Miracle-dz/UniFAR-FTUs huggingface dataset:
Anti‐thymocyte globulin plus etanercept as therapy for myelodysplastic syndromes (MDS): a phase II study

Immunosuppressive therapies have proven valuable in treating patients with myelodysplastic syndromes (MDS). We evaluated the combination of equine anti‐thymocyte globulin (ATGAM®) and the soluble tumour necrosis factor receptor, etanercept (Enbrel®), in a phase II trial. Twenty‐five patients with MDS [4‐refractory anaemia (RA), 2‐RA with ring sideroblasts, 15‐refractory cytopenia with multilineage dysplasia (RCMD), 3‐RCMD and ring sideroblasts, 1‐RA with excess blasts type 1] in International Prognostic Staging System risk groups low (n = 11) or intermediate‐1 (n = 14) were enrolled. All patients were platelet or red cell transfusion‐dependent. Nineteen patients completed therapy with ATG at 40 mg/kg per day for four consecutive days, followed by etanercept, 25 mg subcutaneous twice a week for 2 weeks, every month for 4 months. Thirteen patients had haematological improvement (HI)‐erythroid, 2 HI‐neutrophil, and 6 HI‐platelet. One patient with a co‐existing diagnosis of multiple sclerosis and rheumatoid arthritis had a complete remission. The overall response by intent to treat analysis among the 25 patients was 56% (95% confidence interval 35–56%). Four patients did not complete their first course of therapy and one patient did not survive to the 8‐week post‐treatment assessment. Among patients who completed treatment and survived to the 8‐week assessment, 70% had at least haematological responses lasting for at least 5 to more than 36 months. Thus, combination therapy with ATG and etanercept was active and safe in patients with MDS.
Low‐dose Gemtuzumab‐Ozogamicin as post‐consolidation therapy in elderly patients with acute myeloid leukaemia: a pilot study

T. , Heldmann, K. , Carmi, R. , Parvari, R. , Beit-Or, H. , Goldman, B. , Peleg, L. , Levy-Lahad, E. , Renbaum, P., Legum, S. , Shomrat, R. , Yeger, H. , Benbenisti, D. , Navon, R. , Dror, V. , Shohat, M. , Magal, N. , Navot, N. & Eyal, N. (1998) Prevalence of glucocerebrosidase mutations in the Israeli Askenazi Jewish poulation. Human Mutations, 12, 240–244. Pocovi, M. , Cenarro, A. , Civeira, F. , Torralba, M.A., Perez-Calvo, J.I. , Mozas, P., Giraldo, P., Girait, M. , Myers, R.H. , Cupples, L.A. & Ordovas, J.M. (1998) Beta –glucocerebrosidase gene locus as a link for Gaucher’s disease and familial hypo-alfa-lipoproteinaemia. Lancet, 351, 1919–1923.
Haematological emergencies managing hypercalcaemia in adults and children with haematological disorders

Hypercalcaemia is a common metabolic complication of malignant disease often requiring emergency intervention. Although it is more frequently associated with solid tumours, malignancy‐associated hypercalcaemia (MAH) is seen in a significant number of patients with blood diseases. Its association with myeloma and adult T‐cell leukaemia/lymphoma is well recognized but the incidence of hypercalcaemia in other haematological neoplasms, affecting adults and children, is less clearly defined. Haematologists need to be familiar with the clinical manifestations of, the differential diagnosis to be considered and the most effective management strategies that are currently available for MAH. The key components of management of MAH include aggressive rehydration, specific therapy to inhibit bone resorption and, crucially, treatment of the underlying malignancy. Bisphosphonates have revolutionized the management of MAH over the last 20 years, however the elucidation of molecular pathways implicated in MAH is facilitating the development of more targeted approaches to treatment.
Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations

Mutations in NF1, PTPN11, NRAS, KRAS and CBL have been reported to play a pathogenetic role in juvenile myelomonocytic leukaemia (JMML), a rare myelodyplastic/myeloproliferative neoplasm occurring in children. Recently, mutations in ASXL1 were identified in chronic myelomonocytic leukaemia and other myeloid malignancies. We sequenced exon 12 of ASLX1 in 49 JMML patients, and found 2 novel heterozygous (nonsense and frameshift) mutations, one occurring as a sole lesion, the other was in conjunction with a PTPN11 mutation. ASXL1 cooperates with KDM1A in transcriptional repression and thereby ASXL1 mutations may synergize with or mimic other JMML‐related mutations.
Local photic entrainment of the retinal circadian oscillator in the absence of rods, cones, and melanopsin

