Some exact results on Lindley process with Laplace jumps

We consider a Lindley process with Laplace distributed space increments. We obtain closed form recursive expressions for the density function of the position of the process and for its first exit time distribution from the domain $[0,h]$. We illustrate the results in terms of the parameters of the process. The work is completed by an open source version of the software

On the structural behaviour of existing RC bridges subjected to corrosion effects: Numerical insight

The evaluation of the structural behaviour of existing reinforced concrete (RC) bridges represents one of the most current structural engineering research topics due to their strategic importance, especially if they are subjected to corrosion effects which can lead to a significant reduction of load-bearing capacity of the main structural elements (e.g., the piers). In the last decades, different types of numerical approaches have been proposed for the evaluation of the structural behaviour of these strategic infrastructures, especially after the recent collapses that have affected this type of structures during last years. In this paper, the structural behaviour of an existing RC bridge subjected to corrosion effects due to carbonation is analysed by means of an efficient procedure based on the implementation of a Finite Element Model (FEM) where the main structural elements are implemented using only Timoshenko beam elements. The safety level of the bridge has been evaluated considering different load conditions (e.g. traffic load, seismic action, etc.) calculated according to the Italian Design Code (NTC2018). Finally, a retrofitting intervention is proposed in order to guarantee and adequate safety level of the bridge under the considered different load combinations

Thin corrugated-edge shells inspired by Nervi’s dome: Numerical insight about their mechanical behaviour

During the last decades, the constant evolution of the construction systems has led to the possibility of carrying out increasingly complex architectural project. Among the wide range of construction systems, thin concrete shells with corrugated-edge stand out for their relevance. In this paper, the mechanical behaviour of thin concrete corrugated-edge shell inspired by Nervi’s Flaminio dome has been analysed in detail, considering different load configurations (self-weight, uniform normal pressure and antisymmetric vertical load) and constraints (pure membrane vs. displacements restrained boundary conditions). Non-linear static analysis has been performed to assess the vertical load-bearing capacity of the corrugatededge shell considering a Concrete Damaged Plasticity (CDP) constitutive model and linear and non-linear buckling analyses have been carried out to evaluate the effects of the corrugation on buckling behaviour. The results obtained from linear and non-linear analyses have been compared with those obtained for a concrete thin smooth-edge shell having the same geometric global characteristics. The comparison highlighted improvements provided by corrugated-edge in terms of structural behaviour

The bromodomain and extra-terminal domain degrader MZ1 exhibits preclinical anti-tumoral activity in diffuse large B-cell lymphoma of the activated B cell-like type

AIM: Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidence sustain BET targeting as an anti-cancer approach. BET degraders are chimeric compounds comprising of a BET inhibitor, which allows the binding to BET bromodomains, linked to a small molecule, binder for an E3 ubiquitin ligase complex, triggering BET proteins degradation via the proteasome. These degraders, called proteolysis-targeting chimeras (PROTACs), can exhibit greater target specificity compared to BET inhibitors and overcome some of their limitations, such as the upregulation of the BET proteins themselves. Here are presented data on the anti-tumor activity and the mechanism of action of the BET degrader MZ1 in diffuse large B cell lymphoma (DLBCL) of the activated B-cell like (ABC, ABC DLBCL), using a BET inhibitor as a comparison. METHODS: Established lymphoma cell lines were exposed for 72 h to increasing doses of the compounds. Cell proliferation was evaluated by using an 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide (MTT) assay. Fluorescent-Activated Cell Sorter (FACS) analysis was performed to measure apoptotic activation and RNA sequencing (RNA-Seq) to study the transcriptional changes induced by the compounds. RESULTS: MZ1, and not its negative control epimer cisMZ1, was very active with a median half maximal inhibitory concentration (IC(50)) of 49 nmol/L. MZ1 was more in vitro active than the BET inhibitor birabresib (OTX015). Importantly, MZ1 induced cell death in all the ABC DLBCL cell lines, while the BET inhibitor was cytotoxic only in a fraction of them. BET degrader and inhibitor shared partially similar changes at transcriptome level but the MZ1 effect was stronger and overlapped with that caused cyclin-dependent kinase 9 (CDK9) inhibition. CONCLUSIONS: The BET degrader MZ1 had strong cytotoxic activity in all the ABC DLBCL cell lines that were tested, and, at least in vitro, it elicited more profound effects than BET inhibitors, and encourages further investigations

Integration of Baseline Metabolic Parameters and Mutational Profiles Predicts Long-Term Response to First-Line Therapy in DLBCL Patients: A Post Hoc Analysis of the SAKK38/07 Study.

Accurate estimation of the progression risk after first-line therapy represents an unmet clinical need in diffuse large B-cell lymphoma (DLBCL). Baseline (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) parameters, together with genetic analysis of lymphoma cells, could refine the prediction of treatment failure. We evaluated the combined impact of mutation profiling and baseline PET/CT functional parameters on the outcome of DLBCL patients treated with the R-CHOP14 regimen in the SAKK38/07 clinical trial (NCT00544219). The concomitant presence of mutated SOCS1 with wild-type CREBBP and EP300 defined a group of patients with a favorable prognosis and 2-year progression-free survival (PFS) of 100%. Using an unsupervised recursive partitioning approach, we generated a classification-tree algorithm that predicts treatment outcomes. Patients with elevated metabolic tumor volume (MTV) and high metabolic heterogeneity (MH) (15%) had the highest risk of relapse. Patients with low MTV and favorable mutational profile (9%) had the lowest risk, while the remaining patients constituted the intermediate-risk group (76%). The resulting model stratified patients among three groups with 2-year PFS of 100%, 82%, and 42%, respectively (p < 0.001)

Role of Imaging in the Staging and Response Assessment of Lymphoma:Consensus of the International Conference on Malignant Lymphomas Imaging Working Group

This article comprises the consensus reached to update guidance on the use of PET-CT for staging and response assessment for 18F FDG-avid lymphomas in clinical practice and late-phase trials

Utility of baseline 18FDG-PET/CT functional parameters in defining prognosis of primary mediastinal (thymic) large B-cell lymphoma

The International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of (18)F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P = .001) and PFS (P &lt; .001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P &lt; .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. The IELSG 26 study was registered at www.clinicaltrials.gov as #NCT00944567

Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13).

BACKGROUND The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL. METHODS In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3 + 3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min-max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458. FINDINGS Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67 > 30%, blastoid or pleomorphic variant, p53 overexpression, TP53 mutations and/or deletions). In these patients, ibrutinib and bortezomib were also effective with an ORR of 74%, increasing to 82% during maintenance. With a median follow-up of 25.4 months, the median duration of response was 22.7, and the median PFS was 18.6 months. PFS reached 30.8 and 32.9 months for patients with a CR or Cru, respectively. INTERPRETATION The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features. FUNDING SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen