Tackling heterogeneity in treatment-resistant breast cancer using a broad-spectrum therapeutic approach.

Tumor heterogeneity can contribute to the development of therapeutic resistance in cancer, including advanced breast cancers. The object of the Halifax project was to identify new treatments that would address mechanisms of therapeutic resistance through tumor heterogeneity by uncovering combinations of therapeutics that could target the hallmarks of cancer rather than focusing on individual gene products. A taskforce of 180 cancer researchers, used molecular profiling to highlight key targets responsible for each of the hallmarks of cancer and then find existing therapeutic agents that could be used to reach those targets with limited toxicity.

The Human Affectome Project: A dedication to Jaak Panksepp.

Mapping the neural basis of the Affectome was certainly the goal of Jaak Panksepp as he extended the work of a long line of thinkers from William James to Paul Maclean. Jaak's contribution was not just an incremental step, but a move to embrace feelings as a key component of affective science. His goal was to develop objective behavioral measures as he identified the neural substrates associated with affective states.

The neuroscience of social feelings: mechanisms of adaptive social functioning.

Social feelings have conceptual and empirical connections with affect and emotion. In this review, we discuss how they relate to cognition, emotion, behavior and well-being. We examine the functional neuroanatomy and neurobiology of social feelings and their role in adaptive social functioning.

Using the Key Characteristics of Carcinogens to Develop Research on Chemical Mixtures and Cancer.

Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit.

The neuroscience of positive emotions and affect: Implications for cultivating happiness and wellbeing.

This review paper provides an integrative account regarding neurophysiological correlates of positive emotions and affect that cumulatively contribute to the scaffolding for happiness and wellbeing in humans and other animals. This paper reviews the associations among neurotransmitters, hormones, brain networks, and cognitive functions in the context of positive emotions and affect. Consideration of lifespan developmental perspectives are incorporated, and we also examine the impact of healthy social relationships and environmental contexts on the modulation of positive emotions and affect.

Testing the low dose mixtures hypothesis from the Halifax project.

In 2013, 60 scientists, representing a larger group of 174 scientists from 26 nations, met in Halifax, Nova Scotia to consider whether - using published research - it was logical to anticipate that a mixture of chemicals, each thought to be non-carcinogenic, might act together in that mixture as a . The group identified 89 such chemicals, each one affecting one or more Hallmark(s) - collectively covering all Hallmarks of Cancer - confirming the possibility that a chemical mixture could induce all the Hallmarks and function as a virtual carcinogen, thereby supporting the concern that chemical safety research that does not evaluate mixtures, is incomplete. Based on these observations, the Halifax Project developed the Low-Dose Carcinogenesis Hypothesis which posits "…that low-dose exposures to [mixtures of] disruptive chemicals that are not individually carcinogenic may be capable of instigating and/or enabling carcinogenesis.

The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification.

A sensorimotor control framework for understanding emotional communication and regulation.

Our research team was asked to consider the relationship of the neuroscience of sensorimotor control to the language of emotions and feelings. Actions are the principal means for the communication of emotions and feelings in both humans and other animals, and the allostatic mechanisms controlling action also apply to the regulation of emotional states by the self and others. We consider how motor control of hierarchically organised, feedback-based, goal-directed action has evolved in humans, within a context of consciousness, appraisal and cultural learning, to serve emotions and feelings.

Anticipatory feelings: Neural correlates and linguistic markers.

This review introduces anticipatory feelings (AF) as a new construct related to the process of anticipation and prediction of future events. AF, defined as the state of awareness of physiological and neurocognitive changes that occur within an oganism in the form of a process of adapting to future events, are an important component of anticipation and expectancy. They encompass bodily-related interoceptive and affective components and are influenced by intrapersonal and dispositional factors, such as optimism, hope, pessimism, or worry.

The neuroscience of sadness: A multidisciplinary synthesis and collaborative review.

Sadness is typically characterized by raised inner eyebrows, lowered corners of the mouth, reduced walking speed, and slumped posture. Ancient subcortical circuitry provides a neuroanatomical foundation, extending from dorsal periaqueductal grey to subgenual anterior cingulate, the latter of which is now a treatment target in disorders of sadness. Electrophysiological studies further emphasize a role for reduced left relative to right frontal asymmetry in sadness, underpinning interest in the transcranial stimulation of left dorsolateral prefrontal cortex as an antidepressant target.

Neuroimaging the consciousness of self: Review, and conceptual-methodological framework.

We review neuroimaging research investigating self-referential processing (SRP), that is, how we respond to stimuli that reference ourselves, prefaced by a lexical-thematic analysis of words indicative of "self-feelings". We consider SRP as occurring verbally (V-SRP) and non-verbally (NV-SRP), both in the controlled, "top-down" form of introspective and interoceptive tasks, respectively, as well as in the "bottom-up" spontaneous or automatic form of "mind wandering" and "body wandering" that occurs during resting state. Our review leads us to outline a conceptual and methodological framework for future SRP research that we briefly apply toward understanding certain psychological and neurological disorders symptomatically associated with abnormal SRP.

The feeling of anger: From brain networks to linguistic expressions.

This review of the neuroscience of anger is part of The Human Affectome Project, where we attempt to map anger and its components (i.e., physiological, cognitive, experiential) to the neuroscience literature (i.

Health and Racial Disparity in Breast Cancer.

Breast cancer is the most common noncutaneous malignancy and the second most lethal form of cancer among women in the United States. It currently affects more than one in ten women worldwide. The chance for a female to be diagnosed with breast cancer during her lifetime has significantly increased from 1 in 11 women in 1975 to 1 in 8 women (Altekruse, SEER Cancer Statistics Review, 1975-2007.

Physiological feelings.

The role of peripheral physiology in the experience of emotion has been debated since the 19th century following the seminal proposal by William James that somatic responses to stimuli determine subjective emotion. Subsequent views have integrated the forebrain's ability to initiate, represent and simulate such physiological events. Modern affective neuroscience envisions an interacting network of "bottom-up" and "top-down" signaling in which the peripheral (PNS) and central nervous systems both receive and generate the experience of emotion.

The role of hedonics in the Human Affectome.

Experiencing pleasure and displeasure is a fundamental part of life. Hedonics guide behavior, affect decision-making, induce learning, and much more. As the positive and negative valence of feelings, hedonics are core processes that accompany emotion, motivation, and bodily states.

Assessing the Racial and Ethnic Disparities in Breast Cancer Mortality in the United States.

Breast cancer is the second leading cause of cancer related deaths among women aged 40-55 in the United States and currently affects more than one in ten women worldwide. It is also one of the most diagnosed cancers in women both in wealthy and poor countries. Fortunately, the mortality rate from breast cancer has decreased in recent years due to increased emphasis on early detection and more effective treatments in White population.

Low-Dose Mixture Hypothesis of Carcinogenesis Workshop: Scientific Underpinnings and Research Recommendations.

Background: The current single-chemical-as-carcinogen risk assessment paradigm might underestimate or miss the cumulative effects of exposure to chemical mixtures, as highlighted in recent work from the Halifax Project. This is particularly important for chemical exposures in the low-dose range that may be affecting crucial cancer hallmark mechanisms that serve to enable carcinogenesis.

Objective: Could ongoing low-dose exposures to a mixture of commonly encountered environmental chemicals produce effects in concert that lead to carcinogenesis? A workshop held at the NIEHS in August 2015 evaluated the scientific support for the low-dose mixture hypothesis of carcinogenesis and developed a research agenda.

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.

Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression.

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis.

Environmental immune disruptors, inflammation and cancer risk.

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis.