286. Leczenie raka sutka inhibitorami aromatazy II generacji w materiale WCO

Cel pracyInhibitory aromatazy II generacji (Letrozol, Anastrozol) są stosowane w leczeniu zaawansowanego raka sutka, po niepowodzeniu leczenia tamoksifenem oraz coraz częściej jako leczenie pierwszego rzutu w leczeniu uzupełniającym. W pracy przedstawiono wstępne obserwacje i wyniki leczenia inhibitorami aromatazy chorych z nawrotem raka sutka oraz po niepowodzeniu leczenia tamoksifenem.Materiał i metody31 chorych na nowotwór sutka leczonych było inhibitorami aromatazy II generacji w okresie od 01.01.1995 do 31.12.2000 roku w Wielkopolskim Centrum Onkologii. Wiek chorych sięgał od 43 do 85 lat (średnio 61.7 lat). Leczenie inhibitorami rozpoczęto u 23 chorych z nawrotem raka sutka po niepowodzeniu leczenia tamoksifenem oraz u 8 chorych jako leczenie pierwszego rzutu. Wskazania do leczenia inhibitorami były następujące: rozsiew uogólniony (n=7 chorych), przerzuty do kości (n=7), wznowa miejscowa w bliźnie (n=5), rak sutka zaawansowany, nieoperacyjny (n=3), przerzuty do wątroby (n=3), do węzłów chłonnych okolicy nadobojczykowej (n=2) oraz ze względu na objawy uboczne tamoksifenu (n=4).WynikiŚredni okres leczenia inhibitorami wynosił 13 miesięcy. W 7 przypadkach (22,6%) odstąpiono od dalszego leczenia z powodu: dalszej progresji w kościach (n=4), progresji guza w sutku (n=1), rozsiewu do OUN (n=1) i krwawienia z dróg rodnych (n=1). Średni czas do progresji od momentu rozpoczęcia leczenia wynosił 9 miesięcy (w granicach od 1 do 24 miesięcy).WniosekInhibitory aromatazy II generacji wpływają na zahamowanie rozwoju nawrotowego oraz zaawansowanego raka sutka u części chorych. Tolerancja leczenia jest dobra

70. Meningiomas treated in Greatpoland Cancer Center between 1990–1997

IntroductionWe analyzed correlation between age of patient with anaplastic meningiomas, extension of tumor excision, histopatological recognition and time to recurrence and survival.Material and methodsBetween 1990–1997 7 patients with anaplastic meningioma, 3 patients with haemangiopericytoma, 2 patients with sarcoma meningeum (6 women and 6 men) have been irradiated. 7 patients underwent radical excision of the tumor, 5 patients non radical. The patients were irradiated from limited fields to total dose 56–60 Gy/T mostly by energy Co-60 (9 patients) and photons 9 MV (3 patients).ResultsThere are 6 patients with anaplasticum meningioma still alive. 3 patients living 96–108 months, 3 other 30–39 months. Recurrence was confirmed in two male participants who underwent radical surgery in 12 and 29 month from the start of treatment. The first patient died after 16 months with recurrence of the disease. One patient (39 years old) with heamangiopericytoma lives 40 months after radical surgery without evidence of recurrence. Two patients died – one 11 months after radical surgery (41 years old) and the other one (42 years old) 21 months after non radical surgery. Both patients (24 and 59 years old) with sarcoma died (one after 8 months, and the other one after 21 months).ConclusionsPatient with anaplastic meningiomas have long survival. The extension of tumor excision didn’t influence on survival

