HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study, we demonstrate that CLL cells from TP53-disrupted (TP53 dis) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the TP53 dis subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of HIF-1A mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53 dis tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53 dis leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL.

PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2% to 5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the anaplastic lymphoma kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-) ALCL subtypes, we performed a genome-wide DNA profiling using high-density, single nucleotide polymorphism arrays on a series of 64 cases and 7 cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes, respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an antiapoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication.

The practical role of echocardiography in selection, implantation, and management of patients requiring LVAD therapy.

Viable treatment options for advanced heart failure have not emerged as the number of people afflicted with this condition has grown. Although heart transplantation is the only curative strategy for patients with end-stage heart failure, the relative shortage of donors has led to a worldwide plateau of this option over the past 20 years. The result is an unacceptably high mortality rate among patients with advanced heart failure. Interest in developing alternative curative strategies based on chronic circulatory support, with the aim of prolonging and improving quality of life for these patients, has grown. Patients supported with left ventricular assist devices require structured longitudinal care from a team of providers. An integrated approach using basic echocardiography is critical to patient selection, implantation, and continued surveillance and success of patients with left ventricular assist devices.

Eco-Friendly Production of Polyvinyl Alcohol/Carboxymethyl Cellulose Wound Healing Dressing Containing Sericin.

Wound dressing production represents an important segment in the biomedical healthcare field, but finding a simple and eco-friendly method that combines a natural compound and a biocompatible dressing production for biomedical application is still a challenge. Therefore, the aim of this study is to develop wound healing dressings that are environmentally friendly, low cost, and easily produced, using natural agents and a physical crosslinking technique. Hydrogel wound healing dressings were prepared from polyvinyl alcohol/carboxymethyl cellulose and sericin using the freeze-thawing method as a crosslinking method. The morphological characterization was carried out by scanning electron microscopy (SEM), whereas the mechanical analysis was carried out by dynamic mechanical analysis (DMA) to test the tensile strength and compression properties. Then, the healing property of the wound dressing material was tested by in vitro and ex vivo tests. The results show a three-dimensional microporous structure with no cytotoxicity, excellent stretchability with compressive properties similar to those of human skin, and excellent healing properties. The proposed hydrogel dressing was tested in vitro with HaCaT keratinocytes and ex vivo with epidermal tissues, demonstrating an effective advantage on wound healing acceleration. Accordingly, this study was successful in developing wound healing dressings using natural agents and a simple and green crosslinking method.

Anti-tumor activity of selinexor in combination with antineoplastic agents in chronic lymphocytic leukemia.

Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export protein XPO1, is active as single agent in different hematologic malignancies, including CLL. The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3Kδ inhibitor idelalisib in CLL. Our results showed a significant decrease in CLL cell viability after treatment with selinexor-containing drug combinations compared to each single compound, with demonstration of synergistic cytotoxic effects. Interestingly, this drug synergism was exerted also in the presence of the protective effect of stromal cells. From the molecular standpoint, the synergistic cytotoxic activity of selinexor plus idelalisib was associated with increased regulatory effects of this drug combination on the tumor suppressors FOXO3A and IkBα compared to each single compound. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3Kδ inhibitor in mice treated with the drug combination compared to single agents. Our data provide preclinical evidence of the synergism and potential efficacy of a combination treatment targeting XPO1 and PI3Kδ in CLL.

Tactile multisensing on flexible aluminum nitride.

The integration of a polycrystalline material such as aluminum nitride (AlN) on a flexible substrate allows the realization of elastic tactile sensors showing both piezoelectricity and significant capacitive variation under normal stress. The application of a normal stress on AlN generates deformation of the flexible substrate on which AlN is grown, which results in strain gradient of the polycrystalline layer. The strain gradient is responsible for an additional polarization described in the literature as the flexoelectric effect, leading to an enhancement of the transduction properties of the material. The flexible AlN is synthesized by sputtering deposition on kapton HN (poly 4,4'-oxydiphenyl pyromellitimide) in a highly oriented crystal structure. High orientation is demonstrated by X-ray diffraction spectra (FWHM = 0.55° of AlN (0002)) and HRTEM. The piezoelectric coefficient d(33) and stress sensitive capacitance are 4.7 ± 0.5 pm V(-1) and 4 × 10(-3) pF kPa(-1), respectively. The parallel plate capacitors realized for tactile sensing present a typical dome shape, very elastic under applied stress and sensitive in the pressure range of interest for robotic applications (10 kPa to 1 MPa). The flexibility of the device finalized for tactile applications is assessed by measuring the sensor capacitance before and after shaping the sensing foil on curved surfaces for 1 hour. Bending does not affect sensor's operation, which exhibits an electrical Q factor as high as 210, regardless of the bending, and a maximum capacitance shift of 0.02%.

