Localization and relaxation of singlet exciton formation in conjugated polymers under photoexcitation.

This paper employs a molecular dynamics approach to uncover the time profile of exciton formation, which can be divided into two stages: localization of electron-hole pairs and relaxation process (nuclear and electronic). Under photoexcitation, an electron-hole pair is formed by an electronic transition, and the pair in turn becomes localized through the electron-lattice interaction, which triggers the total energy to shift violently and oscillate. The oscillation during the first 40 fs induces the excitation to step into the second stage, i.e., relaxation. After the relaxation process of about 850 fs, the total energy, lattice energy, and electron energy reach certain values whereas the lattice configuration and electron remain localized, indicating the formation of a singlet exciton.

Lactate dehydrogenase 5 expression in melanoma increases with disease progression and is associated with expression of Bcl-XL and Mcl-1, but not Bcl-2 proteins.

The serum level of lactate dehydrogenase (LDH) is an important predictor of prognosis and treatment response in melanoma patients. It is unknown whether the expression of LDH-5 in tissue sections also has prognostic significance and whether it is related to the expression of the anti-apoptotic proteins, Bcl-2, Bcl-XL and Mcl-1, and endoplasmic reticulum stress protein glucose-regulated protein 78 (GRP78). Identification of an association between LDH-5 expression and anti-apoptotic proteins may have important therapeutic implications for melanoma patients. Sections from 159 pigmented lesions, including nevi and melanoma at different stages of progression were studied by immunohistochemistry. Correlation of LDH-5 expression with clinicopathological factors and with the expression of Bcl-2, Bcl-XL, Mcl-1 and GRP78 was examined. LDH-5 was detected at low levels in 6 of 10 compound nevi (60%) and 6 of 10 dysplastic nevi (60%). The percentage of positive cases was greater in thin (1.0 mm) (95%) and in metastatic melanoma in the skin (100%) and lymph node (81%). The immunoreactive score was highly related to progression of melanoma (P<0.0001). LDH-5 expression was positively associated with increasing tumor thickness (P=0.02) and dermal tumor mitotic rate (P=0.02). LDH-5 above the median immunoreactive score was associated with reduced disease-free survival and overall survival (P<0.02). LDH-5 expression was negatively associated with Bcl-2 expression. In contrast, LDH-5 expression was strongly associated with Bcl-XL and Mcl-1 expression and also positively associated with GRP78 expression (P<0.0001). The low Bcl-2 expression in melanomas with high LDH-5 expression provides an explanation for the poor response of patients with high serum LDH levels to treatment with the Bcl-2 antisense drug 'Genasense'. The strong correlation of LDH-5 expression with Mcl-1 expression suggests that treatment strategies inhibiting the activity of Mcl-1 in melanoma patients should be investigated.

Role and prognostic significance of tumor necrosis factor-related apoptosis-inducing ligand death receptor DR5 in nonsmall-cell lung cancer and precursor lesions.

BACKGROUND: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor, DR5, mediates proapoptotic signals and is implicated in the pathogenesis of many neoplasms including nonsmall-cell lung cancer (NSCLC). METHODS: In this study, immunohistochemical expression of DR5 was examined in 146 cases of stage I and II NSCLC as well as neoplastic precursor lesions and regional lymph node metastases using tissue microarrays. RESULTS: High DR5 expression was observed in 67.1% of primary NSCLC, 55.6% of bronchial squamous carcinoma in situ, 40% of squamous metaplasia, as well as 76.5% of lymph node metastases. In all of these lesions, DR5 expression was significantly higher than in normal bronchial epithelium. Increased expression of DR5 correlated with poorly differentiated tumors and was inversely correlated with bronchioloalveolar carcinomas. There was no correlation with other clinicopathologic variables. A significant association was found between high DR5 expression and reduced overall survival in univariate analysis. Among smokers, high DR5 and tumor stage were independent predictors of reduced disease-free survival in multivariate analysis, however, DR5 was not an independent prognostic marker among the entire cohort of NSCLC. CONCLUSIONS: These findings suggest that DR5 plays a role in the development of early-stage NSCLC and the high levels of DR5 expression suggest that these tumors may be susceptible to novel anticancer agents targeting the DR5 receptor and may improve patient survival, particularly for patients who are smokers.

Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma.

Members of the Bcl-2 family of antiapoptotic proteins (Bcl-2, Bcl-XL and Mcl-1) are key regulators of apoptosis. The purpose of the present study was to examine and better define the role of Bcl-2, Bcl-XL and Mcl-1 in the progression of melanoma. Immunohistochemical staining for Bcl-2, Bcl-XL and Mcl-1 was performed on paraffin sections of 100 cases of benign nevi, primary melanoma and metastatic melanoma. Expression was correlated with histopathologic features, clinical progress and expression of transcription factors (AP-2, MITF and p-Stat3). Bcl-2 was expressed in 100% of benign nevi and thin melanoma (1.0 mm) (88%), subcutaneous (62%) and lymph node metastases (35%). In contrast, Bcl-XL and Mcl-1 were expressed at lower levels in nevi and thin melanoma compared to Bcl-2 but their expression was much higher in thick melanoma and in subcutaneous and lymph node metastases (P<0.0001). Bcl-2 expression was negatively associated with tumor thickness (P<0.05) but Bcl-XL expression increased with increasing tumor thickness (P<0.05) and dermal tumor mitotic rate (P<0.05). Similarly Mcl-1 expression increased with increasing tumor thickness (P<0.09) and dermal tumor mitotic rate (P<0.17). Bcl-2 expression was positively correlated with expression of the transcription factors microphthalmia transcription factor (MITF) and nuclear AP-2 whereas Bcl-XL (and Mcl-1) expression were positively correlated with p-Stat3. This study is the first to show a clear dissociation between changes in Bcl-2 expression (downregulation) and Bcl-XL, Mcl-1 expression (upregulation) during progression of melanoma. The results were also consistent with a role for AP-2 and MITF in regulation of Bcl-2 and pStat3 in regulation of Bcl-XL. These findings have important implications for the development of treatments targeting antiapoptotic proteins in patients with melanoma.

Progression in melanoma is associated with decreased expression of death receptors for tumor necrosis factor-related apoptosis-inducing ligand.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in melanoma by interaction with death receptors TRAIL-R1 (DR4) or TRAIL-R2 (DR5) on melanoma cells or resists apoptosis by interaction with decoy receptors TRAIL-R3 (DcR1) or TRAIL-R4 (DcR2). Studies on cell lines suggest that there is a wide variation in TRAIL death receptor expression; however, their expression on excised human melanoma is not well documented. In view of this, we studied death receptor expression on melanomas using monoclonal antibodies specific for these receptors. Immunohistochemical staining for DR4, DR5, and DcR1/DcR2 was performed on formalin-fixed paraffin-embedded sections of 100 cases of primary melanoma, metastatic melanoma, and benign nevi. Percentage expressions of DR4 versus DR5 in benign nevi, primary melanoma, and melanoma metastases were 40% versus 90%, 69% versus 98%, and 55% versus 66%, respectively. There were significant differences in the mean percentage of DR5-positive cells between different groups of melanocytic lesions. Percent expression was higher in thin (< or =1.0 mm) compared with thick primary melanoma (88.9% versus 66.9%), and expression was less in subcutaneous metastases (49%) and lymph node metastases (30.6%) (P < .005). Expression was also higher in compound nevi (57%) than dysplastic nevi (49%). DcR1/DcR2 was found in 75% of benign nevi, 62% of primary melanomas, and 74% melanoma metastases. The results showed a wide variation in the expression of death receptors for TRAIL between and within primary and metastatic melanoma and a decreased expression on the thick primary melanoma and metastatic melanoma. This suggests that melanoma may not respond to treatment with TRAIL unless given with agents that increase the expression of TRAIL death receptors.

The role of cell cycle regulatory proteins in the pathogenesis of melanoma.