70 Wyniki leczenia chorych na raka sutka w stadium rozsiewu w materiale Wielkopolskiego Centrum Onkologii

WstępLeczenie chorych na raka sutka w stadium rozsiewu (M1) ma charakter paliatywny. Metody leczenia obejmują radioterapię, chemioterapię, hormonoterapię w monoterapii lub jako leczenie skojarzone. Wyniki leczenia są najczęściej złe. Przedstawiamy wyniki leczenia chorych na raka sutka w stadium rozsiewu leczonych w Wielkopolskim Centrum Onkologii.Materiał i metody95 chorych na raka sutka w stadium M1 leczono w latach 1983–1987 w Wielkopolskim Centrum Onkologii. Wiek chorych wahał się od 29 do 74 lat, średnio 51,5 lat. W grupie 65 chorych pierwszym umiejscowieniem przerzutów był kościec, w dalszej kolejności płuca i wątroba. Większość chorych leczona była cytostatykami lub hormonami, u części zastosowano paliatywną radioterapię. Wyniki leczenia opracowano na podstawie historii chorób i przeprowadzonej katamnezie. Grupę badaną poddano 5-letniej obserwacji.Wyniki8 chorych (8,4%) przeżyło 5 lat od momentu rozpoczęcia leczenia zmian przerzutowych. Średni okres przeżycia w całej grupie wyniósł 13,5 miesiąca.WnioskiPomimo złego rokowania leczeniem systemowym udaje się przedłużyć życie części chorych na raka sutka, u których wystąpiły przerzuty odległe

Combined Inhibition of Soluble Epoxide Hydrolase and Renin-Angiotensin System Exhibits Superior Renoprotection to Renin-Angiotensin System Blockade in 5/6 Nephrectomized Ren-2 Transgenic Hypertensive Rats with Established Chronic Kidney Disease

Background/Aims: We found recently that increasing renal epoxyeicosatrienoic acids (EETs) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, shows renoprotective actions and retards the progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). This prompted us to examine if additional protection is provided when sEH inhibitor is added to the standard renin-angiotensin system (RAS) blockade, specifically in rats with established CKD. Methods: For RAS blockade, an angiotensin-converting enzyme inhibitor along with an angiotensin II type receptor blocker was used. RAS blockade was compared to sEH inhibition added to the RAS blockade. Treatments were initiated 6 weeks after 5/6 NX in TGR and the follow-up period was 60 weeks. Results: Combined RAS and sEH blockade exhibited additional positive impact on the rat survival rate, further reduced albuminuria, further reduced glomerular and tubulointerstitial injury, and attenuated the decline in creatinine clearance when compared to 5/6 NX TGR subjected to RAS blockade alone. These additional beneficial actions were associated with normalization of the intrarenal EETs deficient and a further reduction of urinary angiotensinogen excretion. Conclusion: This study provides evidence that addition of pharmacological inhibition of sEH to RAS blockade in 5/6 NX TGR enhances renoprotection and retards progression of CKD, notably, when applied at an advanced stage

Dimethylarginine Dimethylaminohydrolase II Overexpression Attenuates LPS-Mediated Lung Leak in Acute Lung Injury

Acute lung injury (ALI) is a severe hypoxemic respiratory insufficiency associated with lung leak, diffuse alveolar damage, inflammation, and loss of lung function. Decreased dimethylaminohydrolase (DDAH) activity and increases in asymmetric dimethylarginine (ADMA), together with exaggerated oxidative/nitrative stress, contributes to the development of ALI in mice exposed to LPS. Whether restoring DDAH function and suppressing ADMA levels can effectively ameliorate vascular hyperpermeability and lung injury in ALI is unknown, and was the focus of this study. In human lung microvascular endothelial cells, DDAH II overexpression prevented the LPS-dependent increase in ADMA, superoxide, peroxynitrite, and protein nitration. DDAH II also attenuated the endothelial barrier disruption associated with LPS exposure. Similarly, in vivo, we demonstrated that the targeted overexpression of DDAH II in the pulmonary vasculature significantly inhibited the accumulation of ADMA and the subsequent increase in oxidative/nitrative stress in the lungs of mice exposed to LPS. In addition, augmenting pulmonary DDAH II activity before LPS exposure reduced lung vascular leak and lung injury and restored lung function when DDAH activity was increased after injury. Together, these data suggest that enhancing DDAH II activity may prove a useful adjuvant therapy to treat patients with ALI

Pharmacological Blockade of Soluble Epoxide Hydrolase Attenuates the Progression of Congestive Heart Failure Combined With Chronic Kidney Disease: Insights From Studies With Fawn-Hooded Hypertensive Rats