Significance The physiology of the mammalian retina is governed by a molecular circadian clock. The retina is also the sole photoreceptive tissue for the synchronization of the master circadian clock, the suprachiasmatic nucleus (SCN), to light/dark cycles. The SCN synchronizes the phases of peripheral clocks throughout the body. It is unknown whether the retina is entrained by the SCN, or is directly entrained by light/dark signals. We report that the retinal circadian clock synchronizes directly to light/dark cycles, independent of the SCN phase. Unexpectedly, the retina uses photoreceptors distinct from those used for circadian photoreception or vision for this entrainment. Synchronization of the mammalian master circadian pacemaker to the daily light/dark cycle is mediated exclusively through retinal photoreceptors. The mammalian retina itself is also a self-sustained circadian oscillator. Here we report that the retinal molecular circadian clock can be entrained by lighting cycles in vitro, but that rods, cones, and melanopsin (Opn4) are not required for this entrainment. In vivo, retinas of Opn4−/−;rd1/rd1 mice synchronize to light/dark cycles regardless of the phase of the master circadian pacemakers of the suprachiasmatic nuclei or the behavior of the animal. These data demonstrate that the retina uses a separate mechanism for local entrainment of its circadian clock than for entrainment of organism-level rhythmicity.
Some medicinal plants as natural anticancer agents

India is the largest producer of medicinal plants and is rightly called the “Botanical garden of the World”. The medicinal plants, besides having natural therapeutic values against various diseases, also provide high quality of food and raw materials for livelihood. Considerable works have been done on these plants to treat cancer, and some plant products have been marketed as anticancer drugs, based on the traditional uses and scientific reports. These plants may promote host resistance against infection by re-stabilizing body equilibrium and conditioning the body tissues. Several reports describe that the anticancer activity of medicinal plants is due to the presence of antioxidants in them. In fact, the medicinal plants are easily available, cheaper and possess no toxicity as compared to the modern (allopathic) drugs. Hence, this review article contains 66 medicinal plants, which are the natural sources of anticancer agents.
Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response

Significance Type I and type II natural killer T (NKT) cells are unique T-cell types with potent immunomodulatory functions. Because of lack of markers available to track type II NKT cells, this subset has not been as extensively studied as type I NKT cells. In this study we used a unique mouse model as a tool to decipher the developmental requirements, antigen specificity, and functional potential of type II NKT cells. We found that even though type I and type II NKT cells exhibited similar developmental needs, they were functionally distinct. In addition, we demonstrated a means of harnessing the therapeutic potential of these cells in cancer immunity by transforming their tumor-suppressive functions into a protective response. CD1d-restricted natural killer T (NKT) cells are innate-like T cells with potent immunomodulatory function via rapid production of both Th1 and Th2 cytokines. NKT cells comprise well-characterized type I NKT cells, which can be detected by α-galactosylceramide-loaded CD1d tetramers, and less-studied type II NKT cells, which do not recognize α-galactosylceramide. Here we characterized type II NKT cells on a polyclonal level by using a Jα18-deficient IL-4 reporter mouse model. This model allows us to track type II NTK cells by the GFP+TCRβ+ phenotype in the thymus and liver. We found type II NKT cells, like type I NKT cells, exhibit an activated phenotype and are dependent on the transcriptional regulator promyelocytic leukemia zinc finger (PLZF) and the adaptor molecule signaling lymphocyte activation molecule-associated protein (SAP) for their development. Type II NKT cells are potently activated by β-D-glucopyranosylceramide (β-GlcCer) but not sulfatide or phospholipids in a CD1d-dependent manner, with the stimulatory capacity of β-GlcCer influenced by acyl chain length. Compared with type I NKT cells, type II NKT cells produce lower levels of IFN-γ but comparable amounts of IL-13 in response to polyclonal T-cell receptor stimulation, suggesting they may play different roles in regulating immune responses. Furthermore, type II NKT cells can be activated by CpG oligodeoxynucletides to produce IFN-γ, but not IL-4 or IL-13. Importantly, CpG-activated type II NKT cells contribute to the antitumor effect of CpG in the B16 melanoma model. Taken together, our data reveal the characteristics of polyclonal type II NKT cells and their potential role in antitumor immunotherapy.
Síndrome respiratorio agudo severo (SRAS): ¿un mal recuerdo?