The transformation of melanocytes to melanoma cells is characterised by abnormal proliferation resulting from alterations in cell cycle regulatory mechanisms. This occurs through alterations in the two major cell cycle regulatory pathways, the retinoblastoma (Rb) and p53 tumour suppressor pathways. This review summarises the current knowledge of alterations in these two pathways at G1/S transition and specifically the role of the key cell cycle regulatory proteins pRb, p16INK4a (p16), cyclin D1, p27Kip1 (p27), p53 and p21Waf1/Cip1 (p21) in the pathogenesis of melanoma. It also considers their prognostic significance. Current data indicate that alterations of cyclin kinase inhibitor (cdki) levels are implicated in the pathogenesis of melanoma and may be useful prognostic markers. However, large validation studies linked to comprehensive clinical follow up data are necessary to clarify the prognostic significance of cell cycle regulatory proteins in individual patients.

[Nle4-D-Phe7]-alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers.

Epidermal melanin reduces some effects of UV radiation, the major cause of skin cancer. To examine whether induced melanin can provide protection from sunburn injury, 65 subjects completed a trial with the potent synthetic melanotropin, [Nle4-D-Phe7]-alpha-melanocyte-stimulating hormone ([Nle4-D-Phe7]-alpha-MSH) delivered by subcutaneous injection into the abdomen at 0.16 mg/kg for three 10-day cycles over 3 months. Melanin density, measured by reflectance spectroscopy, increased significantly in all [Nle4-D-Phe7]-alpha-MSH-treated subjects. The highest increases were in volunteers with lowest baseline skin melanin levels. In subjects with low minimal erythemal dose (MED) skin type, melanin increased by an average of 41% (from 2.55 to 3.59, P < 0.0001 vs placebo) over eight separate skin sites compared with only 12% (from 4.18 to 4.70, P < 0.0001 vs placebo) in subjects with a high-MED skin type. Epidermal sunburn cells resulting from exposure to 3 MED of UV radiation were reduced by more than 50% after [Nle4-D-Phe7]-alpha-MSH treatment in the volunteers with low baseline MED. Thymine dimer formation was also shown to be reduced by 59% (P = 0.002) in the epidermal basal layer. This study has shown for the first time the potential ability of a synthetic hormone that augments melanin production to provide photoprotection to people who normally burn in direct sunlight.

Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma.

BACKGROUND: Combined naevi are characterised pathologically by the presence of two or more different types of melanocytic naevi in a single lesion. They are prone to clinical and pathological misdiagnosis as melanoma. Misdiagnosis may result in inappropriate treatment, patient anxiety and medicolegal consequences. AIMS: With the aim of reducing the incidence of misdiagnosis, this study documents the clinical and pathological features of a large series of combined naevi and describes how to distinguish them from melanoma. PATIENTS AND METHODS: The slides of skin lesions from 220 patients that were coded as combined naevus between 1990 and 2001 were retrieved from the archival files of the Department of Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, Australia. The clinical notes, letters from referring pathologists (for consultation cases) and slides were reviewed and for each lesion clinical and pathological features were assessed. Thirty-eight cases were excluded either because they included only one naevus component or because there were atypical pathological features in the slides available for review. The remaining 182 cases formed the study population. RESULTS: The patients included 92 females and 87 males (1.1:1). In three cases the gender was not known. Mean and median patient ages were 29.6 and 28 years, respectively. The anatomical site of involvement was the trunk in 64 cases (35.2%), head and neck region in 43 cases (23.6%), upper extremity in 40 cases (22.0%), lower extremity in 18 cases (9.9%) and perineum and buttock region in eight cases (4.4%). In nine cases the site of involvement was not known. A pre-operative clinical diagnosis was recorded in 126 cases; of these, melanoma was suspected clinically in 33 cases (26.2%) while combined naevus was diagnosed clinically in only three cases (2.4%). Histologically, 180 cases included two different naevus components, and in two cases three different naevus components were present. The most common combination was a common acquired naevus of compound type associated with a blue naevus of deep penetrating naevus type; this occurred in 57 cases (31.3%). The referring pathologist recorded a preferred diagnosis in 88 of 122 consultation cases; of these, melanoma was suspected in 23 cases (26.1%) and in 23 cases combined naevus was favoured (26.1%). CONCLUSIONS: Combined naevus is an uncommon type of melanocytic naevus that is frequently misdiagnosed both clinically and pathologically. Knowledge and recognition of the pathological features of combined naevi and the important features that distinguish them from melanomas should reduce the frequency of misdiagnosis.