FLT3-targeted therapy restores GATA1 pathway function in NPM1/FLT3-ITD mutated acute myeloid leukaemia.

One-third of newly diagnosed adult acute myeloid leukaemia (AML) carry FLT3 mutations, which frequently occur together with nucleophosmin (NPM1) mutations and are associated with worse prognosis. FLT3 inhibitors are widely used in clinics with limitations due to drug resistance. AML cells carrying FLT3 mutations in both mouse models and patients present low expression of GATA1, a gene involved in haematopoietic changes preceding AML. Here, we show that FLT3 inhibition induces cellular responses and restores the GATA1 pathway and functions in NPM1/FLT3-ITD mutated AML, thus providing a new mechanism of action for this drug.

Venous thromboembolism in critically ill patients affected by ARDS related to COVID-19 in Northern-West Italy.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. An association between increased venous thromboembolism in patients with pneumonia-related to COVID-19 has not yet been well described. PATIENTS AND METHODS: We aimed to illustrate cases of pulmonary thromboembolism in patients with acute respiratory distress syndrome related to COVID-19 treated in our intensive care unit. The medical records of patients affected by COVID-19 with acute respiratory distress syndrome in our institute from 1/3/2020 to 31/3/2020 were retrospectively reviewed. RESULTS: Our center registered a high prevalence of thromboembolic events among 62 patients affected by acute respiratory distress syndrome related to COVID-19 despite a regular antithrombotic prophylaxis. Out of these, 32 patients were transferred to other hospitals, and 30 were treated in our center. Venous thromboembolism was registered in 12 (19.3%) cases. In particular, 11 diagnoses of pulmonary embolism and 1 diagnosis of deep vein thrombosis were formulated. We described a case series of venous thromboembolism in nine patients treated in our Intensive Care Unit (ICU). Main pulmonary arteries were always involved in these patients. None of them died. CONCLUSIONS: In conclusion, critically ill patients with ARDS related to COVID-19 may have an increased risk of VTE that could be a leading cause of mortality. These patients require a high index of clinical suspicion and an accurate diagnostic approach, in order to immediately start an appropriate anticoagulant treatment.

Signatures of de-domestication in autochthonous pig breeds and of domestication in wild boar populations from MC1R and NR6A1 allele distribution.

Autochthonous pig breeds are usually reared in extensive or semi-extensive production systems that might facilitate contact with wild boars and, thus, reciprocal genetic exchanges. In this study, we analysed variants in the melanocortin 1 receptor (MC1R) gene (which cause different coat colour phenotypes) and in the nuclear receptor subfamily 6 group A member 1 (NR6A1) gene (associated with increased vertebral number) in 712 pigs of 12 local pig breeds raised in Italy (Apulo-Calabrese, Casertana, Cinta Senese, Mora Romagnola, Nero Siciliano and Sarda) and south-eastern European countries (Krskopolje from Slovenia, Black Slavonian and Turopolje from Croatia, Mangalitsa and Moravka from Serbia and East Balkan Swine from Bulgaria) and compared the data with the genetic variability at these loci investigated in 229 wild boars from populations spread in the same macro-geographic areas. None of the autochthonous pig breeds or wild boar populations were fixed for one allele at both loci. Domestic and wild-type alleles at these two genes were present in both domestic and wild populations. Findings of the distribution of MC1R alleles might be useful for tracing back the complex genetic history of autochthonous breeds. Altogether, these results indirectly demonstrate that bidirectional introgression of wild and domestic alleles is derived and affected by the human and naturally driven evolutionary forces that are shaping the Sus scrofa genome: autochthonous breeds are experiencing a sort of 'de-domestication' process, and wild resources are challenged by a 'domestication' drift. Both need to be further investigated and managed.

Design, synthesis and antibacterial evaluation of a polycationic calix[4]arene derivative alone and in combination with antibiotics.

