Ab initio study of the phase diagram of epitaxial BaTiO3

Using a combination of first-principles and effective-Hamiltonian approaches, we map out the structure of BaTiO3 under epitaxial constraints applicable to growth on perovskite substrates. We obtain a phase diagram in temperature and misfit strain that is qualitatively different from that reported by Pertsev et al. [Phys. Rev. Lett. 80, 1988 (1998)], who based their results on an empirical thermodynamic potential with parameters fitted at temperatures in the vicinity of the bulk phase transitions. In particular, we find a region of `r phase' at low temperature where Pertsev et al. have reported an `ac phase'. We expect our results to be relevant to thin epitaxial films of BaTiO3 at low temperatures and experimentally-achievable strains.Comment: 4 pages, with 4 postscript figures embedded. Uses REVTEX and epsf macros. Also available at http://www.physics.rutgers.edu/~dhv/preprints/od_epi/index.htm

Performing oncological procedures during COVID-19 outbreak: a picture from an Italian cancer center

Aim: Since SARS-CoV-2 infection rapidly spread around the world, Italy has quickly become one of the most affected countries. Healthcare systems introduced strict infection control measures to ensure optimal care, especially in frail groups such as cancer patients (pts). This study investigated the efficacy of SARS-CoV-2 pre-procedure screening and whether COVID-19 influenced timely diagnosis and therapy. Methods: Data of oncological procedures of pts with confirmed or suspected cancer diagnosis, treated at Oncology Department or coming from Emergency Department of San Luigi Gonzaga Hospital between June 2020 and March 2021 were retrospectively collected. A nasopharyngeal swab (NPS) was performed in outpatients 24/48 h before procedures. Inpatients were tested by NPS before and after hospitalization. Results: Two hundred and twenty-one pts were included in this analysis. Median age was 73 years, males were 58%. Eastern Cooperative Oncology Group (ECOG) Performance Status was 0 or 1 in 88% of pts. The most frequent cancer type was lung cancer (57%). Stages IV were 77%. Two hundred and forty-three scheduled procedures were performed with diagnostic (n: 142; 58%), therapeutic (n: 55; 23%), and palliative (n: 46; 19%) intent. One hundred and four and 139 procedures were performed in out- and in-pts, respectively. Of the 234 NPS performed, 10 (4%) were positive. Two pts were infected during hospitalization, 8 in community. Most of them were asymptomatic, while only 2 had mild symptoms. Eight procedures (3%) were postponed, 1 cancelled, while 2 were performed in positive pts. Median time to resolution of the infection was 17 days (11–36). Median delay in the procedures was 25 days (14–55). Five pts started systemic treatment, after a median time of 37.5 days (13–57). Conclusions: SARS-CoV-2 infection led to the postponement of a small, but not negligible percentage of oncological procedures. However, the low infection rate observed suggests that structured screening for COVID-19 is critical for the best management of scheduled procedures during pandemic

Integrated Genomic, Functional, and Prognostic Characterization of Atypical Chronic Myeloid Leukemia

Atypical chronic myeloid leukemia (aCML) is a BCR-ABL1-negative clonal disorder, which belongs to the myelodysplastic/myeloproliferative group. This disease is characterized by recurrent somatic mutations in SETBP1, ASXL1 and ETNK1 genes, as well as high genetic heterogeneity, thus posing a great therapeutic challenge. To provide a comprehensive genomic characterization of aCML we applied a high-throughput sequencing strategy to 43 aCML samples, including both whole-exome and RNA-sequencing data. Our dataset identifies ASXL1, SETBP1, and ETNK1 as the most frequently mutated genes with a total of 43.2%, 29.7 and 16.2%, respectively. We characterized the clonal architecture of 7 aCML patients by means of colony assays and targeted resequencing. The results indicate that ETNK1 variants occur early in the clonal evolution history of aCML, while SETBP1 mutations often represent a late event. The presence of actionable mutations conferred both ex vivo and in vivo sensitivity to specific inhibitors with evidence of strong in vitro synergism in case of multiple targeting. In one patient, a clinical response was obtained. Stratification based on RNA-sequencing identified two different populations in terms of overall survival, and differential gene expression analysis identified 38 significantly overexpressed genes in the worse outcome group. Three genes correctly classified patients for overall survival

Comparing T Cell Subsets in Broncho-Alveolar Lavage (BAL) and Peripheral Blood in Patients with Advanced Lung Cancer

Background: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB). Methods: BAL and PB were collected during bronchoscopy for diagnostic and/or therapeutic purposes in patients with monolateral primary lesion. Results: Of 33 patients undergoing BAL and PB sampling, 21 had histologically-confirmed LC. Most cases were locally-advanced or metastatic non-small cell LC. T cell characteristics were not significantly different in t-BAL vs. cl-BAL. Compared to PB, CD8 T cells in BAL presented features of immune activation and exhaustion (high PD-1, low IFN-g production). Accordingly, regulatory CD4 T cells were also higher in BAL vs. PB. When dichotomizing T cell density in t-BAL in high and low, we found that PD-L1 expression in LC was associated with T cell density in t-BAL. T-BAL with high T cell density had higher %IFN-g+CD8 T cells and lower %T-regs. Conclusion: In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome

The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Conjoined Genes as Common Events in Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer. For the last three decades, conventional cytogenetic and molecular approaches allowed the identification of genetic abnormalities having prognostic and therapeutic relevance. Although the current cure rate in pediatric B cell acute leukemia is approximately 90%, it remains one of the leading causes of mortality in childhood. Furthermore, in the contemporary protocols, chemotherapy intensity was raised to the maximal levels of tolerability, and further improvements in the outcome will depend on the characterization and reclassification of the disease, as well as on the development of new targeted drugs. The recent technological advances in genome-wide profiling techniques have allowed the exploration of the molecular heterogeneity of this disease, even though some potentially interesting biomarkers such as conjoined genes have not been deeply investigated yet. In the present study, we performed the transcriptome sequencing (RNA-seq) of 10 pediatric B cell precursor (BCP)-ALL cases with different risk (four standard- and six high-risk patients) enrolled in the Italian AIEOP-BFM ALL2000 protocol, in order to characterize the full spectrum of transcriptional events and to identify novel potential genetic mechanisms sustaining their different early response to therapy. Total RNA was extracted from primary leukemic blasts and RNA-seq was performed by Illumina technology. Bioinformatics analysis focused on fusion transcripts, originated from either inter- or intra-chromosomal structural rearrangements. Starting from a raw list of 9001 candidate events, by employing a custom-made bioinformatics pipeline, we obtained a short list of 245 candidate fusions. Among them, 10 events were compatible with chromosomal translocations. Strikingly, 235/245 events were intra-chromosomal fusions, 229 of which involved two contiguous or overlapping genes, resulting in the so-called conjoined genes (CGs). To explore the specificity of these events in leukemia, we performed an extensive bioinformatics meta-analysis and evaluated the presence of the fusions identified in our 10 BCP-ALL cohort in several other publicly available RNA-seq datasets, including leukemic, solid tumor and normal sample collections. Overall, 14/229 (6.1%) CGs were found to be exclusively expressed in leukemic cases, suggesting an association between CGs and leukemia. Moreover, CGs were found to be common events both in standard- and high-risk BCP-ALL patients and it might be suggestive of a novel potential transcriptional regulation mechanism active in leukemic cells