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Prospective clinical trials with compounds targeting the identified actionable mutations are needed to determine which treatments can indeed improve survival or quality of life by limiting exposure to ineffective drugs in advanced breast cancer.
Using a high throughput-panel sequencing approach to identify actionable mutations in patients with metastatic breast cancer, we identified potential target-related treatment options in a large proportion of our patients, some of which would not have been considered without this data. Prospective clinical trials with compounds targeting the identified actionable mutations are needed to determine which treatments can indeed improve survival or quality of life by limiting exposure to ineffective drugs in advanced breast cancer.Non-melanoma skin cancer is the most common form of cancer worldwide. We previously documented an anti-apoptotic role for CDC25A in cutaneous squamous cell carcinoma (SCC), an activity dependent on its association with 14-3-3 proteins. We hypothesized that targeting CDC25A-14-3-3ε interactions may be an effective strategy for inducing skin cancer cell apoptosis. Co-immunoprecipitation revealed that CDC25A associated with 14-3-3ε, 14-3-3γ and 14-3-3ζ in SCC cells but not normal keratinocytes. 14-3-3ε and CDC25A activated Akt/BAD/Survivin pro-survival signaling. To target the interaction of 14-3-3ε with CDC25A for cancer therapy, we developed two novel phospho-peptides, pS and pT, corresponding to each of the 14-3-3 binding sites of CDC25A, to specifically interfere with 14-3-3ε binding to CDC25A. Peptides pT (IC50 = 22.1 μM), and pS (IC50 = 29 μM) induced SCC cell death and blocked 14-3-3ε binding to CDC25A. pS or pT treatment of SCC xenografts increased apoptotic cell death and decreased pro-survival P-Akt (S473) and Survivin, demonstrating the effectiveness of the peptides in vivo. These findings lay a framework for the further development of peptides to target 14-3-3ε-CDC25A interactions for skin cancer treatment.With the COVID-19 pandemic, the evolutionary fate of SARS-CoV-2 becomes a matter of utmost concern. Mutation D614G in the spike (S) protein has become dominant, and recent evidence suggests it yields a more stable phenotype with higher transmission efficacy. We carry out a structural analysis that provides mechanistic clues on the enhanced infectivity. The D614G substitution creates a sticky packing defect in subunit S1, promoting its association with subunit S2 as a means to stabilize the structure of S1 within the S1/S2 complex. The results raise the therapeutic possibility of immunologically targeting the epitope involved in stabilizing the G614 phenotype as a means of reducing the infection efficacy of SARS-CoV-2. This therapeutic modality would not a-priori interfere directly with current efforts toward the immunological targeting of the RBD epitope; hence, it could be exploited as a complementary treatment.Four of five different monoclonal antibodies (mAbs) that have been crystallized in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S) have remarkably similar primary and secondary loop structures at the heavy chain complementarity-determining regions (HCDR) 1 and 2. selleck inhibitor All these reports give a structural basis for the deceptively difficult problem of accurate peptidomimetic loop mimic design.Functional connectivity (FC) has been widely investigated to understand the cognition and behavior that emerge from human brain. Recently, there is overwhelming evidence showing that quantifying temporal changes in FC may provide greater insight into fundamental properties of brain network. However, scant attentions has been given to characterize the functional dynamics of network organization. To address this challenge, we propose a novel spatio-temporal hub identification method for functional brain networks by simultaneously identifying hub nodes in each static sliding window and maintaining the reasonable dynamics across the sliding windows, which allows us to further characterize the full-spectrum evolution of hub nodes along with the subject-specific functional dynamics. We have evaluated our spatio-temporal hub identification method on resting-state functional resonance imaging (fMRI) data from an obsessive-compulsive disease (OCD) study, where our new functional hub detection method outperforms current methods (without considering functional dynamics) in terms of accuracy and consistency.Nutrigenomic malnutrition during pregnancy and early postnatal life has serious consequences on original organ-programing, growth pattern, puberty and quality of life. The aim of this was to investigate the effect of two notable flavonoids, quercetin and kaempferol, with nutrigenomic potentials on prenatal and early postnatal food restrictions or both on gestational outcomes and the onset of puberty in male and females Wister rats. In three sets of experiments consisting of prenatal, postnatal food deprivations or both, rats were distributed into various treatment groups (n = 6). Prenatal food restriction (PrNFR) was initiated by 50% of ad libitum available diet in pregnancy (days 1-22) simultaneously with quercetin (50, 100 and 200 mg/kg, p.o./day) or kaempferol (50, 100 and 200 mg/kg, p.o./day) until delivery. However, postnatal food restriction (PsNFR) was simulated by litter-increment to 16 pups per mother from postnatal day 2 together with quercetin (50-200 mg/kg, p.o.) or kaempferol (50-200 mg/kg, p.o.) treatments until weaning (day 24) respectively. The last experiment encompasses both protocols with similar treatment protocols. Kaempferol attenuated PrNFR-induced alterations in gestational length compared to PrNFR-control. Quercetin and kaempferol significantly (P less then 0.05) normalized nose-length of pups of rats exposed to PrNFR. Quercetin and kaempferol reduced the number of stillbirths due to PrNFR. Both also reduced the delay in pubertal onset as evidenced by normal onset of balanopreputial-separation and vaginal-opening in the PrNFR, PsNFR and PrNFR-PsNFR male and female rats respectively. Together, quercetin and kaempferol prevents prenatal and postnatal malnutrition-induced altered gestational outcomes and pubertal delays in rats.
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