1p microdeletion in sibs with minimal phenotypic manifestations

We report on two sibs with a paracentric in version of chromosome 1 [inv(1)(p22.3p34.1)] and a small deletion of the same chromosome (p34.1→p34.3). They presented with learning disabilities and disturbed conduct but lacked the more severe manifestations usually associated with autosomal chromosome deletion. Born to an alcoholic mother and later placed in foster care because of abuse and neglect, the behavior abnormalities they present are likely to be associated with their traumatic postnatal experience. Microscopic deletions without significant morphological phenotypic expression have been described but are rarely reported. Most reported cases of interstitial deletion of 1p had associated malformations and psychomotor retardation. These sibs may represent the first evidence that deletion of 1p34.1→1p34.3 may have little impact on the phenotype. Am. J. Med. Genet. 82:107–109, 1999. © 1999 Wiley-Liss, Inc.     

Genetic locus heterogeneity in Lafora's progressive myoclonus epilepsy

In 1995, we mapped a gene for Lafora's progressive myoclonus epilepsy in chromosome 6q23-25. In 1997 and 1998, we reduced the size of the locus to 300 kb, and an international collaboration identified mutations in the protein tyrosine phosphatase gene. Here, we examine for heterogeneity through the admixture test in 22 families and estimate the proportion of linked families to be 75 to 85%. Extremely low posterior probabilities of linkage (Wi), exclusionary LOD scores, and haplotypes identify 4 families unlikely to be linked to chromosome 6q24. Ann Neurol 1999;45:262–265     

A novel fumarate hydratase-deficient HLRCC kidney cancer cell line, UOK268: a model of the Warburg effect in cancer

The role of energy deregulation and altered/adapted metabolism in tumor cells is an increasingly important issue in understanding cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive form of RCC characterized by germline mutation of fumarate hydratase (FH), followed by somatic loss of the remaining wild-type allele and known to be a highly metastatic and lethal malignancy compared to other RCCs. The intrinsic loss of normal tricarboxylic acid (TCA) cycle presumably aids tumorigenesis due to the necessary metabolic alterations required and the enforced dependence on glycolysis derived energy, mimicking the Warburg effect. Thus, there is considerable utility in establishing a preclinical cell model from these tumors to study energy metabolism deregulation, as well as developing new targeted therapeutic approaches for TCA cycle enzyme-deficient cancers. Here, we describe a new immortalized cell line, UOK268, derived from a patient's primary HLRCC-associated kidney cancer. This represents the first primary renal cell line to model TCA cycle gene loss and provides a perfect partner cell line to our previously described metastasis-derived HLRCC-associated cell line, UOK262. We identified a novel germline FH missense mutation, p.His192Asp, and the subsequent loss of heterozygosity in UOK268. The UOK268 cell line expressed mutant FH protein, which localized to the mitochondria, but with loss of almost all catalytic activity. The UOK268 cells had severely compromised oxidative phosphorylation and increased glycolytic flux. Ingenuity pathways analysis of human mitochondria-focused cDNA microarray (hMitChip3) gene chip data confirmed the altered mRNA expression patterns of genes involved in several important pathways, such as lipid metabolism, apoptosis, and energy production/glycolysis. UOK268 provides a unique model of a primary cell line demonstrating an enforced, irreversible Warburg effect and, combined with UOK262, provides a unique in?vitro preclinical model for studying the bioenergetics of the Warburg effect in human cancer.     

Pharmacokinetics and pharmacodynamics of isothiocyanates

Isothiocyanates from Brassica vegetables are of great interest for use in the cure of bacterial infections, as is their potential application in the prevention and treatment of cancer. Although much information is available on their mode of action within the cell, when it comes to the question of whether the necessary pharmacologic concentration has been reached at the target organ, detailed knowledge is still lacking. However, a basic prerequisite for clinical application to humans is knowledge of isothiocyanate pharmacokinetic and dynamic behavior in the human body (e.g., to define intake intervals or to ascertain constant levels of the active compound). In this context, we, therefore, reviewed the available literature on in vitro studies, as well as animal and human intervention trials conducted with isothiocyanate and isothiocyanate-containing food preparations.     

