[Managing of dyspnea in oncology]. / Prise en charge de la dyspnée en oncologie.

The perception of ventilatory effort is common in oncology, especially but not exclusively in the advanced stages of neoplastic disease. Dyspnea is a symptom whose discomfort and anguish it generates in the patient and his/ her entourage require constant management throughout the illness. The first step is to identify and optimize the treatment of comorbidities associated with tumour disease. Relief of respiratory oppression as a symptom requires a multidisciplinary approach. Opiates and benzodiazepines are at the forefront of pharmacological management. The mechanical obstruction that limits ventilatory flow and/or chest ampliation may justify more invasive management, including endoscopic techniques. Oxygen therapy will be considered on a case-by-case basis. Finally, global management includes respiratory revalidation, psychological support and improvement of environmental quality.

La perception d'un effort ventilatoire est fréquente en oncologique en particulier, mais non exclusivement, aux stades avancés de la maladie néoplasique. La dyspnée constitue un symptôme dont l'inconfort et l'angoisse qu'elle génère chez le patient et son entourage nécessitent une prise en charge constante tout au long de la maladie. La première étape est d'identifier et d'optimaliser le traitement des pathologies dyspnéisantes conjointes à la maladie tumorale. Le soulagement de l'oppression respiratoire en tant que symptôme nécessite une approche pluridisciplinaire. Les opiacés et les benzodiazépines sont au premier plan de la prise en charge pharmacologique. La levée d'un obstacle mécanique limitant les débits ventilatoires et/ou l'ampliation thoracique peut justifier des techniques plus invasives, notamment endoscopiques. L'oxygénothérapie sera envisagée au cas par cas. Enfin, la prise en charge globale inclut la revalidation respiratoire, le support psychique et l'amélioration de la qualité de l'environnement.

[Non small cell lung carcinoma in never-smokers at the Liege University Hospital : a retrospective cohort study, 2017-2018]. / Cancer pulmonaire non à petites cellules chez les patients non fumeurs au CHU de Liège : étude rétrospective entre début 2017 et fin 2018.

Lung cancer is the third most common cancer in Belgium in 2017 and remains the leading cause of cancer death worldwide. There is no longer any doubt that the main cause of lung cancer is smoking. However, the prevalence of lung cancer in never-smokers has been increasing overtime. Moreover, it is now recognized that the lung cancer of non-smoker patients has very distinct characteristics. In this retrospective cohort study (N = 520), we describe the characteristics of non-smoker patients and their non-small cell lung carcinoma and compare them to those of smokers. The patients included in this study were whose with a new diagnostic of lung cancer made at the Liège University Hospital of Liège over 2 years round. Non small cell lung cancer occurring in never-smokers patients is more often seen in young and very old patients, more frequent in female, essentially adenocarcinoma and often associated with mutations. This work confirms that lung cancer in never-smokers shows different features than lung cancer seen in patients with a smoking history.

Le cancer pulmonaire est le troisième cancer le plus fréquent en Belgique en 2017 et reste la première cause de décès par cancer dans le monde. Il ne fait plus aucun doute que la cause principale de cancer du poumon est le tabagisme. Il est toutefois apparu, ces dernières décennies, que le pourcentage de patients non fumeurs augmente parmi les patients présentant un cancer du poumon. Par ailleurs, il est dorénavant reconnu que le cancer pulmonaire du patient non fumeur présente des caractéristiques bien distinctes. Dans ce contexte, nous présentons une étude rétrospective reprenant les caractéristiques cliniques et néoplasiques de l'ensemble des patients ayant présenté un carcinome pulmonaire non à petites cellules dans notre institution sur une période de 2 ans (N = 520). Les cancers non à petites cellules observés chez les nonfumeurs sont plus fréquents chez les sujets jeunes ou très âgés, plus fréquents dans le sexe féminin, en très grande majorité des adénocarcinomes, et souvent associés à des mutations. Nous confirmons ainsi qu'il s'agit d'un cancer aux caractéristiques différentes des cancers pulmonaires des patients fumeurs.

[Targeted therapies for non-small cell lung cancer : state of the art in 2021]. / Traitements ciblés et cancer bronchique non à petites cellules : le point en 2021.

The majority of non-small cell lung cancers are diagnosed as advanced disease. Subsets of adenocarcinomas and of squamous cell carcinomas in nonsmokers present a molecular aberration leading to tumour survival. Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) and Repressor Of Silencing1 (ROS1) have been identified and targeted with good efficacy for fifteen years. Newer inhibitors brought even greater efficacy with a generally better tolerability. Other molecular aberrations (Kirsten Rat Sarcoma, Rearranged during Transfection, MET, NeuroTrophic Receptor yrosine kinase) are targets for newly developed, more selective drugs. As more and more patients will benefit from targeted therapies, the identification of molecular aberration is more than ever crucial for optimal lung cancer patient care.

La majorité des cancers pulmonaires non à petites cellules se présentent à un stade avancé. Une faible proportion des adénocarcinomes et des cancers épidermoïdes des non-fumeurs est porteur d'(une) anomalie(s) génétique (s) et moléculaire(s) dont dépend leur survie. Depuis une quinzaine d'années, les anomalies de l'«Epidermal Growth Factor Receptor¼ (EGFR), «Anaplastic Lymphoma Kinase¼ (ALK) et Repressor Of Silencing1 (ROS1) sont connues et ciblées par des inhibiteurs efficaces. De nouvelles générations permettent actuellement d'augmenter leur efficacité thérapeutique pour une toxicité globalement moindre. De nouvelles anomalies («Kirsten Rat Sarcoma¼, «Rearranged during Transfection¼, MET, «NeuroTrophic Receptor tyrosine kinase¼) sont, elles aussi, à présent ciblées de manière efficace. La recherche des anomalies moléculaires dans ces sous-types histologiques est devenue incontournable car elle modifie fondamentalement la prise en charge thérapeutique et le pronostic d'une proportion grandissante de patients.

[Empyema and subacute invasive aspergillosis following drowning]. / Cas clinique.Empyème et aspergillose invasive subaiguë dans les suites d'une inhalation lors d'une noyade.

Empyema and subacute invasive aspergillosis are rare pathologies that should not be overlooked because of the need for early treatment and a different management of bacterial infections which are more frequent. We report the case of a 75-year-old man with subacute invasive aspergillosis and an empyema following drowning and cardiopulmonary arrest.

L'empyème à Aspergillus fumigatus et l'aspergillose invasive subaiguë sont des pathologies rares à ne pas méconnaître au vu de la nécessité d'un traitement précoce et d'une prise en charge différente des infections pleuropulmonaires bactériennes qui sont plus fréquentes. Nous rapportons le cas d'un patient de 75 ans présentant une aspergillose invasive subaiguë, associée à un empyème, dans les suites d'une noyade avec arrêt cardiopulmonaire.

[Neuroendocrine neoplasms : a new era to the top of multidisciplinarity !] / Néoplasies neuroendocrines : une nouvelle ère a l'apogée de la multidisciplinarité !

Neuroendocrine neoplasms are histologically defined by a common neuroendocrine cellular phenotype. These are still considered as rare tumours even though their incidence is increasing. Heterogeneity is everywhere whether in the localization of the primitive cancer, the clinical presentation, the histological classification, the prognosis, as well as in therapeutic options, which clearly justifies specialized multidisciplinary care. Heterogeneity and scarcity explain the still fragmented nature of knowledge in this domain. Thanks to an increase in incidence, a desire for standardization of classification as well as the arrival of major therapeutic advances, such as vectorized internal radiotherapy, the future of neuroendocrine neoplasia seems more than promising and exciting. In our daily clinical practice at CHU Liège, we hope to bring our stone to the building by listing as many cases as possible in national and/or international databases, by centralizing therapeutic discussions within specific multidisciplinary concertations and by participating in multicenter study protocols.

Les néoplasies neuroendocrines sont définies histologiquement par un phénotype cellulaire neuroendocrine commun. Ces néoplasies sont toujours considérées comme des tumeurs rares, bien que leur incidence soit en constante augmentation. L'hétérogénéité est omniprésente, que ce soit dans la localisation du cancer primitif, la présentation clinique, la classification histologique, le pronostic ainsi que dans les diverses options thérapeutiques, justifiant impérativement une prise en charge pluridisciplinaire spécialisée. Cette hétérogénéité et cette rareté expliquent que les connaissances soient parcellaires. Grâce à une majoration d'incidence, une volonté d'uniformisation de classification ainsi que l'arrivée d'avancées thérapeutiques majeures, telles que la radiothérapie interne vectorisée, l'avenir des néoplasies neuroendocrines semble plus que prometteur et palpitant. En pratique clinique quotidienne au CHU de Liège, nous espérons apporter notre pierre à l'édifice en recensant un maximum de cas dans des bases de données nationales et/ou internationales, en centralisant les discussions thérapeutiques au sein de concertations multidisciplinaires dédiées et en participant à des protocoles d'études cliniques multicentriques.

[Small cell lung cancer : update of therapy]. / Le cancer pulmonaire à petites cellules : mise au point thérapeutique.

Small cell lung cancer is a malignant tumour with a poor prognosis. Standard treatment of metastatic stages has been a platinum doublet since 1980, but the addition of immunotherapy has improved prognosis. For locally advanced stages, the combination of radio-chemotherapy remains the treatment of choice, with no evidence at present of the value of immunotherapy in consolidation, and for localized stages, surgery is the first-line therapy. Unfortunately, in the second line, we have no other molecule than the topotecan despite several studies. Prophylactic brain irradiation remains debated even if it has been validated in localized forms. Finally, there is hope with targeted therapy following the development of subtypes of small cell lung cancer but studies remain difficult to conduct.

Le cancer pulmonaire à petites cellules est une tumeur maligne de mauvais pronostic. Le traitement standard des stades métastatiques était un doublet à base de sels de platine depuis 1980, mais l'ajout de l'immunothérapie a, quand même, permis d'améliorer le pronostic. Pour les stades localement avancés, l'association d'une radiochimiothérapie reste le traitement de choix, sans évidence actuellement de l'intérêt d'une immunothérapie en consolidation, et pour les stades localisés, la chirurgie. Malheureusement, en deuxième ligne, nous n'avons pas d'autre molécule que le topotécan malgré plusieurs études. L'irradiation cérébrale prophylactique reste débattue, même si elle a été validée dans les formes localisées. Enfin, il existe un espoir avec une thérapie ciblée suite à la mise en évidence de sous-types de cancers pulmonaires à petites cellules, mais les études restent difficiles à mener.

Could KL-6 levels in COVID-19 help to predict lung disease?

BACKGROUND: Coronavirus disease COVID-19 has become a public health emergency of international concern. Together with the quest for an effective treatment, the question of the post-infectious evolution of affected patients in healing process remains uncertain. Krebs von den Lungen 6 (KL-6) is a high molecular weight mucin-like glycoprotein produced by type II pneumocytes and bronchial epithelial cells. Its production is raised during epithelial lesions and cellular regeneration. In COVID-19 infection, KL-6 serum levels could therefore be of interest for diagnosis, prognosis and therapeutic response evaluation. MATERIALS AND METHODS: Our study retrospectively compared KL-6 levels between a cohort of 83 COVID-19 infected patients and two other groups: healthy subjects (n = 70) on one hand, and a heterogenous group of patients suffering from interstitial lung diseases (n = 31; composed of 16 IPF, 4 sarcoidosis, 11 others) on the other hand. Demographical, clinical and laboratory indexes were collected. Our study aims to compare KL-6 levels between a COVID-19 population and healthy subjects or patients suffering from interstitial lung diseases (ILDs). Ultimately, we ought to determine whether KL-6 could be a marker of disease severity and bad prognosis. RESULTS: Our results showed that serum KL-6 levels in COVID-19 patients were increased compared to healthy subjects, but to a lesser extent than in patients suffering from ILD. Increased levels of KL-6 in COVID-19 patients were associated with a more severe lung disease. DISCUSSION AND CONCLUSION: Our results suggest that KL-6 could be a good biomarker to assess ILD severity in COVID-19 infection. Concerning the therapeutic response prediction, more studies are necessary.

[How I manage... Malignant pleural mesothelioma in 2019]. / Comment je traite Le mésothéliome pleural malin en 2019.

Malignant pleural mesothelioma is a rare disease originating from mesothelial cells of the pleura and is related to asbestos exposure. The tumor is generally extended at the time of diagnosis and the treatment consists of a systemic palliative therapy. Radical approach is limited to very selected patients and is performed in expert centers but without validated schema. Radiotherapy alone is mainly used in palliative intent. Platinum-based chemotherapy in association with pemetrexed is the frontline standard of care and provides a 12-month overall survival. The addition of bevacizumab, an antiangiogenic drug, shows an improvement in median survival. To date, there is no second-line treatment approved for this disease and therefore inclusion in trials is recommended. Currently, various studies are investigating target therapy, immunotherapy and intrapleural perioperative treatment.

Le mésothéliome pleural malin est une tumeur rare, issue des cellules mésothéliales de la plèvre et liée à un contact avec l'amiante. Au moment du diagnostic, la maladie est souvent de stade avancé et est prise en charge par un traitement systémique palliatif. Un traitement radical est réservé pour de rares cas très sélectionnés, au sein de centres experts et ce, sans qu'aucun schéma de prise en charge ne soit validé. La radiothérapie seule est essentiellement utilisée à titre palliatif antalgique. Le traitement systémique de référence consiste en une chimiothérapie à base de cisplatine et pemetrexed permettant une survie globale de 12 mois. L'ajout à la chimiothérapie d'une thérapie ciblée anti-angiogénique, le bévacizumab, a permis une amélioration significative de la survie. A ce jour, il n'y a pas de traitement de 2ème ligne validé et il est donc recommandé d'inclure les patients dans des études cliniques. Actuellement, de multiples études évaluent des thérapies ciblées, des immunothérapies et des traitements intrapleuraux peropératoires.

Orthostatic blood pressure drop and cardiovascular and psychotropic medication dosages in acutely ill geriatric inpatients.

OBJECTIVES: . To investigate the dose-response relationship between cardiovascular or psychotropic medication dosages and falling orthostatic blood pressure in geriatric inpatients. METHODS: . This cross-sectional study included 100 consecutive geriatric inpatients of a Belgian hospital. The end points were the maximum changes of systolic (sBP) and diastolic (dBP) blood pressure in a standing up position at one or three minutes. The dosages of six classes of vascular and five classes of psychotropic medications were expressed in terms of a proportion of defined daily doses (DDD). Bivariate and multivariate linear regression models were used. RESULTS: . The 100 geriatric patients (85 ± 5 years, 58 % women) received 7.7 ± 4 medications (mean DDD: vascular = 1.0, psychotropic = 0.74) on the day of an orthostatic test (lying sBP: 136 ± 21; dBP: 72 ± 14 mm Hg). In a standing position, sBP and dBP fell by 12 ± 17 and 11 ± 5 mmHg, respectively. At the individual level, BP change was not correlated with vascular DDD (sBP: p = 0.07, r2 = 0.04; dBP: p = 0.59; r2 = 0.004) nor with psychotropic DDD (sBP: p = 0.14, r2 = 0.02; dBP: p = 0.82; r2 = 0.0). In multivariate analysis, sBP drop was positively associated with age, diabetes, falls history, and number of medications, but not with the DDD of any of the medication classes, while dBP drop was positively associated with age, diabetes, stroke and anaemia, but again with the DDD of any of the medication classes. CONCLUSION: . No correlation was found between vascular and psychotropic medication dosages and the orthostatic blood pressure drop expressed as a continuous variable.

[Medical thoracoscopy in respiratory medicine: The Liège University Hospital experience]. / La thoracoscopie médicale en pratique pneumologique : expérience du CHU de Liège.

INTRODUCTION: The incidence of pleural disease continues to increase worldwide. Medical thoracoscopy remains the standard method for exploration of the pleural cavity. METHOD: We report the retrospective evaluation, the efficacy and the observed complications in 1024 medical thoracoscopies undertaken in the University Hospital of Liège between 2000 and 2017. RESULTS: In total, 100 pneumothoraces and 400 benign and 501 malignant pleural diseases were identified. The main indication for thoracoscopy remains the diagnosis of an exudative, lymphocytic pleural effusion of unknown aetiology after thoracocentesis. The diagnostic sensibility of thoracoscopy was 99.2% in distinguishing benign from malignant pleural disease. Talc pleurodesis was performed in 69.5% of the total population and in 66.1% of pleural effusions or thickening. Failure of pleurodesis was observed in 11% of the patients with recurrent pneumothorax and in 7.8% of neoplastic pleural effusion. We report a mortality of 0.6% in the 30 days post procedure, long duration of drainage in 8.3% and serious complications in 4.7%. In 22/1024 (2.1%) thoracoscopic evaluation was not feasible because of dense pleural fibrosis. CONCLUSION: Medical thoracoscopy is a safe, well-tolerated procedure with high accuracy in the diagnostic and therapeutic management of pleural disease.

Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer.

Primary triple negative breast cancers (TNBC) are prone to dissemination but sub-clonal relationships between tumors and resulting metastases are poorly understood. Here we use cellular barcoding of two treatment-naïve TNBC patient-derived xenografts (PDXs) to track the spatio-temporal fate of thousands of barcoded clones in primary tumors, and their metastases. Tumor resection had a major impact on reducing clonal diversity in secondary sites, indicating that most disseminated tumor cells lacked the capacity to 'seed', hence originated from 'shedders' that did not persist. The few clones that continued to grow after resection i.e. 'seeders', did not correlate in frequency with their parental clones in primary tumors. Cisplatin treatment of one BRCA1-mutated PDX model to non-palpable levels had a surprisingly minor impact on clonal diversity in the relapsed tumor yet purged 50% of distal clones. Therefore, clonal features of shedding, seeding and drug resistance are important factors to consider for the design of therapeutic strategies.

Publisher Correction: Barcoding reveals complex clonal behavior in patient-derived xenografts of metastatic triple negative breast cancer.

The original version of this Article contained an error in Fig. 4. In the left histogram of the right panel of Fig. 4d, several data points were inadvertently deleted from the histogram during the production process. This error has been corrected in both the PDF and HTML versions of the Article. The original, incorrect version of Fig. 4 is presented in the accompanying Publisher Correction.

Mitochondrial cytochrome c release is caspase-dependent and does not involve mitochondrial permeability transition in didemnin B-induced apoptosis.

Permeability transition, and a subsequent drop in mitochondrial membrane potential (DeltaPsi(m)), have been suggested to be mechanisms by which cytochrome c is released from the mitochondria into the cytosol during apoptosis. Furthermore, a drop in DeltaPsi(m) has been suggested to be an obligate early step in the apoptotic pathway. Didemnin B, a branched cyclic peptolide described to have immunosuppressive, anti-tumour, and anti-viral properties, induces rapid apoptosis in a range of mammalian cell lines. Induction of apoptosis by didemnin B in cultured human pro-myeloid HL-60 cells is the fastest and most complete ever described with all cells being apoptotic after 3 h of treatment. By utilizing the system of didemnin B-induced apoptosis in HL-60 cells, and the potent inhibitors of mitochondrial permeability transition, cyclosporin A and bongkrekic acid, we show that permeability transition as determined by changes in DeltaPsi(m) and mitochondrial Ca2+ fluxing, is not a requirement for apoptosis or cytochrome c release. In this system, changes in mitochondrial membrane potential and cytochrome c release are shown to be dependent on caspase activation, and to occur concurrently with the release of caspase-9 from mitochondria, genomic DNA fragmentation and apoptotic body formation.

A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc.

The Cbfa1/PEBP2 alpha A/AML3 gene plays an essential role in osteogenesis but is also expressed in the T-cell lineage where it has been implicated in lymphoma development as a target for retroviral insertional mutagenesis. As lymphoma cells with til-1 insertion express at least five distinct Cbfa1 isoforms, it is important to establish which, if any, have intrinsic oncogenic potential. We have generated transgenic mice in which the most abundant lymphoma isoform (G1/p57) is expressed under the control of the CD2 locus control region. Co-precipitation analysis of transgenic thymus revealed high levels of Cbfa1 protein in an abundant complex containing the binding cofactor Cbfb. CD2-Cbfa1-G1 mice displayed abnormal T-cell development, with a pronounced skew towards CD8 SP cells in the thymus and developed a low incidence of spontaneous lymphomas (6% at 12 months) with cells of similar phenotype. Strongly synergistic tumour development was seen when CD2-Cbfa1-G1 mice were crossed with lines carrying myc transgenes (CD2-myc or tamoxifen-regulatable CD2-mycER) and Cbfa1 was found to rescue expression of the CD2-myc transgene in pre-leukaemic mice. However, synergy did not appear to be due to a dominant block of myc-induced apoptosis by Cbfa1 as explanted primary tumours and cell lines from CD2-Cbfa1-G1/CD2-mycER mice showed accelerated death on induction with tamoxifen at similar rates to CD2-mycER controls. Moreover, thymocytes from preleukaemic CD2-Cbfa1-G1 mice showed reduced survival in vitro and increased sensitivity to the inhibitory effects of TGF-beta. This study demonstrates that a full-length Cbf alpha-chain gene can act as an oncogene without fusion to a heterologous protein.

Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging.

The Runx2 (Cbfa1, Pebp2alphaA, Aml3) gene was previously identified as a frequent target for transcriptional activation by proviral insertion in T-cell lymphomas of CD2-MYC transgenic mice. We have recently shown that over-expression of the full-length, most highly expressed Runx2 isoform in the thymus perturbs T-cell development, leads to development of spontaneous lymphomas at low frequency and is strongly synergistic with Myc. To gain further insight into the relationship of Runx2 to other lymphomagenic pathways, we tested the effect of combining the CD2-Runx2 transgene either with a Pim1 transgene (E(mu)-Pim1) or with the p53 null genotype, as each of these displays independent synergy with Myc. In both cases we observed synergistic tumour development. However, Runx2 appeared to have a dominant effect on the tumour phenotype in each case, with most tumours conforming to the CD3(+), CD8(+), CD4(+/-) phenotype seen in CD2-Runx2 mice. Neonatal infection of CD2-Runx2 mice with Moloney murine leukaemia virus (Moloney MLV) also led to a dramatic acceleration of tumour onset. Analysis of known Moloney MLV target genes in these lymphomas showed a high frequency of rearrangement at c-Myc or N-Myc (82%), and a significant number at Pim1 or Pim2 (23%), and at Pal1/Gfi1 (18%). These results indicate that Runx2 makes a distinct contribution to T-cell lymphoma development which does not coincide with any of the oncogene complementation groups previously identified by retroviral tagging.

Orthostatic hypotension and associated conditions in geriatric inpatients.

Screening of orthostatic hypotension (OH) was performed in 285 patients aged 75  years. Current drugs, reasons for admission, geriatric syndromes, and confounding medical conditions were collected. Patients with OH (n = 116, 41%) as compared to those without OH (n = 169) more frequently (P < 0.01) presented falls in the last 6  months (62 vs. 40%, P < 0.001), a fall as the reason for the current admission (49 vs. 26%, P < 0.001), feeling of fainting (20 vs. 6%, P = 0.002), syncope (29 vs. 4%, P < 0.001) or functional decline (71 vs. 47%, P = 0.012). No difference was observed between the two groups in terms of age (85 ± 5 vs. 84 ± 4  years), gender (59 vs. 50% female), common geriatric conditions (e.g. malnutrition 46 vs. 58%, dementia 22 vs. 26%), comorbidity or confounding conditions (dehydration 28 vs. 30%, sepsis 2 vs. 6%). No difference was detected in the use of drugs with psychotropic cardiovascular or diuretic effect, or in their associations. Orthostatic hypotension is frequent upon hospital admission and should be screened, particularly in geriatric fallers. This absence of relation between OH and drugs use suggests that non-pharmacological interventions should be first attempted in older inpatients with OH before deciding to reduce or withdraw useful drugs.

Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2.

Evasion of cell death is fundamental to the development of cancer and its metastasis. The role of the BCL-2-mediated (intrinsic) apoptotic program in these processes remains poorly understood. Here we have investigated the relevance of the pro-apoptotic protein BIM to breast cancer progression using the MMTV-Polyoma middle-T (PyMT) transgenic model. BIM deficiency in PyMT females did not affect primary tumor growth, but substantially increased the survival of metastatic cells within the lung. These data reveal a role for BIM in the suppression of breast cancer metastasis. Intriguingly, we observed a striking correlation between the expression of BIM and the epithelial to mesenchymal transition transcription factor SNAI2 at the proliferative edge of the tumors. Overexpression and knockdown studies confirmed that these two genes were coordinately expressed, and chromatin immunoprecipitation analysis further revealed that Bim is a target of SNAI2. Taken together, our findings suggest that SNAI2-driven BIM-induced apoptosis may temper metastasis by governing the survival of disseminating breast tumor cells.

Protein tyrosine kinase inhibitors prevent didemnin B-induced apoptosis in HL-60 cells.

Didemnin B induces rapid apoptosis in human promyeloid HL-60 cells with an optimal concentration of 1 microM (Grubb et al. (1995) Biochem. Biophys. Res. Commum. 215, 1130-1136), but little is known about how it does so. In order to determine whether protein tyrosine phosphorylation is involved in this rapid induction of apoptosis, HL-60 cells were pre-treated with tyrosine kinase inhibitors for 1 h before didemnin B treatment. Genistein, 2,5-dihydroxycinnamic acid methyl ester, and a range of tyrphostins inhibit didemnin B-induced apoptotic morphology in a concentration-dependent manner. DNA fragmentation induced by didemnin B is also inhibited by genistein, 2,5-dihydroxycinnamic acid methyl ester, and tyrphostins.

Reversible denaturation of cyclosporin synthetase by urea.

The reversible denaturation of the multifunctional polypeptide, cyclosporin synthetase, by urea was analyzed. It is possible to discriminate between at least two stages of enzyme denaturation. While at low urea concentration (up to 0.8M) cyclosporin A formation is inhibited, synthesis of the diketopiperazine cyclo-(D-alanyl-N-methylleucyl), a molecule representing a partial sequence of cyclosporin A is still detectable. At higher concentrations of urea the enzyme preparation is totally inactive. This inactivation is a consequence of conformational change(s) of cyclosporin synthetase as shown by fluorescence emission spectra of native and denatured enzyme. These data imply a consecutive folding/defolding mechanism for the different domains forming the multifuntional polypeptide.

Mitochondrial DNA mutation associated with aging and degenerative disease.

Previous theories of aging based on somatic mutation neglected mtDNA, which has a high propensity for mutational error. Knowledge of yeast mtDNA mutations and their functional effects, and of human mtDNA mutations identified in the mitochondrial cytopathies, provides for a concept of aging based on the cumulative effect of mutations affecting human mtDNA. An essential feature of this concept is heteroplasmy, representing mixtures of normal and mutant mtDNA at the cellular and mitochondrial level, resulting in a "tissue mosaic" of focal bioenergetic deficits. Direct evidence for the concept is provided by (i) focal loss of staining for mitochondrially encoded enzymes, such as cytochrome c oxidase, in tissues of aged individuals (humans and rats) and (ii) an age-related increase in deletional mutations in mtDNA demonstrable by application of the polymerase chain reaction to DNA templates from individuals of different ages.