| Il "male del secolo" è sempre più curabile La Repubblica Sono questi alcuni dati presentati in occasione del convegno "Il male curabile, le ultime frontiere contro il cancro", che si tiene oggi, alle 18,30, agli Incontri al Caffè de La Versiliana, a Marina di Pietrasanta (Lucca). "Grazie alle ... Il melanoma ... |
The roles of angiogenesis in development, health, and disease have been studied extensively; however, the studies related to lymphatic system are limited due to the difficulty in observing colorless lymphatic vessels. But recently, with the improved technique, the relative importance of the lymphatic system is just being revealed. We bred transgenic mice in which lymphatic endothelial cells express GFP (Prox1-GFP) with mice in which vascular endothelial cells express DsRed (Flt1-DsRed) to generate Prox1-GFP/Flt1-DsRed (PGFD) mice. The inherent fluorescence of blood and lymphatic vessels allows for direct visualization of blood and lymphatic vessels in various organs via confocal and two-photon microscopy and the formation, branching, and regression of both vessel types in the same live mouse cornea throughout an experimental time course. PGFD mice were bred with CDh5CreERT2 and VEGFR2lox knockout mice to examine specific knockouts. These studies showed a novel role for vascular endothelial cell VEGFR2 in regulating VEGFC-induced corneal lymphangiogenesis. Conditional deletion of vascular endothelial VEGFR2 abolished VEGFA- and VEGFC-induced corneal lymphangiogenesis. These results demonstrate the potential use of the PGFD mouse as a powerful animal model for studying angiogenesis and lymphangiogenesis.
As women continue to live longer, physicians adapt to treating well-described diseases such as breast cancer. Here we provide a comprehensive evidence-based review of the treatment of breast cancer in the elderly patient.
Previous studies conducted to determine optimal treatment for breast cancer have primarily included younger, healthier women. Despite favorable tumor biology, older women are less likely to receive standard of care treatments relative to breast reconstruction, postoperative radiation, and adjuvant chemotherapy. Frailty is cited as a reason for not offering or receiving therapies. There are no strict definitions of frailty for this specific population, but there are general guidelines for older cancer patients, with a lower specificity than desired.
Treatment recommendations for older women vary little from those for younger women. However, the paucity of data for the older age group within trials raises the question of the basis of evidence. Risks of treatment need to be evaluated relative to life expectancy.
Patients with early-stage hepatocellular carcinoma (HCC) are potential candidates for curative treatments such as radiofrequency ablation (RFA), surgical resection (SR), or liver transplantation (LT), which have demonstrated a significant survival benefit. We aimed to estimate the cost-effectiveness of curative and combination treatment strategies among patients diagnosed with HCC during 2002–2010. This study used Ontario Cancer Registry-linked administrative data to estimate effectiveness and costs (2013 USD) of the treatment strategies from the healthcare payer's perspective. Multiple imputation by logistic regression was used to handle missing data. A net benefit regression approach of baseline important covariates and propensity score adjustment were used to calculate incremental net benefit to generate incremental cost-effectiveness ratio (ICER) and uncertainty measures. Among 2,222 patients diagnosed with HCC, 10.5%, 14.1%, and 10.3% received RFA, SR, and LT monotherapy, respectively; 0.5–3.1% dual treatments; and 0.5% triple treatments. Compared with no treatment (53.2%), transarterial chemoembolization (TACE) + RFA (average $2,465, 95% CI: −$20,000–$36,600/quality-adjusted life years [QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500–$28,500/QALY) appears to be the most cost-effective modality with lowest ICER value. The cost-effectiveness acceptability curve showed that if the relevant threshold was $50,000/QALY, RFA monotherapy and TACE+ RFA would have a cost-effectiveness probability of 100%. Strategies using LT delivered the most additional QALYs and became cost-effective at a threshold of $77,000/QALY. Our findings found that TACE+ RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario. These findings highlight the importance of identifying and measuring differential benefits, costs, and cost-effectiveness of alternative HCC curative treatments in order to evaluate whether they are providing good value for money in the real world.
The aim of this article was to estimate the cost-effectiveness of mutually exclusive potentially curative monotherapies such as radiofrequency ablation (RFA), surgical resection (SR), or liver transplantation (LT) and combination therapies with palliative treatment (transarterial chemoembolization, TACE) among patients diagnosed with hepatocellular carcinoma (HCC) during 2002–2010. Compared with no treatment, TACE plus RFA (average $2,465, 95% CI: −$20,000–$36,600/quality-adjusted life years [QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500–$28,500/QALY) appears to be the most cost-effective modality with lowest incremental cost-effectiveness ratio (ICER) value. Our findings found that TACE plus RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario, which may potentially provide good value for money in the real world within the context of an organized healthcare system.
Data on management of atrial fibrillation (AF) in the Balkan Region are scarce. To capture the patterns in AF management in contemporary clinical practice in the Balkan countries a prospective survey was conducted between December 2014 and February 2015, and we report results pertinent to the use of non-vitamin K antagonist oral anticoagulants (NOACs).
A 14-week prospective, multicenter survey of consecutive AF patients seen by cardiologists or internal medicine specialists was conducted in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Montenegro, Romania, and Serbia (a total of about 50 million inhabitants).
Of 2712 enrolled patients, 2663 (98.2%) had complete data relevant to oral anticoagulant (OAC) use (mean age 69.1 ± 10.9 years, female 44.6%). Overall, OAC was used in 1960 patients (73.6%) of whom 338 (17.2%) received NOACs. Malignancy [odds ratio (OR), 95% confidence interval (CI) 2.06, 1.20–3.56], rhythm control (OR 1.64, 1.25–2.16), and treatment by cardiologists were independent predictors of NOAC use (OR 2.32, 1.51–3.54) [all p < 0.01)], whilst heart failure and valvular disease were negatively associated with NOAC use (both p < 0.01). Individual stroke and bleeding risk were not significantly associated with NOAC use on multivariate analysis.
NOACs are increasingly used in AF patients in the Balkan Region, but NOAC use is predominantly guided by factors other than evidence-based decision-making (e.g., drug availability on the market or reimbursement policy). Efforts are needed to establish an evidence-based approach to OAC selection and to facilitate the optimal use of OAC, thus improving the outcomes in AF patients in this large region.
To date, there is little research on health-related quality of life (HRQoL) in Down syndrome (DS), and existing research is variable with regard to reported HRQoL in DS. There are also no HRQoL measures developed specifically to be used with individuals with Down syndrome.
A multi-national, longitudinal, 24-week non-interventional study was conducted in adolescents and adults with DS. HRQoL was assessed (n = 90) using the parent-report KIDSCREEN-27 questionnaire.
HRQoL domain scores were found to be similar to those in the KIDSCREEN-27 European normative group data set on the Physical Well-being, Psychological Well-being, Autonomy and Parent Relations domains. Compared with the normative data set, the adolescent participants with DS in the current study were found to have lower scores on the Social Support and Peers domain and higher scores than the normative group on the School Environment domain. The test-retest reliability of the KIDSCREEN-27 was also examined using the intraclass correlation coefficient (ICC) in a subgroup of stable participants. The KIDSCREEN-27 demonstrated poor-to-moderate test-retest reliability; however, test-retest reliability was assessed using a long time interval between assessment time points.
The findings of this study underline that further research is needed to better understand the nature of HRQoL in DS. Further research using a shorter time interval between assessment time points to examine test-retest reliability is also required.
F. Hoffmann-La Roche Ltd.
Inflammatory rheumatic diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) show a striking female predominance ranging from 3:1 in RA up to 9:1 in SLE. The background for those gender bias is not fully understood yet, but seems to be the result of a complex interaction between sex hormones, (epi-)genetics, and possibly even the composition of gut microbiota. Moreover, time of disease onset, the clinical phenotype including co-morbidities as well as the course of the diseases during life differ between genders. The patient's sex therefore plays an emerging role for individual therapy decisions and co-morbidity screening in rheumatologic care. Male lupus patients, for example, tend to show more severe features such as renal involvement, pleurisy, and serositis, when being compared to female patients. Among RA patients, women are more likely to acquire conditions like thyroid dysfunctions, fibromyalgia, and depression than their male counterparts. These examples emphasize the importance of the patient's gender for the clinical routine and the resulting implications for prevention and therapy. The present article is going to review potential causes for the female predominance of rheumatic diseases and will examine the gender's impact on the disease phenotype, symptom severity, co-morbidities, and quality of life. For reasons of scope, the focus will be on RA and SLE as two of the most important rheumatic diseases with a large socioeconomic impact on society due to their incidence as well as mortality.
Incontinentia pigmenti (IP) is an X-linked genodermatosis affecting the skin and other sites, including the teeth, nails, hair, eyes and nervous system defects in female patients. Generally lethal in males, there are only a few known cases of males surviving this condition. Nuclear factor (NF)-κB essential modulator (NEMO), also known as inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma (IKBKG), constitutes an essential activator of NF-κB. Over 80% of female patients with IP carry a common deletion mutation involving exons 4–10 of the IKBKG/NEMO gene. We present the case of a male infant (XY) with IP with no concomitant complications. Polymerase chain reaction (PCR) assay showed that the exon 4–10 deletion band was significantly stronger in the skin sample than in blood. Subsequently, long-range PCR was performed periodically to confirm the spontaneous regression of mutant cells from his blood. Over a period of 6 years, the 2.6-kb mutant band gradually became weaker, but we did not confirm complete regression. Our patient was a healthy, 8-year-old male child with no complications despite the presence of a 2.6-kb mutant band in his blood. Further follow up is necessary to assess for complications that may develop later.
Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure are also found to relate to outcomes in the geriatric population, but in a differing direction. A higher body mass index, hypercholesterolemia and hypertension are not harmful but even permit better survival at advancing age. This phenomenon is called "reverse epidemiology" or "risk factor paradox" and is also detected in a variety of chronic disease states such as chronic heart failure. Accordingly, a low BMI, blood pressure and cholesterol values are associated with a worse prognosis. Several possible causes are hypothesized to explain this elderly paradox, but this phenomenon remains controversial and its underlying reasons are poorly understood. The aim of this review is to recognize the factors behind this intriguing phenomenon and analyse the consequences that it can bring in the management of the cardiovascular therapy in elderly patient. Finally, a new phenotype identified as "catabolic syndrome" has been postulated.
