number of previous treatment lines had no significantly increased chance of approval, though a trend of approval towards higher treatment lines was detectable. Interpretation: Currently, the German jurisdiction seems to aggravate the clinical implementation of clinically urgently needed molecular therapies

Integrative genomic and transcriptomic analysis of leiomyosarcoma

The molecular genetic landscape of leiomyosarcoma (LMS) is largely unknown. Here, the authors identify frequent DNA copy number alterations, whole-genome duplication, TP53 and RB1 inactivation, alternative telomere lengthening, and genomic imprints of defective DNA repair via homologous recombination as a potential therapeutic target in LMS patients

The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ER alpha-negative breast cancer

Antiestrogen-resistant and triple-negative breast tumors pose a serious clinical challenge because of limited treatment options. We assessed global gene expression changes in antiestrogen-sensitive compared with antiestrogen-resistant (two tamoxifen resistant and two fulvestrant resistant) MCF-7 breast cancer cell lines. The branched-chain amino acid transaminase 1 (BCAT1), which catalyzes the first step in the breakdown of branched-chain amino acids, was among the most upregulated transcripts in antiestrogen-resistant cells. Elevated BCAT1 expression was confirmed in relapsed tamoxifen-resistant breast tumor specimens. High intratumoral BCAT1 levels were associated with a reduced relapse-free survival in adjuvant tamoxifen-treated patients and overall survival in unselected patients. On a tissue microarray (n = 1421), BCAT1 expression was detectable in 58% of unselected primary breast carcinomas and linked to a higher Ki-67 proliferation index, as well as histological grade. Interestingly, BCAT1 was predominantly expressed in estrogen receptor-a-negative/human epidermal growth factor receptor-2-positive (ER alpha-negative/HER-2- positive) and triple-negative breast cancers in independent patient cohorts. The inverse relationship between BCAT1 and ER alpha was corroborated in various breast cancer cell lines and pharmacological long-term depletion of ERa induced BCAT1 expression in vitro. Mechanistically, BCAT1 indirectly controlled expression of the cell cycle inhibitor p27(Kip1) thereby affecting pRB. Correspondingly, phenotypic analyses using a lentiviral-mediated BCAT1 short hairpin RNA knockdown revealed that BCAT1 sustains proliferation in addition to migration and invasion and that its overexpression enhanced the capacity of antiestrogen-sensitive cells to grow in the presence of antiestrogens. Importantly, silencing of BCAT1 in an orthotopic triple-negative xenograft model resulted in a massive reduction of tumor volume in vivo, supporting our findings that BCAT1 is necessary for the growth of hormone-independent breast tumors