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1.  Cancer genomic research at the crossroads: realizing the changing genetic landscape as intratumoral spatial and temporal heterogeneity becomes a confounding factor 
Cancer Cell International  2014;14(1):115.
The US National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) created the Cancer Genome Atlas (TCGA) Project in 2006. The TCGA’s goal was to sequence the genomes of 10,000 tumors to identify common genetic changes among different types of tumors for developing genetic-based treatments. TCGA offered great potential for cancer patients, but in reality has little impact on clinical applications. Recent reports place the past TCGA approach of testing a small tumor mass at a single time-point at a crossroads. This crossroads presents us with the conundrum of whether we should sequence more tumors or obtain multiple biopsies from each individual tumor at different time points. Sequencing more tumors with the past TCGA approach of single time-point sampling can neither capture the heterogeneity between different parts of the same tumor nor catch the heterogeneity that occurs as a function of time, error rates, and random drift. Obtaining multiple biopsies from each individual tumor presents multiple logistical and financial challenges. Here, we review current literature and rethink the utility and application of the TCGA approach. We discuss that the TCGA-led catalogue may provide insights into studying the functional significance of oncogenic genes in reference to non-cancer genetic background. Different methods to enhance identifying cancer targets, such as single cell technology, real time imaging of cancer cells with a biological global positioning system, and cross-referencing big data sets, are offered as ways to address sampling discrepancies in the face of tumor heterogeneity. We predict that TCGA landmarks may prove far more useful for cancer prevention than for cancer diagnosis and treatment when considering the effect of non-cancer genes and the normal genetic background on tumor microenvironment. Cancer prevention can be better realized once we understand how therapy affects the genetic makeup of cancer over time in a clinical setting. This may help create novel therapies for gene mutations that arise during a tumor’s evolution from the selection pressure of treatment.
doi:10.1186/s12935-014-0115-7
PMCID: PMC4236490  PMID: 25411563
2.  Inauguration of the Cameroonian Society of Human Genetics  
The conjunction of “hard genetics” research centers, with well established biomedical and bioethics research groups, and the exceptional possibility to hold the 6th annual meeting of the African Society of Human Genetics (AfSHG, 13th–15th March 2009) was an excellent opportunity to get together in synergy the entire Cameroonian “DNA/RNA scientists” . This laid to the foundation of the Cameroonian Society of Human Genetics (CSHG) that was privilege to hold its inaugural meeting in conjunction to the 6th annual meeting of the AfSHG. The theme was "Human Origin, Genetic Diversity and Health”. The AfSHG and CSHG invited leading African and international scientists in genomics and population genetics to review recent data and provide an understanding of the state-of-knowledge of Human Origin and Genetic Diversity. Overall one opening ceremony eight session, five keynote and guest speakers, 18 invited oral communications, 13 free oral communications, 43 posters and two social events could summarize the meeting. This year’s conference was graced by the presence of one Nobel Prize winner Dr Richard Roberts (Physiology and Medicine 1993). The meeting registered up to ten contributions of Cameroonian scientists from the Diaspora (currently in USA, Belgium, Gambia, Sudan and Zimbabwe). Such Diaspora participation is an opportunity to generate collaborations with home country scientists and ultimately turn the “brain drain” to “brain circulation” that could reduce the impact of the migration of health professional from Africa. Interestingly, the personal implication of the Cameroonian Ministry of Public Heath who opened the meeting in the presence of the Secretary General of the Ministry of Higher Education and a representative of the Ministry of Scientific Research and Innovation was a wonderful opportunity for advocacy of genetic issues at the decision-makers level. Beyond our expectation, a major promise of the Cameroonian government was the creation of the National Human Genome Institute. If this goal comes true, this will be a critical step to bring more genetics for the purpose of Public Health to the Cameroonian people. The sub-Saharan African Region needs significant capacity building in the broad area of basic research in general and Genetics (especially Human Genetics) in particular. In that respect, the existence and current activities of the AfSHG and its impact at the National levels in Africa, is a major development for the continent and an initiative that needs further encouragement from the international community.
PMCID: PMC2984290  PMID: 21532717
Human Genetics ;  Africa
3.  Canadian initiatives for locally advanced breast cancer research and treatment: inaugural meeting of the Canadian Consortium for LABC 
Current Oncology  2011;18(3):139-144.
The inaugural Canadian Consortium for LABC (locally advanced breast cancer) conference was held at Langdon Hall, Cambridge, Ontario, April 11–12, 2010. The meeting focused on current and future directions in labc treatment and research, the specific benefits of labc as a model for clinical and translational research, strategies for increased national and international collaboration, and ongoing clinical trials. Exciting Canadian initiatives in labc research are underway, focusing on identifying molecular signatures that will allow for the development of new tailored therapies. The challenge of identifying patient subgroups for accrual is being addressed through strategies to foster and improve national collaboration. This meeting report includes highlights from each presentation at the conference.
