Publications

2015
Altrock, P.M., Liu, L.L. & Michor, F. The mathematics of cancer: integrating quantitative models. Nat Rev Cancer 15, 12, 730-45 (2015).Abstract
Mathematical modelling approaches have become increasingly abundant in cancer research. The complexity of cancer is well suited to quantitative approaches as it provides challenges and opportunities for new developments. In turn, mathematical modelling contributes to cancer research by helping to elucidate mechanisms and by providing quantitative predictions that can be validated. The recent expansion of quantitative models addresses many questions regarding tumour initiation, progression and metastases as well as intra-tumour heterogeneity, treatment responses and resistance. Mathematical models can complement experimental and clinical studies, but also challenge current paradigms, redefine our understanding of mechanisms driving tumorigenesis and shape future research in cancer biology.
Austin, L.A., Osseiran, S. & Evans, C.L. Raman technologies in cancer diagnostics. Analyst (2015).Abstract

Despite significant effort, cancer still remains a leading cause of death worldwide. In order to reduce its burden, the development and improvement of noninvasive strategies for early detection and diagnosis of cancer are urgently needed. Raman spectroscopy, an optical technique that relies on inelastic light scattering arising from molecular vibrations, is one such strategy, as it can noninvasively probe cancerous markers using only endogenous contrast. In this review, spontaneous, coherent and surface enhanced Raman spectroscopies and imaging, as well as the fundamental principles governing the successful use of these techniques, are discussed. Methods for spectral data analysis are also highlighted. Utilization of the discussed Raman techniques for the detection and diagnosis of cancer in vitro, ex vivo and in vivo is described. The review concludes with a discussion of the future directions of Raman technologies, with particular emphasis on their clinical translation.

Montero, J., et al. Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 160, 5, 977-89 (2015).Abstract
There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo.
Harris, I.S. & Brugge, J.S. Cancer: The enemy of my enemy is my friend. Nature 527, 170-171 (2015).Abstract

Reactive oxygen species have been viewed as stress-inducing molecules that promote cancer initiation. But new evidence indicates that oxidative stress can be beneficial — inhibiting the spread of a cancer to other sites.

Buchbinder, E. & Hodi, F.S. Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade. Journal of Clinical Investigation 125, 9, 3377-3383 (2015).Abstract

The relationship between cancer and the immune system is complex and provides unique therapeutic opportunities. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory molecule that suppresses T cell effector function following initial activation by costimulatory signals. Fully human monoclonal antibodies targeting CTLA-4 have been shown to increase T cell function and antitumor responses in patients with advanced metastatic melanoma. Responses observed with such immune checkpoint therapy can follow a different pattern from that seen with cytotoxic chemotherapy or targeted therapy and may continue after therapy is discontinued. In addition, the toxicities that are associated with anti–CTLA-4 therapy may differ from those of conventional therapies and consist of inflammatory events in parts of the body that do not contain cancerous cells. Early recognition of these inflammatory events and intervention is important, and the identification of predictive biomarkers continues to be an unfulfilled need in the field of immunotherapy. Combinatorial approaches with targeted therapies, radiation therapy, chemotherapy, or other immune checkpoint agonists/antagonists have the potential to increase the efficacy of CTLA-4 blockade.

Xia, H.G., et al. Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death. Journal of Cell Biology 210, 5, 705-16 (2015).Abstract

Hexokinase II (HK2), a key enzyme involved in glucose metabolism, is regulated by growth factor signaling and is required for initiation and maintenance of tumors. Here we show that metabolic stress triggered by perturbation of receptor tyrosine kinase FLT3 in non–acute myeloid leukemia cells sensitizes cancer cells to autophagy inhibition and leads to excessive activation of chaperone-mediated autophagy (CMA). Our data demonstrate that FLT3 is an important sensor of cellular nutritional state and elucidate the role and molecular mechanism of CMA in metabolic regulation and mediating cancer cell death. Importantly, our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. We reveal a new mechanism by which excessive activation of CMA may be exploited pharmacologically to eliminate cancer cells by inhibiting both FLT3 and autophagy. Our study delineates a novel pharmacological strategy to promote the degradation of HK2 in cancer cells.