nia en la provincia del Guangdong (China). Las autoridades chinas guardan silencio acerca de la aparicion de esta enfermedad que se difunde a partir de febrero de 2003. La transmision parece muy rapida, en particular a partir de un hotel localizado en Hong Kong. Este hotel habria albergado a una persona contaminada procedente de la provincia de Guangdong. Algunos viajeros que habian permanecido en este hotel se habian contagiado y partieron hacia Vietnam, Bangkok, Singapur, Canada, Irlanda y los EE.UU. , paises (en particular Canada) en los que la epidemia iba a desarrollarse. El 12 de marzo de 2003, la Organizacion Mundial de la Salud, OMS, publica una alerta mundial proponiendo los criterios de definicion de los casos, asi como el acronimo SRAS, (Sindrome Respiratorio Agudo Severo) para denominar a esta forma de pneumonia atipica. La epidemia se propaga rapidamente por el mundo (China) Hong Kong, Singapur, Canada. ) para alcanzar ya en junio de 2003 a unos treinta paises y a mas 8000 personas (Figura 1). La Direccion General de la Salud “desaconseja los viajes a las zonas endemicas”.
Acute genetic ablation of pendrin lowers blood pressure in mice

Background Pendrin, the chloride/bicarbonate exchanger of β-intercalated cells of the renal connecting tubule and the collecting duct, plays a key role in NaCl reabsorption by the distal nephron. Therefore, pendrin may be important for the control of extracellular fluid volume and blood pressure. Methods Here, we have used a genetic mouse model in which the expression of pendrin can be switched-on in vivo by the administration of doxycycline. Pendrin can also be rapidly removed when doxycycline administration is discontinued. Therefore, our genetic strategy allows us to test selectively the acute effects of loss of pendrin function. Results We show that acute loss of pendrin leads to a significant decrease of blood pressure. In addition, acute ablation of pendrin did not alter significantly the acid-base status or blood K + concentration. Conclusion By using a transgenic mouse model, avoiding off-target effects related to pharmacological compounds, this study suggests that pendrin could be a novel target to treat hypertension.
IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy

Background Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN. Methods The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+ IL-17+ T cells. The number of CD4+ IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+ IL-17+ T cells in renal sclerosis. Results CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was not only observed in most of the infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+ IL-17+ T cells were found in DN, and the number of CD4+ IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A was the key cytokine produced by CD4+ IL-17+ T cells. IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta 1 (TGF-β1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40 and TGF-β1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-β1, but increased the viability of cultured podocytes. Conclusions IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN.
A Health Production Approach to the Economic Analysis of Health Promotion

This thesis focuses on issues relevant to health promotion policy. The household production framework is used to specify a structural equation (MIMIC) model and empirically investigate consumers’ behaviour in order to identify policy-relevant mechanisms using two waves of data from the Finnish health examination survey. Particular attention is paid to the role of an individual’s health-specific knowledge and participation in health education activities. A review of the literature reveals that; current theoretical models do not provide a complete framework for analysing health and knowledge; direct measures of health knowledge are rarely used in empirical health production studies; minimal attention has been paid to the content of the knowledge variable; and only a few studies treated knowledge as endogenous. The novelty of the empirical analysis is the simultaneous estimation of production equations for both health and health related knowledge using both cross-sectional and two-period designs. The influence of overall education is separated from that of health-specific knowledge. The analysis shows that health knowledge has a health promoting effect on most consumption choices studied, and it clearly improves individuals’ ability to produce health in the long run. Participation in heath education improves individual’s level of health knowledge. Formal schooling was found to improve the efficiency of knowledge production process. Individuals’ willingness to invest in knowledge of healthy life-styles appears to decrease by age. The analysis provides some support for considering medical care and consumption experience as sources of information. From the policy perspective, it can be concluded that knowledge has an important role in explaining differences in individuals’ health and it can be influenced by appropriate health education programs. In times of increasing health inequity in the society, the greatest challenge is to design programs that would attract population groups with low educational attainment and in particular young men. Whereas these groups may find information on health affecting consumption potentially worthwhile, the elderly may be more interested in a type of knowledge that yields more instantaneous health gains and well-being.
Inducible and titratable silencing of Caenorhabditis elegans neurons in vivo with histamine-gated chloride channels