PMCID: PMC3108867
Breast neoplasms; cancer treatment; clinical research; translational research; neoadjuvant therapy; biomarkers
6.  INAUGURAL ADDRESS * 
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PMCID: PMC1591185
9.  Inaugural Presidential Address 
Canadian Family Physician  1971;17(11):111-113.
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PMCID: PMC2370278
11.  Inaugural Address * 
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PMCID: PMC2617257  PMID: 13097175
12.  Inaugural Address 
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PMCID: PMC2617165  PMID: 13023419
18.  At the Crossroads: Mucosal Immunology of the Larynx 
Mucosal immunology  2009;2(2):122-128.
The larynx sits at the crossroads between gastrointestinal and respiratory tracts. Besides its intrinsic importance in breathing, swallowing and voice production, the larynx is also exposed to unique immunological challenges. Given the propensity of chronic inflammatory conditions such as chronic laryngitis, which affects up to 20% of Western populations, it is perhaps surprising that our understanding of the immunology of this organ remains relatively limited. However, recent work on the immunological architecture of the laryngeal mucosa, and its changes that result from external challenges and inflammatory conditions, provided valuable insight into the fascinating immunology of this organ. The lessons learnt from these investigations may go beyond devising improved therapy for chronic laryngeal inflammation. Establishing whether and how the laryngeal mucosa may be involved in the modulation of wider mucosal responses may provide novel routes to the treatment of other inflammatory diseases of the respiratory and alimentary tracts such as asthma and inflammatory bowel disease.
doi:10.1038/mi.2008.82
PMCID: PMC2666820  PMID: 19129759
19.  PRION PROTEIN AT THE CROSSROADS OF PHYSIOLOGY AND DISEASE 
Trends in Neurosciences  2011;35(2):92-103.
The presence of the cellular prion protein (PrPC) on the cell surface is critical for the neurotoxicity of prions. Although a number of biological activities have been attributed to PrPC, a definitive demonstration of its physiological function remains elusive. In this review, we will discuss some of the proposed functions of PrPC, focusing on recently suggested roles in cell adhesion, regulation of ionic currents at the cell membrane, and neuroprotection. We will also discuss recent evidence supporting the idea that PrPC may function as a receptor for soluble oligomers of the amyloid β peptide and possibly other toxic protein aggregates. These data suggest surprising new connections between the physiological function of PrPC and its role in neurodegenerative diseases beyond those caused by prions.
doi:10.1016/j.tins.2011.10.002
PMCID: PMC3273588  PMID: 22137337
20.  Childhood infections and asthma: at the crossroads of the hygiene and Barker hypotheses 
Respiratory Research  2001;2(6):324-327.
The hygiene hypothesis states that childhood asthma develops as a result of decreased exposure to infectious agents during infancy and early childhood. This results in the persistence of the neonatal T helper lymphocyte 2 immunophenotype, thereby predisposing the child to atopic disease. While multiple studies support the hygiene hypothesis in asthma ontogeny, the evidence remains inconclusive; multiple other environmental exposures in early childhood also alter predisposition to asthma. Moreover, the current paradigm for asthma development extends far beyond simple childhood environmental exposures to include fetal development, genetic predisposition, and interactions of the developmental state and genetics with the environment.
doi:10.1186/rr81
PMCID: PMC64800  PMID: 11737930
asthma; child; fetal programming; gene by environment; infection
21.  Crossroads in the Combined-Modality Management of Gastroesophageal Junction Carcinomas 
An epidemiologic shift in esophageal and gastric carcinomas has occurred in recent years in the Western world. Adenocarcinoma of the distal esophagus and gastroesophageal junction (GEJ) is now the predominant esophageal carcinoma, and proximal gastric cancers now account for nearly half of gastric carcinomas. Tumors involving the GEJ appear to be a distinct clinical entity that presents a challenge to oncologists due to issues in staging and classification and uncertainties regarding optimal treatment approach. Beyond surgical resection as the primary treatment modality, the roles of neoadjuvant or adjuvant therapies in GEJ cancers are not clearly defined. This article reviews the major randomized trials of combined-modality treatment in populations with esophageal and gastric cancers that included patients with GEJ carcinomas and discusses how the findings relate to and inform the management of GEJ tumors. In general, preoperative or perioperative chemotherapy appears to improve survival, and the addition of neoadjuvant or adjuvant chemoradiotherapy increases locoregional control and appears to improve survival. Although GEJ tumors account for only 20% to 35% of cancers in the most relevant randomized trials, the available data suggest that trimodality therapy with chemotherapy, radiation, and surgery is a reasonable treatment approach for GEJ tumors. Further clinical trials are needed to define the optimal sequencing and combinations of surgery, radiotherapy, and chemotherapy. These trials should include appropriate definitions and stratification of GEJ tumors in order to facilitate translation of findings to treatment practice.
