Diffuse large B-cell lymphoma | EPFL Graph Search

Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats. The causes of diffuse large B-cell lymphoma are not well understood. Usu

Novel therapeutic strategies targeting the B-cell receptor signaling and antigen presentation pathways in non-Hodgkin lymphoma

Elena Battistello

B-cell non-Hodgkin lymphomas (B-NHLs) are a heterogeneous group of tumors deriving from the malignant transformation of B cells. The two most common B-NHL subtypes are follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), which account together for 50-60% of B-NHL cases. The standard of care for advanced or transformed FL and DLBCL is a combination of chemotherapy and the anti-CD20 antibody rituximab (R-CHOP); however, this approach is curative just in a fraction of cases. In addition, despite a good characterization of the genomic lesions present in those tumors, the available targeted therapies are limited and related to only partial responses. Thus, effective and curative treatments for B-NHLs are still missing, imposing the need for the design of new therapeutic strategies for these patients. In this thesis, I characterized the mechanisms of intrinsic and acquired resistance to targeted therapies in B-NHLs and identified novel therapeutic approaches for FL and DLBCL treatment. In the first part of this thesis, I focused on the inhibition of the B cell receptor (BCR) signaling pathway in DLBCL. The propagation of the BCR signal can be blocked using the targeted BTK inhibitor ibrutinib; however, this approach is effective only in a subgroup of DLBCL patients. In my studies, I showed that, in cells intrinsically resistant to ibrutinib, the loss of BTK is compensated by an increased dependency on the PI3K/AKT pathway downstream the BCR. In addition, I proposed to target the SRC kinases which propagate the BCR signal to both BTK and PI3K/AKT, using the new inhibitor masitinib. In cell lines and patients-derived primary samples, I showed that masitinib treatment is effective in both ibrutinib-sensitive and resistant tumors, thus suggesting it as novel therapeutic approach for a broader group of patients. In the second part of this thesis, I characterized the influence of ibrutinib and masitinib treatments on tumor heterogeneity and evolution using single-cells transcriptomics approaches. I showed that, upon long-term targeted treatments, initially sensitive tumors relapse and this is associated with changes in gene expression at the single-cell level. I then identified a set of genes that might contribute to acquired resistance to these drugs. This study will serve as starting point for a broader characterization of the effect of targeted therapies on clonal dynamics and tumor heterogeneity and for the rational design of combinatorial strategies. The last part of this thesis is focused on the characterization of cathepsin S as novel therapeutic target in FL. I showed that, in FL patients, cathepsin S over-activation by a gain-of-function mutation or by gene over-expression promotes lymphomagenesis. I found that cathepsin S has an essential role in regulating the interactions of lymphoma cells with T cells infiltrated in the tumor. Indeed, deletion of cathepsin S leads to a diversification in the repertoire of antigens presented on MHC molecules, which increases tumor immunogenicity. In pre-clinical studies, I showed that cathepsin S inhibition stimulates the activation of a potent anti-tumor immune response and enhances the therapeutic efficacy of current immunotherapies. Thus, inhibition of cathepsin S could represent a novel and promising therapeutic strategy for FL treatment. In follow-up studies, we are identifying specific cathepsin S inhibitors with potential clinical applications.

EPFL2019

A congenital case of intermediate-type fetal rhabdomyoma in an Ardi goat kid

Ahmed Ali, Alessandra Piersigilli

A 5-year-old pregnant Ardi goat presented with dystocia of 36h duration. Vaginal examination showed normal fetal presentation; however, a large neck mass prevented vaginal delivery and cesarean section was performed to deliver the stillborn kid. A well-circumscribed, poorly lobulated subcutaneous mass (12.5cm in diameter) was found on the ventral lateral aspect of the neck. The cut surface was fleshy and tan to pale white in appearance. Histologically, the tumor exhibited moderate to high cellularity and consisted of elongate to ribbon-like myotubes, with many showing differentiation into larger cells having cross-striations. Nuclei were often multiple (2-5+) and peripheral. Neoplastic cells lacked anaplasia and had a low mitotic index (

Taylor & Francis Ltd2016

A Mixed-Phase SiOx Hole Selective Junction Compatible With High Temperatures Used in Industrial Solar Cell Manufacturing

Christophe Ballif, Matthieu Despeisse, Franz-Josef Haug, Andrea Ingenito, Quentin Thomas Jeangros, Mario Joe Lehmann, Xavier Niquille, Gizem Nogay, Josua Andreas Stückelberger, Philippe Wyss

We present a p-type passivating rear contact that complies with integration into standard solar cell manufacturing with phosphorus-diffused front side. Our contact structure consists of a thin SiOx tunneling layer grown by wet chemistry and a stack of layers deposited in one single run by plasma-enhanced chemical vapor deposition. The layers of the stack were tailored to protect the interfacial oxide layer, to act as a source for boron diffusion into the wafer and to connect to the external metallisation with low contact resistivity. We found that this stack tolerated annealing at 900 degrees C over a wide range of dwell times: for 15 min anneals we obtained dark saturation current densities (J(o)) as low as 10 fA center dot cm(-2) (after hydrogenation) and after 12-fold increase of the annealing time to 180 min, J(0) was only increased to 12 fA center dot cm(-2). These values corresponded to implied open circuit voltages (iV(oc)) of 718 and 715 mV, respectively. To test passivating rear contacts under realistic operation conditions, we combined them with an n-type heterojunction into hybrid solar cells. With conversion efficiencies abovementioned 22% and V-oc > 705 mV, these devices demonstrated high level of rear surface passivation. Finally, we demonstrated the integration of the hole selective rear contact with a POCl3 diffusion process. To this end, we added a phosphorus diffusion barrier to our layer stack by depositing one additional layer of amorphous SiOx on top of the stack. For symmetric samples with this layer structure on both sides, we observed iV(oc) values of 714 and 712 mV on n- and p-type silicon wafers after hydrogenation, respectively. Co-diffused cells with POCl3 front diffused emitter and rear passivating contact resulted so far in efficiencies of 20.4% and 20.1% for n- and p-type wafers, respectively.