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Understanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in cancer.SignificanceWe provide a comprehensive systems medicine strategy to unveil oncogenic circuitries and inform novel precision therapy decisions against CNA in cancer. This first clinical multi-omic analysis of chr1q-amp in MM identifies a central PBX1-FOXM1 regulatory axis driving high-risk prognosis, as a novel therapeutic target against chr1q-amp in cancer.

DRESS/DiHS is a complex and potentially fatal drug reaction. Little is known about risk factors and elements that can help to identify patients with a severe reaction early. The aim of the study was to investigate those factors favoring the disease and its severity by analyzing the clinical conditions and therapies preceding the reaction. We conducted a retrospective analysis on patients admitted to our center between 2010 and 2020 who were discharged with a diagnosis of DRESS. We used the RegiSCAR diagnostic criteria. We defined the severity of DRESS using the criteria of Mizukawa et al. We included 25 patients (15 females) with a median age of 66 years. Skin involvement, eosinophilia, and liver injury were the most important aspects. Allopurinol was found to be the most involved drug. Reaction severity was significantly associated with the number of daily medications (p = 0.0067) and an age of at least 68 years (p = 0.013). In addition, 75% of severe cases had at least three comorbidities in history, and most of the severe cases were female. In our study the advanced age, the high number of comorbidities and home therapies, and the inflammatory state were found to be predisposing elements to the development of the disease and its severity.

Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells play an important role in relapse control but can be inhibited by the leukemia cells highly positive for HLA class I. In order to restore NK cell activity after their ex vivo activation, NK cells can be combined with conditioning target cells. In this study, we tested NK cell activity against KG1a (AML cell line) with and without two types of pretreatment&mdash, Ara-C treatment that induced NKG2D ligands (increased activating signal) and/or blocking of HLA&ndash, KIR (killer-immunoglobulin-like receptors) interaction (decreased inhibitory signal). Both treatments improved NK cell killing activity. Compared with target cell killing of NK cells alone (38%), co-culture with Ara-C treated KG1a target cells increased the killing to 80%. Anti-HLA blocking antibody treatment increased the proportion of dead KG1a cells to 53%. Interestingly, the use of the combination treatment improved the killing potential to led to the death of 85% of KG1a cells. The combination of Ara-C and ex vivo activation of NK cells has the potential to be a feasible approach to treat relapsed AML after hematopoietic stem cell transplantation.

Despite encouraging therapeutic advances, multiple myeloma (MM) remains an incurable malignancy. The exciting results of chimaeric antigen receptor (CAR)-based immunotherapy in CD19(+) B-cell malignancies have spurred a great interest in extending the use of the CAR technology to other cancers, including MM. Availability of a specific, tumour-restricted antigen is crucial for the design of successful antibody-based CAR therapy. However, in MM, as in other malignancies, the relative dearth of such antigens-targets represents the main obstacle for the wider pre-clinical development and clinical application of the CAR technology. Here we provide an overview of the current progress and future promises of CAR technology in MM therapy. We highlight that, owing to its complexity, phenotypic and functional heterogeneity and the impact of the microenvironment, MM poses several challenges for CAR-based therapeutic approaches. Nevertheless, for the same reasons, MM can serve as a paradigm for better understanding, optimization and overall improvement of the CAR technology for the benefit of cancer and myeloma patients.

Asthma is a chronic inflammatory disease that represents high hospitalizations and deaths in world. Copaiba oil (CO) is popularly used for relieving asthma symptoms and has already been shown to be effective in many inflammation models. This study aimed to investigate the immunomodulatory relationship of CO in ovalbumin (OVA)-induced allergic asthma. The composition of CO sample analyzed by GC and GC–MS and the toxicity test was performed in mice at doses of 50 or 100 mg/kg (by gavage). After, the experimental model of allergic asthma was induced with OVA and mice were orally treated with CO in two pre-established doses. The inflammatory infiltrate was evaluated in bronchoalveolar lavage fluid (BALF), while cytokines (IL-4, IL-5, IL-17, IFN-γ, TNF-α), IgE antibody and nitric oxide (NO) production was evaluated in BALF and lung homogenate (LH) of mice, together with the histology and histomorphometry of the lung tissue. CO significantly attenuated the number of inflammatory cells in BALF, suppressing NO production and reducing the response mediated by TH2 and TH17 (T helper) cells in both BALF and LH. Histopathological and histomorphometric analysis confirmed that CO significantly reduced the numbers of inflammatory infiltrate in the lung tissue, including in the parenchyma area. Our results indicate that CO has an effective in vivo antiasthmatic effect.

Background and aim: The objective of this cross-sectional study was to evaluate the degree of glycaemic control and the frequency of diabetic complications in Italian people with diabetes who were treated with continuous subcutaneous insulin infusion (CSII). Methods and results: Questionnaires investigating the organisation of diabetes care centres, individuals’ clinical and metabolic features and pump technology and its management were sent to adult and paediatric diabetes centres that use CSII for treatment in Italy. Information on standard clinical variables, demographic data and acute and chronic diabetic complications was derived from local clinical management systems. The sample consisted of 6623 people with diabetes, which was obtained from 93 centres. Of them, 98.8% had type 1 diabetes mellitus, 57.2% were female, 64% used a conventional insulin pump and 36% used a sensor-augmented insulin pump. The median glycated haemoglobin (HbA1c) level was 60 mmol/mol (7.6%). The HbA1c target (i.e. 18 years) was achieved in 43.4% of paediatric and 23% of adult participants. Factors such as advanced pump functions, higher rate of sensor use, pregnancy in the year before the study and longer duration of diabetes were associated with lower HbA1c levels. The most common chronic complications occurring in diabetes were retinopathy, microalbuminuria and hypertension. In the year before the study, 5% of participants reported ≥1 episode of severe hypoglycaemic (SH) episodes (SH) and 2.6% reported ≥1 episode of ketoacidosis. Conclusions: Advanced personal skills and use of sensor-based pump are associated with better metabolic control outcomes in Italian people with diabetes who were treated with CSII. The reduction in SH episodes confirms the positive effect of CSII on hypoglycaemia. Clinical trial registration number: NCT 02620917 (ClinicalTrials.gov).

