Context: The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a prognostic marker in several types of malignant tumors. The prognostic value of HALP score in diffuse large B-cell ...lymphoma (DLBCL) remains unknown.
Aim: We aimed to determine the prognostic value of baseline HALP score in DLBCL patients.
Subjects and Methods: We retrospectively analyzed data from 153 newly diagnosed DLBCL patients treated with R-CHOP or R-CHOP-like regimens at our university hospital center. We evaluated the significance of HALP score as a predictor of response to treatment, overall survival (OS), and event-free survival (EFS).
Results: The median follow-up time for all patients was 40 months. Lower HALP score was found in patients with advanced stages of disease (P = 0.005) and in those with poor response to therapy (P = 0.004). Patients with a HALP score ≤20.8 had significantly worse 5-year OS (47.3% vs. 79.5%, P < 0.001) and 5-year EFS (40.6% vs. 76.7%, P < 0.001). These observations remained statistically significant in the multivariate Cox regression models independently of International Prognostic Index (IPI) and age.
Conclusion: Lower HALP is associated with unfavorable clinicopathological characteristics of DLBCL and seems to be an IPI independent negative prognostic factor. HALP score can be easily and inexpensively applied to timely recognize DLBCL patients under higher risk of unwanted outcomes in everyday clinical practice.
The aim of this study was to develop and evaluate matrix assisted LASER desorption ionization (MALDI) time-of-flight (TOF) mass spectrometry imaging (MSI) of blood smear. Integrated light microscope ...and MALDI IT-TOF mass spectrometer, together with a matrix sublimation device, were used for analysis of blood smears coming from healthy male donors. Different blood plasma removal, matrix deposition, and instrumental settings were evaluated using the negative and positive ionization modes while agreement between the light microscopy images and the lateral distributions of cellular marker compounds served as the MSI quality indicator. Red and white blood cells chemical composition was analyzed using the differential
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expression. Five seconds of exposure to ethanol followed by the 5 min of 9-aminoacridine or α-cyano-4-hydroxycinnamic acid deposition, together with two sets of instrumental settings, were selected for the MALDI TOF MSI experiments. Application of the thin and transparent matrix layers assured good correspondence between the LASER footprints and the preselected regions of interest. Cellular marker
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signals coincided well with the appropriate cells. A metabolite databases search using the differentially expressed
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produced hits which were consistent with the respective cell types. This study sets the foundations for application of blood smear MALDI TOF MSI in clinical diagnostics and research.
Patients with lymphoid malignancies are at increased risk of death or prolonged infection due to COVID-19. Data on the influence of different antineoplastic treatment modalities on outcomes are ...conflicting. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is unclear whether this risk is affected by the choice of the antibody (rituximab vs. obinutuzumab). To elucidate the role of antineoplastic therapy on COVID-19 outcomes, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID-19 between October 2020 and April 2021. A total of 314 patients were identified, 75 untreated, 61 off treatment and 178 on treatment. The mortality rate in untreated and off-treatment patients was 15% and 16%; 9% and 10% had prolonged infection. In the on-treatment group, 3% were still prolonged positive at time of data collection, 62% recovered and 35% died; 42% had prolonged infection. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older patients (
= 0.0078) and those treated with purine analogues (
= 0.012). Prolonged COVID-19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (
= 0.012), especially obinutuzumab, and purine analogues (
= 0.012). Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. These data suggest that increased age and use of purine analogues are main risk factors for increased mortality of COVID-19 in patients with lymphoid malignancies. Obinutuzumab further increases the risk of prolonged disease, but not of death, in comparison to rituximab. Epidemiological considerations should be taken into account when choosing the appropriate antineoplastic therapy for patients with lymphoid malignancies.
Elderly patients make up a significant number of cases of newly diagnosed Hodgkin lymphoma. However, unlike in young patients, the outcomes of elderly patients are poor, and they are ...under-represented in phase III trials. Prior to treatment initiation, geriatric assessment should ideally be performed to address the patient's fitness and decide whether to pursue a curative or palliative approach. The ABVD regimen is poorly tolerated in unfit patients, with high treatment-related mortality. Alternative chemotherapy approaches have been explored, with mixed results obtained concerning their feasibility and toxicity in phase II trials. The introduction of brentuximab vedotin-based regimens led to a paradigm shift in first- and further-line treatment of elderly Hodgkin lymphoma patients, providing adequate disease control within a broader patient population. As far as checkpoint inhibitors are concerned, we are only just beginning to understand the role in the treatment of this population. In relapsed/refractory settings there are few options, ranging from autologous stem cell transplantation in selected patients to pembrolizumab, but unfortunately, palliative care is the most common modality. Importantly, published studies are frequently burdened with numerous biases (such as low numbers of patients, selection bias and lack of geriatric assessment), leading to low level of evidence. Furthermore, there are few ongoing studies on this topic. Thus, elderly Hodgkin lymphoma patients are hard to treat and represent an unmet need in hematologic oncology. In conclusion, treatment needs to be personalized and tailored on a case-by-case basis. In this article, we outline treatment options for elderly Hodgkin lymphoma patients.
