Expression of p53, bcl-2 and nm23 proteins in squamous cell lung cancer

Wstęp: Poznanie profilu molekularnego raka płuca jest niezbędnym elementem postępu w terapii tej choroby. Szczególnie istotna jest charakterystyka markerów apoptozy i zjawiska tworzenia przerzutów ze względu na kluczową rolę tych procesów w rozwoju nowotworu. Celem pracy była ocena ekspresji białek: p53 i bcl-2, produktów genów regulujących proces apoptozy oraz antymetastatycznego białka nm23 w płaskonabłonkowym raku płuca wraz z określeniem związku badanych markerów z podstawowymi parametrami klinicznymi i patologicznymi. Materiał i metody: Do badań zakwalifikowano 30 preparatów tkankowych raka płuca pochodzących od pacjentów poddanych resekcji miąższu płuca. Oznaczenia badanych białek wykonano metodą immunohistochemiczną w preparatach parafinowych. Wyniki: Ekspresja antymetastatycznego białka nm23 występowała rzadziej w przypadkach cechujących się obecnością zatorów z komórek raka w naczyniach krwionośnych oraz przerzutami w węzłach chłonnych. W guzach z przerzutami do węzłów chłonnych znamiennie częściej stwierdzono fenotyp p53+/bcl-2+ niż w przypadkach bez przerzutów. Ekspresja badanych białek nie wykazała związku z przeżyciem w dwuletniej obserwacji. Wnioski: Rezultaty badań wskazują na znaczną heterogenność ekspresji badanych markerów w obrębie raka płaskonabłonkowego płuca oraz potencjalnie niekorzystny wpływ koekspresji p53 i bcl-2. W płaskonabłonkowym raku płuca zmniejszenie ekspresji nm23 wykazuje wyraźny związek z morfologicznymi wykładnikami procesu przerzutowania.Introduction: The evaluation of lung cancer molecular profiles is an essential element of the therapeutic process in that type of neoplasm. The analysis of apoptotic and metastasis-linked proteins is an important goal because of the key role of those processes in carcinogenesis. The aim of this study was to evaluate the expression of apoptosis regulatory proteins p53 and bcl-2 as well as antimetastatic marker nm23 in squamous cell lung cancer, taking into account the clinical and pathological data. Material and methods: Thirty tissue specimens from patients undergoing therapeutic or diagnostic thoracic surgery were included in the study. All markers were assessed with immunohistochemistry method on paraffin-embedded tissue. Results: Nm23 expression was observed less frequently in specimens with cancer cell emboli in blood vessels or lymph node metastasis. In cancers with lymph node metastasis, the coexpression of p53 and bcl-2 was found statistically more often than in lymph node negative cases. There was no correlation between p53, bcl-2 and nm23 expression and 2-years survival time. Conclusions: Our study indicates a marked heterogeneity of p53, bcl-2 and nm23 expression in squamous cell lung cancer and the potentially unfavorable influence of p53 and bcl-2 coexpression. Less frequent nm23 expression seems to be connected with morphological signs of metastatic process

Erlotinib targeted therapy in patient with advanced lung adenocarcinoma

Rak płuca jest najczęstszym nowotworem u mężczyzn i trzecim po raku piersi i jelita grubego u kobiet. Rokowanie w tym nowotworze jest niekorzystne, a rocznie umiera w Polsce około 22 000 osób. Wprowadzenie terapii celowanej stanowi znaczący postęp w leczeniu zaawansowanego raka płuca. Daje szansę na wydłużenie czasu do progresji choroby i wiąże się z mniejszymi skutkami ubocznymi w porównaniu do klasycznej chemioterapii. Skuteczność tej terapii w guzach pozbawionych tego rodzaju mutacji nie jest zadowalająca. W pracy przedstawiono przypadek pacjentki z zaawansowanym gruczolakorakiem płuca, która była leczona erlotynibem. Zastosowane leczenie pozwoliło na utrzymanie stabilizacji choroby przez 31 miesięcy przy zachowaniu bardzo dobrego komfortu życia i kontynuacji pracy zawodowej.Lung cancer is the most common cancer in men and the third most common type of cancer after breast and colon cancer in women. The prognosis for this cancer is unfavorable and die each year in Poland about 22.000 people. The introduction of targeted therapy represents a significant advance in the treatment of advanced lung cancer. It gives an opportunity to extend the time to disease progression and is associated with fewer side effects compared to the classic chemotherapy. The efficacy of this therapy in tumors without a mutation of this type is not satisfactory. We present a case of a patient with advanced adenocarcinoma of the lung, which was treated with erlotinib. This treatment allowed for the maintenance of stable disease for 31 months while maintaining a good quality of life and continue working

