Miracle-dz/UniFAR-FTUs huggingface dataset:
Immunotherapy based approaches in myelofibrosis

ABSTRACT Introduction: Aberrant regulation of the immune system with up-regulation of pro-inflammatory cytokines contributes to disease pathophysiology in myelofibrosis (MF). Therapeutic options for MF associated anemia, thrombocytopenia, and bone marrow fibrosis remain limited. Areas covered: This review focuses on immune based therapies in MF, including immunomodulatory imide drugs (IMiDs), interferons, monoclonal antibodies and targeted agents (SL-401), and checkpoint inhibitors. Published literature was reviewed using available databases (PubMed, Cochrane, Scopus) and web pages (clinicaltrials.gov). IMiDs, such as thalidomide, lenalidomide and pomalidomide, have demonstrated efficacy in treating MF associated cytopenias. Interferon-alpha may be beneficial in early phase MF due to its effects on neoplastic bone marrow. Monoclonal antibodies are designed to target overexpressed antigens on tumor cells and induce targeted cell death by either delivering a toxic payload, or to unleash anti-tumor T-cells by blocking T-cell inhibitory checkpoints. Expert commentary: Immune based therapy is being evaluated in a number of hematologic malignancies with encouraging data in Hodgkins, multiple myeloma, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Ongoing and planned clinical trials of these agents, either alone or in various combinations with other targeted therapies, such as JAK-STAT or histone deacetylase inhibitors, and anti-fibrotic agents, will reveal the full potential of immune therapies in MF.
Combined cytotoxic effect of UV-irradiation and TiO_2 microbeads in normal urothelial cells, low-grade and high-grade urothelial cancer cells

The differentiation of urothelial cells results in normal terminally differentiated cells or by alternative pathways in low-grade or high-grade urothelial carcinomas. Treatments with traditional surgical and chemotherapeutical approaches are still inadequate and expensive, as bladder tumours are generally highly recurrent. In such situations, alternative approaches, using irradiation of the cells and nanoparticles, are promising. The ways in which urothelial cells, at different differentiation levels, respond to UV-irradiation (photolytic treatment) or to the combination of UV-irradiation and nanoparticles (photocatalytic treatment), are unknown. Here we tested cytotoxicity of UV-irradiation on (i) normal porcine urothelial cells (NPU), (ii) human low-grade urothelial cancer cells (RT4), and (iii) human high-grade urothelial cancer cells (T24). The results have shown that 1 minute of UV-irradiation is enough to kill 90% of the cells in NPU and RT4 cultures, as determined by the live/dead viability assay. On the other hand, the majority of T24 cells survived 1 minute of UV-irradiation. Moreover, even a prolonged UV-irradiation for 30 minutes killed <50% of T24 cells. When T24 cells were pre-supplemented with mesoporous TiO_2 microbeads and then UV-irradiated, the viability of these high-grade urothelial cancer cells was reduced to <10%, which points to the highly efficient cytotoxic effects of TiO_2 photocatalysis. Using electron microscopy, we confirmed that the mesoporous TiO_2 microbeads were internalized into T24 cells, and that the cell’s ultrastructure was heavily compromised after UV-irradiation. In conclusion, our results show major differences in the sensitivity to UV-irradiation among the urothelial cells with respect to cell differentiation. To achieve an increased cytotoxicity of urothelial cancer cells, the photocatalytic approach is recommended.
The role of cytoskeleton and adhesion proteins in the resistance to photodynamic therapy. Possible therapeutic interventions

It is known that Photodynamic Therapy (PDT) induces changes in the cytoskeleton, the cell shape, and the adhesion properties of tumour cells. In addition, these targets have also been demonstrated to be involved in the development of PDT resistance. The reversal of PDT resistance by manipulating the cell adhesion process to substrata has been out of reach. Even though the existence of cell adhesion-mediated PDT resistance has not been reported so far, it cannot be ruled out. In addition to its impact on the apoptotic response to photodamage, the cytoskeleton alterations are thought to be associated with the processes of metastasis and invasion after PDT. In this review, we will address the impact of photodamage on the microfilament and microtubule cytoskeleton components and its regulators on PDT-treated cells as well as on cell adhesion. We will also summarise the impact of PDT on the surviving and resistant cells and their metastatic potential. Possible strategies aimed at taking advantage of the changes induced by PDT on actin, tubulin and cell adhesion proteins by targeting these molecules will also be discussed.
Electrochemical sensor based on overoxidized dopamine polymer and 3,4,9,10-perylenetetracarboxylic acid for simultaneous determination of ascorbic acid, dopamine, uric acid, xanthine and hypoxanthine

