Miracle-dz/UniFAR-FTUs huggingface dataset:
Cardiac Surgery and Allogeneic Blood Transfusions

Coronary artery bypass graft (CABG) surgery is a frequently performed intervention for revascularization of the myocardium. Worldwide approximately 1,000,000 patients are undergoing cardiac surgery annually. Nowadays more older patients with more comorbidities are operated, which is possible due to more advanced techniques. Herewith allogeneic blood transfusions play a crucial role in performing of these more complicated treatments. Until the discovery of the AB0-bloodgroups in the early 1900s allogeneic blood transfusions were a high-risk procedure: more than 50% of the recipients of blood died. The discovery of the blood groups followed by the development of citrate as anticoagulant to prevent clotting of blood enabled the start of safer transfusion medicine. Both World Wars and other disasters in the 20th century had a large impact on further development and structural organization of transfusion medicine. Before the introduction of centrifugation techniques in the 1960s whole blood transfusions were used. Since transfusion of red blood cells, platelet concentrates and plasma became possible over time, treatment of more diseases and opportunities for surgical interventions raised. Nowadays due to stringent donor selection and advanced preparation techniques transfusions of blood components became gradually considered as a safe therapy. From the blood components, red blood cells are used for blood loss and other causes of anemia, while plasma and platelets are transfused to treat or as prophylaxis for bleeding disorders. However unexpected adverse effects leading to more transfusion-related complications are the reasons of serious concerns, which resulted in more evidence-based research aiming to reduce the risks of allogeneic blood transfusions. Nowadays in the Western World every year about 50-70 per 1,000 patients receive a blood transfusion (Cobain et al., 2007), while at the age of 80 years approximately one in five persons has been transfused (Kamper-Jorgensen et al., 2009). Per year 75 millions of blood units are collected and transfused worldwide, thereby yearly saving thousands of lives, facilitating more complex surgery as cardiac surgery and making transfusion of different blood components indispensable for treatment of many diseases. The development of modern transfusion medicine represents one of the greatest achievements of medicine in the 20th century. However the safety of allogeneic blood transfusions is high, there are still risks leading to higher morbidity and mortality associated with blood transfusions. Many clinical and laboratory studies are performed in the past years to decrease the risks of allogeneic blood transfusions.
Impact of dexamethasone responsiveness on long term outcome in patients with newly diagnosed multiple myeloma

Dexamethasone (Dex), alone or in combination, is commonly used for treating multiple myeloma. Dex as single agent for initial therapy of myeloma results in overall response rates of 50–60%. It is unclear whether steroid responsiveness reflects any biological characteristic that impacts long‐term outcome. We studied a cohort of 182 patients with newly diagnosed myeloma seen between March 1998 and June 2007, initially treated with single‐agent Dex for at least 4 weeks. The median age at diagnosis was 63 years (range, 39–81) and the median estimated survival was 55 months. At a median duration of therapy of 15 weeks, 91 (50%) patients had a partial response or better, 80 (44%) had less than partial response and the remaining (6%) patients were not evaluable. The median overall survival from diagnosis for the responders was 75 months compared to 71 months for remaining patients, P = 0·6.There was no correlation between baseline disease characteristics and Dex responsiveness. While overall survival was longer for the 130 (70%) patients who proceeded to an autologous stem cell transplant, no correlation was found between survival and Dex responsiveness among either group. Among this cohort of patients with myeloma, failure to respond to single agent steroid did not have an adverse impact on eventual outcome.
Smad1 transcription factor integrates BMP2 and Wnt3a signals in migrating cardiac progenitor cells

