Emerging Therapeutic Strategies in Breast Cancer.

The field of medical oncology is experiencing a period of rapid evolution owing to advances in the fields of genomics, tumor biology, and immunology. These disciplines have provided valuable insights into the heterogeneity between breast tumors, key oncogenic drivers, and the role of the immune system in the natural history of breast cancer. This knowledge is translating into many novel therapeutic strategies using personalized medicines, targeted drug delivery systems, and immunomodulatory agents in the treatment of both the early and metastatic stages of the disease.

Pediatric melanoma: a review.

Background: Malignant melanoma is a rare neoplasm in the pediatric population, but its incidence has risen in recent years.

Methods: The literature was reviewed to define the current clinical and pathologic features of pediatric melanoma, highlighting the similarities and differences between adult and pediatric melanoma.

Results: Distinctive features of this disease, including frequency and type of genetic abnormalities, predisposing conditions, clinical presentation, stage at diagnosis, prognostic features, and frequency of sentinel lymph node positivity are emphasized.

Clinical trials and tribulations: lessons learned from recruiting pregnant ex-smokers for relapse prevention.

The development of smoking cessation and relapse prevention interventions for pregnant and postpartum women is a public health priority. However, researchers have consistently reported substantial difficulty in recruiting this population into clinical trials. The problem is particularly acute for relapse prevention studies, which must recruit women who have already quit smoking because of their pregnancy.

Telomerase confers resistance to caspase-mediated apoptosis.

There is growing evidence that accelerated telomeric attrition and/or aberrant telomerase activity contributes to pathogenesis in a number of diseases. Likewise, there is increasing interest to develop new therapies to restore or replace dysfunctional cells characterized by short telomeric length using telomerase-positive counterparts or stem cells. While telomerase adds telomeric repeats de novo contributing to enhanced proliferative capacity and lifespan, it may also increase cellular survival by conferring resistance to apoptosis.

Immunomodulatory drugs in the treatment of myelodysplastic syndromes.

Purpose Of Review: The aim of this article is to discuss the proposed mechanisms of action, clinical trial data, and clinical implications for use of the immunomodulatory drugs in the treatment of myelodysplastic syndrome.

Recent Findings: The immunomodulatory drugs are a novel, nonteratogenic class of thalidomide analogues that are more potent and less toxic than the parent compound. Lenalidomide, a second generation immunomodulatory drug, has shown substantial remitting activity in myelodysplastic syndrome that is karyotype-dependent.

Relapse and relapse prevention.

Most psychological disorders and problem behaviors are characterized by very high rates of postremittance relapse. Thus, advances in the long-term efficacy of psychological interventions require understanding the causes and processes of relapse, with the ultimate goal of developing strategies that reduce the probability of relapse. Existing psychological theory and interventions relevant to relapse and relapse prevention (RP) are reviewed, with a focus on addictive behaviors.

The role of lenalidomide in the treatment of patients with chromosome 5q deletion and other myelodysplastic syndromes.

Purpose Of Review: The aim of this article is to discuss the relevant pathobiologic effects of lenalidomide and the most recent clinical evidence to support its use in patients with myelodysplastic syndrome.

Recent Findings: Lenalidomide is an immunomodulatory agent with biological activity in several hematologic malignancies, including myelodysplastic syndrome. The precise mechanism yielding benefit in patients with myelodysplastic syndrome and 5q- syndrome is not clear, but various molecular and pathogenic targets have been identified.

Mutagenesis of Glycine 179 modulates both catalytic efficiency and reduced pyridine nucleotide specificity in cytochrome b5 reductase.

Cytochrome b5 reductase (cb5r), a member of the ferredoxin:NADP+ reductase family of flavoprotein transhydrogenases, catalyzes the NADH-dependent reduction of cytochrome b5. Within this family, a conserved "GxGxxP" sequence motif has been implicated in binding reduced pyridine nucleotides. However, Glycine 179, a conserved residue in cb5r primary structures, precedes this six-residue "180GxGxxP185" motif that has been identified as binding the adenosine moiety of NADH.

Efficacy of lenalidomide in myelodysplastic syndromes.

Background: Ineffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia caused by ineffective erythropoiesis is difficult. In patients with myelodysplastic syndromes and symptomatic anemia, we evaluated the safety and hematologic activity of lenalidomide, a novel analogue of thalidomide.

Delta-9 tetrahydrocannabinol (THC) inhibits lytic replication of gamma oncogenic herpesviruses in vitro.

Background: The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC), has been shown to modulate immune responses and lymphocyte function. After primary infection the viral DNA genome of gamma herpesviruses persists in lymphoid cell nuclei in a latent episomal circular form. In response to extracellular signals, the latent virus can be activated, which leads to production of infectious virus progeny.

Cognitive and social learning models of drug dependence: implications for the assessment of tobacco dependence in adolescents.

This paper is part of a series that has the goal of identifying potential approaches toward developing new instruments for assessing tobacco dependence among adolescents. The fundamental assumption underlying the series is that contemporary theories of drug dependence offer a rich source of opportunities for the development of theoretically based assessment tools. The present paper focuses on cognitive and social-learning models of drug dependence and the implications of these models for novel assessment instruments.

Phosphatidylinositol triphosphate kinase-dependent and c-jun NH2-terminal kinase-dependent induction of telomerase by calcium requires Pyk2.

Calcium signaling has been linked to activation of Pyk2, a calcium-dependent, focal adhesion kinase-related, non-receptor tyrosine kinase. Signaling via Pyk2 can activate c-jun NH(2)-terminal kinase (JNK). Calcium has also been shown to activate phosphatidylinositol triphosphate kinase and/or JNK.

It ain't over till it's over: the case for offering relapse-prevention interventions to former smokers.