Diagnosis and treatment of female patients with lung cancer in IV stage

Rokowanie w raku płuca jest niekorzystne. Pięcioletnie przeżycie osiąga zaledwie 13% chorych. Większość pacjentów w momencie rozpoznania ma zaawansowane stadium choroby i wymaga leczenia paliatywnego. Wprowadzenie leków ukierunkowanych molekularnie do terapii raka płuca stanowi istotny postęp związany z opóźnieniem progresji choroby przy zachowaniu dobrego komfortu leczenia. Przedstawiono opis przypadku kobiety, u której wystąpiły trudności diagnostyczne spowodowane obwodowym położeniem raka płuca. Po uzyskaniu rozpoznania pacjentkę leczono erlotynibem w drugiej linii.The prognosis of lung cancer is unfavorable. Five-year survival is achieved only 13% of patients. Most patients have advanced disease and require palliative treatment. The introduction of targeted therapy for the treatment of lung cancer is an important step associated with delay of disease progression while maintaining good life comfort during treatment. We present the case of a woman, in which the diagnostic difficulties were connected with the peripheral location of lung cancer. After the diagnosis, the patient was treated with erlotinib in the second line

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Compound heterozygosity; Genotype; PhenotypeHeterocigosidad compuesta; Genotipo; FenotipoHeterozigositat composta; Genotip; FenotipBackground & Aims Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.1. MD/PhD scholarship from the University of Groningen, Groningen, The Netherlands 2. ESPGHAN Networking Grant 2019 3. ChiLDReN and CTSA National Institutes of Health grants: Ann & Robert H. Lurie Children's Hospital, Chicago: U01DK062436; University of Colorado, Denver: U01DK62453, UL1 TR002535; Baylor college of Medicine, Houston: U01DK103149; Children's Hospital of Philadelphia, Philadelphia: U01DK062481, UL1TR000003; Children's Hospital of Pittsburgh, Pittsburgh: U01DK062466; University of California, San Francisco U01DK062500; University of California, San Francisco CTSI grant UL1TR001872; Riley Hospital for Children, Indianapolis: U01DK084536; Seattle Children’s Hospital, Seattle: DK084575; Children’s Hospital Los Angeles, California: U01DK084538. 4. Unrestrictive research grant from Albireo 5. Unrestrictive research grant from Mirum Pharmaceuticals. 6. C&W de Boer Stichting research grant

Sleep disordered breathing in patients with heart failure

Sleep disordered breathing (SDB) is a common co-morbidity in patients with heart failure(HF). Both its forms — central and obstructive sleep apnea — are highly prevalent in thispopulation. SDB fragments sleep, impairs life quality, worsens exercise tolerance, worsens HFand is an independent predictor of poor prognosis. Still, SDB remains largely undiagnosed.Therefore, early detection of SDB seems to be of primary importance, especially in the presenceof new diagnostic and therapeutic methods. Treatment with continuous positive airwaypressure (CPAP) increases left ventricular ejection fraction and stroke volume in virtually allHF patients with obstructive and in 50% with central sleep apnea. For those in whom centralsleep apnea is not suppressed by CPAP, a trial of adaptive servoventilation is recommended.Although no randomized, controlled trials have shown improvement in mortality, several observationalstudies have shown that effective treatment of both forms of sleep apnea with variouspositive airway pressure devices improves survival of HF patients. Currently, 2 large trials withnewer masked based therapies with adaptive servoventilation are in progress. This article isa brief overview of present knowledge, the pathophysiology, diagnostic approach and therapy ofSDB

Serum levels of apoptosis-related markers (sFasL, TNF-a, p53 and bcl-2) in COPD patients