Brown, K.K., Montaser-Kouhsari, L., Beck, A.H. & Toker, A. MERIT40 Is an Akt Substrate that Promotes Resolution of DNA DAmage Induced by Chemotherapy. Cell Reports 11, 9, 1358-1366 (2015).Abstract

Resistance to cytotoxic chemotherapy drugs, including doxorubicin, is a significant obstacle to the effective treatment of breast cancer. Here, we have identified a mechanism by which the PI3K/Akt pathway mediates resistance to doxorubicin. In addition to inducing DNA damage, doxorubicin triggers sustained activation of Akt signaling in breast cancer cells. We show that Akt contributes to chemotherapy resistance such that PI3K or Akt inhibitors sensitize cells to doxorubicin. We identify MERIT40, a component of the BRCA1-A DNA damage repair complex, as an Akt substrate that is phosphorylated following doxorubicin treatment. MERIT40 phosphorylation facilitates assembly of the BRCA1-A complex in response to DNA damage and contributes to DNA repair and cell survival following doxorubicin treatment. Finally, MERIT40 phosphorylation in human breast cancers is associated with estrogen receptor positivity. Our findings suggest that combination therapy with PI3K or Akt inhibitors and doxorubicin may constitute a successful strategy for overcoming chemotherapy resistance.

 

2014
De Raedt, T., et al. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514, 7521, 247-51 (2014).Abstract
The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.
Patel, A.P., et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396-401 (2014).Abstract

Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy.

