Anti-CD19 monoclonal antibodies for the treatment of relapsed or refractory B-cell malignancies: a narrative review with focus on diffuse large B-cell lymphoma

Purpose: CD19 is a cell surface protein that is found on both healthy and malignant B cells. Accordingly, it has become an important target for novel treatments for non-Hodgkin lymphomas and B-cell leukaemia. Three anti-CD19 monoclonal antibodies with distinct mechanisms of action have been developed for the treatment of B-cell malignancies. Methods: We reviewed the preclinical and clinical data on the development of the newly approved anti-CD19 monoclonal antibodies blinatumomab, tafasitamab and loncastuximab tesirine, and consider their place in the treatment of relapsed or refractory B-cell malignancies. Results: Blinatumomab is a bispecific T-cell engager that binds to both CD19 on B cells and CD3 on T cells, facilitating antibody-dependent cytotoxicity. Blinatumomab significantly prolongs overall survival in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, although cytokine release syndrome and severe neurotoxicity may necessitate discontinuation. Tafasitamab, which has modified anti-CD19 Fab and Fc regions, has significantly enhanced affinity for both CD19 and effector cell receptors compared with unmodified anti-CD19. In L-MIND, tafasitamab plus lenalidomide provided an overall response rate (ORR) of 57.5% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients non-transplant eligible. Loncastuximab tesirine is an antibody–drug conjugate that has been studied as monotherapy and in combination with ibrutinib in 3L + relapsed or refractory DLBCL. The ORR was 48.3% in a phase II trial of loncastuximab tesirine. The optimal place of anti-CD19 monoclonal antibodies in therapy has yet to be determined, but the prospect of improved outcomes for at least some patients with treatment-resistant B-cell malignancies appears likely, particularly in those with limited therapeutic options and poor prognosis

Effect of stators geometry on the resonance sensitivity of capacitive MEMS

open4openFrangi, A.; Laghi, G.; Minotti, P.; Langfelder, G.Frangi, ATTILIO ALBERTO; Laghi, Giacomo; Minotti, Paolo; Langfelder, Giacom

Modello coesivo per l’avanzamento di fratture mediante rilascio nodale di strutture discretizzate con elementi finiti

La simulazione numerica della propagazione di una frattura in MODO I, viaggiante ad elevatavelocità in un acciaio a comportamento duttile è realizzata attraverso un modello coesivo che governa ladistribuzione delle forze di rilascio nodale. Come noto, la ricerca di un valore di tensione all’apice non ha alcunsenso nel caso elastico; infatti, la tensione può essere valutata solo mediante fattori di campo. Nel caso elasto-plastico, incrudimento e softening di origine geometrica o legato al progressivo danneggiamento influisconodecisamente sull’andamento esponenziale del campo tensionale. È possibile comunque individuare un valore diriferimento, di entità finita, mediante estrapolazione delle tensioni elasto-plastiche nella zona di inizio softeningdella frattura. Tale grandezza può essere presa come fattore di riferimento per il calcolo delle forze di rilasciocoesive e quindi dell’energia dissipata. Nel lavoro viene discusso come determinare, dal campo di tensioneelasto-plastico locale, il valore che governa la zona coesiva al variare del T-stress

Modello coesivo per l’avanzamento di fratture mediante rilascio nodale di strutture discretizzate con elementi finiti

La simulazione numerica della propagazione di una frattura in MODO I, viaggiante ad elevatavelocità in un acciaio a comportamento duttile è realizzata attraverso un modello coesivo che governa ladistribuzione delle forze di rilascio nodale. Come noto, la ricerca di un valore di tensione all’apice non ha alcunsenso nel caso elastico; infatti, la tensione può essere valutata solo mediante fattori di campo. Nel caso elasto-plastico, incrudimento e softening di origine geometrica o legato al progressivo danneggiamento influisconodecisamente sull’andamento esponenziale del campo tensionale. È possibile comunque individuare un valore diriferimento, di entità finita, mediante estrapolazione delle tensioni elasto-plastiche nella zona di inizio softeningdella frattura. Tale grandezza può essere presa come fattore di riferimento per il calcolo delle forze di rilasciocoesive e quindi dell’energia dissipata. Nel lavoro viene discusso come determinare, dal campo di tensioneelasto-plastico locale, il valore che governa la zona coesiva al variare del T-stress

Optical properties of highly n-doped germanium obtained by in situ doping and laser annealing

High n-type doping in germanium is essential for many electronic and optoelectronic applications especially for high performance Ohmic contacts, lasing and mid-infrared plasmonics. We report on the combination of in situ doping and excimer laser annealing to improve the activation of phosphorous in germanium. An activated n-doping concentration of 8.8  ×  1019 cm−3 has been achieved starting from an incorporated phosphorous concentration of 1.1  ×  1020 cm−3. Infrared reflectivity data fitted with a multi-layer Drude model indicate good uniformity over a 350 nm thick layer. Photoluminescence demonstrates clear bandgap narrowing and an increased ratio of direct to indirect bandgap emission confirming the high doping densities achieved

Novel mutations in CACNA1F and NYX in Dutch families with X-linked congenital stationary night blindness

PURPOSE: To describe the clinical features and genetic analysis of eight X-linked congenital stationary night blindness (XLCSNB) Dutch patients. METHODS: Electroretinogram (ERG) measurements were assessed in Dutch patients. Molecular genetic testing by denaturing high performance liquid chromatography (DHPLC), single stranded conformation polymorphism (SSCP) analysis, and direct sequencing of the CACNA1F and NYX genes were performed in the patients possessing a negative Schubert Bornschein ERG. RESULTS: Molecular genetic testing of CACNA1F and NYX revealed three novel and two known CACNA1F sequence variants as well as two novel sequence alterations in the NYX gene. While one of the CACNA1F sequence variants (5756G>A, R1919H) has been previously described as a common polymorphism in Japanese families, we did not found this transition in 100 European control alleles. CONCLUSIONS: In a pool of eight diagnosed XLCSNB patients, five showed a sequence variation in the CACNA1F and two in the NYX gene. In only one of the eight patients no sequence alteration could be detected. This might be explained by a mutation in other, as yet unidentified coding or regulatory sequences of NYX or CACNA1F or additional genes

Investigation of the relevant kinetic processes in the initial stage of a double-arcing instability in oxygen plasmas

A numerical investigation of the kinetic processes in the initial (nanosecond range) stage of the double-arcing instability was developed. The plasma-sheath boundary region of an oxygen-operated cutting torch was considered. The energy balance and chemistry processes in the discharge were described. It is shown that the double-arcing instability is a sudden transition from a diffuse (glow-like) discharge to a constricted (arc-like) discharge in the plasma-sheath boundary region arising from a field-emission instability. A critical electric field value of ∼10^7 V/m was found at the cathodic part of the nozzle wall under the conditions considered. The field-emission instability drives in turn a fast electronic-to-translational energy relaxation mechanism, giving rise to a very fast gas heating rate of at least ∼10^9 K/s, mainly due to reactions of preliminary dissociation of oxygen molecules via the highly excited electronic state O2(B^3) populated by electron impact. It is expected that this fast oxygen heating rate further stimulates the discharge contraction through the thermal instability mechanism.Fil: Mancinelli, Beatriz Rosa. Universidad Tecnológica Nacional. Facultad Regional Venado Tuerto; ArgentinaFil: Prevosto, Leandro. Universidad Tecnológica Nacional. Facultad Regional Venado Tuerto; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; ArgentinaFil: Chamorro Garcés, Juan Camilo. Universidad Tecnológica Nacional. Facultad Regional Venado Tuerto; ArgentinaFil: Minotti, Fernando Oscar. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kelly, Hector Juan. Universidad Tecnológica Nacional. Facultad Regional Venado Tuerto; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentin

NPTX1 Regulates Neural Lineage Specification from Human Pluripotent Stem Cells

SummaryNeural induction is the first fundamental step in nervous system formation. During development, a tightly regulated niche modulates transient extracellular signals to influence neural lineage commitment. To date, however, the cascade of molecular events that sustain these signals in humans is not well understood. Here we show that NPTX1, a secreted protein, is rapidly upregulated during neural induction from human pluripotent stem cells (hPSCs). By manipulating its expression, we were able to reduce or initiate neural lineage commitment. A time-course transcriptome analysis and functional assays show that NPTX1 acts in part by binding the Nodal receptor cofactor TDGF1, reducing both Nodal and BMP signaling. Our findings identify one of the earliest genes expressed upon neural induction and provide insight into human neural lineage specification

Progranulin is expressed within motor neurons and promotes neuronal cell survival

<p>Abstract</p> <p>Background</p> <p>Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U) associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival.</p> <p>Results</p> <p><it>In situ </it>hybridisation and immunohistochemical techniques revealed that the <it>progranulin </it>gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human <it>progranulin </it>gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months). This is mediated at least in part through an anti-apoptotic mechanism. Control cells, while expressing basal levels of progranulin do not survive in serum free conditions. Knockdown of progranulin expression using shRNA technology further reduced cell survival.</p> <p>Conclusion</p> <p>Neurons are among the most long-lived cells in the body and are subject to low levels of toxic challenges throughout life. We have demonstrated that progranulin is abundantly expressed in motor neurons and is cytoprotective over prolonged periods when over-expressed in a neuronal cell line. This work highlights the importance of progranulin as neuroprotective growth factor and may represent a therapeutic target for neurodegenerative diseases including motor neuron disease.</p

Invasion status of the common carp Cyprinus carpio in inland waters of Argentina

This study documents the presence of Cyprinus carpio in 119 natural environments and 49 artificial habitats in Argentina, showing an exponential increment of invaded locations over time since it was introduced in the nineteenth century. Geographic expansion patterns revealed that since its initial introduction, species records demonstrate an increment in the central portion of the country only after 1970 and subsequent expansion after 1990 to the north, west and south. Using an environmental similarity index it was determined that more than half the country offers good conditions for C. carpio establishment. Environmental factors and anthropogenic impacts are relevant drivers that can account for the current and future distribution of C. carpio in Argentina.Instituto de Limnología "Dr. Raúl A. Ringuelet