Induction of apoptosis in human retinoblastoma cells by topoisomerase inhibitors

PURPOSE:To examine the apoptotic effect induced in human retinoblastoma Y79 cells by camptothecin, etoposide, and amsacrine, to examine the effect of these drugs on the expression of many apoptosis-related modulators, and to test the antiapoptotic effect exerted by insulin-like growth factor-I (IGF-I). METHODS:Morphologic features of apoptosis were demonstrated using acridine orange- ethidium bromide staining and electron microscopy. DNA fragmentation was determined by means of an in situ cell detection procedure (TdT-dUTP terminal nick-end labeling [TUNEL]) or by electrophoresis on agarose gels and was quantified by enzyme-linked immunosorbent assay. The expression of apoptosis-related modulators was studied by western blot analysis. The processing of latent p53 was examined by means of pulse- chase analysis. RESULTS:Camptothecin, etoposide, and amsacrine induced apoptosis in Y79 cells in a dose-dependent manner; camptothecin was the most efficacious compound. The effect, which was dependent on macromolecular synthesis, appeared after a lag of 8 hours and increased for as long as 24 hours. It was lower in cells treated with IGF-I, a potent mitogenic factor. Camptothecin and etoposide increased the p53 level after 4 hours of treatment, before the onset of apoptosis. This effect seemed to be a consequence of the conversion of latent p53 to one that is transcriptionally active. The drugs also induced an increase in p53-related proteins, such as p21, Bax, and IGF binding protein-3 (IGF-BP3), and caused a significant reduction of the Bcl-2 level. The latter effect was less evident in cells pretreated with IGF-I. CONCLUSIONS:Topoisomerase inhibitors induce apoptosis in Y79 cells. This event is accompanied by a decrease in the expression of Bcl-2, a death antagonist, and an increase in that of Bax, a death agonist. A probable consequence of these modifications is the activation of ICE-like activity with degradation of poly-(adenosine diphosphate [ADP] ribose)-polymerase. Insulin-like growth factor-I exerts an antiapoptotic action in Y79 cells, and this function is most likely reduced by the overexpression of IGF-BP3 that is induced by drug treatment

Contribuição dos humanos, cães e gatos à transmissão do Trypanosoma cruzi na Região do Chaco Argentino

Foi determinada a prevalência da infecção por T. cruzi nos humanos, cães e gatos, pertencentes a 47 rancherías em três povoados rurais; Guanaco Muerto (Córdoba), La Invernada e Amamás (Santiago del Estero), mediante reações seroldgicas e xenodiagnóstico. Poram examinadas 245 pessoas, 123 cães e 14 gatos. A taxa de prevalência na população foi entre 58,7% (GM) e 49,6% (LI). Foram detectados 76% de cães infectados, o que resultou significativamente superior aos 51% encontrados nos humanos. As porcentagens de cães (64,2%) e gatos (63,6%) com parasitemia foram significativamente superiores à correspondente aos humanos (12,5%). Se bem que 79% dos gatos estavam infectados, sua pequena quantidade e seus hábitos de perambulação determinam que sua participação na transmissão doméstica do T. cruzi seja restrita. Não obstante existir em média um maior número de humanos que de cães em cada lar, tanto de sujeitos sãos como infectados (6,5 vs. 3,3 e 3,4 vs. 2,4, respectivamente), foram detectados também na média mais cães que humanos com parasitemia em cada casa (2,1 vs. 1,0). As altas porcentagens de cães infectados e com parasitemia, além do hábito de repouso intra-domiciliário o qual ocasiona estreito contacto entre eles e os barbeiros determinam que os cães sejam os principais provedores de parásitos à disposição para a transmissão, e os hospedeiros mais importantes para /nanutenção da doença de Chagas na Região do Chaco Argentino.Trypanosoma cruzi prevalence rates of human, dog and cat populations from 47 households of 3 rural localities of the phytogeographical Chaqueña area of Argentina were determined both by serological and xenodiagnostic procedures. Human prevalence rates were uniform and ranged from 49.6 to 58.7%. Overall prevalence rate in dogs (75.0%) was significantly higher than in humans (51.0%). The overall proportion of parasitemic individuals assessed by xenodiagnosis was significantly higher in either dog (64.2%) or cat (63.6%) populations than among humans (12.5%). Although both the average number of resident as well as infected individuals per household was higher for people than for dogs (6.5 vs. 3.3, and 3.4 vs. 2.4, respectively), the reverse was recorded when parasitemic individuals were considered (1.0 vs. 2.1). Results are discussed in relation to dog between dogs and people, and dogs and bugs. In the light of present data, dogs must be considered as the major donors of parasites to vector bugs and thus, principal contributors to transmission in this region of Argentina