Significance Inducible silencing of neurons is a powerful method for studying the functions of neural circuits. We describe a system for inducible silencing of Caenorhabditis elegans neurons, based on transgenic C. elegans nematodes engineered to produce the inhibitory Drosophila histamine-gated chloride channel (HisCl1) in specific neurons. The activity of HisCl1-expressing neurons is acutely and reversibly silenced by exogenous histamine, which C. elegans absorbs from the media. In addition to completely silencing neurons, the histamine-HisCl1 system can be used to titrate neural activity, demonstrating quantitative relationships between neural activity and behavior. The histamine-HisCl1 system is complementary to other methods of monitoring and manipulating neuronal activity, providing opportunities for combinatorial control of circuits. Recent progress in neuroscience has been facilitated by tools for neuronal activation and inactivation that are orthogonal to endogenous signaling systems. We describe here a chemical-genetic approach for inducible silencing of Caenorhabditis elegans neurons in intact animals, using the histamine-gated chloride channel HisCl1 from Drosophila and exogenous histamine. Administering histamine to freely moving C. elegans that express HisCl1 transgenes in neurons leads to rapid and potent inhibition of neural activity within minutes, as assessed by behavior, functional calcium imaging, and electrophysiology of neurons expressing HisCl1. C. elegans does not use histamine as an endogenous neurotransmitter, and exogenous histamine has little apparent effect on wild-type C. elegans behavior. HisCl1-histamine silencing of sensory neurons, interneurons, and motor neurons leads to behavioral effects matching their known functions. In addition, the HisCl1-histamine system can be used to titrate the level of neural activity, revealing quantitative relationships between neural activity and behavioral output. We use these methods to dissect escape circuits, define interneurons that regulate locomotion speed (AVA, AIB) and escape-related omega turns (AIB), and demonstrate graded control of reversal length by AVA interneurons and DA/VA motor neurons. The histamine-HisCl1 system is effective, robust, compatible with standard behavioral assays, and easily combined with optogenetic tools, properties that should make it a useful addition to C. elegans neurotechnology.
A retrospective case control study of recombinant factor VIIa in patients with intracranial haemorrhage caused by trauma

Rita Campanelli Letizia Lupo Gabriela Fois Gianluca Viarengo Vassili Jemos Vittorio Rosti Giovanni Barosi Biotechnology Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, Unit of Clinical Epidemiology and Centre for the Study of Myelofibrosis, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, Immunohaematology and Transfusion Service, Apheresis and Cell Therapy Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, and Unit of Haematopancreatic Surgery, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. E-mail: m.massa@smatteo.pv. it
Microparticles, malignancy and thrombosis

Microparticles (MPs) are considered to be important biological effectors of several different physiological and pathological processes. There is increasing evidence of their role in haemostasis and thrombosis, and also of their importance in cancer cell survival, invasiveness and metastasis. The level of circulating MPs has been assessed in many different disease states, and there are reports that patients with malignancy and patients with thrombosis have increased levels of circulating MPs and MP‐dependent thrombogenic potential. Research into the function and effect of MPs is currently hampered by a lack of standardization in the methods used to identify and quantify them. As these methods improve it is likely that MP assays will be of use both diagnostically and therapeutically in the future.
Diverse cells at the origin of lung adenocarcinoma

Oncogenic mutations in Kirsten rat sarcoma viral oncogene homologue (K-RAS) are found in a broad range of aggressive cancers in many tissues and are common in the most prevalent form of lung cancer, adenocarcinoma (1). Despite knowledge of K-RAS mutations for many years, patients with K-RAS mutant tumors remain without an effective targeted therapy option. This has generated considerable interest in the mechanisms of oncogenesis and the cell types susceptible to this form of transformation. In PNAS, Mainardi et al. (2) and Sutherland et al. (3) take complementary approaches to interrogate the ability of different epithelial cell populations to give rise to proliferative lesions and tumors in the lung. Like earlier studies by Xu et al., also published in PNAS (4), the authors conclude that several distal lung epithelial cell types are potentially capable of hyperproliferation or tumor initiation in response to oncogenic K-Ras activation. Taken together with the first reports of K-Ras–induced lung tumors in mouse models (5, 6), the important take-home message is that the precise identity of cells that are transformed and the kind of tumors that are generated depend on multiple factors. These include the cell type in which K-Ras is activated, the developmental timing, the potential for inflammation by use of adenoviral vectors, and the specific genetic modifiers. These results will help to inform ideas about tumor initiation in the human lung.
Cerebral blood flow control in small vessel disease

In normal conditions CBF is maintained over a wide range of perfusion pressures (ca. 60~150 mm Hg) by two main control systems, i.e. mechanoregulation, referring to CA, and chemoregulation, also known as cerebrovascular CO2 responsiveness reflecting the vasodilatory capacity of the cerebral vasculature. Cerebral microangiopathy, i.e. SVD, is associated with hypertension and other vascular risk factors, being a major cause of stroke and vascular dementia. Previous studies reported affected mechano- and chemoregulation in longstanding diabetes mellitus with both microvascular complications and CAN. Also dynamic CA has been demonstrated to be affected bilaterally in patients suffering from lacunar infarction, strongly suggesting a link between impaired autoregulatory capacity and SVD. In this thesis we focused on T2DM and SCD representing two different forms of SVD, both associated with diffuse vasculopathy of the small arteries, resulting in multiple lacunar infarctions and generalized white matter lesions. Cerebral autoregulatory capacity and CO2 responsiveness were studied in both diseases and compared with control subjects.