Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma

Germline mutations of the PTEN tumor-suppressor gene, on 10q23, cause Cowden syndrome, an inherited hamartoma syndrome with a high risk of breast, thyroid and endometrial carcinomas and, some suggest, melanoma. To date, most studies which strongly implicate PTEN in the etiology of sporadic melanomas have depended on cell lines, short-term tumor cultures and noncultured metastatic melanomas. The only study which reports PTEN protein expression in melanoma focuses on cytoplasmic expression, mainly in metastatic samples. To determine how PTEN contributes to the etiology or the progression of primary cutaneous melanoma, we examined cytoplasmic and nuclear PTEN expression against clinical and pathologic features in a population-based sample of 150 individuals with incident primary cutaneous melanoma. Among 92 evaluable samples, 30 had no or decreased cytoplasmic PTEN protein expression and the remaining 62 had normal PTEN expression. In contrast, 84 tumors had no or decreased nuclear expression and 8 had normal nuclear PTEN expression. None of the clinical features studied, such as Clark's level and Breslow thickness or sun exposure, were associated with cytoplasmic PTEN expressional levels. An association with loss of nuclear PTEN expression was indicated for anatomical site (p = 0.06) and mitotic index (p = 0.02). There was also an association for melanomas to either not express nuclear PTEN or to express p53 alone, rather than both simultaneously (p = 0.02). In contrast with metastatic melanoma, where we have shown previously that almost two-thirds of tumors have some PTEN inactivation, only one-third of primary melanomas had PTEN silencing. This suggests that PTEN inactivation is a late event likely related to melanoma progression rather than initiation. Taken together with our previous observations in thyroid and islet cell tumors, our data suggest that nuclear-cytoplasmic partitioning of PTEN might also play a role in melanoma progression.     

The expanding role of PTEN in neoplasia: a molecule for all seasons? Commentary re: M. A. Davies, et al., Adenoviral-mediated expression of MMAC/PTEN inhibits proliferation and metastasis of human prostate cancer cells. Clin. Cancer Res., 8: 1904-1914, 2002.

Not since the discovery of p53 has another molecule received as much attention as PTEN. In the 5 years since the discovery of PTEN, encoding a dual specificity phosphatase tumor suppressor on 10q23, it has been shown to be a susceptibility gene for an inherited cancer syndrome, Cowden syndrome, and for several developmental disorders; it has been shown to play a prominent role in normal murine and human development; and it has been shown to be instrumental in cell cycle arrest, apoptosis, and/or possibly cell migration and cytoskeletal affairs. Initial work on cancer cell lines had suggested that PTEN caused every type of cancer because it was reported that a relatively high frequency of a variety of cancer cell lines, whether derived from solid tumors or hematological malignancies, had homozygous or compound heterozygous genetic alterations involving PTEN. Such data, together with the germ-line human and murine model data, suggested that PTEN mutations occurred "early" in sporadic tumorigenesis. However, subsequent painstaking work in noncultured primary tumors and in careful in vitro overexpression studies over the last 4 years demonstrated that the mechanism of PTEN inactivation can be varied and might be cell type dependent. Furthermore, apart from sporadic endometrial carcinoma, PTEN alteration in noncultured sporadic neoplasias likely occurs "late," promoting progression and metastasis. The article by Davies et al. (Clin Cancer Res., 8: 1904-1914, 2002) sheds light on all of these issues when they report on data that derive from a "triple threat" strategy, i.e., in vitro, in vivo, and ex vivo, to demonstrate that adenoviral infection of PTEN into PTEN-null PC3 prostate cancer cell lines results in decreased metastatic potential without significantly altering tumor size via the predominant mechanism of G(1) cell cycle arrest but not apoptosis.     

Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue.

PURPOSE: Genetic alterations were previously identified in normal epithelia adjacent to invasive cancers. The aim of this study was to determine DNA methylation in histologically normal tissues from multiple geographic zones adjacent to primary breast tumors. EXPERIMENTAL DESIGN: First, methylation status of a 4-kb region of RASSF1A promoter was interrogated using oligonucleotide-based microarray in 144 samples (primary tumors, 47; adjacent normals, 69; reduction mammoplasty tissues, 28). Second, allelic imbalance (AI)/loss of heterozygosity (LOH) surrounding RASSF1A promoter were analyzed in 30 samples (tumors, 8; adjacent normals, 22). Third, global methylation screening of 49 samples (tumors, 12; adjacent normals, 25; reduction mammoplasty, 12) was done by differential methylation hybridization. Real-time quantitative methylation-specific PCR was used to validate the microarray findings. RESULTS: DNA methylation in the core RASSF1A promoter was low in reduction mammoplasty tissues (P=0.0001) when compared with primary tumors. The adjacent normals had an intermediate level of methylation. The regions surrounding the core were highly methylated in all sample types. Microsatellite markers showed AI/LOH in tumors and some of the adjacent normals. Concurrent AI/LOH and DNA methylation in RASSF1A promoter occurred in two of six tumors. Global methylation screening uncovered genes more methylated in adjacent normals than in reduction mammoplasty tissues. The methylation status of four genes was confirmed by quantitative methylation-specific PCR. CONCLUSIONS: Our findings suggest a field of methylation changes extending as far as 4 cm from primary tumors. These frequent alterations may explain why normal tissues are at risk for local recurrence and are useful in disease prognostication.     

