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

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

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

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

Loneliness and its predictors among older adults prior to and during the COVID-19 pandemic: Cross-sectional and longitudinal survey findings from participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort in the USA

Objectives We aimed to ascertain the prevalence of perceived loneliness among older adults following the onset of the COVID-19 pandemic and to examine factors contributing to the perception of loneliness. Design Cross-sectional and longitudinal data from the Atherosclerosis Risk in Communities (ARIC) Study cohort. Setting The ARIC Study cohort, a prospective cohort that recruited (1987-1989) participants from four distinct communities in the USA. Participants 2984 ARIC cohort members. Primary and secondary outcomes Perceived loneliness assessed using the University of California at Los Angeles (UCLA) UCLA three-item Loneliness Scale telephone interviews conducted May-October 2020 and prior to March 2020. Results Of the total 5037 participants alive in 2020, 2984 (56.2%) responded to the UCLA three-item questionnaire (mean age 82.6 (SD 4.6) years, 586 (19.6%) black participants, 1081 (36.2%) men), of which 66 (2.2%) reported having had a COVID-19 infection during the observation period. The proportion of participants reporting feeling lonely was 56.3% (n=1680). Among participants with repeat measures of loneliness (n=516), 35.2% (n=182) reported feeling more lonely following pandemic onset. Self-rated health and emotional resilience were strongly associated with self-perceived loneliness. The burden of COVID-19 infections, concern about the pandemic and decreased self-reported physical activity were greater among black as compared with white participants and among those with an educational attainment of less than high school as compared with high school or more. Conclusion Findings from this study document the increase in perceived loneliness among older adults during the COVID-19 pandemic in the USA

Practical issues in early switching from intravenous to oral antibiotic therapy in children with uncomplicated acute hematogenous osteomyelitis: Results from an italian survey

Background: The European Society of Pediatric Infectious Diseases (ESPID) guidelines for acute hematogenous osteomyelitis (AHOM) have been published recently. In uncomplicated cases, an early (2-4 days) switch to oral empirical therapy, preferentially with flucloxacillin, is recommended in low methicillin-resistant Staphylococcus aureus settings. We conducted a survey with the aim of evaluating the behaviors of Italian pediatricians at this regard. Methods: An open-ended questionnaire investigating the empiric therapy adopted in uncomplicatedAHOMchildren according to age was sent by email to 31 Italian pediatric clinics taking care of children with infectious diseases, and results were analyzed. Results: The preferred intravenous (IV) regimen was a penicillin plus an aminoglycoside (n = 10; 32.3%) in children aged &lt;3 months, and a combination of a third-generation cephalosporin plus oxacillin (n = 7; 22.6%), or oxacillin alone (n = 6; 19.4%) in those 653 months. In every age class, amoxicillin-clavulanate was the first-choice oral antibiotic. Other antibiotics largely used orally included clindamycin, rifampicin, and trimethoprim/sulfamethoxazole. Flucloxacillin was never prescribed. Only 3 centers switched to oral therapy within 7 days in children 653 months of age. The most commonly reported reason influencing the time to switch to oral therapy concerned caregivers\u2019 adherence to oral therapy. Conclusion: Adherence to guidelines was poor, and early transition to oral therapy in the clinical practice was rarely adopted. Given the large use of potentially effective, but poorly studied, oral antibiotics such as amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, and rifampicin, our data may stimulate further studies of this regard

Cardiomyocyte Specific Ablation of p53 Is Not Sufficient to Block Doxorubicin Induced Cardiac Fibrosis and Associated Cytoskeletal Changes

Doxorubicin (Dox) is an anthracycline used to effectively treat several forms of cancer. Unfortunately, the use of Dox is limited due to its association with cardiovascular complications which are manifested as acute and chronic cardiotoxicity. The pathophysiological mechanism of Dox induced cardiotoxicity appears to involve increased expression of the tumor suppressor protein p53 in cardiomyocytes, followed by cellular apoptosis. It is not known whether downregulation of p53 expression in cardiomyocytes would result in decreased rates of myocardial fibrosis which occurs in response to cardiomyocyte loss. Further, it is not known whether Dox can induce perivascular necrosis and associated fibrosis in the heart. In this study we measured the effects of acute Dox treatment on myocardial and perivascular apoptosis and fibrosis in a conditional knockout (CKO) mouse model system which harbours inactive p53 alleles specifically in cardiomyocytes. CKO mice treated with a single dose of Dox (20 mg/kg), did not display lower levels of myocardial apoptosis or reactive oxygen and nitrogen species (ROS/RNS) compared to control mice with intact p53 alleles. Interestingly, CKO mice also displayed higher levels of interstitial and perivascular fibrosis compared to controls 3 or 7 days after Dox treatment. Additionally, the decrease in levels of the microtubule protein α-tubulin, which occurs in response to Dox treatment, was not prevented in CKO mice. Overall, these results indicate that selective loss of p53 in cardiomyocytes is not sufficient to prevent Dox induced myocardial ROS/RNS generation, apoptosis, interstitial fibrosis and perivascular fibrosis. Further, these results support a role for p53 independent apoptotic pathways leading to Dox induced myocardial damage and highlight the importance of vascular lesions in Dox induced cardiotoxicity

High-Definition DNA Methylation Profiles from Breast and Ovarian Carcinoma Cell Lines with Differing Doxorubicin Resistance

Acquired drug resistance represents a frequent obstacle which hampers efficient chemotherapy of cancers. The contribution of aberrant DNA methylation to the development of drug resistant tumor cells has gained increasing attention over the past decades. Hence, the objective of the presented study was to characterize DNA methylation changes which arise from treatment of tumor cells with the chemotherapeutic drug doxorubicin. DNA methylation levels from CpG islands (CGIs) linked to twenty-eight genes, whose expression levels had previously been shown to contribute to resistance against DNA double strand break inducing drugs or tumor progression in different cancer types were analyzed. High-definition DNA methylation profiles which consisted of methylation levels from 800 CpG sites mapping to CGIs around the transcription start sites of the selected genes were determined. In order to investigate the influence of CGI methylation on the expression of associated genes, their mRNA levels were investigated via qRT-PCR. It was shown that the employed method is suitable for providing highly accurate methylation profiles, comparable to those obtained via clone sequencing, the gold standard for high-definition DNA methylation studies. In breast carcinoma cells with acquired resistance against the double strand break inducing drug doxorubicin, changes in methylation of specific cytosines from CGIs linked to thirteen genes were detected. Moreover, similarities between methylation profiles obtained from breast and ovarian carcinoma cell lines with acquired doxorubicin resistance were found. The expression levels of a subset of analyzed genes were shown to be linked to the methylation levels of the analyzed CGIs. Our results provide detailed DNA methylation information from two separate model systems for acquired doxorubicin resistance and suggest the occurrence of similar methylation changes in both systems upon exposure to the drug

Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicity

Normal tissue damage limits the efficacy of anticancer therapy. For anthracyclines, the clinically most relevant adverse effect is cardiotoxicity. The mechanisms involved are poorly understood and putative cardioprotectants are controversially discussed. Here, we show that the lipid-lowering drug lovastatin protects rat H9c2 cardiomyoblasts from doxorubicin in vitro. Protection by lovastatin is related to inhibition of the Ras-homologous GTPase Rac1. It rests on a reduced formation of DNA double-strand breaks, resulting from the inhibition of topoisomerase II by doxorubicin. Doxorubicin transport and reactive oxygen species are not involved. Protection by lovastatin was confirmed in vivo. In mice, lovastatin mitigated acute doxorubicin-induced heart and liver damage as indicated by reduced mRNA levels of the pro-fibrotic cytokine connective tissue growth factor (CTGF) and pro-inflammatory cytokines, respectively. Lovastatin also protected from doxorubicin-provoked subacute cardiac damage as shown by lowered mRNA levels of CTGF and atrial natriuretic peptide. Increase in the serum concentration of troponin I and cardiac fibrosis following doxorubicin treatment were also reduced by lovastatin. Whereas protecting the heart from harmful doxorubicin effects, lovastatin augmented its anticancer efficacy in a mouse xenograft model with human sarcoma cells. These data show that statins lower the incidence of cardiac tissue injury after anthracycline treatment in a Rac1-dependent manner, without impairing the therapeutic efficacy

The cancer patient and cardiology

Advances in cancer treatments have improved clinical outcomes, leading to an increasing population of cancer survivors. However, this success is associated with high rates of short- and long-term cardiovascular (CV) toxicities. The number and variety of cancer drugs and CV toxicity types make long-term care a complex undertaking. This requires a multidisciplinary approach that includes expertise in oncology, cardiology and other related specialties, and has led to the development of the cardio-oncology subspecialty. This paper aims to provide an overview of the main adverse events, risk assessment and risk mitigation strategies, early diagnosis, medical and complementary strategies for prevention and management, and long-term follow-up strategies for patients at risk of cancer therapy-related cardiotoxicities. Research to better define strategies for early identification, follow-up and management is highly necessary. Although the academic cardio-oncology community may be the best vehicle to foster awareness and research in this field, additional stakeholders (industry, government agencies and patient organizations) must be involved to facilitate cross-discipline interactions and help in the design and funding of cardio-oncology trials. The overarching goals of cardio-oncology are to assist clinicians in providing optimal care for patients with cancer and cancer survivors, to provide insight into future areas of research and to search for collaborations with industry, funding bodies and patient advocates. However, many unmet needs remain. This document is the product of brainstorming presentations and active discussions held at the Cardiovascular Round Table workshop organized in January 2020 by the European Society of Cardiology.</p