Significance Prospective cardiac cells emerge during gastrulation and undergo long-range migration toward the ventral midline, where they fuse to give rise to a single contractile tube, which subsequently undergoes complex morphogenesis. How cardiac progenitor cells are guided in their movement by extrinsic signals is still enigmatic. We previously identified wingless-type family member (Wnt) 3a as an important guidance signal. Here we used live video microscopy in chick embryos to uncover a role for bone morphogenetic proteins (BMPs) in the control of cardiac progenitor cell migration. Functional approaches, complementation, and rescue experiments reveal cooperation between BMP signalling and the Wnt/glycogen synthase kinase 3 beta pathway: both converge to stabilize activated SMA and MAD related protein. Insights into the molecular integration of signaling pathways in migrating cells affect our understanding of cardiac malformations during embryo development. In vertebrate embryos, cardiac progenitor cells (CPCs) undergo long-range migration after emerging from the primitive streak during gastrulation. Together with other mesoderm progenitors, they migrate laterally and then toward the ventral midline, where they form the heart. Signals controlling the migration of different progenitor cell populations during gastrulation are poorly understood. Several pathways are involved in the epithelial-to-mesenchymal transition and ingression of mesoderm cells through the primitive streak, including fibroblast growth factors and wingless-type family members (Wnt). Here we focus on early CPC migration and use live video microscopy in chicken embryos to demonstrate a role for bone morphogenetic protein (BMP)/SMA and MAD related (Smad) signaling. We identify an interaction of BMP and Wnt/glycogen synthase kinase 3 beta (GSK3β) pathways via the differential phosphorylation of Smad1. Increased BMP2 activity altered migration trajectories of prospective cardiac cells and resulted in their lateral displacement and ectopic differentiation, as they failed to reach the ventral midline. Constitutively active BMP receptors or constitutively active Smad1 mimicked this phenotype, suggesting a cell autonomous response. Expression of GSK3β, which promotes the turnover of active Smad1, rescued the BMP-induced migration phenotype. Conversely, expression of GSK3β-resistant Smad1 resulted in aberrant CPC migration trajectories. De-repression of GSK3β by dominant negative Wnt3a restored normal migration patterns in the presence of high BMP activity. The data indicate the convergence of BMP and Wnt pathways on Smad1 during the early migration of prospective cardiac cells. Overall, we reveal molecular mechanisms that contribute to the emerging paradigm of signaling pathway integration in embryo development.
Human breast cancer metastases to the brain display GABAergic properties in the neural niche

Significance Breast cancer patients typically develop brain metastases years after their initial diagnosis. During this clinical latency, cancer cells must evolve and adapt to the neural microenvironment to colonize. We hypothesized that breast cancer cells may assume brain-like properties to survive in the brain. Our results suggest that metastases overexpress many variables related to the γ-aminobutyric acid (GABA) and were able to proliferate by metabolizing GABA as a biosynthetic energy source. The expression of brain-like properties by breast cancer cells could be a malignant adaptation required for metastasis to the brain, which could potentially be exploited to develop new therapy for breast cancer patients. Dispersion of tumors throughout the body is a neoplastic process responsible for the vast majority of deaths from cancer. Despite disseminating to distant organs as malignant scouts, most tumor cells fail to remain viable after their arrival. The physiologic microenvironment of the brain must become a tumor-favorable microenvironment for successful metastatic colonization by circulating breast cancer cells. Bidirectional interplay of breast cancer cells and native brain cells in metastasis is poorly understood and rarely studied. We had the rare opportunity to investigate uncommonly available specimens of matched fresh breast-to-brain metastases tissue and derived cells from patients undergoing neurosurgical resection. We hypothesized that, to metastasize, breast cancers may escape their normative genetic constraints by accommodating and coinhabiting the neural niche. This acquisition or expression of brain-like properties by breast cancer cells could be a malignant adaptation required for brain colonization. Indeed, we found breast-to-brain metastatic tissue and cells displayed a GABAergic phenotype similar to that of neuronal cells. The GABAA receptor, GABA transporter, GABA transaminase, parvalbumin, and reelin were all highly expressed in breast cancer metastases to the brain. Proliferative advantage was conferred by the ability of breast-to-brain metastases to take up and catabolize GABA into succinate with the resultant formation of NADH as a biosynthetic source through the GABA shunt. The results suggest that breast cancers exhibit neural characteristics when occupying the brain microenvironment and co-opt GABA as an oncometabolite.
Final analysis of the UKLG LY02 trial comparing 6–8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograft in patients <65 years with poor prognosis histologically aggressive NHL

This trial involved 457 patients and sought to assess the value of early intensification with autologous transplantation in patients with poor prognosis histologically aggressive non‐Hodgkin lymphoma (NHL) showing a response to initial CHOP (cyclosphosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Randomization was made at the time of diagnosis with 223 assigned to continuing CHOP and 234 to 3 cycles of CHOP followed by a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Analysis was on an intention to treat basis. After the initial three cycles of CHOP 19% of the whole group were in complete response (CR) and 53% in partial remission (PR). At the end of treatment 86% of patients in the CHOP arm had responded with 58% in CR. In the high‐dose therapy arm the overall response rate was 83% with 64% in CR (difference between arms not significant). The progression‐free survival (PFS) and overall survival at 5 years for the continuing CHOP arm were 38% and 50% respectively, and for the autograft arm were 44% and 50% (differences not significant). Of the patients who attained CR and subsequently relapsed, there were no long‐term survivors in the autograft recipients compared to 46% of the continuing CHOP recipients (P = 0·0008). In conclusion, no survival benefit was demonstrated for an early autograft in first response.
Infrared thermography to quantify the risk of breast cancer

From the last decades, infrared thermography is quite often associated with things other than clinical medicine. For example, the chemical, automobile, aeronautic industries and civil engineering. However, thermography is where infrared images of the breast are analyzed by board certified thermographers and an abnormal thermogram is reported as the significant risk for the existence of breast tumor (Ng, 2009). Thermography is a painless, noninvasive, no radiation, as well as being cheaper and faster, easier access. The aim of this review was to identify the views of clinicians on the use of thermography for quantifying the risk of breast cancer. We used articles published recently in a reliable database. Thermography has been convicted over the years; it has been labeled by subjective interpretation. Most of the reviewed articles agree that mammography is currently the main examination chosen by doctors for the screening of breast cancer (Acharya et al., 2010; Kennedy et al., 2009). However, several studies have reported promising results for the technique (Wang et al., 2010). Additionally, some authors suggest that thermography is complementary to other diagnostic methods, and that the best strategy for the early detection of breast cancer would be to use them together (Kennedy et al., 2009; Hersh, 2004). The combination of thermal imaging with other tests would increase accuracy, sensitivity and specificity of the evaluation and allow a better quantification of the risk of breast cancer.
Urine peptidome analysis predicts risk of end‐stage renal disease and reveals proteolytic pathways involved in autosomal dominant polycystic kidney disease progression

Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slowly progressive bilateral renal cyst growth ultimately resulting in loss of kidney function and end‐stage renal disease (ESRD). Disease progression rate and age at ESRD are highly variable. Therapeutic interventions therefore require early risk stratification of patients and monitoring of disease progression in response to treatment. Methods: We used a urine peptidomic approach based on capillary electrophoresis‐mass‐spectrometry (CE‐MS) to identify potential biomarkers reflecting the risk for early progression to ESRD in the Consortium of Radiologic Imaging in Polycystic Kidney Disease (CRISP) cohort. Results: A biomarker‐based classifier consisting of 20 urinary peptides allowed the prediction of ESRD within 10‐13 years of follow‐up in patients 24‐46 years of age at baseline. The performance of the biomarker score approached that of height‐adjusted total kidney volume (htTKV) and the combination of the biomarker panel with htTKV improved prediction over either one alone. In young patients (<24 years at baseline), the same biomarker model predicted a 30 mL/min/1.73 m2 glomerular filtration rate decline over 8 years. Sequence analysis of the altered urinary peptides and the prediction of the involved proteases by in silico analysis revealed alterations in distinct proteolytic pathways, in particular matrix metalloproteinases and cathepsins. Conclusion: We developed a urinary test that accurately predicts relevant clinical outcomes in ADPKD patients and suggests altered proteolytic pathways involved in disease progression.
Allergic rhinitis is a local disease: the role of local IgE production, basophils and mast cells

textabstractThe introduction to this thesis summarizes the literature which indicates that there is a discrepancy between sensitisation and allergic disease. Two aspects which might play a role in this discrepancy are the differences between production and funtion of local versus systemic lgE and the differences in mast cell and basophil function in the blood compared to in the tissues. Mast cells, basophils and IgE are key players in the allergic inflammation. The aim of the studies described in this thesis was to focus on these differences between local and systemic function of these key factors. The research questions addressed in this thesis are: Mast cells and basophils seem to play an important role in the pathogenesis of allergic rhinitis. Do the phenotypes of mast cells and basophilic cells changed by allergen provocation in the nasal mucosa of allergic rhinitis patients (Chapter 3)? The developmental relationship bet\veen mast cells and basophils has not yet been totally resolved. What is the relation bet\veen basophil progenitors, mast cell progenitors, basophils and mast cells in the circulation and in the nasal mucosa (Chapter 3)? Allergic mucosa inflammation is regulated by the local production and release of several Th2 cytokines. Which increase in cytokines and chemokines is correlated to inflammatory cells and symptomatology of the patient? What is the time line of the various cytokines and chemokines after allergen provocation (Chapter 4)? Is it possible to develop a method to detect specific lgE in tissues. Does production of specific IgE take place locally in the nasal mucosa (Chapter 5)? Where do basophils and mast-cell of allergic rhinitis patients acquire IgE (Chapter 5)? To adress these questions multiple blood samples and biopsies of the nasal mucosa of allergic patients were taken before, during and after allergen provocation. Cellular infiltrates in these biopsies were compared to those in biopsies of normal controls. Cell phenotypes, production and release of mediators and cytokines were studied using immunohistochemical techniques and in situ hybridisation.
Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI‐0052 (marizomib) in a human plasmacytoma xenograft murine model

Our previous study showed that the novel proteasome inhibitor NPI‐0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade™, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM‐xenografts demonstrated that NPI‐0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase‐1 clinical trial of NPI‐0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI‐0052 using human MM xenograft murine model. Our results showed that NPI‐0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin‐like (CT‐L, β5), trypsin‐like (T‐L, β2), and caspase‐like (C‐L, β1) activities in extra‐vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (<24 h). Tissue distribution analysis of radiolabeled compound (3H‐NPI‐0052) in mice demonstrated that NPI‐0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S‐bearing mice with NPI‐0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.
UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5