BACKGROUND: The biological basis for the adverse prognosis of chr1q gain/amplification (1q+) present in ~30% of patients with multiple myeloma (MM) remains ill-defined. The transcription factor (TF) Pre-B-cell leukaemia homeobox 1 (PBX1), encoded on chr1q, acts as master regulator of early hematopoiesis and as an oncogene in leukemia and other malignancies. Herein, we hypothesized that PBX1 orchestrates proliferative regulatory networks that underpin the poor prognosis associated with 1q+ in MM. METHODS: We employed qPCR for mRNA quantification, western blotting and immunohistochemistry for protein analysis, lentiviral shRNA-mediated knock-down, Hoechst/Annexin V staining and flow-cytometry for apoptosis and cell cycle analysis, ChIPseq for cistrome and RNAseq after knock-down for transcriptome analysis. Additional data were obtained from MMRF/CoMMpass, Blueprint Consortium and Arkansas datasets. Computational analysis of clinical and "-omics" data was performed using standard bioinformatic work-flows; pathway enrichment analysis using EnrichR and GSEA. RESULTS: Combined genomic (WGS/WES) and transcriptomic (RNAseq) analysis of the CoMMpass dataset identified a subgroup of 1q+ MM patients (60%) characterized by aberrant PBX1 overexpression and amplification (PBX1amp); survival analysis revealed significantly worse outcome of this subgroup compared to 1q+ non-PBX1amp (p Depletion of PBX1 using 2 validated shRNAs was toxic to the 1q+ MM1.S t(14;16) and U266 t(11;14) myeloma cell lines (MMCL) in vitro, revealing a novel myeloma cell addiction to PBX1. Transcriptome analysis of PBX1-depleted cells showed significant de-regulation of genes (MM1.S: 753down/320up; U266: 598 down/288up) highly enriched in cell cycle and proteasome/ER stress response pathways. Flow-cytometric analysis confirmed that PBX1-depleted myeloma cells undergo cell cycle arrest (G0/1 phase) and apoptosis (n=3; p Genome-wide binding profiling of PBX1 identified 7,354 significantly enriched peaks shared between MM1.S and U266 MMCL. These peaks were distributed at active promoters (~50%) and active enhancers (~30%), as defined by ChromHMM maps; the PBX1 consensus binding motif was identified as top hit upon motif enrichment analysis. Transcriptome-cistrome integration identified 728 and 282 genes directly activated or repressed, respectively, by PBX1 in MM1.S cells. Again, pathway enrichment analysis of PBX1 direct targets demonstrated significant over-representation of cell cycle and proliferation pathways, as well as positive regulation of various metabolic processes (oxidative phosphorylation, glycolysis, unfolded protein response). Strikingly, enrichment analysis against public ChIPseq datasets revealed significant overlap with gene targets of FOXM1 (200) and E2F (150) TF, suggesting the presence of a united PBX1-FOXM1-E2F regulatory circuitry. In fact, PBX1 binding was detected at an active FOXM1 enhancer and at the E2F1/2 promoters, while FOXM1 and E2F1/2 mRNA levels decreased significantly upon PBX1 depletion in two MMCL. To further explore the PBX1-FOXM1 interaction, we overlaid the FOXM1-depleted transcriptome with the PBX1 network in MM.1S cells. This identified 160 genes to be co-regulated by PBX1 and FOXM1, including genes previously linked to myeloma cell drug resistance (NEK2, TOP2A, AURKA); however, PBX1 expression was not altered in FOXM1-depleted cells, suggesting that PBX1 is functionally upstream of FOXM1. Additional analysis across 814 primary MM patient CoMMpass transcriptomes confirmed significant co-expression of PBX1 with FOXM1, E2F1/2 and another 67 PBX1-FOXM1 highly expressed, co-regulated gene targets, conferring poor OS (p CONCLUSIONS: We found that genetic amplification and overexpression of PBX1 defines an ultra high-risk subgroup of 1q+ MM with proliferative features. Myeloma cells are addicted to aberrant PBX1 expression. As well as essential metabolic pathways, PBX1 regulates cell cycle progression by direct transcriptional regulation of FOXM1 and of its target genes. These data reveal PBX1 as a critical biological link between chr1q gain/amplification and poor prognosis in a subset of MM patients. Disclosures Auner: Karyopharm: Consultancy; Amgen: Other: Consultancy and Research Funding; Takeda: Consultancy. Caputo:GSK: Research Funding. Karadimitris:GSK: Research Funding.

The dynamics of globalization mean we face a reality wherein leaders are called upon to communicate effectively in cultural situations unfamiliar to them. This situation brings new challenges for communication and leadership educators. Our article describes a cultural immersion experience called The Cagli Project, where communication and leadership students learn effective intercultural communication skills for leadership formation while studying in Italy. The philosophical and experiential aspects of the program are described along with leadership outcomes. The article ends with a discussion of the transferability of this model to alternative programs. Perhaps nothing has had a more profound effect on human communication and hence leadership in the past half century than the movement of people around the globe and the growing diversity of world society. Globalization is the mantra that seems to be driving much that is new in higher education today. It has its roots in the “global economy” and seems most relevant to the business disciplines, but there is a sub-text to globalization that resonates throughout all our institutions, and that is diversity (Caputo, 2011).

