Tumor localization of radiolabeled antibodies against carcinoembryonic antigen in patients with carcinoma: a critical evaluation.

Purified, [131I]-labeled goat antibodies against carcinoembryonic antigen, which have been shown to localize in human carcinoma in nude mice, were injected into 27 patients with carcinoma. Patients were scanned with a scintillation camera at various intervals. In 11 patients, radioactivity was detectable in the tumor 48 hours after injection. Computerized subtraction of blood-pool radioactivity provided clearer pictures in positive cases, but in 16 patients the scans remained doubtful or negative. To study the specificity of [131I]-antibody localization, we gave some patients simultaneous injections of [125I]-labeled normal IgG. Both isotopes were measured by means of scintillation counting in tumors and normal tissues recovered after surgery. The results demonstrated that only the anti-CEA antibodies localized in tumors. However, the total antibody-derived radioactivity in the tumor was only about 0.001 of the injected dose. We conclude that, despite the present demonstration of specificity, this method of tumor detection is not yet clinically useful.

A proposal for an international retinoblastoma staging system.

BACKGROUND: Although intra-retinal tumor has long been staged presurgically according to the Reese-Ellsworth (R-E) system, retinoblastoma differs from other pediatric neoplasms in never having had a widely accepted classification system that encompasses the entire spectrum of the disease. Comparisons among studies that consider disease extension, risk factors for extra-ocular relapse, and response to therapy require a universally accepted staging system for extra-ocular disease. PROCEDURE: A committee of retinoblastoma experts from large centers worldwide has developed a consensus classification that can encompass all retinoblastoma cases and is presented herein. Patients are classified according to extent of disease and the presence of overt extra-ocular extension. In addition, a proposal for substaging considering histopathological features of enucleated specimens is presented to further discriminate between Stage I and II patients. RESULTS: The following is a summary of the classification system developed-Stage 0: Patients treated conservatively (subject to presurgical ophthalmologic classifications); Stage I: Eye enucleated, completely resected histologically; Stage II: Eye enucleated, microscopic residual tumor; Stage III: Regional extension [(a) overt orbital disease, (b) preauricular or cervical lymph node extension]; Stage IV: Metastatic disease [(a) hematogenous metastasis: (1) single lesion, (2) multiple lesions; (b) CNS extension: (1) prechiasmatic lesion, (2) CNS mass, (3) leptomeningeal disease]. A proposal is also presented for substaging of enucleated Stages I and II eyes. CONCLUSIONS: The proposed staging system is the product of an international effort to adopt a uniform staging system for patients with retinoblastoma to cover the whole spectrum of the disease.

Konenäköinvestoinnin soveltuvuus- ja esikannattavuustukimus sahalaitoksessa

Diplomityön tavoitteena oli selvittää sahalaitokselle mahdollisen konenäköinvestoinninsoveltuvuus ja kannattavuus. Tutkimus rajattiin vaihtoehtojen tunnistamisen ja investoinnin kannattavuuden alustavaan analyysiin. Tutkimuksessa arvioitiin konenäkötekniikan mahdollisuuksia sahateollisuusprosessissa yleisesti sekä erityisesti sahatavaran pitkittäis- ja poikittaissuuntaisissa sahatavaran pinnantarkastuksissa. Konenäköjärjestelmien toimittajia ja heidän referenssejään haastattelemalla saatiin selvitettyä tarjottujen järjestelmien tekninen soveltuvuus. Tutkimus liitettiin työn toimeksiantajan toimintastrategiaan, jotta voitiin arvioida mahdollisimman kattavasti kaikki investoinnilla saavutettavat hyödyt. Kannattavuuslaskentaa varten arvioitiin investoinnilla saavutettavat nettotuotot suunnitellulle pitoajalle. Laskennassa käytettiin perinteisiä investointilaskentamenetelmiä kuten nykyarvomenetelmää, takaisinmaksuaikaa ja sisäistä korkokantaa. Poikittaissuuntainen sahatavaran pinnantarkastus tuoreen ja kuivan tavaran tasaamolla todettiin teknisesti toteuttamiskelpoiseksi vaihtoehdoksi. Kyseisessä vaihtoehdossa liitännäisinvestointien määrän arvioidaan jäävän melko vähäisiksi. Konenäköinvestoinnin voidaan arvioida kannattavan, muttakannattavuuden edellytyksenä on vahva johdon ja muun henkilöstön sitoutuminen uuteen haasteeseen.

Nouvelles armes thérapeutiques contre le mélanome de stade IV [New therapeutic weapons in stage IV melanoma].

The treatment of stage IV melanoma has been revolutionized over the last years with the development of immunotherapies that, for the first time, have shown a significant benefit in overall survival, as well as with extremely effective targeted therapies, that also led to improved survival. These results are the fruits of an important translational research effort that allowed a rational approach with a very fast clinical development. The treatment of metastatic melanoma is, therefore, an illustration of the new paradigms of modern molecular research in oncology. In this review, we will present the various agents that have made the proof of their clinical benefit, as well as the scientific discoveries that allowed their development. Some of the remaining questions will be touched upon with the ongoing clinical trials. Inclusion of patients in these studies remains the top priority to improve on the clinical care.