Significance Toll-like receptors (TLRs) are key innate immune receptors that sense pathogen- or danger-associated molecules. The members of the TLR family can be classified into two groups based on their subcellular localization patterns—cell surface vs. endolysosomes—but how individual TLR is targeted to its destination is largely unknown. UNC93B1 was regarded to specifically bind the endolysosomal TLRs in the endoplasmic reticulum and deliver them to endolysosomes with no role for the surface-localized TLRs. In this study, we demonstrate that TLR5, a cell surface receptor for bacterial protein flagellin, also binds UNC93B1 and requires it for plasma membrane localization and signaling, thus revealing a previously unappreciated role of UNC93B1 in the regulation of the TLR family. The proper trafficking and localization of Toll-like receptors (TLRs) are important for specific ligand recognition and efficient signal transduction. The TLRs sensing bacterial membrane components are expressed on the cell surface and recruit signaling adaptors to the plasma membrane upon stimulation. On the contrary, the nucleotide-sensing TLRs are mostly found inside cells and signal from the endolysosomes in an acidic pH-dependent manner. Trafficking of the nucleotide-sensing TLRs from the endoplasmic reticulum to the endolysosomes strictly depends on UNC93B1, and their signaling is completely abolished in the 3d mutant mice bearing the H412R mutation of UNC93B1. In contrast, UNC93B1 was considered to have no role for the cell surface-localized TLRs and signaling via TLR1, TLR2, TLR4, and TLR6 is normal in the 3d mice. Unexpectedly, we discovered that TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling. TLR5 physically interacts with UNC93B1, and the cells from the 3d or UNC93B1-deficient mice not only lack TLR5 at the plasma membrane but also fail to secret cytokines and to up-regulate costimulatory molecules upon flagellin stimulation, demonstrating the essential role of UNC93B1 in TLR5 signaling. Our study reveals that the role of UNC93B1 is not limited to the TLRs signaling from the endolysosomes and compels the further probing of the mechanisms underlying the UNC93B1-assisted differential targeting of TLRs.
Эпидемиологическая и клинико-генетическая характеристика болезни Паркинсона (на примере Железногорска)

Parkinson’s disease (PD) is the second most common human neurodegenerative disorder. Genetically, PD may be considered as both a monogenous and multifactorial disease. At the moment, much consideration is being given to a search for genetic markers for the LRRK2 6055G>T mutation in exon 41, which plays a role in the development of both monogenous and sporadic cases of PD. The paper presents the results of a 4-year epidemiological study of PD in the town of Zheleznogorsk (Krasnoyarsk Territory). Objective: to study the epidemiology and clinical and genetic features of PD. Patients and methods . There were three observation groups: 1) 135 patients with PD, including 72.6% with previously diagnosed PD and 27.4% with new-onset PD; 2) 44 patients (75% of women and 25% of men) with PD who underwent molecular genetic examination; 3) 30 healthy volunteers (66.7% of women and 33.3% of men) – a control group. The observation groups were matched for gender and age (p>0.05). The study included a retrospective analysis of medical documentation, a prospective clinical and epidemiological study, and a cohort study of genetic predictors for PD. Results and discussion. The weighted mean prevalence of PD in Zheleznogorsk was 124.2 per 100,000 population; morbidity, 13.8 per 100,000 in 2013; mortality was minimal (0 case per 100,000 in 2010 and 2012 and 1.1 case in 2012 and 2013. The genetic markers rs1427263, rs11176013, and rs11564148 of the LRRK2 6055G>T mutation linked to the PARK8 locus on chromosome 12q12 were unassociated with the development of PD among the dwellers of Zheleznogorsk. The frequency of the genetic marker rs7966550 (the homozygous genotype C/C) in the group of PD patients was higher than in that of healthy volunteers (44.5% vs 16.5%). No specific features were found in the pattern and clinical presentations of PD with regard to single-nucleotide polymorphism markers.
Paroxysmal nocturnal haemoglobinuria clones in children with acquired aplastic anaemia: a prospective single centre study

Valentina Maggini* Alessandra Pugi* David Coletta Michele Vietri Betti Giusti Domenico Prisco Alessandro Mugelli Francesco Lapi Alfredo Vannacci Department of Preclinical and Clinical Pharmacology, Interuniversitary Center of Molecular Medicine and Applied Biophysics (CIMMBA), University of Florence, Pharmacovigilance Centre of Tuscan County, Florence, General Practioner AUSL 11, Empoli, Department of Medical and Surgical Critical Care, University of Florence – AOU Careggi, Atherothrombotic Disease Center, and Regional Authority for Healthcare Services of Tuscany, Epidemiology Unit, Florence, Italy. E-mail: alfredo.vannacci@unifi.it *V.M. and A.P. contributed equally to this work References