1977
Cotton, D.J., et al. Rapid, shallow breathing after Ascaris suum antigen inhalation: role of vagus nerves. J Appl Physiol Respir Environ Exerc Physiol 42, 1, 101-6 (1977).Abstract
In five treadmill-exercising, unsedated dogs, we studied the effect of inhaled Ascaris suum antigen aerosols on minute volume of ventilation (VE), respiratory frequency (f), tidal volume (VT), total pulmonary resistance (RL), and dynamic pulmonary compliance (CLdyn), before and during cooling of the vagus nerves. With the vagi warm, inhaled antigen increased VE (mean + 62%; P less than 0.01)by increasing f (mean + 180%; P less than 0.01), despite a decrease in VT (mean - 42%; P less than 0.01). RL increased (mean + 170%; P less than 0.001) and CLdyn decreased (mean - 43%; P less than 0.005). With the vagi cool, inhaled antigen no longer affected VE, f, or VT (P greater than 0.5), although RL still increased and CLdyn still decreased. Inhalation of a bronchodilator, terbutaline, prevented the broncho-constriction induced by antigen but did not prevent the ventilatory response. We conclude that vagal afferent pathways mediate the ventilatory response to inhaled antigen and suggest that the primary stimulus for this response is not airway narrowing.
1976
Kaul, A.F. & Harshfield, J.C. Letter: Stability of aspirin in combination with propoxyphene hydrochloride and propoxyphene napsylate. N Engl J Med 294, 16, 907 (1976).
Ahmed, A.E. & Anders, M.W. Metabolism of dihalomethanes to formaldehyde and inorganic halide. I. In vitro studies. Drug Metab Dispos 4, 4, 357-61 (1976).Abstract
Metabolism of dihalomethanes by rat liver cytosol fractions yielded formaldehyde and inorganic halide as products. Loss of metabolic activity resulting from dialysis of the cytosol was restored with glutathione. Cysteine could not substitute for GSH. No other cofactor was found to be required for activity. The optimum conditions for this biotransformation with respect to time, temperature, protein concentration, and pH were determined. Rates of metabolism of dihalomethanes showed the following order: CH2i2 greater than CH2Br2 congruent to CH2BrCi greater than CH2Ci2. Administration of the enzyme inducer, phenobarbital, to rats did not alter this metabolic pathway nor did repeated administration of CH2Br2 or CH2Ci2 change the rate of metabolism. The enzyme catalyzing this reaction was localized in the liver. Compounds known to serve as substrates for various GSH transferases inhibited the reaction as did those capable of interacting with sulfhydryl groups.
PetitClerc, C. Quantitative fractionation of alkaline phosphatase isoenzymes according to their thermostability. Clin Chem 22, 1, 42-8 (1976).Abstract
Continuous monitoring of heat denaturation of a mixture of alkaline phosphatase isoenzymes at 60 degrees C and pH 7.5 permits the simultaneous direct identification and quantitation of three isoenzymes: the placental isoenzyme, the L-phenylalanine-sensitive intestinal isoenzyme, and the liver isoenzyme (hepatocytic). The isoenzyme that is principally of bone origin cannot be identified as such without the help of other diagnostic aids and the patient's medical history. All human tissues contain alkaline phosphatase, many organs more than one of the isoenzymes. Liver alkaline phosphatase, which constitutes 40-50% of normal serum alkaline phosphatase activity, was measured in the serum of persons with various liver diseases. Its activity exceeded normal in all types of liver disease; in 80% of cases this increase was accompanied by increased gamma-glutamyl-transferase activity, but the quantitative correlationship (r = 0.54) was not as good as expected if both enzymes come from the same source and are indices of liver dieases. Liver alkaline phosphatase activity increases in the blood early in liver disease, before most liver tests show abnormalities. The other major isoenzyme of normal serum probably represents a mixture of isoenzymes from bone and reticulo-endothelial and vascular tissues, which all contain the same "very heat-labile" alkaline phosphatase. Cord blood and children's sera contain mostly this very heat-labile isoenzyme.
Feller, R.P., Shannon, I.L., Matranga, L.F., Osborne, H.W. & Perez, R.S. Reduction of enamel solubility by sodium monophosphate. J Dent Res 55, 3, 510-4 (1976).Abstract
The preponderance of evidence indicates that sodium monofluorophosphate exerts a highly beneficial effect on dental caries incidence and enamel solubility. Optimal effects are obtained with a concentration of 4 X 10(3) ppm fluoride, by a four-minute application and by adjusting the pH to 4.0. The reaction of sodium monofluorophosphate with enamel is not temperature dependent. Sodium monofluorophosphate is significantly more protective than sodium fluoride in aqueous solutions at all equivalent fluoride concentrations and in pastes at concentrations exceeding 8 X 10(3) ppm fluoride.
1975
Golovistikov, I.N. [Ability of antilymphocyte sera to counteract the allogeneic inhibition of hematopoietic stem cells]. Dokl Akad Nauk SSSR 223, 5, 1245-7 (1975).
Halaris, A.E., Belendiuk, K.T. & Freedman, D.X. Antidepressant drugs affect dopamine uptake. Biochem Pharmacol 24, 20, 1896-7 (1975).
Hendrickson, W.A. & Ward, K.B. Atomic models for the polypeptide backbones of myohemerythrin and hemerythrin. Biochem Biophys Res Commun 66, 4, 1349-56 (1975).
Jallon, J.M., Risler, Y. & Iwatsubo, M. Beef liver L-Glutamate dehydrogenase mechanism: presteady state study of the catalytic reduction of 2.oxoglutarate by NADPH. Biochem Biophys Res Commun 67, 4, 1527-36 (1975).
Isaac, O. & Thiemer, K. [Biochemical studies on camomile components/III. In vitro studies about the antipeptic activity of (--)-alpha-bisabolol (author's transl)]. Arzneimittelforschung 25, 9, 1352-4 (1975).Abstract
(--)-alpha-Bisabolol has a primary antipeptic action depending on dosage, which is not caused by an alteration of the pH-value. The proteolytic activity of pepsin is reduced by 50 percent through addition of bisabolol in the ratio of 1/0.5. The antipeptic action of bisabolol only occurs in case of direct contact. In case of a previous contact with the substrate, the inhibiting effect is lost.
Rogol, A.D., Ben-David, M., Sheats, R., Rodbard, D. & Chrambach, A. Charge properties of human pituitary and amniotic fluid prolactins. Endocr Res Commun 2, 6-7, 379-402 (1975).Abstract
The apparent isoelectric points (pI) in isoelectric focusing (IF) of human pituitary and amniotic fluid prolactin (hPRL), both non-iodinated and iodinated, were determined. Unresolved mixtures of pituitary hPRL isohormones E and F, and of at least five isohormones found in amniotic fluid, and plasma hPRL exhibit an average pI value of 6.5 - 6.7. Transient state pH values observed or previously reported for hPRL components range from pH 5.9 to 6.8 after correction to standard conditions. At pH 8.1, the major isohormone, hPRL-F, carriers a charge of 2.2 net protons per molecule. The net charge differences among isohormones E, F and G are compatible with acquisition or loss of single charged groups per 20,000 molecular weight. This net charge is similar to that of the least prolactin-bioactive major isohormone of human growth hormone (hGH-B), while the hGH with a bioactivity comparable to that of hPRL exhibits a net charge of 3.4 valence units. The "large" isohormones J and H increased net charges, by a factor of 2-3, in direct proportion to their size increments.

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