Chronic fatigue syndrome: A debilitating and complex disorder characterized by profound fatigue that lasts 6 months or longer, is not improved by bed rest, and may be worsened by physical or mental activity. Abbreviated CFS. Persons with CFS most often function at a substantially lower level of activity than they were capable of before the onset of the illness. In addition to these key defining characteristics, patients report various nonspecific symptoms, including weakness, muscle pain, impaired memory and/or mental concentration, insomnia, and postexertional fatigue lasting more than 24 hours. In some cases, CFS can persist for years. The cause or causes of CFS have not been identified, and no specific diagnostic tests are available. Moreover, because many illnesses have incapacitating fatigue as a symptom, care must be taken to exclude other known and often treatable conditions before a diagnosis of CFS is made. Also known as chronic fatigue and immune dysfunction syndrome (CFIDS) and myalgic encephalomyelitis (ME).
Surgeon Major Thomas Heazle Parke (1857–1893) was a doctor from Drumsna, County Roscommon, who after completing his education at the Royal College of Surgeons in Ireland joined the British army as a medical officer. After several years of serving in Ireland and Egypt, he volunteered to be medical officer of the Emin Pasha Relief Expedition of 1887–1889. This was to become Henry Morton Stanley's largest, longest and most controversial African expedition. The epic journey saw Stanley, his eight European officers and 800 African porters take almost 3 years to cross the African continent from West to East via the Congo River, Southern Sudan and Uganda. During this time, Parke had to single-handedly deal with the myriad diseases and injuries that beset the expedition's members. Barely 200 of the Zanzibari, Sudanese and Somali porters survived, and two British officers also perished. In completing the expedition, Parke became the first Irishman to cross Africa, and he had also become the first European to lay eyes on the 'Mountains of the Moon' or 'Ruwenzori'. He returned home to great acclaim, and was bestowed copious honours and fellowships. His account of the expedition, My Experiences in Equatorial Africa, was a bestseller. However, his own health never recovered from the hardships of his time in Africa, and he died suddenly in 1893. His statue stands outside the Natural History Museum in Dublin.
Belize, hosting one of the British Army's overseas training areas, provides access to challenging terrain and austere environments, which allows the delivery of training to soldiers on survival and combat within the jungle environment. A 26-year-old infanteer on exercise in Belize presented with progressive bilateral dry, painful, oedematous hands, secondary to the harsh environmental conditions of the jungle and inadequate drying of his hands resulting in his inability to perform his combat duties. The symptoms completely resolved with drying, emollient application and analgesia. While there are no reported cases of immersion hand, comparisons can be made with the well-reported warm weather immersion foot. This case highlights the importance of force preparation and soldier education for units deploying to the jungle. Simple preventive measures, including adequate 'wet–dry' drills and use of emollients can reduce the prevalence of immersion hand, a preventable condition, which can have a significant impact on the overall combat effectiveness of the unit.
We describe the case of a woman presenting with transient ischaemic attack, who was found to have a papillary fibroelastoma arising from the aortic wall, an extremely rare location. We describe the multimodality imaging techniques used in diagnosing this patient and review the most recent literature on evaluation and management of patients with cardiac papillary fibroelastomas.
Leachate is a polluting liquid which may cause harmful effects on human health or the environment without a tightly control manner. The leachate management is an important part of the design and operation of bioreactor landfills. To detect the leachate distribution in Laogang Landfill, China, the measurement of electrical resistivity tomography (ERT) was carried out in three areas with different ages. ERT method proved to be an effective non-invasive geophysical method in bioreactor landfills, and the physical properties of waste samples obtained by boreholes were tested in a laboratory. The correlation between the resistivity and the moisture content was described by Archie's law. The result shows that the moisture content of fresh waste is inhomogeneous, while that of aged waste increases with depth. A pseudo 3D model of the moisture content was proposed to improve the understanding of leachate distribution and exhibit the accuracy of the ERT method.
Jakarta Post | Five signs of tongue cancer to watch out for Jakarta Post The malady, which is a type of mouth cancer, usually started from early form squamous cells, which are flat, scale-like cells that cover the surface of the mouth, lips and tongue. When it spreads, tongue cancer affects the system that controls the flow ... |
Shreveport Times | 'I can't give up': Two Bossier police families fight cancer Shreveport Times Battling cancer has not been a solitary fight for Angela Grooms or Robert Parker. From first hearing the word "cancer" from a doctor, to dealing with the side effects of chemotherapy and radiation treatments, both Bossier Parish residents said they ... |
Extensive liver resections are common, and bleeding is frequent in these operations. Impaired regeneration after partial hepatectomy (PHx) may contribute to liver failure. We thus assessed the impact of acute bleeding on the liver regeneration progress after PHx and explored possible contributing molecular mechanisms. In rats, the regeneration progress was delayed and attenuated with PHx and bleeding and was not restored with colloid resuscitation. Livers restored their initial volume by postoperative day (POD) 2 after PHx through hepatocyte proliferation vs. POD 4 in the PHx and bleeding group, primarily by hepatocyte hypertrophy. With bleeding, hepatocyte proliferation was hindered in two mechanisms: by inhibiting cells from starting proliferation and by causing hindrance in G1/S progression. Liver hypoxia was prominent, with significant prolonged up-regulation of hypoxia-inducible factors (HIF) and HIF-targeted genes only in the PHx and bleeding group. Gene expression profiling revealed alterations in numerous genes that belong to critical pathways, including cell cycle, DNA replication, PI3K-Akt, purine, and pyrimidine metabolism. Because liver surgery is frequently performed in patients with a predamaged liver, an improper regenerative process after PHx and bleeding might lead to decompensation. The results hint at specific pathways to target in order to improve liver regeneration during PHx and bleeding.—Matot, I., Nachmansson, N., Duev, O., Schulz, S., Schroeder-Stein, K., Frede, S., Abramovitch, R. Impaired liver regeneration after hepatectomy and bleeding is associated with a shift from hepatocyte proliferation to hypertrophy.