The growing antibiotic resistance phenomenon continues to stimulate the search for new compounds and strategies to combat bacterial infections. In this study, we designed and synthesized a new polycationic macrocyclic compound (2) bearing four N-methyldiethanol ammonium groups clustered and circularly organized by a calix[4]arene scaffold. The in vitro activity of compound 2, alone and in combination with known antibiotics (ofloxacin, chloramphenicol or tetracycline), was assessed against strains of Staphylococcus aureus (ATCC 6538 and methicillin-resistant isolate 15), S. epidermidis (ATCC 35984 and methicillin-resistant isolate 57), and Pseudomonas aeruginosa (ATCC 9027 and antibiotic-resistant isolate 1). Calix[4]arene derivative 2 showed significant antibacterial activity against ATCC and methicillin-resistant Gram positive Staphylococci, improved the stability of tetracycline in water, and in combination with antibiotics enhanced the antibiotic efficacy against Gram negative P. aeruginosa by an additive effect.

Taking advantage from phenotype variability in a local animal genetic resource: identification of genomic regions associated with the hairless phenotype in Casertana pigs.

Casertana is an endangered autochthonous pig breed (raised in south-central Italy) that is considered to be the descendant of the influential Neapolitan pig population that was used to improve British breeds in the 19th century. Casertana pigs are characterized by a typical, almost complete, hairless phenotype, even though a few Casertana pigs are normal haired. In this work, using Illumina PorcineSNP60 BeadChip data, we carried out a genome-wide association study and an FST analysis with this breed by comparing animals showing the classical hairless phenotype (n = 81) versus pigs classified as haired (n = 15). Combining the results obtained with the two approaches, we identified two significant regions: one on porcine chromosome (SSC) 7 and one on SSC15. The SSC7 region contains the forkhead box N3 (FOXN3) gene, the most plausible candidate gene of this region, considering that mutations in another gene of the same family (forkhead box N1; Foxn1 or FOXN1) are responsible for the nude locus in rodents and alopecia in humans. Another potential candidate gene, rho guanine nucleotide exchange factor 10 (ARHGEF10), is located in the SSC15 region. FOXN3 and ARHGEF10 have been detected as differentially expressed in androgenetic and senescent alopecia respectively. This study on an autochthonous pig breed contributes to shed some light on novel genes potentially involved in hair development and growth and demonstrates that local animal breeds can be valuable genetic resources for disclosing genetic factors affecting unique traits, taking advantage of phenotype variability segregating in small populations.

Launching the dialogue: Safety and innovation as partners for success in advanced manufacturing.

Emerging and novel technologies, materials, and information integrated into increasingly automated and networked manufacturing processes or into traditional manufacturing settings are enhancing the efficiency and productivity of manufacturing. Globally, there is a move toward a new era in manufacturing that is characterized by: (1) the ability to create and deliver more complex designs of products; (2) the creation and use of materials with new properties that meet a design need; (3) the employment of new technologies, such as additive and digital techniques that improve on conventional manufacturing processes; and (4) a compression of the time from initial design concept to the creation of a final product. Globally, this movement has many names, but "advanced manufacturing" has become the shorthand for this complex integration of material and technology elements that enable new ways to manufacture existing products, as well as new products emerging from new technologies and new design methods. As the breadth of activities associated with advanced manufacturing suggests, there is no single advanced manufacturing industry. Instead, aspects of advanced manufacturing can be identified across a diverse set of business sectors that use manufacturing technologies, ranging from the semiconductors and electronics to the automotive and pharmaceutical industries. The breadth and diversity of advanced manufacturing may change the occupational and environmental risk profile, challenge the basic elements of comprehensive health and safety (material, process, worker, environment, product, and general public health and safety), and provide an opportunity for development and dissemination of occupational and environmental health and safety (OEHS) guidance and best practices. It is unknown how much the risk profile of different elements of OEHS will change, thus requiring an evolution of health and safety practices. These changes may be accomplished most effectively through multi-disciplinary, multi-sector, public-private dialogue that identifies issues and offers solutions.

Taking stock of the occupational safety and health challenges of nanotechnology: 2000-2015.