X-linked intellectual disability

The intellectual disability is found in approximately 2-3% of the population in a mild-to-moderate form and 0.5-1% in a moderate-to-severe form. The mutations on the chromosome X are responsible for both syndromic and non-syndromic intellectual disability. In the syndromic forms behavioral disorders, autism and/or seizures are frequent

Midterm Outcomes of the Nellix Endovascular Aneurysm Sealing System: A Dual-Center Experience

Purpose: To report midterm outcomes of the Nellix Endovascular Aneurysm Sealing (EVAS) System in the treatment of abdominal aortic aneurysm (AAA). Methods: Between September 2013 and July 2014, 64 AAA patients (mean age 76.6±6.8 years; 61 men) were treated with the EVAS system at 2 centers (only procedures performed at least 12 months prior to the analysis were included). Most patients were treated for a stable AAA, while 1 patient was treated for a ruptured aneurysm. Mean aneurysm diameter was 57.3±9.3 mm. The proximal neck measured a mean 21.5±3.3 mm in diameter and 27.0±12.1 mm long; the neck angle was 16.9°±19.3°. Eleven (17.2%) patients were treated outside the instructions for use (IFU). Results: Technical success was achieved in 63 (98.4%) of 64 patients; 1 type Ia endoleak was treated intraoperatively. One (1.6%) aneurysm-related death occurred at 4 months due to a secondary aortoenteric fistula. Overall, endoleaks occurred in 3 (4.7%) patients (2 type Ia, 1 type II). The estimated rates for 18-month overall survival, freedom from aneurysm-related death, and freedom from secondary interventions were 92.7%, 98.4%, and 95.0%, respectively. Patients treated outside the IFU had a significantly higher incidence of device-related complications (p=0.03). Conclusion: The use of the Nellix device in everyday clinical practice is safe and offers promising midterm results. The risk of secondary aortoenteric fistula requires further analysis. Longer follow-up is needed to assess the actual efficacy of the device, although the risk of migration with late endoleak seems low

Remote assessments of the archaeological heritage situation in Afghanistan

Analysis of spatial and temporal patterns in looting and destruction at archaeological sites using satellite imagery has become a focus of multiple research groups working on cultural heritage in conflict zones, especially in areas controlled by the Islamic State in Syria and Iraq. In this paper, we apply similar methods to investigate looting and destruction at archaeological sites in the Islamic Republic of Afghanistan, where Taliban-related cultural heritage destruction events have also frequently made international headlines. Using the time depth provided by high-resolution, time-stamped DigitalGlobe satellite and BuckEye aerial images as well as CORONA and other historical satellite images and maps, we quantitatively document spatial and temporal patterns in destruction from looting, agricultural activity, military occupation, urban growth, mining, and other kinds of development at over 1000 previously known archaeological sites across Afghanistan. This analysis indicates that several common narratives about cultural heritage destruction in Afghanistan may require revision. Specifically, we conclude that significant amounts of systematic looting of archaeological sites in Afghanistan already occurred before Taliban-related conflicts, that there has been little increase in systematic looting in Taliban-controlled areas post-2001, and that the most pressing threats to Afghanistan’s heritage sites come from development activities, including agricultural expansion, urban growth, and future mining. The analysis demonstrates that the situation in Afghanistan both parallels and contrasts with that seen in the post-Arab-Spring Middle East