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•Single-cell MALDI TOF MS imaging of CD19+ lymphocytes was developed.•Single-cell MS provides CD19+ lymphocytes’ classification accuracy >90 %.•CD19+ lymphocytes’ mass spectra show ...numerous specific changes in CLL.•Metabolic pathways affected in CLL include single-carbon metabolism and apoptosis.
Modern mass spectrometry imaging (MSI) enables single cells’ metabolism exploration. Aims of this study were development of the single-cell MSI of human CD19+ lymphocytes and metabolic profiling of chronic lymphocytic leukemia (CLL).
Blood donor (BD) samples were used for the optimization of CD19+ lymphocyte isolation and single-cell matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) MSI. Independent set of 200 CD19+ lymphocytes coming from 5 CLL patients and 5 BD was used for the CD19+ lymphocytes classification assessment and the untargeted metabolic profiling. CLL vs BD lymphocyte classification was performed using partial least squares-discriminant analysis (PLS-DA) using normalized single-cell mass spectra recorded in 300–600 and 600–950 Da ranges was applied.
Accuracy assessed by 10-fold cross-validation of CD19+ lymphocyte PLS-DA classification reached >90.0 %. Volcano plots showed 106 significantly altered m/z signals in CLL of which 9 were tentatively annotated. Among tentatively annotated m/z signals formaldehyde and glutathione metabolites and tetrahydrofolate stand out.
A method for single-cell MALDI TOF MSI of CD19+ lymphocytes was successfully developed. The method confirmed the significance of oxidative stress and single-carbon metabolism, pyruvate and fatty acid metabolism and apoptosis in CLL and it provided metabolic candidates for diagnostic applications.
Function of Circle of Willis Vrselja, Zvonimir; Brkic, Hrvoje; Mrdenovic, Stefan ...
Journal of cerebral blood flow and metabolism,
04/2014, Letnik:
34, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Nearly 400 years ago, Thomas Willis described the arterial ring at the base of the brain (the circle of Willis, CW) and recognized it as a compensatory system in the case of arterial occlusion. This ...theory is still accepted. We present several arguments that via negativa should discard the compensatory theory. (1) Current theory is anthropocentric; it ignores other species and their analog structures. (2) Arterial pathologies are diseases of old age, appearing after gene propagation. (3) According to the current theory, evolution has foresight. (4) Its commonness among animals indicates that it is probably a convergent evolutionary structure. (5) It was observed that communicating arteries are too small for effective blood flow, and (6) missing or hypoplastic in the majority of the population. We infer that CW, under physiologic conditions, serves as a passive pressure dissipating system; without considerable blood flow, pressure is transferred from the high to low pressure end, the latter being another arterial component of CW. Pressure gradient exists because pulse wave and blood flow arrive into the skull through different cerebral arteries asynchronously, due to arterial tree asymmetry. Therefore, CW and its communicating arteries protect cerebral artery and blood–brain barrier from hemodynamic stress.
Coronavirus infectious disease (CoVID-19), caused by recently identified coronavirus SARS-CoV-2, is characterized by inconsistent clinical presentations. While many infected individuals remain ...asymptomatic or show mild respiratory symptoms, others develop severe pneumonia or even respiratory distress syndrome. So far, SARS-CoV-2 is reported to be able to infect lungs, intestines, blood vessels, bile ducts, conjunctiva, macrophages, T lymphocytes, heart, liver, kidneys and the brain. More than a third of cases displayed neurological involvement, and in many severely ill patients, multiple organ injury and infection was documented. However, less than 1% of patients had a detectable level of SARS-CoV-2 in the blood, raising a question of how the virus spreads throughout the body. We propose that nerve terminals in orofacial mucosa, eyes and olfactory neuroepithelium act as entry points for the brain invasion, allowing SARS-CoV-2 to infect the brainstem. By exploiting the subcellular membrane compartments of infected cells, a feature common to all coronaviruses, SARS-CoV-2 is capable to disseminate from the brain to periphery via vesicular axonal transport and passive diffusion through axonal endoplasmic reticula, causing multiple organ injury independently of an underlying respiratory infection. The proposed model clarifies a wide range of clinically observed phenomena in CoVID-19 patients, such as neurological symptoms unassociated with lung pathology, findings of protracted presence of the virus in samples obtained from recovered patients, exaggerated immune response, multiple organ failure in severe cases with variable course and dynamics of the disease. The proposed model provides novel insights into CoVID-19 and its potential long-term sequelae, and establishes a framework for further investigations.
Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, plays oncogenic or antitumoral roles in malignant tumors depending on the type of tumor cell. However, how this ...histone modifier affects the progression of prostate cancer (PCa) is still unknown. Here we analyzed sequenced gene expression data and tissue microarray to explore the expression features and prognostic value of KDM6B in PCa. Further, we performed in vitro cell biological experiments and in vivo nude mouse models to reveal the biological function, upstream and downstream regulation mechanism of KDM6B. In addition, we investigated the effects of a KDM6B inhibitor, GSK-J4, on PCa cells. We showed that KDM6B overexpression was observed in PCa, and elevated KDM6B expression was associated with high Gleason Score, low serum prostate-specific antigen level and shorted recurrence-free survival. Moreover, KDM6B prompted proliferation, migration, invasion and cell cycle progression and suppressed apoptosis in PCa cells. GSK-J4 administration could significantly suppress the biological function of KDM6B in PCa cells. KDM6B is involved in the development of castration-resistant prostate cancer (CRPC), and combination of MDV3100 plus GSK-J4 is effective for CRPC and MDV3100-resistant CRPC. Mechanism exploration revealed that androgen receptor can decrease the transcription of KDM6B and that KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with smad2/3 to prompt the expression of cyclin D1. In conclusion, our study demonstrates that KDM6B is an androgen receptor regulated gene and plays oncogenic roles by promoting cyclin D1 transcription in PCa and GSK-J4 has the potential to be a promising agent for the treatment of PCa.
Anesthetics are essential agents that are frequently used in clinical practice to induce a reversible loss of consciousness and sensation by depressing the central nervous system. The inhalational ...anesthetics isoflurane and sevoflurane are preferred due to their rapid induction and recovery times and ease of administration. Despite their widespread use, the exact molecular mechanisms by which these anesthetics induce anesthesia are not yet fully understood. In this study, the age-dependent effects of inhalational anesthetics on two demyelination models were investigated: congenital (B4galnt1-null) and chemically induced (cuprizone). Various motor and cognitive tests were used to determine sensitivity to isoflurane and sevoflurane anesthesia. B4galnt1-null mice, which exhibit severe motor deficits due to defects in ganglioside synthesis, showed significant impairments in motor coordination and balance in all motor tests, which were exacerbated by both anesthetics. Cuprizone-treated mice, which mimic the demyelination in B4galnt1-null mice, also showed altered, age-dependent sensitivity to anesthesia. The study showed that older mice exhibited more pronounced deficits, with B4galnt1-null mice showing the greatest susceptibility to sevoflurane. These differential responses to anesthetics suggest that age and underlying myelin pathology significantly influence anesthetic effects.
Keratins (KRTs) are intermediate filament proteins that interact with multiple regulatory proteins to initiate signaling cascades. Keratin 13 (KRT13) plays an important role in breast cancer ...progression and metastasis. The objective of this study is to elucidate the mechanism by which KRT13 promotes breast cancer growth and metastasis.
The function and mechanisms of KRT13 in breast cancer progression and metastasis were assessed by overexpression and knockdown followed by examination of altered behaviors in breast cancer cells and in xenograft tumor formation in mouse mammary fat pad. Human breast cancer specimens were examined by immunohistochemistry and multiplexed quantum dot labeling analysis to correlate KRT13 expression to breast cancer progression and metastasis.
KRT13-overexpressing MCF7 cells displayed increased proliferation, invasion, migration and in vivo tumor growth and metastasis to bone and lung. Conversely, KRT13 knockdown inhibited the aggressive behaviors of HCC1954 cells. At the molecular level, KRT13 directly interacted with plakoglobin (PG, γ-catenin) to form complexes with desmoplakin (DSP). This complex interfered with PG expression and nuclear translocation and abrogated PG-mediated suppression of c-Myc expression, while the KRT13/PG/c-Myc signaling pathway increased epithelial to mesenchymal transition and stem cell-like phenotype. KRT13 expression in 58 human breast cancer tissues was up-regulated especially at the invasive front and in metastatic specimens (12/18) (p < 0.05). KRT13 up-regulation in primary breast cancer was associated with decreased overall patient survival.
This study reveals that KRT13 promotes breast cancer cell growth and metastasis via a plakoglobin/c-Myc pathway. Our findings reveal a potential novel pathway for therapeutic targeting of breast cancer progression and metastasis.
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