1,721,217 research outputs found
Six-year results of the CLL14 study—redefining long-term outcomes in chronic lymphocytic leukemia management
No full textExpression and function of protein kinase CK2 in Hodgkin lymphoma
Full text linkHodgkin lymphoma (HL) is a lymphoid tissue neoplasia accounting for almost 0.6% of all cancers. The neoplastic cells of Hodgkin and Reed-Sternberg cells (HRS) represent less than 1% of all the tumor bulk which is mainly composed by an heterogenous group of reactive cells of the immune system. The abnormalities of transcriptional factors and genes involved in hematopoietic cells differentiation justify the typical immunophenotype of HRS, being positive for CD30, CD15 and the immuno-checkpoint PD-L1 but usually negative for CD20. The survival of neoplastic cells is favored by the activation of NF-κB, JAK/STAT e PI3K pathways, which play a key role in the pathogenesis of this disease.
Protein casein kinase 2 (CK2) is a serine/threonine kinase ubiquitously expressed in eukaryotic cells, constitutively active, consisting of two catalytic (α) and two non-catalytic (β) subunits assembled to form a tetramer. It is involved in a broad variety of cellular processes, among which survival, proliferation, differentiation, DNA damage and other stress responses. This kinase has been found overexpressed in several solid tumors and hematologic malignancies. It has been fully demonstrated that CK2 acts as a potent antiapoptotic factor that promotes a “non-oncogene addiction” phenotype in cancer cells. In particular, it was shown that many B-cell derived tumors, like multiple myeloma, mantle cell lymphoma and chronic lymphocytic leukemia, rely on high CK2 activity and that its genetic and chemical inhibition induces malignant cell death without significantly affecting normal B lymphocytes. However, the involvement of CK2 in the pathogenesis of HL is still unclear.
By means of western blotting, real time PCR, immunofluorescence, flow cytometry and subcellular fractionation we analyzed the expression of CK2 subunit and the effect of Ck2 inhibition in four HL cell lines (L-428, L-540, KM-H2, HDLM-2), Kasumi-1 (a cell lines derived from a patient with acute myeloid leukemia) and age-matched B lymphocytes from a healthy donor, as controls. Immunohistochemistry on tissue microarray was also used. Apoptosis was assessed by flow cytometry using Annexin V/Propidium Iodine test and PARP cleavage by western blotting.
We observed that CK2α was overexpressed while CK β was expressed at lower levels in all HL cell lines as compared to normal B cells. The α catalytic subunit CK2 was localized both in the nucleus and the cytosol, while the β subunit was mainly cytosolic in HL cell lines. These data were confirmed on primary nodes of patients with HL using tissue microarray. This aberrant expression of protein CK2 was not associated with different mRNA levels of CSNK2A1 and CSNK2B, genes coding for the α and β subunit respectively. We observed that CK2 substrates namely NF-κB, STAT3, AKT were constitutively phosphorylated on activatory serine amino acids (NF-κB Ser529, STAT3 Ser727, AKT Ser473, AKT Ser129) in HL cell lines. The pharmacological inhibition of CK2 with the clinical inhibitor CX-4945/silmitasertib mediates time- and dose-dependent apoptosis and dephosphorylation of CK2 targets at activatory residues. Moreover, we demonstrated that silmitasertib was able to decrease the expression of the immuno-checkpoint CD297/PD-L1 but not of CD30, and to enhance the cytotoxicity caused by monomethyl auristatin E (MMAE), the microtubule inhibitor conjugated to an anti-CD30 monoclonal antibody in the brentuximab vedotin drug.