PMCID: PMC2632556  PMID: 19259307
22.  At the Crossroads: Development and evaluation of a dementia caregiver group intervention to assist in driving cessation 
Deciding when an individual with dementia must reduce or stop driving can be a stressful issue for family caregivers. The purpose of this study was to develop a group intervention to assist these caregivers with driving issues and to provide a preliminary evaluation of the comparative effectiveness of this At the Crossroads intervention. Participants were randomized to one of three arms: (1) active intervention (four 2-hour manualized educational/support group meetings; n=31); (2) written materials only (subjects received written materials after a pre-test; n=23); and (3) control (subjects received written materials after a post-test; n=12). Subjects were administered a battery of self-report and interview-based questionnaires at baseline and again two months later. At follow-up, the active intervention group scored significantly better than both other groups on key outcome variables, including self-efficacy, communication, and preparedness. The At the Crossroads caregiver intervention appears to effectively provide education and support needed for caregivers to address driving-related issues with their loved ones.
PMCID: PMC2679525  PMID: 19064472
Driving; Dementia; Alzheimer’s Disease; Caregiver; Transportation; Independence; Stress; Support Group; Intervention
23.  Mitochondria in cancer: at the crossroads of life and death 
Chinese Journal of Cancer  2011;30(8):526-539.
Mitochondrial processes play an important role in tumor initiation and progression. In this review, we focus on three critical processes by which mitochondrial function may contribute to cancer: through alterations in glucose metabolism, the production of reactive oxygen species (ROS) and compromise of intrinsic apoptotic function. Alterations in cancer glucose metabolism include the Warburg effect, leading to a shift in metabolism away from aerobic respiration toward glycolysis, even when sufficient oxygen is present to support respiration. Such alterations in cellular metabolism may favor tumor cell growth by increasing the availability of biosynthetic intermediates needed for cellular growth and proliferation. Mutations in specific metabolic enzymes, namely succinate dehydrogenase, fumarate hydratase and the isocitrate dehydrogenases, have been linked to human cancer. Mitochondrial ROS may contribute to cancer via DNA damage and the activation of aberrant signaling pathways. ROS-dependent stabilization of the transcription factor hypoxia-inducible factor (HIF) may be a particularly important event for tumorigenesis. Compromised function of intrinsic apoptosis removes an important cellular safeguard against cancer and has been implicated in tumorigenesis, tumor metastasis, and chemoresistance. Each of the major mitochondrial processes is linked. In this review, we outline the connections between them and address ways these mitochondrial pathways may be targeted for cancer therapy.
doi:10.5732/cjc.011.10018
PMCID: PMC3336361  PMID: 21801601
Mitochondria; cancer; metabolism; apoptosis; reactive oxygen species
24.  Clinical development of insulin-like growth factor receptor—1 (IGF-1R) inhibitors: At the crossroad? 
Investigational New Drugs  2012;30(6):2433-2442.
Summary
Insulin like growth factor receptor (IGF-1R) targeting became one of the most investigated areas in anticancer drug development during the last decade. Strategies aiming to block IGF-1R activity include monoclonal antibodies, tyrosine kinase inhibitors and anti-ligands antibodies. Initial enthusiasm quickly encountered challenges. Unfortunately the validation of the efficacy of IGF-1R targeted agents in large clinical trials failed, however anecdotal single agent activity was seen in early studies. Consequently, questions regarding the selection of right target population and the appropriate trial design are arising. Despite the plethora of clinical trials conducted no predictive biomarker has been validated so far and resistance mechanisms to IGF-1R inhibitors remain unclear. The other issue to be addressed is how to best combine IGF-1R inhibitors with other therapeutic approaches. This review highlights the most relevant clinical data emphasizing the main tumor types where IGF-1R inhibition showed potential interest. We also tried to extract based on clinical and translational data some candidate biomarkers that could help better to select patient population who potentially could benefit most from this therapeutic approach.
doi:10.1007/s10637-012-9811-0
PMCID: PMC3484277  PMID: 22415797
IGF-1R inhibitors; Monoclonal antibodies; Tyrosine kinase inhibitors; Predictive biomarker
25.  Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence 
Current Pharmaceutical Design  2013;19(34):6064-6093.
Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of food-stuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol-based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.
doi:10.2174/13816128113199990407
PMCID: PMC3782695  PMID: 23448440
Resveratrol; clinical trials; cardiovascular; cancer; nutraceutical; polyphenol.

Results 1-25 (342150)