SARS-CoV-2 variants have emerged with enhanced pathogenicity and transmissibility, and escape from pre-existing immunity, suggesting first-generation vaccines and monoclonal antibodies may now be ...less effective. Here we present an approach for preventing clinical sequelae and the spread of SARS-CoV-2 variants. First, we affinity matured an angiotensin-converting enzyme 2 (ACE2) decoy protein, achieving 1000-fold binding improvements that extend across a wide range of SARS-CoV-2 variants and distantly related, ACE2-dependent coronaviruses. Next, we demonstrated the expression of this decoy in proximal airway when delivered via intranasal administration of an AAV vector. This intervention significantly diminished clinical and pathologic consequences of SARS-CoV-2 challenge in a mouse model and achieved therapeutic levels of decoy expression at the surface of proximal airways when delivered intranasally to nonhuman primates. Importantly, this long-lasting, passive protection approach is applicable in vulnerable populations such as the elderly and immune-compromised that do not respond well to traditional vaccination. This approach could be useful in combating COVID-19 surges caused by SARS-CoV-2 variants and should be considered as a countermeasure to future pandemics caused by one of the many pre-emergent, ACE2-dependent CoVs that are poised for zoonosis.
Efficient delivery of gene therapy vectors across the blood-brain barrier (BBB) is the holy grail of neurological disease therapies. A variant of the neurotropic vector adeno-associated virus (AAV) ...serotype 9, called AAV-PHP.B, was shown to very efficiently deliver transgenes across the BBB in C57BL/6J mice. Based on our recent observation that this phenotype is mouse strain dependent, we used whole-exome sequencing-based genetics to map this phenotype to a specific haplotype of lymphocyte antigen 6 complex, locus A (Ly6a) (stem cell antigen-1 Sca-1), which encodes a glycosylphosphatidylinositol (GPI)-anchored protein whose function had been thought to be limited to the biology of hematopoiesis. Additional biochemical and genetic studies definitively linked high BBB transport to the binding of AAV-PHP.B with LY6A (SCA-1). These studies identify, for the first time, a ligand for this GPI-anchored protein and suggest a role for it in BBB transport that could be hijacked by viruses in natural infections or by gene therapy vectors to treat neurological diseases.
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This study unravels a new transport mechanism across the blood-brain barrier and identifies LY6A (SCA-1) as the receptor for adeno-associated virus (AAV)-PHP.B and AAV-PHP.eB capsids. Importantly, LY6A is not expressed in several strains of mice and is non-existent in primates, limiting the usefulness of those capsids to nonclinical applications.
Learning Objectives
After completing this course, the reader will be able to:
Define the main oral prodrugs of fluorouracil.
Know the indications of the new oral prodrugs of fluorouracil.
Review the ...main toxicities and drug interactions of oral prodrugs of fluorouracil.
Evaluate the benefit(s) of using an oral prodrug of fluorouracil compared with classical treatments.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Although 5‐fluorouracil (5‐FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. 5‐FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract and breast as well as the head and neck, with single‐agent response rates of only 10%‐30%. Although 5‐FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than one‐third of patients achieve objective responses. Recent research has focused on the biomodulation of 5‐FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, 5‐FU leads to several toxicities. The toxicity profile of 5‐FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand‐foot syndrome (palmar‐plantar erythrodysesthesia), stomatitis, and neuro‐ and cardiotoxicities are associated with continuous infusions. Other adverse effects associated with both bolus‐dose and continuous‐infusion regimens include nausea and vomiting, diarrhea, alopecia, and dermatitis. All these reasons explain the need for more effective and less toxic fluoropyrimidines.
In the first part of this review, we briefly present the metabolic pathways of 5‐FU responsible for the efficacy and toxicity of this drug. This knowledge is also necessary to understand the target(s) of biomodulation.
The second part is devoted to a review of the literature on three recent prodrugs of 5‐FU, i.e., capecitabine, UFT (ftorafur FTO plus uracil), and S‐1 (FTO plus 5‐chloro‐2,4‐dihydroxypyridine plus potassium oxonate). The pharmacological principles that have influenced the development of these new drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity and toxicity, are presented.
The literature was analyzed until March 2002. This review is intended to be as exhaustive as possible since it was conceived as a work tool for readers wanting to go further.
The genus Hippopotamus dispersed from Africa to Europe during the Pleistocene and the taxon is testified from different Italian localities. Despite the large number of available specimens, ...Hippopotamus is mainly documented by fragmentary remains and detailed stratigraphic and/or geographic data are often absent or uncertain. In Italy, hippopotamuses are recorded in at least 100 fossiliferous localities spanning from the late Early Pleistocene to the Late Pleistocene. At present, three different Pleistocene species are recognised: H. antiquus from Early to Middle Pleistocene, H. amphibius from Middle to Late Pleistocene and H. pentlandi from late Middle-early Late Pleistocene Sicilian localities. Upper Valdarno basin (Tuscany), Chiusi basin (Tuscany), Colfiorito basin (Umbria), Sant'Oreste (Latium), Puntali Cave (Sicily) and Acquedolci (Sicily) are just a few fossiliferous Italian sites where significative findings of Hippopotamus were collected during the 19th and 20th centuries.
•Neuropathology of brain tissue is compared between bulbar-onset (bALS) and spinal-onset ALS (sALS).•Both bALS and sALS present with similar anatomical regions of involvement and similar types of ...pathology.•Specific regions of interest associated to speech/language functions may be differentially involved in bALS.•Some bALS cases may present with pathological features atypical to ALS.•Majority of existing studies have methodological biases, therefore, further work is required.
ALS is a multisystem disorder affecting motor and cognitive functions. Bulbar-onset ALS (bALS) may be preferentially associated with cognitive and language impairments, compared with spinal-onset ALS (sALS), stemming from a potentially unique neuropathology. The objective of this systematic review was to compare neuropathology findings reported for bALS and sALS subtypes in studies of cadaveric brains. Using Cochrane guidelines, we reviewed articles in MEDLINE, Embase, and PsycINFO databases using standardized search terms for ALS and neuropathology, from inception until July 16th 2016. 17 studies were accepted for analysis. The analysis revealed that both subtypes presented with involvement in motor and frontotemporal cortices, deep cortical structures, and cerebellum and were characterized by neuronal loss, spongiosis, myelin pallor, and ubiquitin+ and TDP43+ inclusion bodies. Changes in Broca and Wernicke areas – regions associated with speech and language processing – were noted exclusively in bALS. Further, some bALS cases presented with atypical pathology such as neurofibrillary tangles and basophilic inclusions, which were not found in sALS cases. Given the limited number of studies, all with methodological biases, further work is required to better understand neuropathology of ALS subtypes.
We test the assumption of hydrostatic equilibrium in an X-ray luminosity selected sample of 50 galaxy clusters at 0.15 < z < 0.3 from the Local Cluster Substructure Survey (LoCuSS). Our weak-lensing ...measurements of M
500 control systematic biases to sub-4 per cent, and our hydrostatic measurements of the same achieve excellent agreement between XMM–Newton and Chandra. The mean ratio of X-ray to lensing mass for these 50 clusters is
$\mathrel {\beta _{\rm X}}\;= 0.95\pm 0.05$
, and for the 44 clusters also detected by Planck, the mean ratio of Planck mass estimate to LoCuSS lensing mass is
$\mathrel {\beta _{\rm P}}\;= 0.95\pm 0.04$
. Based on a careful like-for-like analysis, we find that LoCuSS, the Canadian Cluster Comparison Project, and Weighing the Giants agree on
$\mathrel {\beta _{\rm P}}\;\simeq 0.9{\rm -}0.95$
at 0.15 < z < 0.3. This small level of hydrostatic bias disagrees at ∼5σ with the level required to reconcile Planck cosmology results from the cosmic microwave background and galaxy cluster counts.
The partitioning of carbon dioxide (CO2) released by soils at Vulcano Island (Aeolian Islands, Italy) was performed by combining the CO2 flux and the carbon isotope measurements. Based on this ...method, the amount of CO2 of volcanic origin was quantified six times during the period 2015–2018. The data analysis allowed us to establish the correlation between CO2 soil degassing and changes in the contribution of volcanic fluids. Carbon isotope determinations were performed in situ to enhance the coverage of data collection in space and time. These data were combined with both the CO2 contents in the ground gases and the soil CO2 flux. The amount of volcanic CO2 was distinguished from that of biogenic origin by implementing a three-component mixing model. The results of this study indicate that the increase in CO2 output in September 2018 reflects the increase in volcanic gas emissions. The measurement method and analysis presented in this work are sufficiently general to be applicable to the monitoring programs of active volcanoes.
•Carbon isotope and CO2 flux measurements improves techniques of volcano monitoring.•Evaluation of deep-seated CO2 by soils allows tracking changes in the volcanic activity.•The volcanic input of CO2 has been detected in September 2018 at Vulcano – Aeolian Island, Italy.•Isotope signature of CO2 identifies the sources of the soil gases.