Staff and client views of the role of the correctional client: Conflict and its implications for treatment

Summary A comparison was made between staff and inmate conceptions of the inmate role in two correctional settings differing significantly in terms of degree of concern for custody as opposed to concern for rehabilitation. At each setting the ideas of the treatment and custodial staff were investigated separately. With the exception of the treatment staff at the custodial setting, it was foud that each institutional staff viewed the average inmate as significantly more active and aggressive, more dependent and less socially responsible than did the institution's clients. In an effort to contain this conflict, and at the same time make greater use of the clients' felt capacity for greater responsibility-taking, a program is suggested which would couple graduated demands for the client's pro-social adjustment with increases in the freedom of action permitted him.The custodial institution's treatment staff, alone of the four samples of staff considered, viewed the client as significantly more capable of responsibility-taking than did the client himself. It is hypothesized that this staff may have felt impelled to defend its position as rehabilitators in a custodial setting by exaggerating somewhat their clients' potential for rehabilitation.The clients at the two settings also differed significantly in that the clients at the rehabilitative setting attributed greater activism to the average inmate than did the clients at the custodial setting. It is hypothesized that this difference is a function of the greater freedom of action permitted at the rehabilitative setting as well as the greater youthfulness and lesser institutional sophistication of the client population from which that sample was drawn.

---

Zusammenfassung In zwei Besserungsanstalten, in denen man sich in signifikant unterschiedlichem Ausmaß um die Verwahrung oder um die Rehabilitation kümmerte, wurde zwischen dem Personal und den Insassen ein Vergleich der Auffassungen von der Rolle des Insassen angestellt. In jeder Einrichtung wurden die Meinungen des Behandlungs- und des Aufsichtspersonals getrennt untersucht. Mit Ausnahme des Behandlungsteams der mehr auf Verwahrung hin orientierten Einrichtung fand man, daß jedes Anstaltssystem den durchschnittlichen Insassen signifikant für aktiver und aggressiver, abhängiger und weniger sozial verantwortlich hielt als sich die Klienten der Institution selbst sahen. In der Bemühung, diesen Konflikt einzugrenzen und gleichzeitig mehr Gebrauch von der von den Klienten empfundenen Fähigkeit zur Übernahme größerer Verantwortung zu machen, wird ein Programm vorgeschlagen, das gesteigerte Anforderungen an die soziale Anpassung des Klienten mit einer Vermehrung der ihm zugestandenen Handlungsfreiheit koppelt.Von den vier untersuchten Personalgruppen betrachtete allein das Behandlungsteam der mehr auf Verwahrung hin orientierten Einrichtung den Klienten signifikant als fähiger zur Übernahme von Verantwortung als der Klient selbst. Es wird vermutet, daß dieses Team sich vielleicht dazu gedrängt fühlte, seine rehabilitative Position in einer Verwahrungseinrichtung zu verteidigen, indem es die rehabilitativen Möglichkeiten seiner Klienten etwas übertrieb.Die Klienten unterschieden sich in beiden Einrichtungen insofern signifikant voneinander, als die Klienten in der Rehabilitationseinrichtung dem durchschnittlichen Insassen größere Aktivität zuschrieben als die Klienten in der Verwahrungseinrichtung. Man nimmt an, daß dieser Unterschied eine Funktion der größeren Handlungsfreiheit ist, die in der Rehabilitationseinrichtung zugestanden wird, wie auch des jüngeren Alters und der geringeren institutioneilen Erfahrung der Klientenpopulation, aus der jene Stichprobe entnommen wurde.