JMJD6 is known to localize in the nucleus exerting histone arginine demethylase and lysyl hydroxylase activities. A novel localization of JMJD6 in the extracellular matrix, resulting from its secretion as a soluble protein, was unveiled by a new anti-JMJD6 mAb called P4E11 which was developed to identify new targets in the stroma. Recombinant JMJD6 binds with collagen type I (Coll-I), and distinct JMJD6 peptides interfere with collagen fibrillogenesis, collagen-fibronectin interaction, and adhesion of human tumor cells to the collagen substrate. P4E11 and collagen binding to JMJD6 are mutually exclusive because the amino acid sequences of JMJD6 necessary for the interaction with Coll-I are part of the conformational epitope recognized by P4E11. In mice injected with mouse 4T1 breast carcinoma cells, treatment with P4E11 reduced fibrosis at the primary tumor and prevented lung metastases. Reduction of fibrosis has also been documented in human breast and ovarian tumors (MDA-MB-231 and IGROV1, respectively) xenotransplanted into immunodeficient mice treated with P4E11. In summary, this study uncovers a new localization and function for JMJD6 that is most likely independent from its canonical enzymatic activities, and demonstrates that JMJD6 can functionally interact with Coll-I. P4E11 mAb by inhibiting JMJD6/Coll-I interaction, which represents a new opportunity to target fibrotic and tumor diseases.—Miotti, S., Gulino, A., Ferri, R., Parenza, M., Chronowska, A., Lecis, D., Sangaletti, S., Tagliabue, E., Tripodo, C., Colombo, M. P. Antibody-mediated blockade of JMJD6 interaction with collagen I exerts antifibrotic and antimetastatic activities.
Co-localization of dopamine with other classical neurotransmitters in the same neuron is a common phenomenon in the brain of vertebrates. In mammals, some dopaminergic neurons of the ventral tegmental area and the hypothalamus have a glutamatergic co-phenotype. However, information on the presence of this type of dopaminergic neurons in other vertebrate groups is very scant. Here, we aimed to provide new insights on the evolution of this neuronal co-phenotype by studying the presence of a dual dopaminergic/glutamatergic neuron phenotype in the central nervous system of lampreys. Double immunofluorescence experiments for dopamine and glutamate in adult sea lampreys revealed co-localization of both neurotransmitters in some neurons of the preoptic nucleus, the nucleus of the postoptic commissure, the dorsal hypothalamus and in cerebrospinal fluid-contacting cells of the caudal rhombencephalon and rostral spinal cord. Moreover, co-localization of dopamine and glutamate was found in dopaminergic fibres in a few brain regions including the lateral pallium, striatum, and the preoptic and postoptic areas but not in the brainstem. Our results suggest that the presence of neurons with a dopaminergic/glutamatergic co-phenotype is a primitive character shared by jawless and jawed vertebrates. However, important differences in the distribution of these neurons and fibres were noted among the few vertebrates investigated to date. This study offers an anatomical basis for further work on the role of glutamate in dopaminergic neurons.
Publication date: Available online 8 August 2017
Source:Asian Pacific Journal of Tropical Medicine
Author(s): Imran Shahid, Waleed Hassan AlMalki, Mohammed Wanees AlRabia, Mohammed Hasan Mukhtar, Shaia Saleh R. Almalki, Saad Ahmed Alkahtani, Sami S. Ashgar, Hani S. Faidah, Muhammad Hassan Hafeez
ObjectiveTo explore inhibitory effects of genome-specific, chemically synthesized siRNAs (small interference RNA) against NS3 gene of hepatitis C virus (HCV) 1a genotype in stable Huh-7 (human hepatoma) cells as well as against viral replication in serum-inoculated Huh-7 cells.MethodsStable Huh-7 cells persistently expressing NS3 gene were produced under antibiotic gentamycin (G418) selection. The cell clones resistant to 1 000 μg antibiotic concentration (G418) were picked as stable cell clones. The NS3 gene expression in stable cell clone was confirmed by RT- PCR and Western blotting. siRNA cell cytotoxicity was determined by MTT cell proliferation assay. Stable cell lines were transfected with sequence specific siRNAs and their inhibitory effects were determined by RT-PCR, real-time PCR and Western blotting. The viral replication inhibition by siRNAs in serum inoculated Huh-7 cells was determined by real-time PCR.ResultsRT-PCR and Western blot analysis confirmed NS3 gene and protein expression in stable cell lines on day 10, 20 and 30 post transfection. MTT cell proliferation assay revealed that at most concentrated dose tested (50 nmol/L), siRNA had no cytotoxic effects on Huh-7 cells and cell proliferation remained unaffected. As demonstrated by the siRNA time-dependent inhibitory analysis, siRNA NS3-is44 showed maximum inhibition of NS3 gene in stable Huh-7 cell clones at 24 (80%, P =0.013) and 48 h (75%, P = 0.002) post transfection. The impact of siRNAs on virus replication in serum inoculated Huh-7 cells also demonstrated significant decrease in viral copy number, where siRNA NS3-is44 exhibited 70% (P < 0.05) viral RNA reduction as compared to NS3-is33, which showed a 64% (P < 0.05) decrease in viral copy number. siRNA synergism (NS3-is33 + NS3-is44) decreased viral load by 84% (P < 0.05) as compared to individual inhibition by each siRNA (i.e., 64%–70% (P < 0.05) in serum-inoculated cells. Synthetic siRNAs mixture (NS5B-is88 + NS3-is33) targeting different region of HCV genome (NS5B and NS3) also decreased HCV viral load by 85% (P < 0.05) as compared to siRNA inhibitory effects alone (70% and 64% respectively, P < 0.05).ConclusionssiRNAs directed against NS3 gene significantly decreased mRNA and protein expression in stable cell clones. Viral replication was also vividly decreased in serum infected Huh-7 cells. Stable Huh-7 cells expressing NS3 gene is helpful to develop anti-hepatitis C drug screening assays. siRNA therapeutic potential along with other anti-HCV agents can be considered against hepatitis C.