Objective There is widespread evidence that cancer confers an increased risk of deep venous thrombosis (DVT). This risk is thought to vary among different cancer types. The purpose of this study is ...to better define the incidence of thrombotic complications among patients undergoing surgical treatment for a spectrum of prevalent cancer diagnoses in contemporary practice. Methods All patients undergoing one of 11 cancer surgical operations (breast resection, hysterectomy, prostatectomy, colectomy, gastrectomy, lung resection, hepatectomy, pancreatectomy, cystectomy, esophagectomy, and nephrectomy) were identified by Current Procedural Terminology and International Classification of Diseases, Ninth Revision codes using the American College of Surgeons National Surgical Quality Improvement Program database (2007-2009). The study endpoints were DVT, pulmonary embolism (PE), and overall postoperative venous thromboembolic events (VTE) within 1 month of the index procedure. Multivariate logistic regression was utilized to calculate adjusted odds ratios for each endpoint. Results Over the study interval, 43,808 of the selected cancer operations were performed. The incidence of DVT, PE, and total VTE within 1 month following surgery varied widely across a spectrum of cancer diagnoses, ranging from 0.19%, 0.12%, and 0.28% for breast resection to 6.1%, 2.4%, and 7.3%, respectively, for esophagectomy. Compared with breast cancer, the incidence of VTE ranged from a 1.31-fold increase in VTE associated with gastrectomy (95% confidence interval, 0.73-2.37; P = .4) to a 2.68-fold increase associated with hysterectomy (95% confidence interval, 1.43-5.01; P = .002). Multivariate logistic regression revealed that inpatient status, steroid use, advanced age (≥60 years), morbid obesity (body mass index ≥35), blood transfusion, reintubation, cardiac arrest, postoperative infectious complications, and prolonged hospitalization were independently associated with increased risk of VTE. Conclusions The incidence of VTE and thromboembolic complications associated with cancer surgery varies substantially. These findings suggest that both tumor type and resection magnitude may impact VTE risk. Accordingly, such data support diagnosis and procedural-specific guidelines for perioperative VTE prophylaxis and can be used to anticipate the risk of potentially preventable morbidity.
Barth syndrome (BTHS) is an X-linked recessive genetic disorder due to mutations in the Tafazzin (TAFAZZIN) gene that lead to cardiac and skeletal muscle mitochondrial dysfunction. Previous studies ...in humans with BTHS demonstrate that the defects in muscle mitochondrial oxidative metabolism result in an enhanced reliance on anaerobic metabolism during exercise to meet energy demands of muscular work. During exercise, the liver normally increases glucose production via glycogenolysis and gluconeogenesis to match the elevated rate of muscle glucose uptake and meet the ATP requirements of working muscle. However, the impact of Tafazzin deficiency on hepatic glucose production and the pathways contributing to hepatic glucose production during exercise is unknown. Therefore, the purpose of this study was to quantify in vivo liver gluconeogenesis and glycogenolysis in Tafazzin knockdown mice at rest and during acute exercise. METHODS: Male TAFAZZIN shRNA transgenic (TG) and wild-type (WT) mice completed exhaustive treadmill running protocols to test exercise tolerance. Mice underwent .sup.2 H- and .sup.13 C-stable isotope infusions at rest and during a 30-minute treadmill running bout to quantify hepatic glucose production and associated nutrient fluxes under sedentary conditions and during acute exercise. Circulating and tissue (skeletal muscle and liver) samples were obtained during and following exercise to assess static metabolite levels. RESULTS: TG mice reached exhaustion sooner during exhaustive treadmill running protocols and exhibited higher plasma lactate concentrations after exhaustive exercise compared to WT mice. Arterial glucose levels were comparable between genotypes at rest, but higher in TG mice compared to WT mice during exercise. Consistent with the higher blood glucose, TG mice showed increased endogenous glucose production owing to elevated glycogenolysis compared to WT mice during exercise. Total gluconeogenesis, gluconeogenesis from glycerol, gluconeogenesis from phosphoenolpyruvate, pyruvate cycling, total cataplerosis, and anaplerotic fluxes were similar between TG and WT mice at rest and during exercise. However, lactate dehydrogenase flux and TCA cycle fluxes trended higher in TG mice during exercise. Liver glycogen content in TG was higher in TG vs. controls. CONCLUSION: Our data in the Tafazzin knockdown mouse suggest that elevated anaerobic metabolism during rest and exercise previously reported in humans with BTHS are supported by the finding of higher hepatic glycogenolysis.
Fossil remains from the latest Messinian of Casino Basin (Tuscany, Italy) are known since the beginning of the nineteenth century. Among the others, the mammal assemblage includes Mesopithecus ...pentelicus, Tapirus arvernensis, Propotamochoerus provincialis and scarce and poorly preserved remains of a hippopotamid, consisting of a mandibular symphysis fragment, an apical fragment of a lower canine, some isolated lower incisors, a fragmented second upper premolar and a second lower molar. These specimens were initially referred as Hippopotamus hipponensis and later ascribed to the new species Hippopotamus pantanellii (recently reported as Hexaprotodon? pantanellii). However, this attribution has been disputed during the past years. The hippopotamid remains from the Casino Basin are revised here in order to clarify their systematic position and to infer paleobiogeographic and evolutionary patterns within the Mediterranean fossil record of Hippopotamidae. The morphology of the remains collected from the Casino Basin more closely resembles the African than the Asian hippopotamids' lineage and therefore the Tuscan remains should be more properly referred as Archaeopotamus pantanellii. The latter species probably dispersed into Tuscany from the Iberian Peninsula where the presence of Archaeopotamus crusafonti is well documented.
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