Characterization of membrane vesicles circulating in the serum of patients with common acute lymphoblastic leukemia.

Common acute lymphoblastic leukemia antigen detected by radioimmunoassay in the serum of patients with common acute lymphoblastic leukemia was found to be exclusively associated with the pellet of the serum samples obtained by ultracentrifugation at 100,000 X g. The pellets were shown to contain membrane vesicles or fragments which were characterized by electron microscopy and determination of enzymatic activity. The pelleted fragments had an apparent diameter ranging between 60 and 260 nm and showed a trilaminar membrane structure. On freeze-fracture preparations, the fragments with concave profile, corresponding to the external fracture face of plasma membrane, displayed an intramembrane particle density (ranging from 0 to 750 particles per micron2) which is similar to that recorded on the corresponding fracture face of intact cells from the common lymphoblastic leukemia antigen positive leukemic cell line (Nalm-1) or of vesicles shed in the culture medium by Nalm-1 cells. Furthermore, analysis of the membrane enzyme marker 5'-nucleotidase in the pellet of patient's sera, showed that the presence of this enzyme correlated with that of common lymphoblastic leukemia antigen, but the quantitative relationship between the two surface constituents was not linear. The results suggest that the two markers are located on the same membrane fragments, but that their individual distribution on the shed fragments is heterogeneous.

Methylation of CpG island promoters in uveal melanoma.

BACKGROUND: Inactivation of tumour-related genes by promoter hypermethylation is a common epigenetic event in the development of a variety of tumours. AIM: To investigate in primary uveal melanoma the status of promoter methylation of genes thought to be involved in tumour development: p16, TIMP3, RASSF1, RARB, FHIT, hTERT and APC. METHODS: Gene promoter methylation was studied by methylation-sensitive single-strand conformation analysis and dot-blot assay in a series of 23 primary uveal melanomas. All DNA samples were obtained from paraffin-embedded formalin-fixed tissue blocks. RESULTS: hTERT promoter methylation was found with a relatively high frequency (52%). Promoter methylation of p16, TIMP3, RASSF1, RARB, FHIT and APC was a rare event. For none of these genes did promoter methylation exceed 15% of tumour samples, and, for some genes (FHIT and APC), no methylation was found at all. Furthermore, promoter methylation was absent in 39% (9/23) of cases. In only 22% (5/23) of cases was hypermethylation of at least two promoters observed. CONCLUSIONS: Promoter methylation of hTERT is a regular event in uveal melanoma. Hypermethylation of the other genes studied does not seem to be an essential element in the development of this tumour. As promoter methylation of APC, RASSF1 and RARB is often observed in cutaneous melanoma, these results suggest that different epigenetic events occur in the development of cutaneous and uveal melanoma.

Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination.

Inherited mutations in human PALB2 are associated with a predisposition to breast and pancreatic cancers. PALB2's tumor-suppressing effect is thought to be based on its ability to facilitate BRCA2's function in homologous recombination. However, the biochemical properties of PALB2 are unknown. Here we show that human PALB2 binds DNA, preferentially D-loop structures, and directly interacts with the RAD51 recombinase to stimulate strand invasion, a vital step of homologous recombination. This stimulation occurs through reinforcing biochemical mechanisms, as PALB2 alleviates inhibition by RPA and stabilizes the RAD51 filament. Moreover, PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion. Finally, we show that PALB2-deficient cells are sensitive to PARP inhibitors. Our studies provide the first biochemical insights into PALB2's function with piBRCA2 as a mediator of homologous recombination in DNA double-strand break repair.

Kunnossapidon kehitysmalli sanomalehtipainon tuotannon luotettavuuden, tuottavuuden ja tuotteen laadun turvaamiseksi

Diplomityössä käsitellään ne toimet, jotka Esa Lehtipaino Oy:ssä tarvitsee tehdä kunnossapidon kehittämiseksi sanomalehtipainoprosessin kunnossapidossa. Työssä käytettiin luotettavuuskeskeisen ja kokonaisvaltaisen tuottavuuskeskeisen kunnossapidon strategioiden osia sekä PSK Standardisoinnin PSK 5705:2006standardin mukaista menetelmää määrittämään kunnossapidon kannalta tärkeimmät kohteet ja osa-alueet. PSK 5705:2006 on kunnonvalvonnan värähtelymittausten mittaustoiminnan suunnitteluun luotu standardi, jonka perusteella rakennettiin sanomalehtipainoprosessiin sopiva tuotantolaitteiston luokitusjärjestelmä. Luokituksenperusteella kohdennetaan kunnossapidon resurssit tuotantojärjestelmän luotettavuuden kannalta oikeisiin, tuottavimpiin kohteisiin. Tuotantohenkilöstön kunnossapitohenkilökunnalle tekemien vikailmoitusten välitykseen rakennettiin Microsoft Access -pohjainen Vikaloki-lomake. Kunnossapitotoiminnan kehityksen tuloksien seuraamiseksi määritettiin PSK 6201:2003 standardin mukainen tuotannon kokonaistehokkuutta kuvaava KNL-luku. KNL-luvusta luotiin ennuste kunnossapidon kehittämistarpeista regressioanalyysin avulla. Kehitysmalli esittää, että kohdeyrityksessä tulee toiminnan kehittäminen aloittaa päivittämällä tietokonepohjainen toiminnanohjausjärjestelmä, johon lisätään ennakoivat suunnitellut kunnossapitotoimet. Toimet määriteltiin yllämainitun kriittisyysluokituksen perusteella.