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Men with non-metastatic prostate cancer who receive androgen deprivation therapy risk loss of bone mineral density and fractures, but both bisphosphonates and denosumab can improve their bone health. (Source: CancerNetwork)
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PSD-95 is a major synaptic scaffolding protein that plays a key role in bidirectional synaptic plasticity, which is a process important for learning and memory. It is known that PSD-95 shows increased dynamics upon induction of plasticity. Yet the underlying structural and functional changes in PSD-95 that mediate its role in plasticity remain unclear. Here we show that phosphorylation of PSD-95 at Ser561 in its GK domain, which is mediated by the partitioning defective 1 (Par1) kinases, regulates a conformational switch and is important for bidirectional plasticity. Using a fluorescence resonance energy transfer (FRET) biosensor, we show a phosphomimetic mutation of Ser561 promotes an intramolecular interaction between GK and the nearby SH3 domain, leading to a closed conformation; while a non-phosphorylatable S561A mutation or inhibition of Par1 kinase activity decreases SH3-GK interaction, causing PSD-95 to adopt an open conformation. In addition, S561A mutation facilitates the interaction between PSD-95 and its binding partners. Fluorescence recovery after photobleaching (FRAP) imaging reveals the S561A mutant shows increased stability, while the phosphomimetic S561D mutation increases PSD-95 dynamics at the synapse. Moreover, molecular replacement of endogenous PSD-95 with the S561A mutant blocks dendritic spine structural plasticity during chemical long-term potentiation (LTP) and long-term depression (LTD). Endogenous Ser561 phosphorylation is induced by synaptic NMDA receptor activation, and the SH3-GK domains exhibit a Ser561 phosphorylation-dependent switch to a closed conformation during synaptic plasticity. Our results provide novel mechanistic insight into the regulation of PSD-95 in dendritic spine structural plasticity through phosphorylation-mediated regulation of protein dynamics and conformation.
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The Ror family receptor tyrosine kinases, Ror1 and Ror2 play important roles in regulating developmental morphogenesis and tissue- and organogenesis, but their roles in tissue regeneration in adult animals remains largely unknown. In this study, we examined the expression and function of Ror1 and Ror2 during skeletal muscle regeneration. Using an in vivo skeletal muscle injury model, we show that expression of Ror1 and Ror2 in skeletal muscles is induced transiently by the inflammatory cytokines, TNF-α and IL-1β, after injury, and that inhibition of TNF-α and IL-1β by neutralizing antibodies suppresses expression of Ror1 and Ror2 in injured muscles. Importantly, expression of Ror1, but not Ror2, was induced primarily in Pax7-positive satellite cells (SCs) after muscle injury, and administration of neutralizing antibodies decreased the proportion of Pax7-positive proliferative SCs after muscle injury. We also found that stimulation of a mouse myogenic cell line, C2C12 cells, with TNF-α or IL-1β induced expression of Ror1 via NF-κB activation, and that suppressed expression of Ror1 inhibited their proliferative responses in SCs. Intriguingly, SCs-specific depletion of Ror1 decreased the number of Pax7-positive SCs after muscle injury. Collectively, these findings indicate for the first time that Ror1 has a critical role in regulating SC proliferation during skeletal muscle regeneration. We conclude that Ror1 might be a suitable target in the development of diagnostic and therapeutic approaches to manage muscular disorders.
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One of the hallmarks of Alzheimer's disease (AD) is the formation of extracellular amyloid plaques that consist mainly of abnormally aggregated forms of amyloid β (Aβ) peptides. These peptides are generated by γ-secretase-catalyzed cleavage of a dimeric membrane-bound C-terminal fragment (C99) of the amyloid precursor protein (APP). While C99 homodimerization has been linked to Aβ; production and changes in the aggregation-determining Aβ42/Aβ40 ratio, the motif through which C99 dimerizes has remained controversial. Here we have used two independent assays to gain insight into C99 homodimerization in the context of the membrane of live cells: bioluminescence resonance energy transfer (BRET) and the Tango membrane protein-protein interaction assays, which were further confirmed by traditional pull-down assays. Our results indicate a four amino acid region within the C99 transmembrane helix (T43-V44-I45-V46; (TVIV)) as well as its local secondary structure as critical determinants for homodimerization. These four amino acids are also a hotspot of familial AD (FAD)-linked mutations that both decrease C99 homodimerization and γ-secretase cleavage and alter the initial cleavage site to increase the Aβ42/40 ratio.