Sequelles fonctionnelles et qualite de vie apres duodenopancreatectomie cephalique S. Le Page, S. Caputo, F. Kwiatkowski, P. Berard, C. Gouillat But de l’etude : La duodenopancreatectomie cephalique est une intervention lourde dont les consequences physiologiques sont potentiellement deleteres sur la qualite de vie. Ce travail retrospectif unicentrique pilote avait pour but d’evaluer les effets des sequelles fonctionnelles de l’operation sur la qualite de vie des patients traites par duodenopancreatectomie cephalique. Patients et methode : Trente malades indemnes de recidive plus d’un an apres une duodenopancreatectomie cephalique ont repondu au questionnaire GIQLI (Gastro Intestinal Quality of Life Index) et a un questionnaire « specifique » evaluant en detail les sequelles fonctionnelles. Resultats : Le taux d’acceptabilite etait de 100 %. La coherence interne du questionnaire GIQLI etait bonne (coefficient α de Cronbach = 0,85). Le score total moyen du GIQLI etait de 94 (intervalle de confiance a 95 % -IC95 %- = [86-101]) pour un score ideal de 144. La qualite de vie etait significativement alteree par la steatorrhee, la prise d’un traitement antidiarrheique ou d’un traitement enzymatique substitutif. Conclusion : Par rapport a la reference pour la population normale, la duodenopancreatectomie cephalique est associee globalement a une alteration de la qualite de vie de 25 %, bien que plus d’un quart des patients conservent une qualite de vie normale. L’alteration de la qualite de vie apres duodenopancreatectomie cephalique apparait en rapport avec les sequelles digestives de l’operation. Le score GIQLI pourrait etre utilise pour evaluer les differents montages chirurgicaux.

An optical gain pattern-dependence suppression technique in Semiconductor Optical Amplifiers is presented, and its validity numerically demonstrated. It is applied to a simple all-optical ultra-fast de-multiplexer scheme for Optical Time Domain Multiplexed signals.

A non-adiabatic theoretical model including all fast gain dynamics in SOAs is presented. It emerges that an adiabatic theory cannot properly describe the impact of the TPA on high-energy ultrafast pulses propagating in SOAs.

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterised by motor impairment, cognitive decline and psychiatric disorders. Dysphagia is a pathologic condition that increases morbidity and mortality of the affected people because of its complications: malnutrition, dehydration, airways obstruction and aspiration pneumonia. Patients with HD may develop dysphagia with the progression of the disease. Our aim was to evaluate, in a group of HD patients, the prevalence of dysphagia, its correlation with motor and cognitive disorders and patient’s functionality. We recruited 37 patients with a genetically confirmed HD, attending the Ambulatory for Huntington’s chorea of the Neurological Science Department of Bari University, and evaluated them with Bedside Swallowing Assessment Scale (BSAS) of Smithard modified by Masotti for dysphagic symptoms, and with the Unified Huntington’s Disease Rating Scale (UHDRS) for HD. We considered both total score and partial scores of UHDRS-Motor. A group of 46 controls matched for sex and age, was recruited to normalise the scores of the BSAS on sex and age. According to the BSAS, the 36,6% of our HD patients was dysphagic. There was no correlation between dysphagia and motor, cognitive or functional impairment. The group of dysphagic patients did not present with more severe choreic movements in the Oro Buccal District, compared to the not dysphagic ones. In our HD patients, dysphagia seemed not to be correlated to movement impairment, including hypekinesias in Oro Buccal District. In addition, it did not imply more severe invalidity, according to Total Functional Capacity and Functional Assessment scales, which evaluate patient’s capacity in feeding in a single item. Severe dysphagia seems a not frequent symptom in HD. However, more focused evaluation is needed to confirm its impact on clinical outcome of the disease.