Design, synthesis, and evaluation of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones as inhibitors of poly(ADP-ribose) polymerase

The design, synthesis, and biological evaluation of potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are reported. A novel series of 3,4-dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones were designed using a combination of protein structure-based drug design, molecular modeling, and structure-activity relationships (SAR). These novel submicromolar inhibitors possess a tricyclic ring system conformationally restricting the benzamide in the preferred cis orientation. The compounds were designed to optimize space-filling and atomic interactions within the NAD+ binding site of PARP-1. Previously described and newly adapted methods were applied to syntheses of these tricyclic inhibitors. Various modifications were made to the diazepinoindolones at the 6- and 7-positions in order to study this region of the active site and optimize noncovalent interactions. The electron density of derivative 28 bound to chicken PARP-1 revealed that the oxime makes a tight hydrogen bond with the catalytic gamma-carboxylate of glutamic acid (Glu) 988 in accordance with our original designs and models. Most of the compounds have been evaluated for inhibition of human PARP-1. Selected inhibitors were also tested for the ability to potentiate the cytotoxic effect of the DNA-damaging agent Topotecan.     

Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer

BACKGROUND:

It has not been well established whether genetic variations can be biomarkers for clinical outcome of gemcitabine therapy. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of gemcitabine metabolic and transporter genes that are associated with toxicity and efficacy of gemcitabine‐based therapy in patients with locally advanced pancreatic cancer.

METHODS:

The authors evaluated 17 SNPs of the CDA,dCK, DCTD, RRM1, hCNT1‐3, and hENT1 genes in 149 patients with locally advanced pancreatic cancer who underwent gemcitabine‐based chemoradiotherapy. The association of genotypes with neutropenia, tumor response to therapy, overall survival, and progression‐free survival (PFS) was analyzed by logistic regression, log‐rank test, Kaplan‐Meier plot, and Cox proportional hazards regression.

RESULTS:

The CDA A‐76C, dCK C‐1205T, RRM1 A33G, and hENT1 C913T genotypes were significantly associated with grade 3 to 4 neutropenia (P = .020, .015, .003, and .017, respectively).The CDA A‐76C and hENT1 A‐201G genotypes were significantly associated with tumor response to therapy (P = .017 and P = .019). A combined genotype effect of CDA A‐76C, RRM1 A33G, RRM1 C‐27A, and hENT1 A‐201G on PFS was observed. Patients carrying 0 to 1 (n = 64), 2 (n = 50), or 3 to 4 (n = 17) at‐risk genotypes had median PFS times of 8.3, 6.0, and 4.2 months, respectively (P = .002).

CONCLUSIONS:

The results indicated that some polymorphic variations of drug metabolic and transporter genes may be potential biomarkers for clinical outcome of gemcitabine‐based therapy in patients with locally advanced pancreatic cancer. Cancer 2010. © 2010 American Cancer Society.     

Re-embedding trust: unravelling the construction of modern diets

Recent controversies surrounding the food industry and its contribution to diet-related illnesses provide fertile ground for re-examining where power lies in food systems. A review of the literature reveals a wide range of powerful actors, contradictory assessments about consumer power and numerous examples of producers and medical authorities expending significant effort to shape the criteria by which consumers exercise choice. Expertise from the fields of marketing, advertising, psychology and nutrition science has been marshalled for close to a century to create commodity contexts that are sympathetic to mass-produced foods. In the last quarter of the twentieth century, however, a new dynamic entered the equation: the battle between technical rationality and reflexive consumers. Consumers are questioning the credentials of foods and those who promote them and, simultaneously, are seeking hope and help from the food system. As a result, health claims have become a most important ingredient in the fight for competitive advantage. This paper describes how the re-embedding of trust in a food supply dominated by corporations is being attempted through the nutritionalization of the food supply. On the basis of two studies, the authors identify the actors, processes, ideological basis and points of resistance that comprise what they are terming an emergent ‘diets-making complex’ (DMC). By intensifying the influence of science and nutritional claims in dietary discourse, the DMC has the potential to circumscribe policy options about food and health, because appeals to individual health are obscuring a social view of the food supply.     

Multipotent adipose stromal cells and breast cancer development: Think globally,act locally

It has long been appreciated that stromal cells within the breast tumor microenvironment contribute to mammary carcinogenesis. However, to date, very little is known regarding the role of local adipose‐derived stromal cells (ASCs) in the development of breast cancer. Based on pathological, epidemiological and experimental data, we postulate that breast‐derived ASCs are unique mesenchymal stem‐like cells that play a critical role in the development of breast cancer and discuss the global implications of this working model in terms of breast cancer prevention, early detection, and new targeted therapies. Mol. Carcinog. © 2010 Wiley‐Liss, Inc.