Viilujen lujuuslajittelun kehittäminen

Työn lähtökohtana on viilujen lujuuslajittelun kehittäminen. Lujuuslajittelun on tarkoitus perustua viilujen paino- ja tiheyseroihin, joilla on vaikutusta viilujen lujuusominaisuuksiin. Viilujen paino- ja tiheyserojen selvittäminen on tarkoi-tus toteuttaa punnituksen avulla ja siihen kuuluva laitteisto oli jo alustavasti suunniteltu. Teoriaosan avulla tutustuttiin viilujen ja vanerin valmistukseen liittyviin pro-sesseihin, puun tiheyteen ja lujuuteen liittyviin tekijöihin ja eri tekijöiden vaikutuksiin viilujen ja vanereiden lujuusominaisuuksissa. Työn kokeellinen osa voidaan jakaa selkeästi kahteen tutkimusalueeseen. Ensimmäisessä oli tarkoitus selvittää viiluissa esiintyvien paino- ja tiheyserojen vaihteluita ja niiden vaikutuksia viilujen lujuusominaisuuksiin ja sitä kautta myös valmiiden levyrakenteiden ominaisuuksiin. Viilutasolla tutkittiin tiheyden vaikutusta poikittaisveto- ja taivutuslujuuteen ja vaneritasolla tiheyden vaikutusta taivutuslujuu-teen. Raaka-aineina tutkimuksissa ja lujuuskokeissa käytettiin koivu-, kuusi- ja poppeliviiluja. Työn toinen osa keskittyi viilujen punnituksen testaamiseen ja kehittämiseen. Tutkittavien puulajien kohdalla viiluista löytyi huomattavia paino- ja tiheyseroja, joiden vaikutukset näkyivät erityisesti viilujen ja vanerien taivutuslujuuksien arvoissa. Punnituksen tulokset osoittivat, että riittävän tuotekehityksen myötä viilujen punnitukseen perustuva lajittelu olisi mahdollista toteuttaa tutkitun menetelmän avulla. Vanerirakenteissa havaittujen taivutuslujuuserojen perusteella lujuuslajittelulle olisi käyttöä ja siitä olisi hyötyä levyrakenteiden suunnittelussa.

Das GRADE-System: ein internationaler Ansatz zur Vereinheitlichung der Graduierung von Evidenz und Empfehlungen in Leitlinien. [The GRADE System: an international approach to standardize the graduation of evidence and recommendations in guidelines]

Clinical practice guidelines have become an important source of information to support clinicians in the management of individual patients. However, current guideline methods have limitations that include the lack of separating the quality of evidence from the strength of recommendations. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group, an international collaboration of guideline developers, methodologists, and clinicians have developed a system that addresses these shortcomings. Core elements include transparent methodology for grading the quality of evidence, the distinction between quality of the evidence and strength of a recommendation, an explicit balancing of benefits and harms of health care interventions, an explicit recognition of the values and preferences that underlie recommendations. The GRADE system has been piloted in various practice settings to ensure that it captures the complexity involved in evidence assessment and grading recommendations while maintaining simplicity and practicality. Many guideline organizations and medical societies have endorsed the system and adopted it for their guideline processes.

Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose.

In mice, vaccination with high peptide doses generates higher frequencies of specific CD8+ T cells, but with lower avidity compared to vaccination with lower peptide doses. To investigate the impact of peptide dose on CD8+ T cell responses in humans, melanoma patients were vaccinated with 0.1 or 0.5 mg Melan-A/MART-1 peptide, mixed with CpG 7909 and Incomplete Freund's adjuvant. Neither the kinetics nor the amplitude of the Melan-A-specific CD8+ T cell responses differed between the two vaccination groups. Also, CD8+ T cell differentiation and cytokine production ex vivo were similar in the two groups. Interestingly, after low peptide dose vaccination, Melan-A-specific CD8+ T cells showed enhanced degranulation upon peptide stimulation, as assessed by CD107a upregulation and perforin release ex vivo. In accordance, CD8+ T cell clones derived from low peptide dose-vaccinated patients showed significantly increased degranulation and stronger cytotoxicity. In parallel, Melan-A-specific CD8+ T cells and clones from low peptide dose-vaccinated patients expressed lower CD8 levels, despite similar or even stronger binding to tetramers. Furthermore, CD8+ T cell clones from low peptide dose-vaccinated patients bound CD8 binding-deficient tetramers more efficiently, suggesting that they may express higher affinity TCRs. We conclude that low peptide dose vaccination generated CD8+ T cell responses with stronger cytotoxicity and lower CD8 dependence.