Mobil Exploration and Producing Technical Center (Mobil), E-Systems (EMASS{reg_sign}), Convex Computer Corporation and Geco-Prakla/Schlumberger completed an extensive field test of D-2 helical scan recording technology to prove its viability, stability and field worthiness in a production marine seismic acquisition environment. D-2 helical scan video recording technology was proven in this test to be field worthy, stable and reliable. This technology has the desirable characteristics of very dense, compact storage, very low error rate, high data transfer rate affords a solution to one of the oil and gas industry`s most urgent needs -- control the exponentially increasing data media requirements in acquisition, processing and archival storage. Marine acquisition technology for the future will follow the trend toward more data channels sampled more densely in time and space recorded from more and longer streamer cables. Data volumes will continue to grow to unmanageable levels unless some new, dense, high data rate media is used from the raw data acquisition stage through the entire cycle to archival storage and management. D-2 feasibility and advantages were clearly demonstrated in this 59 day field test. 2,250 linear kilometers of data were recorded on 9 small D-2 cassettes and on 1,360 IBM-3480 cartridges from 90,050 shotsmore » of a mixture of 320, 480 and 960 channels each. The total data volume was 215 gigabytes, and the entire 2,250 kilometers of data recorded on 9 D-2 cassettes easily fit into a standard business brief case. This same volume of data recorded on 9 track 2,400 foot reels at 6,250 BPI would require 1,890 reels of tape weighing approximately 1,890 pounds.« less

A 70-year-old man, with an untreated and histologically undefined (of his own free will) lung cancer (diagnosed 5 years before) was admitted to our ambulatory for increasing dyspnoea and progressive exercise intolerance. Apical four-chamber echocardiographic findings (panel A) were a large and fixed bilobate …

(1978). Description and analysis of nonverbal communication: A functional approach. Paper in Linguistics: Vol. 11, No. 1-2, pp. 115-153.

A class of variable-frequency sinusoidal oscillators requiring only a single active element is analyzed. The frequency of oscillation is approximately proportional (directly or inversely) to the square root of the gm of the active element. The analysis is carried out in two steps. The first step allows one to write the relation between the frequency and the circuit parameters almost by inspection, and also to determine easily an upper bound on the loading. The second step is a more detailed analysis yielding certain circuit constraints which must be met in order that the relations determined in the first step be valid. Two experimental circuits are described and compared to the theory.

Aims Ostium secundum atrial septal defect (osASD) is one of the most common cardiac malformations. Few data are available on the familial recurrence of congenital heart disease (CHD), in particular, in a large group of patients with isolated osASD. The aim is to investigate the familial recurrence of CHD in up to third-degree relatives from a large sample of consecutively enrolled patients with osASD, taking into account the influence of degree of relatedness (as number of relatives). Methods and results From January 1998 to December 2002, we enrolled 583 patients with osASD and 408 healthy subjects, referred to our tertiary centre. We hypothesized that a positive family history required at least one relative with CHD to constitute a risk factor. In this model of analysis, the null hypothesis is a similar familial history between cases and controls. Among 583 patients with osASD, 109 (19%) had at least one relative with CHD. Among the 408 healthy subjects studied, only 23 (6%) had a family history of CHD. A familial recurrence of CHD was demonstrated in 72 of 312 (23%) patients with isolated osASD and in 37 of 271 (13.6%) patients with non-isolated osASD. Familial recurrence of isolated osASD was demonstrated in 22 of 312 patients (7%) with an isolated osASD and only in six of 271 patients (2.2%) with non-isolated osASD. The familial recurrence risk of isolated osASD in patients with isolated osASD was higher in sibs, especially in sisters (33.3%). Conclusion This study underscores the role of genetic factors in the determination of CHD, particularly osASD. Our results could represent the basis for further studies to calculate a ‘value of family history’ to adapt the familial recurrence to the real size of each family group. In this way, we could select families with a ‘tendency’ to develop CHD, particularly osASD. In these families, we could analyse the genetic pattern to establish abnormalities and the bases of CHD.

This study sought to evaluate global and regional left ventricular (LV) function before and early after device closure of atrial septal defects (ASDs) in patients with normal pulmonary pressure. Global LV diastolic function was unaffected by ASD closure. An improvement in global LV systolic function at rest resulted in an increase in stroke volume at rest. Nevertheless, total cardiac output did not change after the procedure, because of a decrease in heart rate at rest counterbalancing the increase in stroke volume. Thus, lateral and inferior LV regional systolic function were preserved after device implantation. Moreover, no changes in regional LV diastolic function were highlighted during the study.