Expression of CD3-ζ on T-cells in primary cervical carcinoma and in metastasis-positive and -negative pelvic lymph nodes

Lymphocytic infiltrate is often present in cervical cancer lesions, possibly reflecting an ongoing, but ineffective, immune response to the tumour. Recently, evidence has accumulated for systemically impaired T-cell functions in cancer patients, associated with decreased expression of signal-transducing zeta (ζ) chain dimer molecules on circulating T-cells and NK-cells. Here, we report on the intralesional down-regulation of ζ chain expression on T-cells in cervical carcinoma. Paraffin-embedded or snap-frozen sections from 24 different cervical cancer specimens were studied. Paraffin-embedded tumour-positive (n = 7) and tumour-negative (n = 15) pelvic lymph nodes were also included in the study. Immunostaining was performed on consecutive sections with antibodies specific for CD3-ɛ or the CD3-associated ζ chain dimer. Antigen retrieval by sodium citrate/microwave treatment was essential for ζ staining of paraffin sections. The amount of ζ positive cells was quantitated and related to the number of CD3-ɛ+ cells in corresponding tumour areas. Of the 24 cervical cancer specimens studied, ζ chain dimer expression was reduced in seven cases and strongly reduced in the other 17 samples. In tonsil control sections, CD3-ɛ and CD3-ζ were always co-expressed in almost equal numbers. Also, both tumour-negative and -positive lymph nodes showed ζ chain expression which equalled that of CD3-ɛ expression. These data indicate that a decreased expression of signal-transducing ζ molecules on tumour-infiltrating T-cells is frequent in cervical cancer. The apparently unimpaired ζ chain expression within draining lymph nodes suggests that local tumour-derived factors at the primary site are instrumental in ζ chain down-regulation. © 1999 Cancer Research Campaig

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases

PURPOSE: In this retrospective study we compared the clinical outcome of early vs delayed excision of lymph node metastases in patients with penile squamous cell carcinoma. MATERIALS AND METHODS: A total of 40 patients with a T2-3 penile carcinoma with lymph node metastases were included in this study. All patients initially presented with bilateral impalpable lymph nodes. In 20 patients (50%) metastases were removed when they became clinically apparent during meticulous followup (median interval 6 months, range 1 to 24). There were 20 patients (50%) who underwent resection of inguinal metastases detected on dynamic sentinel node biopsy before they became palpable. The histopathological characteristics of the tumors and lymph nodes were reevaluated. RESULTS: The 2 populations were similar in terms of patient age, T-stage, pathological tumor grade, vascular invasion and infiltration depth. Disease specific 3-year survival of patients with positive lymph nodes detected during surveillance was 35% and in those who underwent early resection, 84% (log rank p = 0.0017). In multivariate analysis early resection of occult inguinal metastases detected on dynamic sentinel node biopsy was an independent prognostic factor for disease specific survival (p = 0.006). CONCLUSIONS: Early resection of lymph node metastases in patients with penile carcinoma improves surviva

Snow cover sensitivity to black carbon deposition in the Himalayas : from atmospheric and ice core measurements to regional climate simulations

We applied a climate-chemistry global model to evaluate the impact of black carbon (BC) deposition on the Himalayan snow cover from 1998 to 2008. Using a stretched grid with a resolution of 50 km over this complex topography, the model reproduces reasonably well the remotely sensed observations of the snow cover duration. Similar to observations, modelled atmospheric BC concentrations in the central Himalayas reach a minimum during the monsoon and a maximum during the post-and pre-monsoon periods. Comparing the simulated BC concentrations in the snow with observations is more challenging because of their high spatial variability and complex vertical distribution. We simulated spring BC concentrations in surface snow varying from tens to hundreds of mu g kg(-1), higher by one to two orders of magnitude than those observed in ice cores extracted from central Himalayan glaciers at high elevations (>6000ma.s.l.), but typical for seasonal snow cover sampled in middle elevation regions (<6000ma.s.l.). In these areas, we estimate that both wet and dry BC depositions affect the Himalayan snow cover reducing its annual duration by 1 to 8 days. In our simulations, the effect of anthropogenic BC deposition on snow is quite low over the Tibetan Plateau because this area is only sparsely snow covered. However, the impact becomes larger along the entire Hindu-Kush, Karakorum and Himalayan mountain ranges. In these regions, BC in snow induces an increase of the net short-wave radiation at the surface with an annual mean of 1 to 3Wm(-2) leading to a localised warming between 0.05 and 0.3 degrees C

The contribution of MIB 1 in the accurate grading of vulvar intraepithelial neoplasia.

AIM: To determine the interobserver variation in scoring presence and grade of vulvar intraepithelial neoplasia (VIN) in haematoxylin/eosin (H/E) slides, MIB 1 slides, and the combined use of H/E and MIB 1 slides. METHODS: 10 slides were stained with H/E and MIB 1 with each of the following diagnoses: normal vulvar skin, VIN 1, VIN 2, and VIN 3. Six observers first scored the H/E slides separately from the MIB 1 slides and second the combined H/E and MIB 1 slides. RESULTS: Unweighted group kappa for MIB 1 was 0.62 and the weighted group kappa was 0.91. This was significantly better than the unweighted group kappa for H/E slides (0.47, p = 0.023) as well as the weighted group kappa for H/E slides (0.82, p = 0.014). There was no improvement by the combined use of H/E and MIB 1 slides. VIN 2 is far less confused with VIN 3 in the combined use of H/E and MIB 1 slides (9%) than in H/E slides (38%) (p = 0.007). There is a tendency to grade VIN in a two tailed grading system rather than a three tailed grading system, which became more apparent with the combined use of H/E and MIB 1 slides. CONCLUSIONS: The interobserver variation with sole use of MIB 1 is better than with the use of H/E stain in VIN. The use of MIB 1 in grading VIN diminishes confusion between VIN 2 and VIN 3 fourfold. A two tailed grading system for VIN seems already to work in daily practice

Immunogenicity, including vitiligo, and feasibility of vaccination with autologous GM-CSF-transduced tumor cells in metastatic melanoma patients

PURPOSE: To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients. PATIENTS AND METHODS: Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays. RESULTS: The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1- and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon-gamma on specific antigenic stimulation. CONCLUSION: We conclude that vaccination with GM-CSF-transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigatio