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Background: Signaling through mTOR and somatostatin pathway is implicated in thyroid cancer development. Method: We evaluated everolimus, an mTOR inhibitor and pasireotide, a multi receptor somatostatin analogue as potential therapy of thyroid cancer focusing on the in vitro and in vivo efficacy, as well as possible mechanism to explain any observed interaction. Results: Both everolimus and pasireotide inhibit the growth of thyroid cancer cell lines in vitro with varied efficacy that correlates with tumor origin and somatostatin receptor (SSTR) expression profile of the cell lines. In vitro activity of everolimus show positive correlation with the expression of SSTR types 1, 4 and 5 (CC: 0.9; 0.85, 0.87) while pasireotide activity show negative correlation with SSTR2 (CC: -0.87). Although there is greater modulation of pS6 when pasireotide is combined with everolimus, there is no significant abrogation of the expected feedback upregulation of AKT induced by everolimus. Also, the combination is not significantly better than each agent alone in short and long term in vitro assays. Continuous administration of everolimus at a low dose as opposed to high intermittent dosing schedule has greater antitumor efficacy against thyroid cancer xenografts in vivo. Pasireotide LAR has modest in vivo efficacy and the combination of everolimus and pasireotide LAR achieve greater tumor growth inhibition than each agent alone in TPC-1 xenograft model of thyroid cancer (p = 0.048). Conclusion: Our findings provide support for the clinical evaluation of everolimus and pasireotide in thyroid cancer and other neuroendocrine tumors. [ABSTRACT FROM AUTHOR]

Magnetosomes intracellularly biomineralized by Magnetotactic bacteria (MTB) are membrane-enveloped nanoparticles of the magnetic minerals magnetite (Fe 3 O 4) or greigite (Fe 3 S 4). MTB thrive in oxic-anoxic interface and exhibit magnetotaxis due to the presence of magnetosomes. Because of the unique characteristic and bionavigation inspiration of magnetosomes, MTB has been a subject of study focused on by biologists, medical pharmacologists, geologists, and physicists since the discovery. We herein first briefly review the features of MTB and magnetosomes. The recent insights into the process and mechanism for magnetosome biomineralization including iron uptake, magnetosome membrane invagination, iron mineralization and magnetosome chain assembly are summarized in detail. Additionally, the current research progress in biotechnological applications of magnetosomes is also elucidated, such as drug delivery, MRI image contrast, magnetic hyperthermia, wastewater treatment, and cell separation. This review would expand our understanding of biomineralization and biotechnological applications of bacterial magnetosomes. [Display omitted] • General feature of magnetotactic bacteria and magnetosomes are reviewed. • Magnetosome mineralization processes and mechanism are proposed in detail. • Magnetosomes appear extensive applications in biomedicine and environment. • The prospects for future studies of bacterial magnetosomes were discussed. [ABSTRACT FROM AUTHOR]

Poly ( ADP) ribose polymerase ( PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer ( SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥50% reduction in IC50) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin ( CC = 0.672; P = 0.048) and DNA- PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel ( GLS, UBEC2, HACL1, MSI2, and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell-specific manner. This potentiation correlates with platinum sensitivity, DNA- PKcs expression and a 5-gene expression profile. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, the compressible non-isentropic Navier–Stokes–Poisson (NSP) system is considered in and the influences of internal electric field on the qualitative behaviors of solutions are analyzed. We observe that the electric field leads to the rotating phenomena in charge transport and reduces the speed of fluid motion, but it does not influence the transport of charge density and the heat diffusion. Indeed, we show that both density and temperature of the NSP system converge to their equilibrium state at the same rate as the non-isentropic compressible Navier–Stokes system, but the momentum decays at the rate , which is slower than the rate for the pure compressible Navier–Stokes system. These convergence rates are also shown to be optimal for the non-isentropic compressible NSP system. [Copyright &y& Elsevier]

Abstract: The global in-time semiclassical and relaxation limits of the bipolar quantum hydrodynamic model for semiconductors are investigated in . We prove that the unique strong solution exists and converges globally in time to the strong solution of classical bipolar hydrodynamical equation in the process of semiclassical limit and that of the classical drift–diffusion system under the combined relaxation and semiclassical limits. [Copyright &y& Elsevier]