Engineered nanomaterials significantly entered commerce at the beginning of the 21st century. Concerns about serious potential health effects of nanomaterials were widespread. Now, approximately 15 years later, it is worthwhile to take stock of research and efforts to protect nanomaterial workers from potential risks of adverse health effects. This article provides and examines timelines for major functional areas (toxicology, metrology, exposure assessment, engineering controls and personal protective equipment, risk assessment, risk management, medical surveillance, and epidemiology) to identify significant contributions to worker safety and health. The occupational safety and health field has responded effectively to identify gaps in knowledge and practice, but further research is warranted and is described. There is now a greater, if imperfect, understanding of the mechanisms underlying nanoparticle toxicology, hazards to workers, and appropriate controls for nanomaterials, but unified analytical standards and exposure characterization methods are still lacking. The development of control-banding and similar strategies has compensated for incomplete data on exposure and risk, but it is unknown how widely such approaches are being adopted. Although the importance of epidemiologic studies and medical surveillance is recognized, implementation has been slowed by logistical issues. Responsible development of nanotechnology requires protection of workers at all stages of the technological life cycle. In each of the functional areas assessed, progress has been made, but more is required.

Renal haemodynamics and severity of carotid atherosclerosis in hypertensive patients with and without impaired renal function.

BACKGROUND AND AIM: Renal resistance index (RRI), assessed by Duplex-Doppler sonography, has been classically considered as a mere expression of intrarenal vascular resistance. Recent studies, however, have showed that RRI is also influenced by upstream factors, especially arterial compliance, confirming its possible role as a marker of systemic vascular alterations. Several studies have shown that carotid intima-media thickness (cIMT) and carotid plaques (cP), assessed by ultrasonography, are documented markers of subclinical organ damage as well as expression of progressive atherosclerotic disease, and that they get worse with the progressive deterioration of renal function. The study was aimed to evaluate the relationship between RRI and severity of carotid atherosclerosis in hypertensive subjects with and without impaired renal function. METHODS AND RESULTS: The study population, including 263 hypertensive patients (30-70 years), was split into 3 groups based on cIMT and presence of cP (cIMT ≤ 0.9 mm and no cP; cIMT > 0.9 mm and no cP; cP). All patients were also divided into 2 subgroups (normal renal function; CKD stage I-IV). A stepwise increase in RRI corresponding to the groups of progressive severity of carotid atherosclerosis was observed (respectively 0.61 ± 0.07, 0.65 ± 0.06, 0.68 ± 0.06; p < 0.001). A strong positive correlation was observed between RRI and cIMT in the whole population (r = 0.43; p < 0.001) and in the subgroups with (r = 0.42; p < 0.001) and without (r = 0.39; p < 0.001) CKD. These associations remained statistically significant even after adjustment for various confounding factors. CONCLUSION: Showing a close association between RRI and severity of carotid atherosclerosis, our results strengthen the concept that RRI is a marker of systemic vascular changes.

Occupational safety and health criteria for responsible development of nanotechnology.

Organizations around the world have called for the responsible development of nanotechnology. The goals of this approach are to emphasize the importance of considering and controlling the potential adverse impacts of nanotechnology in order to develop its capabilities and benefits. A primary area of concern is the potential adverse impact on workers, since they are the first people in society who are exposed to the potential hazards of nanotechnology. Occupational safety and health criteria for defining what constitutes responsible development of nanotechnology are needed. This article presents five criterion actions that should be practiced by decision-makers at the business and societal levels-if nanotechnology is to be developed responsibly. These include (1) anticipate, identify, and track potentially hazardous nanomaterials in the workplace; (2) assess workers' exposures to nanomaterials; (3) assess and communicate hazards and risks to workers; (4) manage occupational safety and health risks; and (5) foster the safe development of nanotechnology and realization of its societal and commercial benefits. All these criteria are necessary for responsible development to occur. Since it is early in the commercialization of nanotechnology, there are still many unknowns and concerns about nanomaterials. Therefore, it is prudent to treat them as potentially hazardous until sufficient toxicology, and exposure data are gathered for nanomaterial-specific hazard and risk assessments. In this emergent period, it is necessary to be clear about the extent of uncertainty and the need for prudent actions.

Overview of Risk Management for Engineered Nanomaterials.