---

Résumé On a fait une comparaison entre les conceptions du personnel et celles des pensionnaires quant au rôle du pensionnaire dans deux institutions correctionnelles différant de façon significative dans ce sens que l'une était plutôt orientée vers la détention, tandis que l'autre avait un but de réadaptation. Dans chaque institution, le point de vue du personnel traitant et du personnel gardien a été examiné séparément. A l'exception du personnel traitant de l'institution de détention, on a trouvé que chaque personnel institutionnel considérait le pensionnaire moyen comme significativement plus actif et agressif, plus dépendant et moins responsable socialement que ne le pensaient les pensionnaires de l'institution. Dans le but de dominer ce conflit, et en même temps de faire un plus grand usage de la capacité ressentie par les pensionnaires de prendre davantage de responsabilités, on suggère un programme de réadaptation sociale progressive du pensionnaire combiné avec une augmentation de sa liberté d'action. Le personnel traitant de l'institution de détention est le seul, parmi les 4 types de personnel considérés, à avoir jugé le pensionnaire comme étant, de façon significative, plus capable de prendre des responsabilités que ne le pensait le pensionnaire lui-même. On suppose que ce personnel doit s'être senti obligé de défendre sa fonction de réadaptation dans un milieu de détention en exagérant quelque peu le potentiel de réadaptation de ses pensionnaires.Les pensionnaires des deux institutions différaient également de façon significative dans ce sens que les pensionnaires de l'institution à but de réadaptation attribuaient au pensionnaire moyen un plus grand activisme que ne le faisaient les pensionnaires de l'institution de détention. On pense que cette différence est fonction de la plus grande liberté d'action accordée dans l'institution à but de réadaptation, de même que de la plus grande jeunesse et de la moindre sophistication institutionnelle de la population de pensionnaires dont cet échantillon a été tiré.

     

The effects of nebulized salbutamol, external positive end-expiratory pressure, and their combination on respiratory mechanics, hemodynamics, and gas exchange in mechanically ventilated chronic obstructive pulmonary disease patients

We hypothesized that combined salbutamol and external positive end-expiratory pressure (PEEPe) may present additive benefits in chronic obstructive pulmonary disease (COPD) exacerbation. In 10 anesthetized, mechanically ventilated, and bronchodilator-responsive COPD patients exhibiting moderate intrinsic PEEP (PEEPi), we assessed respiratory system (rs) mechanics, hemodynamics, and gas exchange at (a) baseline (zero PEEPe [ZEEPe]), (b) 30 min after 5 mg of nebulized salbutamol administration (ZEEPe-S), (c) 30 min after setting PEEPe at baseline PEEPi level (PEEPe), and (d) 30 min after 5 mg of nebulized salbutamol administration with PEEPe maintained unchanged (PEEPe-S). Return of determined variable values to baseline values was confirmed before PEEPe application. Relative to ZEEPe, (a) at ZEEP-S, PEEPi (4.8 +/- 0.7 versus 7.0 +/- 1.1 cm H(2)O), functional residual capacity change (115.6 +/- 23.1 versus 202.1 +/- 46.0 mL), minimal rs (airway) resistance (9.3 +/- 1.4 versus 11.8 +/- 2.2 cm H(2)O.L(-1).s(-1)), and additional rs resistance (5.2 +/- 1.4 versus 7.2 +/- 1.3 cm H(2)O.L(-1).s(-1)) were reduced (P < 0.01), and hemodynamics were improved; (b) at PEEPe, PEEPi (3.7 +/- 1.3 cm H(2)O) was reduced (P < 0.01), and gas exchange was improved; and (c) at PEEPe-S, PEEPi (2.0 +/- 1.2 cm H(2)O) was minimized, and rs mechanics (static rs elastance included), hemodynamics, and gas exchange were improved. Conclusively, in carefully preselected COPD patients, bronchodilation/PEEPe exhibits additive benefits.     

Recommendations for evaluating accreditation guideline outcomes assessment methods for accredited environmental health programs in the United States

This paper was written to provide guidance to the National Environmental Health Science and Protection Accreditation Council (EHAC) on obtaining recognition either from the U.S. Department of Education (USDE) or from the Council for Higher Education Accreditation (CHEA), with respect to outcomes assessment. The authors provide suggestions for expansion of existing EHAC accreditation criteria, including those related to outcomes assessment. Comparisons are made between EHAC and two other accrediting agencies currently recognized by USDE. The authors provide a detailed list of recommendations and a copy of EHAC's current outcomes assessment tool.     

Can left prefrontal rTMS be used as a maintenance treatment for bipolar depression?

Numerous studies have examined the acute antidepressant effects of prefrontal transcranial magnetic stimulation (TMS). However, there is little information on whether TMS can be used as a maintenance treatment to maintain normal mood once subjects have responded. We describe seven adults with bipolar depression who responded acutely to TMS and were then treated with TMS weekly for up to 1 year. TMS was carried out over the left prefrontal cortex at 110% motor threshold, 5 Hz for 8 s for 40 trains. Three subjects completed 1 full year of weekly TMS with an average Hamilton Rating Scale for Depression of 13 (sd = 5.9) over the year. These data suggest but do not prove that TMS might eventually be used as an adjunctive maintenance treatment for at least some patients with bipolar depression. Much work remains.