Introduction: Taking into account important role of apoptosis in COPD pathogenesis, we wanted to asses the serum levels of markers involved in apoptosis regulation, including apoptosis inducers such as TNF-a, sFasL or p53 protein and apoptosis inhibitor bcl-2 and, in addition, to compare these markers with selected COPD parameters. Material and methods: In 181 patients (60 women) with COPD (age was 62.2+ 9.37 years; FEV1% 55.2 + 19.98 %) and in 29 controls (11 women), serum levels of TNF-a, sFasL, p53 and bcl-2 were evaluated by the enzyme-linked immunosorbent assay (ELISA) method. Results: In COPD patients the mean sFasL level was 0.092 ± 0.077 ng/ml and mean TNF-a level was 2.911 ± 3.239 pg/ml. There were no differences in serum sFasL and TNF-a in COPD patients and control group. TNF-a and sFasL did not correlate with COPD parameters such as FEV1%, BMI, RV% (percentage of predicted value of residual volume) or BODE. Although we tried to evaluate bcl-2 and p53 protein serum levels with two different tests, measurable levels of bcl-2 were only detected in 15 patients and p53 in only 3 patients. Bcl-2 values were from 0.418 to 11.423 ng/ml and p53 from 90.772 to 994.749 pg/ml. Conclusions: We didn’t observe any differences in serum levels of pro- and antiapoptotic markers in COPD patients and the control group or correlations between the markers studied and COPD parameters

Współistnienie zespołu obturacyjnego bezdechu śródsennego i przewlekłej obturacyjnej choroby płuc

Wstęp: Zespół obturacyjnego bezdechu śródsennego (OBŚ) i przewlekła obturacyjna choroba płuc (POChP) mogą prowadzić do przewlekłej hipowentylacji pęcherzykowej. Współistnienie zespołu OBŚ i POChP to zespół nakładania. Celem pracy było określenie związku między zaawansowaniem POChP a wystąpieniem przewlekłej hipowentylacji pęcherzykowej u chorych z zespołem OBŚ oraz wpływu przewlekłej hipowentylacji pęcherzykowej u osób z zespołem nakładania na nasilenie zaburzeń oddechowych w czasie snu. Materiał i metody: Badaniem objęto 64 otyłych chorych (BMI 40 &#177; 6,5 kg/m2) z zespołem OBŚ (AHI > 15, średnio 52 &#177; 22) i współistniejącą POChP. Analizowano wyniki badań polisomnograficznych, spirometrycznych i gazometrycznych. Wyniki: Przewlekła hipowentylacja pęcherzykowa występowała u 67% chorych, w tym u 60,5% chorych, u których badanie spirometryczne wskazywało na POChP w stadium umiarkowanym, u 85% pacjentów w stadium ciężkim i u wszystkich osób w stadium bardzo ciężkim. U chorych z przewlekłą hipowentylacją pęcherzykową stwierdzono mniejsze niż u pozostałych badanych FVC (2,7 &#177; 0,8 l v. 3,6 &#177; 0,9 l; p < 0,001) i FEV1 (1,7 &#177; 0,6 l v. 2,2 &#177; 0,5 l; p < 0,001) oraz mniejsze średnie SaO2 w czasie zakończenia śródsennych bezdechów obturacyjnych i okresów spłyconego oddechu (75 &#177; 10% v. 84 &#177; 5%; p < 0,001). Wnioski: Przewlekłą hipowentylację pęcherzykową stwierdza się u większości otyłych chorych z umiarkowaną i ciężką postacią zespołu OBŚ i współistniejącą POChP, w tym także umiarkowanie nasiloną. Wystąpienie przewlekłej hipowentylacji pęcherzykowej u otyłych chorych z zespołem OBŚ i współistniejącą POChP zależy od zmniejszenia FVC i FEV1, ale nie od obniżenia wskaźnika FEV1/FVC. Występowanie przewlekłej hipowentylacji pęcherzykowej u otyłych pacjentów z zespołem OBŚ i współistniejącą POChP wiąże się ze znacznym niedotlenieniem krwi tętniczej w czasie śródsennych bezdechów obturacyjnych i okresów spłyconego oddechu. Pneumonol. Alergol. Pol. 2011; 79, 2: 99-108Introduction: Both obstructive sleep apnea (OSA) syndrome and chronic obstructive pulmonary disease (COPD) may lead to chronic alveolar hypoventilation. The coexistence of OSA syndrome and COPD has been named the overlap syndrome. The aim of the study was to elucidate the relationship between the severity of COPD and the occurrence of chronic alveolar hypoventilation in patients with OSA syndrome. Material and methods: The material of the study consisted of 64 obese (BMI 40 &#177; 5.5 kg/m2) patients with OSA syndrome (AHI >15, mean 52 &#177; 23) and coexisting COPD (FEV1/FVC < 70%). The results of polysomnographic, spirometric and arterial blood gases studies have been evaluated. Results: Chronic alveolar hypoventilation has been found in 67% of the patients: in 60.5% of patients in the spirometric stage II, in 85% of patients in the stage III and in all the patients in the stage IV of COPD. In the patients with chronic alveolar hypoventilation as compared with the remaining patiens there were: lower FVC (2.7 &#177; 0.8 L v. 3.6 &#177; 0.9 L; p < 0.001), FEV1 (1.7 &#177; 0.6 L v. 2.2 &#177; 0.5 L; p < 0.001) and mean SaO2 during obstructive sleep apneas and hypopneas (75 &#177; 10% v. 84 &#177; 5%; p < 0.001). Conclusions: Chronic alveolar hypoventilation occurs in most of the obese patients with moderate and severe OSA syndrome and coexisting COPD, including most of the patients with moderately impaired ventilatory function. The occurrence of chronic alveolar hypoventilation in the course of the overlap syndrome is related to the restrictive ventilatory pattern and the lower mean and minimal SaO2 during obstructive sleep apneas and hypopneas. Pneumonol. Alergol. Pol. 2011; 79, 2: 99-10

