Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Not exactly tales for boys: Gender and difference in the writings of Joseph Conrad

In Joseph Conrad\u27s tales, representations of women and of feminine generic forms like the romance are often present in fugitive ways. Conrad\u27s use of allegorical feminine imagery, fleet or deferred introductions of female characters, and hybrid generic structures that combine features of masculine tales of adventure and intrigue and feminine dramas of love or domesticity have all inspired extensive commentary. Many critics have argued that Conrad\u27s fictions are aesthetically flawed by the inclusion of women and love plots; thus Thomas Moser has questioned why Conrad did not cut them out altogether (99). Yet a thematics of gender suffuses Conrad\u27s narrative strategies. Even in tales that contain no significant female characters or obvious love plots, Conrad portrays men whose gender identifications are not always clearly discrete; in subtle acts of displacement, Conrad introduces elusive feminine presences into male/male relationships. One instance of Conrad\u27s ambiguous deferrals at the generic level occurs in The Secret Agent; late in the novel, the Assistant Commissioner tells the Home Secretary, From a certain point of view we are here in the presence of a domestic drama (204). That point of view, which the detective tacitly refrains from claiming as his own, recasts a political threat as a sexual or domestic crisis and situates Winnie Verloc, with all her marital secrets, at the center of the action. In my dissertation, I investigate this identifiably feminine point of view, which is present in fugitive ways throughout Conrad\u27s canon. Focusing on current feminist, historicist, and psychoanalytic debates about subjectivity, female iconography, fetishism, genre theory, narrative satire, audience address, and the gaze, I explore how issues of gender and difference inform Conrad\u27s fictions at both structural and thematic levels. Conrad\u27s narrative strategies are articulated through a language of sexual difference that provides the vocabulary and the grammar for tales examining European class and racial---as well as gender---paradigms and their effects both in Europe and in the colonies. Yet this language is more than merely descriptive, for it permits dialogic tensions and interpretive indeterminacies incompatible with the uncritical reproduction of Victorian ideologic (and generic) norms and goals

The Rapid interaction: A qualitative study of provider approaches to implementing Rapid ART

Background: Offering antiretroviral therapy (ART) to patients directly following an HIV diagnosis ("Rapid ART") improves clinical outcomes and is feasible and acceptable for patients and providers. Despite this, implementation of Rapid ART is not yet standard practice in the USA. Structural-level implementation guidance is available, but research at the individual provider level that explores the patient-provider interaction itself remains scarce. The Consolidated Framework for Implementation Research (CFIR) provides a nuanced guide to investigating the less visible, more social elements of implementation like the knowledge and feelings of people, and the influences of culture and resources on individual approaches. Methods: We conducted a multi-site qualitative study, exploring intervention commonalities across three HIV clinic environments: an HIV primary care clinic; an HIV/STI testing, treatment, and prevention clinic; and a large federally qualified health center (FQHC). Qualitative data were gathered from 27 provider informants-Rapid ART program staff and clinicians-using an interview guide developed using the CFIR. An experienced qualitative team conducted a comprehensive thematic analysis and identified cross-cutting themes in how providers approach and engage in the Rapid interaction, as well as longer-form narratives from providers that describe more fully what this interaction looks like for them. Results: Three main themes represent the range and content of individual provider approaches to the Rapid interaction: (1) patient-centeredness; (2) emotional support and partnership; and (3) correcting misperceptions about HIV. Each theme encompassed both conceptual approaches to offering Rapid ART and concrete examples of messaging to the patient that providers used in the Rapid interaction. We describe and show examples of these themes, offer key take-aways for implementation, and provide expanded narratives of providers' personal approaches to the Rapid interaction. Conclusions: Exploration of provider-level approaches to Rapid ART implementation, as carried out in the patient-provider Rapid interaction, contributes a critical layer of evidence for wider implementation. It is our hope that, together with existing research showing positive outcomes and core components of systems-level implementation, these findings add to an instructive body of findings that facilitates the implementation of Rapid ART as an enhanced model of HIV care.</p

Size does matter: why polyploid tumor cells are critical drug targets in the war on cancer.

Tumor evolution presents a formidable obstacle that currently prevents the development of truly curative treatments for cancer. In this perspective, we advocate for the hypothesis that tumor cells with significantly elevated genomic content (polyploid tumor cells) facilitate rapid tumor evolution and the acquisition of therapy resistance in multiple incurable cancers. We appeal to studies conducted in yeast, cancer models and cancer patients, which all converge on the hypothesis that polyploidy enables large phenotypic leaps, providing access to many different therapy-resistant phenotypes. We develop a flow-cytometry based method for quantifying the prevalence of polyploid tumor cells, and show the frequency of these cells in patient tumors may be higher than is generally appreciated. We then present recent studies identifying promising new therapeutic strategies that could be used to specifically target polyploid tumor cells in cancer patients. We argue that these therapeutic approaches should be incorporated into new treatment strategies aimed at blocking tumor evolution by killing the highly evolvable, therapy resistant polyploid cell subpopulations, thus helping to maintain patient tumors in a drug sensitive state