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| OncLive | Dr. Cohen on Challenges with Immunotherapy in Head and Neck Cancer OncLive Ezra Cohen, MD, associate director, Moores Cancer Center at the University of California, San Diego, discusses challenges with immunotherapy in head and neck cancer. It is difficult with a disease like head and neck cancer that has both a viral ... |
Socrative is an online assessment and student response tool that provides opportunities to increase student engagement in the classroom. We used Socrative as an online homework completing platform to increase students' exam scores in physics. To explore the relationships among factors and the educational effectiveness of Socrative, data from 85 undergraduate students' final and midterm grades, and their responses to an attitude survey were used. The ANCOVA results demonstrated that the use of Socrative positively influenced students' exam scores and a fairly significant correlation was found between students' attitudes toward Socrative and final exam scores. Moreover, the results of the survey showed that students have moderately positive attitudes toward the use of Socrative as an online homework assignment platform. This empirical study indicates that the use of Socrative can go beyond engaging and motivating students and can be used as an online homework completing tool.
The study presents the results of a project in which a series of digital games were used for teaching Mathematics to first, fourth, and sixth-grade primary school students (ages 6–7, 8–9, and 11–12). Mathematics was selected as the teaching subject because of the difficulties students face in understanding basic math concepts. Although digital games are used quite extensively for educational purposes, they are scarcely used for teaching Mathematics. The games were developed by the classes' teachers using Microsoft's Kodu Game Lab. The learning outcomes were compared to two other groups of students. The first was taught using the model proposed by Driver and Oldham while the second was taught conventionally. Data was collected using questionnaires and evaluation sheets. A total of 201 students participated in the study coming from three schools in Athens, Greece. Results indicated that students in the games group outperformed, in most cases, students in the other groups. Students' views for the games were highly positive. The implications for software engineers and education administrators are also discussed.
Publication date: 28 September 2017
Source:Journal of Controlled Release, Volume 262
Author(s): Lei Wu, Min Liu, Wei Shan, Xi Zhu, Lijia Li, Zhirong Zhang, Yuan Huang
Ligand-functionalization can increase the affinity of nanoparticles (NPs) with targeted cells. However, one major defect of ligands still exists in oral administration: limited receptor recognition. The hindrance of mucus network and deactivation of enzymes severely challenge the targeting efficiency of macromolecular ligands. Inspired by "molecular exchange" between intestinal microbiota and host cells, we anchored microbiota metabolite butyrate on classical "mucus-inert" polyethylene glycol (PEG) NPs. Butyrate has unique advantages of low molecule weight, high hydrophilicity and chemical stability. Interestingly, in vitro mucus-permeability and in vivo mucus distribution of PEG NPs were not impaired by butyrate-functionalization. Enhanced cellular uptake was achieved via specific interaction between butyrate and the monocarboxylate transporter (MCT) on cell membranes, which subsequently ameliorated transepithelial transport and intestinal absorption in the ileum. In vitro safety assessment validated the non-toxicity of butyrate-modification. Finally, insulin-loaded Bu-PEG NPs generated a stronger hypoglycemic response on diabetic rats and 2.87-fold higher oral bioavailability compared with bare PEG NPs. This study demonstrated that butyrate-functionalization could improve the intestinal absorption of macromolecules by overcoming multiple obstacles in the gastrointestinal tract, providing a promising active targeting strategy for oral administration.
In early childhood, the allergen-specific IgG repertoire is mainly directed to animal and vegetable food molecules and infrequently to airborne molecules. It is unknown whether this early pattern is maintained throughout childhood.
To investigate the evolution of IgG and IgE responses to a broad panel of allergenic molecules from birth to age 10yrs.
We examined the sera collected between birth and age 10yrs from participants in the German Multicentre Allergy Study, a birth cohort born in 1990. The IgE (cut-off ≥0.30 ISU) and IgG (cut-off ≥0.10 ISU) responses to 35 genuine allergenic molecules were measured with a multiplex microarray approach (ImmunoCAP ISAC™).
IgE responses were mostly directed against a restricted group of airborne molecules, with a sequence and prevalence hierarchy (Phl p 1 > Bet v 1 > Fel d 1 > Phl p 5 > Der p 2 > Der p 1) largely maintained over time. Conversely, the IgG repertoire was much broader, starting with animal foodborne, then spreading to vegetable foodborne and finally to airborne molecules. A strong and persistent IgG response to a given airborne molecule almost invariably preceded or accompanied an IgE response to that molecule.
The evolution of IgG and IgE responses throughout childhood differs widely at population level. IgG responses are mostly directed to animal food allergens while IgE responses are dominated by airborne allergens. However, a strong IgG response almost invariably precedes or accompanies the appearance of IgE to the same molecule in specifically sensitized subjects.
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Maturation of human natural killer cells (NK cells) as defined by accumulation of cell surface expression of CD57 is associated with increased cytotoxic character and TNF and IFN-γ production upon target cell recognition. Notably, multiple studies point to a unique role for CD57+ NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacological inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL-15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK cell maturation including T-BET, ZEB2 and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded ex vivo in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFN-γ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity (ADCC). In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy.
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Pancreatic adenocarcinomas (PDAC) harbour recurrent functional mutations of the master DNA damage response kinase ATM which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC.