The polarization response in InAs quantum dots: theoretical correlation between composition and electronic properties.

III-V growth and surface conditions strongly influence the physical structure and resulting optical properties of self-assembled quantum dots (QDs). Beyond the design of a desired active optical wavelength, the polarization response of QDs is of particular interest for optical communications and quantum information science. Previous theoretical studies based on a pure InAs QD model failed to reproduce experimentally observed polarization properties. In this work, multi-million atom simulations are performed in an effort to understand the correlation between chemical composition and polarization properties of QDs. A systematic analysis of QD structural parameters leads us to propose a two-layer composition model, mimicking In segregation and In-Ga intermixing effects. This model, consistent with mostly accepted compositional findings, allows us to accurately fit the experimental PL spectra. The detailed study of QD morphology parameters presented here serves as a tool for using growth dynamics to engineer the strain field inside and around the QD structures, allowing tuning of the polarization response.

Hypothermia: a double-edged sword.

Therapeutic hypothermia is currently used to reduce neurological ischemic damage in postcardiac arrest patients. Nevertheless, it has been associated with relevant side effects such as infections, bleeding, hypotension and hyperkalemia. Although hypothermia-induced coronary spasm is rare, its occurrence needs to be considered attentively as it adds a high risk of ventricular arrhythmias and cardiac arrest in patients with already-existing critical heart conditions.

Conformable AlN Piezoelectric Sensors as a Non-invasive Approach for Swallowing Disorder Assessment.

Deglutition disorders (dysphagia) are common symptoms of a large number of diseases and can lead to severe deterioration of the patient's quality of life. The clinical evaluation of this problem involves an invasive screening, whose results are subjective and do not provide a precise and quantitative assessment. To overcome these issues, alternative possibilities based on wearable technologies have been proposed. We explore the use of ultrathin, compliant, and flexible piezoelectric patches that are able to convert the laryngeal movement into a well-defined electrical signal, with extremely low anatomical obstruction and high strain resolution. The sensor is based on an aluminum nitride thin film, grown on a soft Kapton substrate, integrated with an electrical charge amplifier and low-power, wireless connection to a smartphone. An ad-hoc designed laryngeal motion simulator (LMS), which is able to mimic the motions of the laryngeal prominence, was used to evaluate its performances. The physiological deglutition waveforms were then extrapolated on a healthy volunteer and compared with the sEMG (surface electromyography) of the submental muscles. Finally, different tests were conducted to assess the ability of the sensor to provide clinically relevant information. The reliability of these features permits an unbiased evaluation of the swallowing ability, paving the way to the creation of a system that is able to provide a point-of-care automatic, unobtrusive, and real-time extrapolation of the patient's swallowing quality even during normal behavior.

Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL.

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells.

Echocardiographic evaluation of right ventricular-arterial coupling in pulmonary hypertension.

Pulmonary hypertension (PH) is a hemodynamic condition characterized by chronically elevated mean pulmonary artery pressure (m-PAP ≥ 25 mmHg) measured at rest by right heart catheterization (RHC). It includes a pre-capillary and a post-capillary form. Pulmonary artery hypertension (PAH) is a pre-capillary form of PH potentially generated by several heterogeneous systemic disorders, whose main hemodynamic change is represented by severely increased pulmonary vascular resistance (PVR). In order to preserve an efficient right ventricular-arterial (RV-PA) coupling, the right ventricle (RV) adapts to this chronic increase of its afterload, with a compensatory hypertrophy, until RV dilatation and dysfunction occur. Right ventricular (RV) function and especially RV-PA coupling assessment showed to be very important prognostic markers in this subset of patients, especially for those with pre-capillary PH. The aim of this review is to provide a pathophysiological insight into the spectrum of RV adaptive changes occurring in response to chronic increase of RV afterload and to present the role of echocardiographic parameters as possible tools for early non-invasive evaluation of RV-PA coupling, before overt heart failure ensues.

A body-weight-supported visual feedback system for gait recovering in stroke patients: A randomized controlled study.