A novel electrode based on 3,4,9,10-perylenetetracarboxylic acid (PTCA) and overoxidized dopamine polymer (PDAox) was developed for the simultaneous determination of ascorbic acid (AA), dopamine (DA), uric acid (UA), xanthine (XN) and hypoxanthine (HXN). The developed sensors exhibited an excellent catalytic activity, high sensitivity and good selectivity toward the oxidation of AA, DA, UA, XN and HXN. Scanning electron microscopy (SEM), cyclic voltammetry (CV), different pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) were employed to characterize the sensor. The peak separations between AA–DA, DA–UA, UA–XN and XN–HXN were large, up to 0.15, 0.18, 0.37 and 0.4 V, respectively. The calibration curves for AA, DA, UA, XN and HXN were obtained in the ranges of 76 μM to 3.9 mM, 0.60 to 253 μM, 1.8 to 238 μM, 5.1 to 289 μM and 3.8 to 293 μM with detection limits (S/N = 3) of 25.3 μM, 0.20 μM, 0.60 μM, 1.7 μM and 1.3 μM, respectively. The integration of PDAox and PTCA in the sensor opens up a facile and promising method for the simultaneous determination of above five substances.
Twin studies reveal specific imbalances in the mucosa‐associated microbiota of patients with ileal Crohn's disease

Background: Large interindividual variation in the composition of the intestinal microbiota between unrelated individuals has made it challenging to identify specific aspects of dysbiosis that lead to Crohn's disease (CD). Methods: To reduce variations in exposure during establishment of the gut flora and the influence of genotype, we studied the mucosa‐associated microbiota of monozygotic twin pairs that were discordant (n = 6) or concordant (n = 4) for CD. DNA was extracted from biopsies collected from 5 locations between the ileum and rectum. Bacterial 16S ribosomal RNA genes were amplified and community composition assessed by terminal‐restriction fragment length polymorphism, cloning and sequencing, and quantitative real‐time polymerase chain reaction (PCR). Results: The microbial compositions at all biopsy locations for each individual were similar, regardless of disease state, but there were differences between individuals. In particular, individuals with predominantly ileal CD had a dramatically lower abundance (P < 0.001) of Faecalibacterium prausnitzii and increased abundance (P < 0.03) of Escherichia coli compared to healthy co‐twins and those with CD localized in the colon. This dysbiosis was significantly correlated to the disease phenotype rather than genotype. Conclusions: The reduced abundance of F. prausnitzii and increased abundance of E. coli are indicative of an ileal CD phenotype, distinct from colonic CD, and the relative abundances of these specific bacterial populations are promising biomarker candidates for differential diagnosis of CD and eventually customized treatment.
Luminally expressed gastrointestinal biomarkers

ABSTRACT Introduction: A biomarker is a measurable indicator of normal biologic processes, pathogenic processes or pharmacological responses. The identification of a useful biomarker is challenging, with several hurdles to overcome before clinical adoption. This review gives a general overview of a range of biomarkers associated with inflammatory bowel disease or colorectal cancer along the gastrointestinal tract. Areas covered: These markers include those that are already clinically accepted, such as inflammatory markers such as faecal calprotectin, S100A12 (Calgranulin C), Fatty Acid Binding Proteins (FABP), malignancy markers such as Faecal Occult Blood, Mucins, Stool DNA, Faecal microRNA (miRNA), other markers such as Faecal Elastase, Faecal alpha-1-antitrypsin, Alpha2-macroglobulin and possible future markers such as microbiota, volatile organic compounds and pH. Expert commentary: There are currently a few biomarkers that have been sufficiently validated for routine clinical use at present such as FC. However, many of these biomarkers continue to be limited in sensitivity and specificity for various GI diseases. Emerging biomarkers have the potential to improve diagnosis and monitoring but further study is required to determine efficacy and validate clinical utility.
Visual Art in Physical Rehabilitation: Experiences of People with Neurological Conditions

Aims: The aims of this study were to understand the experience of participation in visual art from the perspective of adults undergoing outpatient physical rehabilitation and to determine whether art has a place in this context. Method: This qualitative study involved interviewing adults who attended a weekly art class run by a qualified art teacher and occupational therapists in an outpatient physical rehabilitation setting. Nine participants with neurological conditions discussed their experience of the programme and the goals they were working towards or had achieved through painting. Findings: The themes that emerged from the study show that art contributed to the participants meeting their individual rehabilitation goals. It also assisted the participants in using time, increasing enjoyment, regaining confidence and planning for engagement in future activities. All these achievements were seen by the participants to contribute to their rehabilitation or recovery. The identified themes align with the aims of rehabilitation and are similar to findings from many other studies investigating the use of art by people affected by illness or disability. Conclusion: The findings of this study inform clinical practice in the use of visual art with clients in rehabilitation and validate its place in a physical rehabilitation programme.
Associations between ABCB1/MDR1 gene polymorphisms and Crohn's disease: A gene‐wide study in a pediatric population

Background: Functional studies support the involvement of the MDR1 gene in the pathways leading to Crohn's disease (CD). Two common single nucleotide polymorphisms (SNPs), C3435T and G2677T/A, thought to alter the function of the corresponding P‐glycoprotein, have shown inconsistent associations with CD. We investigated whether DNA variants in the MDR1 gene were associated with susceptibility for CD and specific phenotypes in children. Methods: A case–control study was conducted at 3 gastroenterology clinics across Canada. Children with CD and population‐ or hospital‐based controls were included. CD cases were classified using the Montreal Classification. Thirteen tag‐SNPs and the C3435T variant in the MDR1 gene were genotyped. Single‐SNP allelic, genotype as well as gene‐wide haplotype associations with CD and its phenotypes at diagnosis were assessed. Results: A total of 270 CD cases and 336 controls were studied. Most cases were male (56.3%), had disease location L3±L4 (58.1%), and an inflammatory phenotype B1±p (88.5%). Allelic association analysis revealed that SNP rs17327442 was significantly associated with overall susceptibility to CD (odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.50–0.99, P = 0.04) but this association did not withstand corrections for multiple testing (q‐value = 0.56). Genotype–phenotype analysis indicated that 2 SNPs (rs10248420, P = 0.007, q‐value = 0.07; rs2032583, P = 0.01, q‐value = 0.07) were significantly associated with colonic disease. Five SNPs, rs1128503 (P = 0.02), rs1202184 (P = 0.008), rs1202186 (P = 0.02), rs2091766 (P = 0.03), and rs2235046 (P = 0.03) were nominally associated with noninflammatory CD. Specific haplotypes comprising of the tag‐SNPs were significantly associated with either colonic or noninflammatory CD. Conclusions: Our comprehensive gene‐wide analysis suggests that the MDR1 gene may be associated with clinical phenotypes of CD in children.
Newer developments in idiopathic pulmonary fibrosis in the era of anti-fibrotic medications

ABSTRACT Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease with a fatal prognosis. Over the last decade, the concepts in pathobiology of pulmonary fibrosis have shifted from a model of chronic inﬂammation to dysregulated ﬁbroproliferative repair in genetically predisposed patients. Although new breakthrough treatments are now available that slow the progression of the disease, several newer anti-inflammatory and anti-fibrotic drugs are under investigation. Patients with IPF often have coexistent conditions; prompt detection and interventions of which may improve the overall outcome of patients with IPF. Here, we summarize the present understanding of pathogenesis of IPF and treatment options for IPF in the current landscape of new anti-fibrotic treatment options.
Health information privacy and e-healthcare

E-healthcare offers tremendous benefits to healthcare stakeholders. Nonetheless, that very same technology poses unprecedented challenges to patient and consumer privacy. While technology itself may resolve some security concerns through encryption and other control mechanisms, privacy issues are too critical to be left to technological resolutions alone. Furthermore, industry self-regulation efforts have not allayed the fears of privacy advocates nor staved off efforts to increase government regulation of privacy interests. This article examines the challenges of health information privacy from ethical, legal and technological perspectives.
Controlled invasive mechanical ventilation strategies in obese patients undergoing surgery

ABSTRACT Introduction: The obesity prevalence is increasing in surgical population. As the number of obese surgical patients increases, so does the demand for mechanical ventilation. Nevertheless, ventilatory strategies in this population are challenging, since obesity results in pathophysiological changes in respiratory function. Areas covered: We reviewed the impact of obesity on respiratory system and the effects of controlled invasive mechanical ventilation strategies in obese patients undergoing surgery. To date, there is no consensus regarding the optimal invasive mechanical ventilation strategy for obese surgical patients, and no evidence that possible intraoperative beneficial effects on oxygenation and mechanics translate into better postoperative pulmonary function or improved outcomes. Expert commentary: Before determining the ideal intraoperative ventilation strategy, it is important to analyze the pathophysiology and comorbidities of each obese patient. Protective ventilation with low tidal volume, driving pressure, energy, and mechanical power should be employed during surgery; however, further studies are required to clarify the most effective ventilation strategies, such as the optimal positive end-expiratory pressure and whether recruitment maneuvers minimize lung injury. In this context, an ongoing trial of intraoperative ventilation in obese patients (PROBESE) should help determine the mechanical ventilation strategy that best improves clinical outcome in patients with body mass index≥35kg/m2.
Defining the role of recombinant activated factor VII in pediatric cardiac surgery: Where should we go from here?*

Objectives: Postoperative hemorrhage is a recognized complication of pediatric cardiac surgery. Both the immature coagulation system and increased susceptibility to hemodilution increase the likelihood of pediatric patients developing coagulopathy when compared with adult counterparts. Treatment options remain limited. Recombinant factor VII (rFVIIa) is a hemostatic agent increasingly used to reduce hemorrhage in other surgical settings, the role of which is unclear in this population. This article systematically reviews the published literature on the use of rFVIIa in pediatric cardiac surgery. Data Sources and Study Selection: A systematic literature search identified reports of rFVIIa administration in pediatric patients undergoing cardiac surgery. Where possible, individual patient-specific data were extracted and pooled statistical analysis was performed. Data Extraction and Synthesis: Twenty-nine articles reporting on the administration of rFVIIa to 169 patients were identified. rFVIIa has been administered to patients with predefined congenital abnormalities of hemostasis to arrest hemorrhage refractory to other interventions and prophylactically in the hope of reducing blood loss. Treatment regimens vary widely, in terms of both first and cumulative dose. Data on chest tube blood loss and two markers of coagulation were pooled and analyzed, and significant improvements were demonstrated. Mortality was 4.4% for the entire cohort but 20% of patients on extracorporeal membrane oxygenation suffered significant thromboembolic complications. Conclusions: rFVIIa has an increasingly accepted role in the management of patients with congenital coagulopathies undergoing major surgery. However, randomized trials are required to define the role of rFVIIa as an adjunct to control major hemorrhage in the pediatric cardiac surgical population. Any future work must focus not only on benefits but also on patient safety, particularly, risk of morbid thromboembolic complication.
Oral valganciclovir for colonic dilatation in ulcerative colitis associated with human cytomegalovirus infection.

To the Editor: Toxic megacolon is a rare complication of severe ulcerative colitis (UC) exacerbation defined as a clinical syndrome accompanied by radiographic evidence of colonic dilatation that in most cases must be treated aggressively with surgical intervention; human cytomegalovirus (HCMV) infection is a potential cause mainly in immunocompromised or critically ill patients. We describe a case of initial colonic dilatation on acute UC with superimposed HCMV infection successfully treated with oral valganciclovir. A 69-year-old woman patient affected by distal UC since 1999 was hospitalized on April 2009 for a severe disease flare-up. She had 10 bloody bowel movements per day, abdominal pain with tenderness and fever (38.7 C), with a blood pressure of 110/ 70 mmHg and a pulse rate of 80 beats/ min. The laboratory studies were normal except for an erythrocyte sedimentation rate of 78, mm/hr, a hypoalbuminemia of 2.4 g/dL, and a kaliemia of 3.4 mEq/L; blood and stools cultures showed no infection. In the past she was treated with infliximab (4 infusions from September to December 2007) and she was currently treated with azathioprine for steroid dependence. Therapy with steroid intravenous (methylprednisolone 1 mg/kg/die) and parenteral nutrition was started. After 4 days the symptoms were stable with development of colonic dilatation at plain abdomen x-ray (Fig. 1) and CT scan. Proctoscopy without air insufflation showed multiple large and bloody ulcers, lesion in the rectum with severe endoscopical activity; rectal biopsies revealed HCMV nuclear inclusions in epithelial and lamina propria cells with perivascular infiltrate suggestive for vascular damage at haematoxylin and eosin stain. The pp65-antigenemia on peripheral leukocytes was performed showing a positivity of 8 fluorescent nuclei/2 10 leukocytes; a serologic determination of IgM antiHCMV was negative. Treatment with oral valganciclovir, maintaining the same steroid treatment, was started (450 mg bid) for 14 days, obtaining a rapid clinical response with complete clinical remission after 7 days of treatment; afterward the steroids were gradually reduced. A daily planned plain abdomen x-ray was carried out showing a progressive improvement of the colonic dilatation. A pp65-antigenemia assay was repeated after 10 days of treatment with a negative result. To our knowledge, this is the first case of initial colon dilatation in UC complicated by HCMV infection successfully treated with oral valganciclovir. Valganciclovir is an orally administered prodrug of the standard anti-HCMV drug ganciclovir, well tolerated and efficacious in the treatment of HCMV retinitis in patients with AIDS and as prophylaxis against HCMV infection in solid organ transplant high-risk patients. It provides greater systemic ganciclovir exposure than oral ganciclovir, thus reducing the risk of viral resistance when used for prophylaxis in high-risk solid organ transplant recipients, with better
5‐aminosalicylic acid interferes in the cell cycle of colorectal cancer cells and induces cell death modes

Introduction: Epidemiological data suggests that 5‐aminosalicylic acid (5‐ASA), a nonsteroidal antiinflammatory drug used in the treatment of inflammatory bowel diseases, prevents colorectal cancer development in these patients, although the mechanisms remain incompletely understood. Methods and Results: Here we report that 5‐ASA prevents growth of several colorectal cancer cell lines by interfering in the cell cycle, i.e., an S‐phase and G2/M phase arrest, dependent on 5‐ASA dosage and concentration, together with an increased mitotic index. In addition, prolonged cell cycle arrest by repeated 5‐ASA treatment induced apoptosis and caused abnormal spindle organization leading to mitotic catastrophe, another form of cell death. Conclusion: These observations illustrate that 5‐ASA has chemopreventive and chemotherapeutic properties. (Inflamm Bowel Dis 2010;)
TLR5 is not required for flagellin‐mediated exacerbation of DSS colitis

Background: The two forms of human inflammatory bowel disease, Crohn's disease (CD) and ulcerative colitis (UC), are both associated with loss of tolerance to gut microbial antigens. The dominant antigen recognized by antibody and T‐cell responses in patients with CD is bacterial flagellin. Flagellin is also the only known ligand for Toll‐like receptor 5 (TLR5), a key protein in innate immunity. Although flagellin activates TLR5 to produce inflammatory responses in many cell types in the gut, there is conflicting evidence as to whether TLR5 is harmful or protective in CD and murine colitis models. A recent study found that administration of flagellin enemas to mice along with dextran sodium sulfate (DSS) made their colitis worse. Methods: We sought to determine whether this exacerbation was due to TLR5 ligation, or to TLR5‐independent adaptive immune responses to flagellin as an antigen, by using a transposon insertional mutant of the Escherichia coli H18 flagellin, 2H3, which lacks TLR5 stimulatory activity. Results: We found that flagellin enemas produced only a mild exacerbation of DSS colitis, and that 2H3 was equivalent to or worse than wildtype flagellin. Moreover, we found that DSS colitis was more severe in TLR5−/− mice than wildtype C57BL/6 mice. Conclusions: Together, these results suggest that flagellin‐mediated exacerbation of colitis is independent of TLR5. (Inflamm Bowel Dis 2010;)