An association between congestive heart failure (CHF) and chronic kidney disease (CKD) results in extremely poor patient survival rates. Previous studies have shown that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, improves the survival rate in CHF induced by aorto-caval fistula (ACF) and attenuates CKD progression. This prompted us to examine if sEH inhibitor treatment would improve the outcome if both experimental conditions are combined. Fawn-hooded hypertensive (FHH) rats, a genetic model showing early CKD development was employed, and CHF was induced by ACF. Treatment with an sEH inhibitor was initiated 4 weeks after ACF creation, in FHH and in fawn-hooded low-pressure (FHL) rats, a control strain without renal damage. The follow-up period was 20 weeks. We found that ACF FHH rats exhibited substantially lower survival rates (all the animals died by week 14) as compared with the 64% survival rate observed in ACF FHL rats. The former group showed pronounced albuminuria (almost 30-fold higher than in FHL) and reduced intrarenal EET concentrations. The sEH inhibitor treatment improved survival rate and distinctly reduced increases in albuminuria in ACF FHH and in ACF FHL rats, however, all the beneficial actions were more pronounced in the hypertensive strain. These data indicate that pharmacological blockade of sEH could be a novel therapeutic approach for the treatment of CHF, particularly under conditions when it is associated with CKD

Flexibility of a biotinylated ligand in artificial metalloenzymes based on streptavidin—an insight from molecular dynamics simulations with classical and ab initio force fields

In the field of enzymatic catalysis, creating activity from a non catalytic scaffold is a daunting task. Introduction of a catalytically active moiety within a protein scaffold offers an attractive means for the creation of artificial metalloenzymes. With this goal in mind, introduction of a biotinylated d6-piano-stool complex within streptavidin (SAV) affords enantioselective artificial transfer-hydrogenases for the reduction of prochiral ketones. Based on an X-ray crystal structure of a highly selective hybrid catalyst, displaying significant disorder around the biotinylated catalyst [η6-(p-cymene)Ru(Biot-p-L)Cl], we report on molecular dynamics simulations to shed light on the protein–cofactor interactions and contacts. The results of these simulations with classical force field indicate that the SAV-biotin and SAV-catalyst complexes are more stable than ligand-free SAV. The point mutations introduced did not affect significantly the overall behavior of SAV and, unexpectedly, the P64G substitution did not provide additional flexibility to the protein scaffold. The metal-cofactor proved to be conformationally flexible, and the S112K or P64G mutants proved to enhance this effect in the most pronounced way. The network of intermolecular hydrogen bonds is efficient at stabilizing the position of biotin, but much less at fixing the conformation of an extended biotinylated ligand. This leads to a relative conformational freedom of the metal-cofactor, and a poorly localized catalytic metal moiety. MD calculations with ab initio potential function suggest that the hydrogen bonds alone are not sufficient factors for full stabilization of the biotin. The hydrophobic biotin-binding pocket (and generally protein scaffold) maintains the hydrogen bonds between biotin and protein

Activated Leukocyte Cell Adhesion Molecule Expression and Shedding in Thyroid Tumors

Activated leukocyte cell adhesion molecule (ALCAM, CD166) is expressed in various tissues, cancers, and cancer-initiating cells. Alterations in expression of ALCAM have been reported in several human tumors, and cell adhesion functions have been proposed to explain its association with cancer. Here we documented high levels of ALCAM expression in human thyroid tumors and cell lines. Through proteomic characterization of ALCAM expression in the human papillary thyroid carcinoma cell line TPC-1, we identified the presence of a full-length membrane-associated isoform in cell lysate and of soluble ALCAM isoforms in conditioned medium. This finding is consistent with proteolytically shed ALCAM ectodomains. Nonspecific agents, such as phorbol myristate acetate (PMA) or ionomycin, provoked increased ectodomain shedding. Epidermal growth factor receptor stimulation also enhanced ALCAM secretion through an ADAM17/TACE-dependent pathway. ADAM17/TACE was expressed in the TPC-1 cell line, and ADAM17/TACE silencing by specific small interfering RNAs reduced ALCAM shedding. In addition, the CGS27023A inhibitor of ADAM17/TACE function reduced ALCAM release in a dose-dependent manner and inhibited cell migration in a wound-healing assay. We also provide evidence for the existence of novel O-glycosylated forms and of a novel 60-kDa soluble form of ALCAM, which is particularly abundant following cell stimulation by PMA. ALCAM expression in papillary and medullary thyroid cancer specimens and in the surrounding non-tumoral component was studied by western blot and immunohistochemistry, with results demonstrating that tumor cells overexpress ALCAM. These findings strongly suggest the possibility that ALCAM may have an important role in thyroid tumor biology