The treatment of nicotine dependence based on bupropion SR and educational support - a one year observation and analysis of the reasons of relapses

Tobacco dependence is a chronic, relapsing disease causing an enormous burden of deaths. The aim of the study was a one year evaluation of the efficacy of bupropion SR supported by an educational program in the treatment of nicotine dependence and analysis of the reasons of relapses. 54 smokers were enrolled. The 12-month continuous abstinence rate was 28,3%. The most common cause of relapses in the treatment period was craving for cigarettes, in the post-treatment period stress

Common variant p.D19H of the hepatobiliary sterol transporter ABCG8 increases the risk of gallstones in children

Introduction Gallstones are increasingly common in children. Genetic analyses of adult cohorts demonstrated that the sterol transporter ABCG8 p.D19H and Gilbert UGT1A1*28 variants enhance the odds of developing gallstones. The genetic background of common lithiasis in children remains unknown. Methods Overall, 214 children with gallstone disease (1 month–17 years, 107 boys) were inclueded. The control cohorts comprised 214 children (age 6–17 years, 115 boys) and 172 adults (age 40–92 years, 70 men) without gallstones. The ABCG8 p.D19H and UGT1A1*28 polymorphisms as well as ABCB4 (c.504C>T rs1202283, c.711A>T rs2109505) and NPC1L1 variants (p.V1296V rs217434, c.−18C>A rs41279633) were genotyped using TaqMan assays. Serum concentrations of plant sterols and cholesterol precursors were measured by gas chromatography/mass spectrometry. Results The ABCG8 risk allele was associated with an increased risk of stones (OR = 1.82, p = .03). Children carrying the p.19H allele presented with lower serum concentrations of surrogate markers of intestinal cholesterol absorption and decreased ratios of phytosterols to the cholesterol precursor desmosterol. Carriers of the common NPC1L1 rs217434 allele had an increased gallstone risk compared with stone-free adults (OR 1.90, p < .01). This variant also affected the ratio of phytosterols to cholesterol precursors (p = .03). Other tested variants were not associated with gallstone risk. Conclusions The p.D19H ABCG8 and, to a lesser extent, NPC1L1 rs217434 variants increase the risk of early-onset gallstone formation. These results point to the presence of a common lithogenic pathway in children and adults

Case Report: Adenosine kinase deficiency diagnosed 10 years after liver transplantation: Novel phenotypic insights

Adenosine kinase (ADK) deficiency is a rare inborn error of methionine and adenosine metabolism. So far, a total of 27 patients with ADK deficiency have been reported. Here, we describe the first Polish patient diagnosed with ADK deficiency, aiming to highlight the clinical presentation of disease, emphasize diagnostic difficulties, and report the long-term follow-up. Six-month-old patient presented with cholestatic liver disease, macrocytic anemia, developmental delay, generalized hypotonia, delayed brain myelination, and elevated levels of serum methionine. A decrease of mitochondrial respiratory chain complex II and III activity were found in the postnuclear supernatants obtained from skeletal muscle biopsy. The patient underwent living-donor liver transplantation (LTx) at 14 months of age. Ten-year follow-up after LTx revealed a preserved good liver function, persistent regenerative macrocytic anemia, progressive neurological disease but disappearance of brain MR changes, short stature, and cortisol deficiency. Whole exome sequencing revealed the patient to be affected with two novel ADK variants, which pathogenicity was confirmed biochemically by demonstration of elevated concentration of S-adenosylhomocysteine