Cerebellar ataxia and exercise intolerance in Erdheim-Chester disease

Background: Erdheim-Chester disease (ECD), a rare disorder of monocyte/macrophage lineage, has been related to cerebellar dysfunction. To increase the awareness of this rare, protean disease, an unusual, myasthenia-like onset of ECD is reported. Case presentation: A 42-year-old man presented with a 6-year history of mild evening fatigability in his four limbs followed by motor and cognitive symptoms associated with cerebellar atrophy, dentate nuclei and dentato-thalamic pathway degeneration. Magnetic resonance imaging revealed hyperintense signals in T2 and fluid-attenuated inversion recovery sequences within the pons, cerebellar white matter, dentate nuclei and globi pallidi in the absence of any contrast enhancement. Whole-body bone scintigraphy with 99Technetium - methylene diphosphonate and fluorodeoxyglucose-positron emission tomography both revealed symmetric uptake in the lower extremities a finding suggestive of a diagnosis of ECD. Histological examination revealed diffuse infiltration of CD 68+ histiocytes with foamy cytoplasms in the presence of B-type of Rapidly Accelerated Fibrosarcoma protein kinase (BRAF)V600E activating mutation in tumor cells. Conclusion: In patients with myasthenia-like symptoms who test negatively for myasthenia gravis, neurodegenerative diseases, and disorders of the hypothalamus, a diagnosis of ECD should be taken into consideration

Jacobi Polynomials as su(2, 2) Unitary Irreducible Representation

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The psychological impact of COVID-19 pandemic on patients with neuroendocrine tumors: Between resilience and vulnerability

The COVID-19 pandemic has added another layer of complexity to the fears of patients with neuroendocrine tumors (NETs). Little is known regarding the psychological impact of the COVID-19 outbreak on patients with gastroenteropancreatic or bronchopulmonary (BP) NETs. We longitudinally surveyed the mental symptoms and concerns of NET patients during the plateau phase of the first (W1) and second epidemic waves (W2) in Italy. Seven specific constructs (depression, anxiety, stress, health-related quality of life, NET-related quality of life, patient–physician relationship, psychological distress) were investigated using validated screening instruments, including DASS-21, EORTC QLQ-C30, EORTC QLQ GI.NET21, PDRQ9 and IES-R. We enrolled 197 patients (98 males) with a median age of 62 years. The majority of the patients had G1/G2 neoplasms. Some 38% of the patients were on active treatment. At W1, the prevalence of depression, anxiety and stress was 32%, 36% and 26% respectively. The frequency of depression and anxiety increased to 38% and 41% at W2, whereas no modifications were recorded in the frequency of stress. Poor educational status was associated with higher levels of anxiety at both W1 (odds ratio [OR] = 1.33 ± 0.22; p =.07) and W2 (OR = 1.45 ± 0.26; p =.03). Notably, post-traumatic stress symptoms were observed in the 58% of the patients, and both single marital status (OR = 0.16, 95% confidence interval [CI] = 0.06–0.48; p =.0009) and low levels of formal education (OR = 0.47, 95% CI = 0.23–0.99; p =.05) predicted their occurrence. No significant deteriorations of health-related quality of life domains were observed from W1 to W2. High patient care satisfaction was documented despite the changes in health systems resource allocation. NET patients have an increased risk of developing post-traumatic stress symptoms as result of the COVID-19 pandemic. Specific screening measures and psychological interventions should be implemented in NET clinics to prevent, recognize and treat mental distress in this vulnerable population

Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence

The chaperone Hsp60 is pro-carcinogenic in certain tumor types by interfering with apoptosis and with tumor cell death. In these tumors, it is not yet known whether doxorubicin anti-tumor effects include a blockage of the pro-carcinogenic action of Hsp60. We found a doxorubicin dose-dependent viability reduction in a human lung mucoepidermoid cell line that was paralleled by the appearance of cell senescence markers. Concomitantly, intracellular Hsp60 levels decreased while its acetylation levels increased. The data suggest that Hsp60 acetylation interferes with the formation of the Hsp60/p53 complex and/or promote its dissociation, both causing an increase in the levels of free p53, which can then activate the p53-dependent pathway toward cell senescence. On the other hand, acetylated Hsp60 is ubiquitinated and degraded and, thus, the anti-apoptotic effect of the chaperonin is abolished with subsequent tumor cell death. Our findings could help in the elucidation of the molecular mechanisms by which doxorubicin counteracts carcinogenesis and, consequently, it would open new roads for the development of cancer treatment protocols targeting Hsp60