Occupational exposure to engineered nanomaterials (ENMs) is considered a new and challenging occurrence. Preliminary information from laboratory studies indicates that workers exposed to some kinds of ENMs could be at risk of adverse health effects. To protect the nanomaterial workforce, a precautionary risk management approach is warranted and given the newness of ENMs and emergence of nanotechnology, a naturalistic view of risk management is useful. Employers have the primary responsibility for providing a safe and healthy workplace. This is achieved by identifying and managing risks which include recognition of hazards, assessing exposures, characterizing actual risk, and implementing measures to control those risks. Following traditional risk management models for nanomaterials is challenging because of uncertainties about the nature of hazards, issues in exposure assessment, questions about appropriate control methods, and lack of occupational exposure limits (OELs) or nano-specific regulations. In the absence of OELs specific for nanomaterials, a precautionary approach has been recommended in many countries. The precautionary approach entails minimizing exposures by using engineering controls and personal protective equipment (PPE). Generally, risk management utilizes the hierarchy of controls. Ideally, risk management for nanomaterials should be part of an enterprise-wide risk management program or system and this should include both risk control and a medical surveillance program that assesses the frequency of adverse effects among groups of workers exposed to nanomaterials. In some cases, the medical surveillance could include medical screening of individual workers to detect early signs of work-related illnesses. All medical surveillance should be used to assess the effectiveness of risk management; however, medical surveillance should be considered as a second line of defense to ensure that implemented risk management practices are effective.

Field application of the Nanoparticle Emission Assessment Technique (NEAT): task-based air monitoring during the processing of engineered nanomaterials (ENM) at four facilities.

In early 2006, the National Institute for Occupational Safety and Health created a field research team whose mission is to visit a variety of facilities engaged in the production, handling, or use of engineered nanomaterials (ENMs) and to conduct initial emission and exposure assessments to identify candidate sites for further study. To conduct the assessments, the team developed the Nanoparticle Emission Assessment Technique (NEAT), which has been used at numerous facilities to sample multiple engineered nanomaterials. Data collected at four facilities, which volunteered to serve as test sites, indicate that specific tasks can release ENMs to the workplace atmosphere and that traditional controls such as ventilation can be used to limit exposure. Metrics such as particle number concentration (adjusted for background), airborne mass concentration, and qualitative transmission electron microscopy were used to determine the presence, nature, and magnitude of emissions and whether engineered nanomaterials migrated to the workers' breathing zone. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a PDF file containing information on facilities, a description of processes/tasks, existing controls, and sampling strategy, and a PDF file containing TEM images according to facility and task.].

Evaluation of the potential airborne release of carbon nanofibers during the preparation, grinding, and cutting of epoxy-based nanocomposite material.

The National Institute for Occupational Safety and Health conducted an initial, task-based comparative assessment to determine the potential for release of carbon nanofibers (CNFs) during dry material handling, wet cutting, grinding, and sanding (by machine and hand) of plastic composite material containing CNFs. Using a combination of direct-reading instruments and filter-based air sampling methods for airborne mass and transmission electron microscopy (TEM), concentrations were measured and characterized near sources of particle generation, in the breathing zone of the workers, and in the general work area. Tasks such as surface grinding of composite material and manually transferring dry CNFs produced substantial increases in particle number concentration (range = 20,000-490,000 1-cm(-3)). Concomitant increases in mass concentration were also associated with most tasks. Nearly 90% of all samples examined via TEM indicated that releases of CNFs do occur and that the potential for exposure exists. These findings also indicate that improperly designed, maintained, or installed engineering controls may not be completely effective in controlling releases. Unprotected skin exposure to CNFs was noted in two instances and indicated the need for educating workers on the need for personal protective equipment. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a PDF file containing information on materials, evaluated processes, personal protective equipment, and existing ventilation/engineering controls.].

Development of risk-based nanomaterial groups for occupational exposure control.

Given the almost limitless variety of nanomaterials, it will be virtually impossible to assess the possible occupational health hazard of each nanomaterial individually. The development of science-based hazard and risk categories for nanomaterials is needed for decision-making about exposure control practices in the workplace. A possible strategy would be to select representative (benchmark) materials from various mode of action (MOA) classes, evaluate the hazard and develop risk estimates, and then apply a systematic comparison of new nanomaterials with the benchmark materials in the same MOA class. Poorly soluble particles are used here as an example to illustrate quantitative risk assessment methods for possible benchmark particles and occupational exposure control groups, given mode of action and relative toxicity. Linking such benchmark particles to specific exposure control bands would facilitate the translation of health hazard and quantitative risk information to the development of effective exposure control practices in the workplace. A key challenge is obtaining sufficient dose-response data, based on standard testing, to systematically evaluate the nanomaterials' physical-chemical factors influencing their biological activity. Categorization processes involve both science-based analyses and default assumptions in the absence of substance-specific information. Utilizing data and information from related materials may facilitate initial determinations of exposure control systems for nanomaterials.

Nanoparticle Emission Assessment Technique (NEAT) for the identification and measurement of potential inhalation exposure to engineered nanomaterials--Part B: Results from 12 field studies.

The National Institute for Occupational Safety and Health (NIOSH) conducted field studies at 12 sites using the Nanoparticle Emission Assessment Technique (NEAT) to characterize emissions during processes where engineered nanomaterials were produced or used. A description of the NEAT appears in Part A of this issue. Field studies were conducted in research and development laboratories, pilot plants, and manufacturing facilities handling carbon nanotubes (single-walled and multi-walled), carbon nanofibers, fullerenes, carbon nanopearls, metal oxides, electrospun nylon, and quantum dots. The results demonstrated that the NEAT was useful in evaluating emissions and that readily available engineering controls can be applied to minimize nanomaterial emissions.

Nanoparticle emission assessment technique (NEAT) for the identification and measurement of potential inhalation exposure to engineered nanomaterials--part A.

There are currently no exposure limits specific to engineered nanomaterial nor any national or international consensus standards on measurement techniques for nanomaterials in the workplace. However, facilities engaged in the production and use of engineered nanomaterials have expressed an interest in learning whether the potential for worker exposure exists. To assist with answering this question, the National Institute for Occupational Safety and Health established a nanotechnology field research team whose primary goal was to visit facilities and evaluate the potential for release of nanomaterials and worker exposure. The team identified numerous techniques to measure airborne nanomaterials with respect to particle size, mass, surface area, number concentration, and composition. However, some of these techniques lack specificity and field portability and are difficult to use and expensive when applied to routine exposure assessment. This article describes the nanoparticle emission assessment technique (NEAT) that uses a combination of measurement techniques and instruments to assess potential inhalation exposures in facilities that handle or produce engineered nanomaterials. The NEAT utilizes portable direct-reading instrumentation supplemented by a pair of filter-based air samples (source-specific and personal breathing zone). The use of the filter-based samples are crucial for identification purposes because particle counters are generally insensitive to particle source or composition and make it difficult to differentiate between incidental and process-related nanomaterials using number concentration alone. Results from using the NEAT at 12 facilities are presented in the companion article (Part B) in this issue.

Clinical correlates of renal dysfunction in hypertensive patients without cardiovascular complications: the REDHY study.

Our study was aimed to assess the clinical correlates of different degrees of renal dysfunction in a wide group of non-diabetic hypertensive patients, free from cardiovascular (CV) complications and known renal diseases, participating to the REDHY (REnal Dysfunction in HYpertension) study. A total of 1856 hypertensive subjects (mean age: 47+/-14 years), attending our hypertension centre, were evaluated. The glomerular filtration rate (GFR) was estimated by the simplified Modification of Diet in Renal Disease Study prediction equation. A 24-h urine sample was collected to determine albumin excretion rate (AER). Albuminuria was defined as an AER greater than 20 microg min(-1). We used the classification proposed by the US National Kidney Foundation's guidelines for chronic kidney disease (CKD) to define the stages of renal function impairment. In multiple logistic regression analysis, the probability of having stage 1 and stage 2 CKD was significantly higher in subjects with greater values of systolic blood pressure (SBP) and with larger waist circumference. SBP was also positively related to stage 3 CKD. Stage 3 and stages 4-5 CKD were inversely associated with waist circumference and directly associated with serum uric acid. Age was inversely related to stage 1 CKD and directly related to stage 3 CKD. The factors associated with milder forms of kidney dysfunction are, in part, different from those associated with more advanced stages of renal function impairment.