Epigenetic regulation of ID4 in the determination of the BRCAness phenotype in breast cancer.

BRCAness breast tumors represent a group of sporadic tumors characterized by a reduction in BRCA1 gene expression. As BRCA1 is involved in double-strand breaks (DSBs) repair, dysfunctional BRCA pathway could make a tumor sensitive to DNA damaging drugs (e.g., platinum agents). Thus, accurately identifying BRCAness could contribute to therapeutic decision making in patients harboring these tumors. The purpose of this study was to identify if BRCAness tumors present a characteristic methylation profile and/or were related to specific clinico-pathological features. BRCAness was measured by MLPA in 63 breast tumors; methylation status of 98 CpG sites within 84 cancer-related genes was analyzed by MS-MLPA. Protein and mRNA expressions of the selected genes were measured by quantitative real-time PCR and Western Blot. BRCAness was associated with younger age, higher nuclear pleomorphism, and triple-negative (TN) status. Epigenetically, we found that the strongest predictors for BRCAness tumors were the methylations of MLH1 and PAX5 plus the unmethylations of CCND2 and ID4. We determined that ID4 unmethylation correlated with the expression levels of both its mRNA and protein. We observed an inverse relation between the expressions of ID4 and BRCA1. To the best of our knowledge, this is the first report suggesting an epigenetic regulation of ID4 in BRCAness tumors. Our findings give new information of BRCAness etiology and encourage future studies on potential drug targets for BRCAness breast tumors.

Development and evaluation of a portable sham transcranial magnetic stimulation system.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a relatively noninvasive brain stimulation technology that can focally stimulate the human cortex. One significant limitation of much of the TMS research to date concerns the nature of the placebo or sham conditions used. When TMS pulses are delivered repetitively (especially prefrontal TMS), it is often experienced as painful. Most sham TMS techniques produce identical sounds to active TMS, but they do not cause much, if any, scalp or facial sensation or discomfort. This is a serious problem when investigators are attempting to evaluate the effects of TMS by using traditional sham techniques because of unintended systematic differences between real and sham TMS groups (ie, confounds). As long as traditional approaches to sham TMS are used, the validity of the inferences regarding the efficacy of TMS will be limited. Although some other sophisticated systems have been developed to address these concerns, they tend to be expensive and lack portability. Portability will likely become more and more important as TMS applications expand into different clinical areas (eg, TMS in the postanesthesia care unit after surgery). METHODS: This study describes a portable electrical TMS sham system (eSham system) modeled after the James Long System that was designed to produce similar scalp sensations as real TMS. Preliminary results are presented on 9 healthy adults who received both real and eSham 10 Hz repetitive TMS (rTMS) (at 80%, 100%, and 120% of resting motor threshold) over the prefrontal cortex and rated the sensation quality (pain, tingling, sharpness, piercing, electric, tugging, pinching), tolerability, and location. RESULTS: Real TMS and eSham TMS were rated similarly across all seven sensory dimensions examined. Real and eSham TMS were also rated similarly with respect to tolerability and perceived location of the TMS-induced sensations. CONCLUSIONS: The eSham system may be a simple, affordable, and portable approach to providing convincing sham TMS for future clinical trials. This study provides preliminary evidence supporting the use of the eSham system. Future larger-scale studies are warranted.

Fifteen minutes of left prefrontal repetitive transcranial magnetic stimulation acutely increases thermal pain thresholds in healthy adults.

BACKGROUND: Transcranial magnetic stimulation (TMS) of the motor cortex appears to alter pain perception in healthy adults and in patients with chronic neuropathic pain. There is, however, emerging brain imaging evidence that the left prefrontal cortex is involved in pain inhibition in humans. OBJECTIVE: Because the prefrontal cortex may be involved in descending pain inhibitory systems, the present pilot study was conducted to investigate whether stimulation of the left prefrontal cortex via TMS might affect pain perception in healthy adults. METHODS: Twenty healthy adults with no history of depression or chronic pain conditions volunteered to participate in a pilot laboratory study in which thermal pain thresholds were assessed before and after 15 min of repetitive TMS (rTMS) over the left prefrontal cortex (10 Hz, 100% resting motor threshold, 2 s on, 60 s off, 300 pulses total). Subjects were randomly assigned to receive either real or sham rTMS and were blind to condition. RESULTS: Subjects who received real rTMS demonstrated a significant increase in thermal pain thresholds following TMS. Subjects receiving sham TMS experienced no change in pain threshold. CONCLUSIONS: rTMS over the left prefrontal cortex increases thermal pain thresholds in healthy adults. Results from the present study support the idea that the left prefrontal cortex may be a promising TMS cortical target for the management of pain. More research is needed to establish the reliability of these findings, maximize the effect, determine the length of effect and elucidate possible mechanisms of action.

Different neural substrates mediate cocaine seeking after abstinence versus extinction training: a critical role for the dorsolateral caudate-putamen.

Cue-induced reinstatement of extinguished drug seeking is a preclinical model of relapse. However, relapse typically occurs after abstinence rather than explicit extinction training. We show that inactivation of the dorsolateral caudate-putamen, but not other structures previously implicated in reinstatement, attenuates cocaine seeking after abstinence. This suggests that there is limited overlap in the substrates of cocaine seeking after abstinence versus extinction, and that habit learning exerts greater control over drug seeking than regions implicated in stimulus-reward associations.

Efforts to improve the follow-up of patients with abnormal Papanicolaou test results.

BACKGROUND: We describe and evaluate efforts to improve the follow-up care of patients with abnormal Papanicolaou test results at an academic family practice center at Shadyside Hospital in Pittsburgh. METHODS: From 1994 to 1996, 1796 patients received Papanicolaou testing; 147 (8 percent) of the smears had abnormal findings--16 percent had atypia, 83 percent had dysplasia, and 1 percent had carcinoma in situ. Patients received follow-up care based on a formalized protocol using educational input, logistic aids, and automated prompting. RESULTS: Overall follow-up success rates and colposcopy completion rates increased dramatically. Whereas 36 percent of patients with abnormal findings on Papanicolaou smears had been overdue for follow-up in 1990, only 13 percent were overdue in 1996 after our interventions. Patients assigned to Papanicolaou testing for follow-up of abnormal findings failed to receive a test in 9 of 45 (20 percent) cases, but those assigned to colposcopy follow-up failed to receive a test in only 10 of 102 (10 percent) of cases. Appointment failure rates at colposcopy clinic dropped from 56 percent in 1993 to 12 percent in 1996. Colposcopic biopsy was far superior to Papanicolaou test for detecting precursors of cervical cancer at follow-up. CONCLUSIONS: Educational programs, formalized approaches to care, transportation assistance, and reminder systems are not only practical but also can dramatically improve the outcome of cervical cancer screening programs.