This paper concerns the stationary subsonic or sonic–subsonic solution of the electric potential driven problem to the isentropic hydrodynamic model for semiconductors. We give a necessary and sufficient condition to ensure the existence of this kind of solution. Specifically, there exists a subsonic or sonic–subsonic solution to this problem if and only if 0 ≤ ϕ r ≤ ϕ ̄ , with the number ϕ ̄ = O 1 τ . Here, ϕ r is the right side electric potential and τ is the relaxation time. Moreover, there is a number ϕ ̃ ∈ (0 , ϕ ̄ ] such that when ϕ r = ϕ ̃ , there exists a sonic–subsonic solution. In this way, we show the influence of the relationship between the boundary value of the electric potential and the semiconductor effect on the existence of this kind of solution. Finally, we prove the uniqueness of subsonic solution by the energy method under the assumption that ϕ r and ϕ r τ are both small enough. [ABSTRACT FROM AUTHOR]

Fluoropyridine-based chemotherapy remains the most widely used treatment for colorectal cancer (CRC). In this study, we investigated the mechanism by which the natural product Scutellaria baicalensis (Huang Qin; HQ) and one of its main components baicalin enhanced 5-fluorouracil (5-FU) antitumor activity against CRC. Cell proliferation assays, cell cycle analysis, reverse-phase protein array (RPPA) analysis, immunoblot analysis, and qRT-PCR were performed to investigate the mechanism(s) of action of HQ and its active components on growth of CRC cells. HQ exhibited in vitro antiproliferative activity against drug resistant human CRC cells, against human and mouse CRC cells with different genetic backgrounds and normal human colon epithelial cells. In vivo animal models were used to document the antitumor activity of HQ and baicalin. The mechanism of growth inhibitory activity of HQ is due to inhibition of proliferative signaling pathways including the CDK-RB pathway. In addition, HQ enhanced the antitumor effects of 5-FU and capecitabine in vivo. Furthermore, we identified baicalin as an active component of HQ. The combination of baicalin and 5-FU demonstrated synergistic activity against 5-FU-resistant RKO-R10 cells. The combination significantly inhibited in vivo tumor growth greater than each treatment alone. RPPA results showed that the signaling pathway alterations in CRC cells were similar following HQ and baicalin treatment. Together, these results indicate that HQ and its component baicalin enhance the effect of 5-fluorouracil-based chemotherapy via inhibition of CDK-RB pathway. These findings may provide the rational basis for developing agents that can overcome the development of cellular drug resistance. 9Q3bw5kPrTjBvtYuEHSNma Video Abstract [ABSTRACT FROM AUTHOR]

Sunlight radiation is a main environmental factor which affects anthocyanin synthesis. To clarify the regulatory mechanism of sunlight on the synthesis of anthocyanin in apple peel, bagged apples were exposed to diverse intensities of sunlight through different shading treatments. Under an increased solar ultraviolet-B (UV-B) light intensity, the concentration of anthocyanin in apple peels was consistent with the Michaelis–Menten equation. Under lower sunlight intensities, diphenyleneiodonium chloride (DPI, an inhibitor of plasma membrane NAD(P)H oxidase) treatment increased both the concentration of cyanidin-3-glycoside and the activity of dihydroflavonol 4-reductase (DFR). However, under higher sunlight intensities, DPI treatment decreased the concentrations of cyanidin-3-glycoside and quercetin-3-glycoside, as well as the activities of DFR and UDP-glycose: flavonoid 3-O-glycosyltransferase (UFGT). These results indicate that, under low sunlight intensity, anthocyanin synthesis in apple peel was limited by the supply of the substrate cyanidin, which was regulated by the DFR activity. Nevertheless, after exposure to high sunlight intensity, the anthocyanin produced in the apple peel was dependent on UFGT activity. [ABSTRACT FROM AUTHOR]