Most people who attempt to quit tobacco smoking eventually relapse. Although treatment strategies have been developed to prevent smoking relapse, they tend to be available only to the small proportion of smokers who enroll in intensive smoking cessation treatments. It is argued that freestanding relapse-prevention interventions could be offered to persons who recently ceased smoking, whether they used a formal treatment program or quit on their own.

The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus interacts preferentially with the terminal repeats of the genome in vivo and this complex is sufficient for episomal DNA replication.

The genome of Kaposi's sarcoma-associated herpesvirus (KSHV) persists in latently infected cells as a circular episome. The latency-associated nuclear antigen (LANA) has been shown to tether viral DNA fragments to chromosomes and is proposed to maintain the KSHV genome. In order to identify the in vivo-binding sites for LANA on the whole KSHV genome and to analyse the function of this protein-DNA interaction, different in vivo systems have been developed.

The increasing recalcitrance of smokers in clinical trials II: Pharmacotherapy trials.

Irvin and Brandon (Nicotine & Tobacco Research, 2, 79-84, 2000) reported a significant decline in reported abstinence rates between 1977 and 1996 from clinical trials of cognitive-behavioral smoking cessation treatments based on coping skills training. The present study extends that approach to the analysis of pharmacotherapy trials. A literature search identified 59 studies, published between 1983 and 2000 and conducted in the U.

Telomerase is regulated by c-Jun NH2-terminal kinase in ovarian surface epithelial cells.

Telomerase activity is present in >90% of all tumors and appears to be regulated by the phosphatidylinositol 3-kinase signaling pathway. Here we demonstrate that Akt is not involved in the signaling cascade for telomerase regulation in ovarian surface epithelial cells. However, we showed that c-Jun NH2-kinase induces telomerase activity, that inhibition of JNK by JIP abrogates telomerase activity, and that JNK expression activates transcription of a reporter gene fused to the hTERT promoter sequence.

Calcium-mediated telomerase activity in ovarian epithelial cells.

Though the potential of telomerase as an anti-cancer target is evident, information about regulation of telomerase remains fragmentary. In the present study, we examined the role of calcium, an essential cellular signaling molecule, in the regulation of telomerase. We found that calcium induced de novo telomerase activity in telomerase-negative ovarian surface epithelial (OSE) cell lines but not in primary cultures of OSE.

An IkappaBalpha inhibitor causes leukemia cell death through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism.

Treatment of U937 cells with an IkappaBalpha phosphorylation inhibitor, Bay 11-7085, induced a rapid phosphorylation of p38 mitogen-activated protein (MAP) kinase, significant apoptosis, extensive necrosis, and a weak phosphorylation of MAP kinase kinase. Bay 11-7085 had no effect on the basal levels of phosphorylated IkappaBalpha but completely inhibited phorbol 12-myristate 13-acetate-induced phosphorylation of IkappaBalpha. Although Bay 11-7085 prevented phorbol 12-myristate 13-acetate-induced NF-kappaB nuclear translocation, SN50, a specific inhibitor of nuclear translocation and function of NF-kappaB, did not induce any significant nuclear/DNA fragmentation, caspase 3 activation, or cell death.

False-positive reduction in CAD mass detection using a competitive classification strategy.

High false-positive (FP) rate remains to be one of the major problems to be solved in CAD study because too many false-positively cued signals will potentially degrade the performance of detecting true-positive regions and increase the call-back rate in CAD environment. In this paper, we proposed a novel classification method for FP reduction, where the conventional "hard" decision classifier is cascaded with a "soft" decision classification with the objective to reduce false-positives in the cases with multiple FPs retained after the "hard" decision classification. The "soft" classification takes a competitive classification strategy in which only the "best" ones are selected from the pre-classified suspicious regions as the true mass in each case.

A statistical methodology for mammographic density detection.

A statistical methodology is presented based on a chi-square probability analysis that allows the automated discrimination of radiolucent tissue (fat) from radiographic densities (fibroglandular tissue) in digitized mammograms. The method is based on earlier work developed at this facility that shows mammograms may be considered as evolving from a linear filtering operation where a random input field is passed through a 1/f filtering process. The filtering process is reversible which allows the solution of the input field with knowledge obtained from the raw image (the output).

Effects of physician supply on early detection of breast cancer.

Background: There are few studies examining the effects of physician supply on health-related outcomes. We hypothesized that increasing physician supply and, in particular, increasing primary care supply would be related to earlier detection of breast cancer.

Methods: Information on incident cases of breast cancer occurring in Florida in 1994 (n = 11,740) was collected from the state cancer registry.

Increasing supplies of dermatologists and family physicians are associated with earlier stage of melanoma detection.

Background: Physicians are important in the early detection of melanoma. We investigated whether primary care physician supply and the supply of dermatologists were related to stage at diagnosis for malignant melanoma.

Methods: From the state tumor registry in Florida in 1994, we identified incident cases of malignant melanoma for which stage at diagnosis was available (N = 1884).

Comparing the toxicity of digoxin and digitoxin in a geriatric population: should an old drug be rediscovered?

Background: Little information is available regarding toxicity rates of the two available forms of cardiac glycosides (digoxin, digitoxin) when used in elderly patients.

Methods: We retrospectively analyzed the charts of all patients more than 60 years of age who were chronically managed with a cardiac glycoside and were hospitalized during the period January 1995 through January 1998. Toxicity was defined as any clinical event that required either a reduction in dose of the drug or its discontinuance.

On the statistical nature of mammograms.

We show that digitized mammograms can be considered as evolving from a simple process. A given image results from passing a random input field through a linear filtering operation, where the filter transfer function has a self-similar characteristic. By estimating the functional form of the filter and solving the corresponding filtering equation, the analysis shows that the input field gray value distribution and spectral content can be approximated with parametric methods.