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Churches are often floodlit at night to show off their architecture – but the lights are preventing bats from roosting in the ancient buildings
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Analysis of fossils from six Patagotitan mayorum dinosaurs suggests the animals may have weighed 62 tonnes and measured more than 35 metres from nose to tail
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The aim of the study was to compare the phytoextraction abilities of six tree species (Acer platanoides L., Acer pseudoplatanus L., Betula pendula Roth, Quercus robur L., Tilia cordata Miller, Ulmus laevis Pall.), cultivated on mining sludge contaminated with arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), thallium (Tl), and zinc (Zn). All six tree species were able to survive on such an unpromising substrate. However, A. platanoides and T. cordata seedlings grown on the polluted substrate showed significantly lower biomass than control plants (55.5 and 45.6%, respectively). As, Cd, Cu, Pb, and Tl predominantly accumulated in the roots of all the analyzed tree species with the following highest contents: 1616, 268, 2432, 547, and 856 mg kg−1, respectively. Zn was predominantly localized in shoots with the highest content of 5801 and 5732 mg kg−1 for U. laevis and A. platanoides, respectively. A. platanoides was the most effective in Zn phytoextaction, with a bioconcentration factor (BCF) of 8.99 and a translocation factor (TF) of 1.5. Furthermore, with the exception of A. pseudoplatanus, the analyzed tree species showed a BCF > 1 for Tl, with the highest value for A. platanoides (1.41). However, the TF for this metal was lower than 1 in all the analyzed tree species. A. platanoides showed the highest BCF and a low TF and could, therefore, be a promising species for Tl phytostabilization. In the case of the other analyzed tree species, their potential for effective phytoextraction was markedly lower. Further studies on the use of A. platanoides in phytoremediation would be worth conducting.
Environmental pollution due to primitive e-waste dismantling activities has been intensively investigated over the last decade in the south-eastern coastal region of China. In the present study, we investigated the distribution and composition of polycyclic aromatic hydrocarbons (PAHs) in soils and plants around e-waste recycling sites in Longtang, Guangdong province, South China. The results indicated that PAH concentrations in rhizosphere soil and non-rhizosphere soil were in the range of 133 to 626 ng/g and 60 to 816 ng/g, respectively, while PAH levels in plant tissue were 96 to 388 ng/g in shoots and 143 to 605 ng/g in roots. PAHs were enriched in rhizosphere soils in comparison with non-rhizosphere soils. The concentrations of PAHs in plant tissues varied greatly among plant cultivars, indicating that the uptake of PAHs by plants is species-dependent. Different profiles of PAHs in the soil and the corresponding plant tissue implied that PAH uptake and translocation by plants were selective.The total daily intakes of PAHs and carcinogenic PAHs through vegetables at the e-waste recycling site were estimated to be 99 and 22 ng/kg/day, respectively, suggesting that potential health risks associated with the consumption of contaminated vegetables should not be ignored.
This animal study is to investigate the accuracy of navigation-guided mandibular distraction osteogenesis with a special designed distraction device by TBNavis-CMFS navigation system.
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Lung cancer is the most common cancer that cannot be ignored and cause death with late health care. Currently, CT can be used to help doctors detect the lung cancer in the early stages. In many cases, the diagnosis of identifying the lung cancer depends on the experience of doctors, which may ignore some patients and cause some problems. Deep learning has been proved as a popular and powerful method in many medical imaging diagnosis areas. In this paper, three types of deep neural networks (e.g., CNN, DNN, and SAE) are designed for lung cancer calcification. Those networks are applied to the CT image classification task with some modification for the benign and malignant lung nodules. Those networks were evaluated on the LIDC-IDRI database. The experimental results show that the CNN network archived the best performance with an accuracy of 84.15%, sensitivity of 83.96%, and specificity of 84.32%, which has the best result among the three networks.
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Ferric nitrilotriacetate (Fe-NTA) is a highly reactive compound used to induce degenerative disorders through oxidative stress (OS). Zanthoxylum heitzii (Z. heitzii) is a spice used as a medicinal plant to treat a variety of illnesses. This study investigated the ability of extracts from the leaves, fruits, roots, and barks of Z. Heitzii to inhibit Fe-NTA mediated oxidative damage in rats. The supernatant of rat liver homogenates was pretreated with the extracts for one hour before the induction of oxidative damage using a solution of Fe-NTA (400 mM). The activities of superoxide dismutase (SOD), catalase, and peroxidases were measured together with the marker of lipid peroxidation and the level of glutathione. The pretreated groups showed a significant increase in the activity of SOD, catalase, and peroxidases. The methanolic extract from the leaves of Z. heitzii (36.78 ± 3.30) and aqueous extract from the fruits (37.01 ± 2.52) showed the highest activities of SOD in the liver. The lowest concentration of MDA was found in the liver, and the glutathione was greater in the brain. Conclusively, these results suggest that Z. heitzii might be a chemoprotector which may be used in for prevention of distinct types of diseases induced by oxidative stress.
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Fe-doped TiO2 (Fe/TiO2) film photocatalyst was prepared by sol-gel and dip-coating process and pulse arc plasma method. The effect of pulse number on the CO2 reduction performance with the Fe/TiO2 was investigated in this study. In addition, the effect of reductants such as H2O, H2, and NH3/H2O on the CO2 reduction performance with the Fe/TiO2 photocatalyst was also investigated. The characteristics of the prepared Fe/TiO2 film coated on a netlike glass fiber which is a base material were analyzed by SEM, EPMA, EDX, and EPMA. Furthermore, the CO2 reduction performance of the Fe/TiO2 film was tested under a Xe lamp with or without ultraviolet (UV) light. The results show that the CO2 reduction performance with the pulse number of 100 is the best with H2O and/or H2 as reductant under UV light illumination, while that with the pulse number of 500 is the best when NH3/H2O is used as reductant. On the other hand, the CO2 reduction performance with the pulse number of 500 is the best under every reductant condition without UV light illumination. The highest CO2 reduction performance with the Fe/TiO2 is obtained under H2 + H2O/CO2 condition, and the best moral ratio of total reductants to CO2 is 1.5 : 1.
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Aconitum species are poisonous plants that have been used in Western medicine for centuries. In the nineteenth century, these plants were part of official and folk medicine in the Slov...
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Up to one half of the population in Africa, Asia and Latin America has little access to high-quality biomedical services and relies on traditional health systems. Medical pluralism is thus in many developing c...
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Traditional ecological knowledge among indigenous communities plays an important role in retaining cultural identity and achieving sustainable natural resource management. Hundreds of millions of people mostly...
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I was pleased to read this excellent summary,1 as it offers structured guidance for the management of disorders of the temporomandibular joint (TMJ), which are sometimes difficult to treat. I agree that there is a lack of evidence for some recommended treatments and, as a result, an evidence-based approach is difficult.
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The goal of allergen-specific immunotherapy is the induction of protective immune responses in the absence of anaphylactic reactions. We have previously shown that Fel d 1, the major cat allergen, displayed in a repetitive fashion on virus-like particles (VLPs) may fulfill these criteria. Specifically, Fel d 1 on VLPs induced strongly increased IgG responses compared to the free allergen in mice while anaphylactic reactions were essentially abolished. Here we extend these findings to human mast cells and offer a mechanistic explanation for the reduced anaphylactic activity. By performing allergen binding studies and cellular activation assays, we demonstrate that the inability of Fel d 1 displayed on VLPs to activate mast cells is based on a biophysical as well as a biochemical mechanism. Firstly, Fel d 1 on VLPs showed a strongly impaired ability to bind to surface-bound IgE as assessed by Surface Plasmon Resonance (SPR) as well as flow cytometry. Secondly, despite residual binding, repetitively displayed allergen on VLPs failed to cause mast cell activation.
These findings indicate that repetitively displaying allergens on VLPs increases their immunogenicity while reducing their potential to cause anaphylactic reactions by essentially eliminating IgE-mediated activation of mast cells.
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We aimed to determine whether pretreatment metabolic tumor volume of the primary tumor (T-MTV) or T classification would be a better predictor of laryngectomy-free survival (LFS) and overall survival (OS) after chemoradiotherapy in patients with locally advanced laryngeal or hypopharyngeal cancer requiring total laryngectomy. We analyzed 85 patients using a Cox proportional hazards model and evaluated its usefulness by Akaike's information criterion. A T-MTV cutoff value was determined by time-dependent receiver operating characteristic curve analysis. Interobserver reliability for measuring T-MTV was estimated by the intraclass correlation coefficient (ICC). After adjustment for covariables, T-MTV, irrespective of whether a continuous or dichotomized variable, and T classification remained independent predictors of LFS and OS. Large T-MTV (>28.7 ml) was associated with inferior LFS [hazard ratio (HR), 4.16; 95% confidence interval (CI), 1.97–8.70; P = 0.0003] and inferior OS (HR, 3.18; 95% CI, 1.47–6.69; P = 0.004) compared with small T-MTV (≤28.7 ml). The T-MTV model outperformed the T classification model in predicting LFS and OS (P = 0.007 and 0.01, respectively). The 3-year LFS and OS rates for patients with small versus large T-MTV were 68% versus 9% (P < 0.0001) and 77% versus 25% (P < 0.0001), respectively, while those for patients with T2-T3 versus T4a were 61% versus 31% (P = 0.003) and 71% versus 48% (P = 0.10), respectively. The ICC was 0.99 (95% lower confidence bound, 0.99). Given the excellent interobserver reliability, T-MTV would serve better than T classification to identify patients who benefit from the larynx preservation approach.
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not only a well-established immunotherapy for hematologic malignancies, but is potentially useful for treating solid tumors refractory to available therapies. However, application of allo-HSCT to solid tumors is limited, despite the beneficial anti-tumor effects, by the risk of graft-versus-host disease (GVHD). CD4+ T cells have been implicated in several aspects of GVHD, and suppress anti-tumor CD8+ T cell responses. In the present study, we investigated clinically applicable allo-HSCT protocols designed to maximize anti-tumor effects while reducing the risk of GVHD. We used a mouse model of allo-HSCT with subcutaneous tumors. We found that myeloablative conditioning was associated with better inhibition of tumor growth but with severe acute GVHD. Early administration of anti-CD4 mAb substantially ameliorated GVHD, while preserving anti-tumor effects, leading to improved survival in myeloablative allo-HSCT. Late administration of anti-CD4 mAb also ameliorated GVHD to some extent. Donor lymphocyte infusion (DLI) in GVHD mice treated with anti-CD4 mAb further suppressed tumor growth without exacerbating GVHD. Collectively, our results suggest that myeloablative allo-HSCT followed by anti-CD4 mAb treatment and DLI may be a potent and safe immunotherapy for patients with cancers refractory to available therapies.
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This animal study is to investigate the accuracy of navigation-guided mandibular distraction osteogenesis with a special designed distraction device by TBNavis-CMFS navigation system.
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