The initial boundary value problem for the compressible barotropic Navier–Stokes equations is investigated in the case that the initial density has a jump discontinuity across an interior closed curve in two-dimensional bounded domain. If the initial data is a small perturbation of the constant state and the interior closed curve is near a circle inside the domain, the global existence and large time behavior of the piecewise strong solution is shown, in particular, the jump of the fluid density across the convecting curve decays exponentially in time. [ABSTRACT FROM AUTHOR]

Summary Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is “hijacked” to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target. [ABSTRACT FROM AUTHOR]

Background: SCLC has limited treatment options and inadequate preclinical models. Promising activity of arsenic trioxide (ASO) recorded in conventional preclinical models of SCLC supported the clinical evaluation of ASO in patients. We assessed the efficacy of ASO in relapsed SCLC patients and in corresponding patient-derived xenografts (PDX).Methods: Single arm, Simon 2-stage, phase II trial to enroll patients with relapsed SCLC who have failed at least one line of therapy. ASO was administered as an intravenous infusion over 1-2 h daily for 4 days in week 1 and for 2 days in weeks 2-6 of an 8-week cycle. Treatment continued until disease progression. Pretreatment tumor biopsy was employed for PDX generation through direct implantation into subcutaneous pockets of SCID mice without in vitro manipulation and serially propagated for five generations. Ex vivo efficacy of cisplatin (3 mg/kg i.p. weekly) and ASO (3.75 mg/kg i.p. every other day) was tested in PDX representative of platinum sensitive and platinum refractory SCLC.Results: The best response in 17 evaluable patients was stable disease in 2 (12 %), progressive disease in 15 (88 %) patients and median time-to-progression of seven (range 1-7) weeks. PDX was successfully grown in 5 of 9 (56 %) transplanted biopsy samples. Serially-propagated PDXs preserved characteristic small cell histology and genomic stability confirmed by immunohistochemistry, short tandem repeat (STR) profiling and targeted sequencing. ASO showed in vitro cytotoxicity but lacked in vivo efficacy against SCLC PDX tumor growth.Conclusions: Cisplatin inhibited growth of PDX derived from platinum-sensitive SCLC but was ineffective against PDX from platinum-refractory SCLC. Strong concordance between clinical and ex vivo effects of ASO and cisplatin in SCLC supports the use of PDX models to prescreen promising anticancer agents prior to clinical testing in SCLC patients. Trial Registration The study was registered at http://www.clinicaltrials.gov (NCT01470248). [ABSTRACT FROM AUTHOR]

Summary The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer target. We identified a small-molecule Bcl2-BH4 domain antagonist, BDA-366, that binds BH4 with high affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival molecule to a cell death inducer. BDA-366 suppresses growth of lung cancer xenografts derived from cell lines and patient without significant normal tissue toxicity at effective doses. mTOR inhibition upregulates Bcl2 in lung cancer cells and tumor tissues from clinical trial patients. Combined BDA-366 and RAD001 treatment exhibits strong synergy against lung cancer in vivo. Development of this Bcl2-BH4 antagonist may provide a strategy to improve lung cancer outcome. [ABSTRACT FROM AUTHOR]

Summary Platinum-based chemotherapeutics represent a mainstay of cancer therapy, but resistance limits their curative potential. Through a kinome RNAi screen, we identified microtubule-associated serine/threonine kinase 1 (MAST1) as a main driver of cisplatin resistance in human cancers. Mechanistically, cisplatin but no other DNA-damaging agents inhibit the MAPK pathway by dissociating cRaf from MEK1, while MAST1 replaces cRaf to reactivate the MAPK pathway in a cRaf-independent manner. We show clinical evidence that expression of MAST1, both initial and cisplatin-induced, contributes to platinum resistance and worse clinical outcome. Targeting MAST1 with lestaurtinib, a recently identified MAST1 inhibitor, restores cisplatin sensitivity, leading to the synergistic attenuation of cancer cell proliferation and tumor growth in human cancer cells and patient-derived xenograft models. [ABSTRACT FROM AUTHOR]

Summary Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer. [ABSTRACT FROM AUTHOR]