Comprehensively our data point out a pivotal role of CK2a in the survival, as well as the activation of some key signaling pathways, in HL and identify this kinase as a targetable kinase for the development of new effective therapy for this neoplastic disease. Remarkably a skewed expression between CK2 subunits has never been reported in other hematological cancers
Therapeutic Monoclonal Antibody Therapies in Chronic Autoimmune Demyelinating Neuropathies
Full text linkAutoimmune diseases of the peripheral nervous system have so far been treated mainly with exogenous high-dose intravenous immunoglobulins (IVIg), that act through several mechanisms, including neutralization of pathogenic autoantibodies, modulation of lymphocyte activity, interference with antigen presentation, and interaction with Fc receptors, cytokines, and the complement system. Other therapeutic strategies have recently been developed, in part to address the increasing shortage of IVIg, prime among which is the use of B cell depleting monoclonal antibodies, or small molecule inhibitors targeting the B-cell specific kinases. Rituximab, a chimeric monoclonal antibody against CD20 + B lymphocytes, is currently the most used, especially in anti-MAG antibody neuropathy and autoimmune neuropathies with antibodies to nodal/paranodal antigens that are unresponsive to IVIg. After several reports of its efficacy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), rituximab is currently under investigation in three Phase 2 trials in CIDP. In addition, the possible role of complement activation in the pathogenesis of chronic autoimmune neuropathies has brought into consideration drugs that can block the complement cascade, such as eculizumab, a monoclonal antibody already assessed in acute polyradiculoneuropathies, and approved for myasthenia gravis. Preliminary data on eculizumab in multifocal motor neuropathy have been published, but randomized controlled studies are pending. Moreover, the neonatal Fc receptor, that recycles IgGs by preventing their lysosome degradation, is an important and attractive pharmacological target. Antibodies against FcRn, which reduce circulating IgG (both pathogenic and non-pathogenic) have been developed. The FcRn blocker efgartigimod, a humanized IgG1-derived Fc fragment, which competitively inhibits the FcRn, has recently been approved for the treatment of myasthenia gravis and is currently under investigation in CIDP. In addition, the anti-human FcRn monoclonal antibody rozanolixizumab is currently being assessed in phase 2 trials in CIDP. However, none of the abovementioned monoclonal antibodies is currently approved for treatment of any immune-mediated neuropathies. While more specific and individualized therapies are being developed, the possibility of combined treatments targeting different pathogenic mechanisms deserves consideration as well. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01222-x
Prospects of antibody therapies in Chronic Autoimmune Neuropathies (CIDP, MMN, Anti-MAG)
No full textEditorial: Immune system interactions in hematological tumor microenvironments: pathways to innovative treatments
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Hospital Falls: retrospective analysis of risk factors and prevention strategies in a healthcare organization in northern Italy
No full textBackground: Hospital falls represent a critical patient safety issue, despite being potentially preventable events. Effective management is carried out through clinical risk assessment and requires a thorough evaluation of risk factors, incident reporting, and the implementation of targeted interventions. This study focuses on analyzing falls in a healthcare organization in Northern Italy during the period 2020-2022, examining variables such as risk factors, fall locations, and clinical and organizational consequences. Objective: To quantify and analyze hospital falls within the examined healthcare organization, stratifying by age, gender, operational unit, fall location, intrinsic and extrinsic factors, and assessing the impact on patients in terms of diagnostic tests, reported injuries, and management of incident reporting forms. Additionally, the study aims to evaluate existing organizational proposals for fall management adopted by the healthcare organization. Materials and methods: A retrospective, multicenter study conducted across five hospitals in a healthcare organization in Northern Italy, based on incident reporting data from 2020 to 2022. Statistical analysis includes the Kruskal-Wallis test, Dunn's test, Fisher's exact test, and the Chi-square test for continuous and categorical variables. Results: In a study of 1,032 incident reporting cases in a hospital, most falls (0.85% of the total) occurred primarily in hospital rooms (64.2%). The most common extrinsic factors included inappropriate footwear (17%). The medical area (58.33%) was the most affected by falls. Among intrinsic factors, 28% of cases showed cognitive deficits, while 13% had urinary and fecal urgency. Significant injuries were reported in 26% of patients, including contusions and fractures, with 23 sentinel events. Comparing the five hospitals (Hospital 1, Hospital 2, Hospital 3, Hospital 4, Hospital 5), falls were most frequent in hospital rooms (67.18%), with the most common extrinsic factors including inappropriate footwear (up to 26.3%). Significant intrinsic factors included cognitive deficits (up to 40%) and urinary/fecal urgency (up to 13.1%). Patient injuries were reported in approximately 28% of cases, with various hospitals highlighting specific issues such as incomplete incident reporting forms. Discussion: Hospital falls are influenced by multiple factors, including physical environments and patients' clinical conditions. Educational interventions and procedural reviews have contributed to improved risk management. It is essential to promote a hospital safety culture through integrated strategies addressing both human and organizational factors. Conclusions: Effective management of falls in hospitals within the Northern Italy healthcare organization requires multidimensional approaches and targeted interventions based on evidence. Implementing initiatives such as staff training and procedural revisions is crucial to improving patient safety and optimizing healthcare services
Bruton tyrosine kinase inhibitors: can they be optimized for the treatment of neuroinflammatory disorders?
No full textResponse to "Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients"
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