OBJECTIVE: The aim of this study was to determine the effectiveness of a novel body-weight-supported (BWS) gait training system with visual feedback, called Copernicus® (Rehalife, Italy). This computerized device provides comfortable, regular and repeatable locomotion in hemiplegic patients. Through visual real-time monitoring of gait parameters, patients are trained to transfer weight loading alternately on both feet. DESIGN: A single-blind, randomized controlled study. A single center used a computer-generated randomization code to allocate treatments. SETTING: Intensive rehabilitation unit (IRU) at the Institute S. Anna (Italy). PARTICIPANTS: 63 first-ever stroke patients (39 men, age: 66.1 ± 9.6 years; 61.6 % with left-sided lesion) randomly distributed into three demographically/clinically matched groups. TREATMENTS: All groups were treated five times a week for 2 -h sessions for six consecutive weeks. The first group ("control") underwent a conventional physical therapy; the second group performed advanced BWS gait training sessions without visual feedback (Experimental VF- group); whereas the third group used BWS with visual feedback stimulation (Experimental VF+ group). MAIN OUTCOME MEASURES: Absolute changes were recorded using conventional clinical scales and kinematic measurement of static gait balance from baseline to follow-up. RESULTS: Significant interaction Group*Time effects scales (F2,126 = 5.1, p-level = 0.005, η²p = 0.25; F2,126 = 4.7, p-level = 0.007, η²p = 0.19; respectively) were detected in the Functional Independence Measure and Tinetti-Balance scales. Post hoc analysis demonstrated that the recovery of motor functioning was greater for the VF + group with respect to other groups (all p's ≤ 0.001). A similar pattern of findings was also obtained with a stabilometric analysis, demonstrating a better clinical improvement in static balance after VF + treatment. CONCLUSION: The proposed advanced rehabilitation system with visual feedback was more effective in improving gait recovery with respect to conventional and high-tech therapies without a sensor feedback.

Impaired myocardial strain in early stage of Duchenne muscular dystrophy: its relation with age and motor performance.

Duchenne muscular dystrophy (DMD) is complicated by an early and progressive left ventricular (LV) dysfunction. Despite the reduction of ejection fraction (EF) usually manifests in the second decade, subtle alterations in LV mechanics can be detected earlier. Longitudinal and circumferential LV deformation, evaluated by speckle tracking echocardiography (STE), are considered sensitive markers of early dysfunction. We retrospectively examined clinical and echocardiographic data of 32 DMD children with preserved LV function. According to the median age, patients were then divided into younger and older than 9 years, and compared to 24 age-matched healthy subjects. Six-minute-walk test (6MWT), North Star Ambulatory Assessment (NSAA), and a comprehensive cardiac evaluation were performed. Although EF was within the normal range, DMD patients had significantly lower values than healthy controls, and the same occurred for the remaining conventional systolic and diastolic indices. Global longitudinal strain (GLS) was reduced in all patients (older and younger, both p < 0.001). Global circumferential strain (GCS) was reduced only in older patients (< 0.001). Both GLS and GCS worsened with age in DMD patients (GLS p = 0.005; GCS p = 0.024). GLS was significantly worse in the apical segments and in the postero-lateral wall. GCS in the antero-septal, anterior and antero-lateral segments was significantly reduced in older patients, with a prevalent involvement of the sole septal wall in the younger boys. 6MWT appeared to be correlated inversely to GLS and directly to EF. A longitudinal evaluation should be scheduled in DMD boys to assess the global cardiac performance over time and to evaluate the impact of therapies.

Piezoelectricity and Biocompatibility of Flexible ScxAl(1-x)N Thin Films for Compliant MEMS Transducers.

There is huge research activity in the development of flexible and biocompatible piezoelectric materials for next-generation compliant micro electro-mechanical systems (MEMS) transducers to be exploited in wearable devices and implants. This work reports for the first time on the development of flexible ScxAl(1-x)N films deposited by sputtering technique onto polyimide substrates, assessing their piezoelectricity and biocompatibility. Flexible ScxAl(1-x)N films have been analyzed in terms of morphological, structural, and piezoelectric properties. ScxAl(1-x)N layer exhibits a good surface roughness of 4.40 nm and moderate piezoelectricity with an extracted effective piezoelectric coefficient (d33eff) value of 1.87 ± 0.06 pm/V, in good agreement with the diffraction pattern analysis results. Cell viability assay, performed to study the interaction of the ScxAl(1-x)N films with human cell lines, shows that this material does not have significant effects on tested cells. Furthermore, the ScxAl(1-x)N layer, integrated onto a flexible device and analyzed by bending/unbending measurements, shows a peak-to-peak open-circuit voltage (VOC) of 0.32 V and a short-circuit current (ISC) of 0.27 µA, with a generated power of 19.28 nW under optimal resistive load, thus demonstrating the potential of flexible ScxAl(1-x)N films as active layers for next-generation wearable/implantable piezoelectrics.

Experimental investigation of different regimes of mode-locking in a high repetition rate passively mode-locked semiconductor quantum-dot laser.

We report experimental investigations on a two-section 16-GHz repetition rate InAs/GaAs quantum dot passively mode-locked laser. Near the threshold current, pseudo-periodic Q-switching with complex dynamics is exhibited. Mode-locking operation regimes characterized by different repetition rates and timing jitter levels are encountered up to twice the threshold current. Evolution of the RF spectrum and optical spectrum with current is compared. The different mode-locked regimes are shown to be associated with different spectral and temporal shapes, ranging from 1.3 to 6 ps. This point is discussed by introducing the existence of two different supermodes. Repetition rate evolution and timing jitter increase is attributed to the coupling between the dominant and the secondary supermodes.

Multimodality imaging for thromboembolic risk assessment in atrial fibrillation.

: Atrial fibrillation is the most widely represented sustained arrhythmia in the world. Thromboembolic risk assessment represents the main clinical challenge associated with this condition, requiring enormous medical, social and economical efforts. Several pieces of evidence in literature highlight how clinical risk factors are not enough for a correct thromboembolic risk stratification of patients with atrial fibrillation, since thromboembolic events have been proven to occur even in patients with low clinical risk scores. A comprehensive multimodality imaging approach, with special regard to echocardiography and new technologies seems to be the best method for this purpose. The aim of this review is to propose a hybrid thromboembolic risk stratification system that combinines clinical evaluation with instrumental clues on left atrial remodeling, fibrosis and deformation which, could be useful especially for patients classified at low thromboembolic risk according to clinical scores.

Ten Years of 2D Longitudinal Strain for Early Myocardial Dysfunction Detection: A Clinical Overview.

In recent years, the role of left ventricular ejection fraction (EF) as the gold standard parameter for the evaluation of systolic function has been questioned, and many efforts have been concentrated in the clinical validation of new noninvasive tools for the study of myocardial contractility. Improvement in the accuracy of speckle-tracking echocardiography has resulted in a large amount of research showing the ability of two-dimensional strain to overcome EF limitations in the majority of primary and secondary heart diseases. Currently, global longitudinal strain (GLS) is considered the most accurate and sensitive parameter for the assessment of early left ventricular dysfunction. This review summarizes the advantages that this measurement can provide in several clinical settings. Moreover, the important cautions that should be considered in making the choice to use GLS also are addressed. Finally, a special focus on bull's-eye polar maps for the assessment of regional changes of longitudinal function and the usefulness of these maps in the differential diagnosis of several diseases is provided.

Impairment of elastic properties of the aorta in bicuspid aortic valve: relationship between biomolecular and aortic strain patterns.

Aims: Bicuspid aortic valve (BAV) is associated with aortic wall alterations. We aimed to detect any correlation between aortic elasticity and genetic and biomolecular patterns of elastin. Methods and results: Forty-nine BAV patients (mean age: 38 ± 17.05) were prospectively enrolled. A blood sample was drawn for analysis of a single nucleotide polymorphism of elastin gene (ELN rs2071307) responsible for misfolding of elastin, and for the amount of elastin soluble fragments (ESF) in the plasma. Aortic dimensions and elastic properties were determined by echocardiography, aortic stiffness (AS) by M-mode analysis, and longitudinal strain (LS) of the ascending aorta (AA) by speckle-tracking echocardiography; values of aortic strain were compared with 45 age-matched subjects (mean age: 33 ± 9.67) with tricuspid aortic valve (TAV). BAV patients had greater aortic dimensions [Valsalva sinus (P = 0.004), sinotubular junction (P = 0.013), AA (P < 0.001)] and stiffness (P = 0.002) but lower LS (P = 0.04) than those with TAV. Results from comparisons of mutated genotype patients (AA, n = 10) with heterozygous (GA, n = 21) and wild-types ones (GG, n = 16) revealed that the presence of mutation was associated with increased ESF (P = 0.010 GG vs. GA; P = 0.035 GA vs. AA), larger AA (P = 0.019 GG vs. GA; P = 0.001 GG vs. AA), and lower LS (P = 0.032 GG vs. AA). Patients with a dilated AA showed greater ESF (P < 0.001), greater AS (P = 0.007), and lower LS of the AA (P = 0.002) than those with a normal AA. The same parameters were not significantly different comparing patients with moderate or severe aortic valve disease and patients with less than moderate valve disease. Conclusions: Our results show a close correlation between genetic and biomolecular patterns of elastin and mechanical properties of the aorta in patients with BAV.

Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.

Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4+ cells into cytotoxic effectors required the presence of CD8+ cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma.