Preparing for the future of healthcare: Digital health literacy among medical students in Lahore, Pakistan.

Objective: Digital Health Literacy (DHL) is becoming a cardinal competence for all healthcare professionals (HCPs) including medical students for meaningful digital transformation of healthcare. As medical students need to navigate an increasingly digitalized healthcare environment, thus the study's objective was to assess digital health literacy among medical students. Methods: This cross-sectional analytical study was conducted at King Edward Medical University, Lahore from October 2022 to August 2023. Medical students were asked to complete a pen and paper questionnaire of the Digital Health Literacy Instrument (DHLI) after informed consent. DHLI covers seven categories: operational skills, information searching strategy, analyzing the usefulness of online information, navigational abilities, contributing user-generated material to internet-based platforms, and privacy protection. SPSS was used for data analysis. Results: Eight hundred ninety one medical students, from first year to final year, participated in the study. The overall mean score for DHL was 63.5 (SD=8.82). Medical students achieved a score of 83.2% of total score in their operational abilities, and 82.3% proficiency in privacy protection, which were deemed highly desirable. Furthermore, they achieved a satisfactory level in navigation skill (76.0%), information searching (73.1%), adding content (71.0%), determining the significance of data (70.1%), and assessing data reliability (68.7%), based on the overall score. A significant relationship was observed between the performance level of DHL domains and gender with higher scores in males in all domains except protecting privacy, which was higher in females and clinical years students (p-value < 0.05). Conclusion: The assessment of the DHL of medical students was deemed desirable. But certain obstacles were encountered in few domains of DHL i.e., data reliability, relevance determination, and content augmentation. It is imperative to elevate the level of DHL of medical students to harness the potential of digital technologies in enhancing healthcare.

Single-cell RNA sequencing in double-hit lymphoma: IMPDH2 induces the progression of lymphoma by activating the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: IMPDH2 is the rate-limiting enzyme of the de novo GTP synthesis pathway and has a key role in tumors; however, the specific mechanism underlying IMPDH2 activity in diffuse large B cell lymphoma (DLBCL) is still undetermined. This study aims to explore the potential mechanism of IMPDH2 in DLBCL, and its possible involvement in double-hit lymphoma (DHL), i.e., cases with translocations involving MYC and BCL2 and/or BCL6. METHODS: Using single-cell sequencing and bioinformatics analysis to screen for IMPDH2. Exploring the differential expression of IMPDH2 and its correlation with prognosis through multiplexed immunofluorescence analysis. Using CCK8, EdU, clone formation assay, and animal model to analyze biological behavior changes after inhibiting IMPDH2. Explaining the potential mechanism of IMPDH2 in DLBCL by Western blot and multiplexed immunofluorescence. RESULTS: Prognostic risk model was constructed by single-cell sequencing, which identified IMPDH2 as a DHL-related gene. IMPDH2 was highly expressed in cell lines and tissues, associated with poor patient prognosis and an independent prognostic factor. In vitro and in vivo experiments showed that IMPDH2 inhibition significantly inhibited DHL cell proliferation. Flow cytometry showed apoptosis and cycle arrest. Western blot results suggested that c-Myc regulated the activation of PI3K/AKT/mTOR signaling pathway by IMPDH2 to promote tumor development in DHL. Moreover, multiplex immunofluorescence revealed decreased T-cell infiltration within the tumor microenvironment exhibiting concurrent high expression of IMPDH2 and PD-L1. CONCLUSIONS: Our results suggest that IMPDH2 functions as a tumor-promoting factor in DHL. This finding is expected to generate novel insights into the pathogenesis of these patients, thereby identifying potential therapeutic targets.

Induction treatment in high-grade B-cell lymphoma with a concurrent MYC and BCL2 and/or BCL6 rearrangement: a systematic review and meta-analysis.

Background and aim: High-grade B cell lymphomas with concomitant MYC and BCL2 and/or BCL6 rearrangements (HGBCL-DH/TH) have a poor prognosis when treated with the standard R-CHOP-like chemoimmunotherapy protocol. Whether this can be improved using intensified regimens is still under debate. However, due to the rarity of HGBCL-DH/TH there are no prospective, randomized controlled trials (RCT) available. Thus, with this systematic review and meta-analysis we attempted to compare survival in HGBCL-DH/TH patients receiving intensified vs. R-CHOP(-like) regimens. Methods: The PubMed and Web of Science databases were searched for original studies reporting on first-line treatment in HGBCL-DH/TH patients from 08/2014 until 04/2022. Studies with only localized stage disease, ≤10 patients, single-arm, non-full peer-reviewed publications, and preclinical studies were excluded. The quality of literature and the risk of bias was assessed using the Methodological Index for Non-Randomized Studies (MINORS) and National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Random-effect models were used to compare R-CHOP-(like) and intensified regimens regarding 2-year overall survival (2y-OS) and 2-year progression-free survival (2y-PFS). Results: Altogether, 11 retrospective studies, but no RCT, with 891 patients were included. Only four studies were of good quality based on aforementioned criteria. Intensified treatment could improve 2y-OS (hazard ratio [HR]=0.78 [95% confidence interval [CI] 0.63-0.96]; p=0.02) as well as 2y-PFS (HR=0.66 [95% CI 0.44-0.99]; p=0.045). Conclusions: This meta-analysis indicates that intensified regimens could possibly improve 2y-OS and 2y-PFS in HGBCL-DH/TH patients. However, the significance of these results is mainly limited by data quality, data robustness, and its retrospective nature. There is still a need for innovative controlled clinical trials in this difficult to treat patient population. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022313234.

Antitumor Effects of Poplar Propolis on DLBCL SU-DHL-2 Cells.

Propolis is resinous natural product produced by Western honeybees using beeswax and plant and bud exudates, which has a wide range of biological activities, including antioxidation, antibacterial, anti-inflammation, immune regulation, antitumor, and so on. Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer, and accounts for about 30% of all lymphomas. The effect of poplar propolis on DLBCL has not been reported. The IC50 of propolis on the proliferation of DLBCL SU-DHL-2 cell line and its proteins and gene expressions were detected by CCK-8 kit, label-free proteomic, and RT-PCR. The results showed that the IC50 of propolis at the 5 × l05/mL cell for 24 h was 5.729 µg/mL. Label-free-based proteomics analysis showed that there were 115 differentially expressed proteins (61 up-regulated and 54 down-regulated proteins) between IC50 dose-treated and solvent control groups. There were 32.47% differential proteins located in the nucleus, 20.78% in the cytoplasm, and 14.29% in mitochondria. The most significant different pathway (p = 0.0016) of protein enrichment was ferroptosis (including glutamate-cysteine ligase regulatory subunit, ferritin, and heme oxygenase). The relative expression trend of 17 of the total 22 genes selected according to proteomics results was in line with their encoded protein. The highest protein-protein interaction was serine/threonine-protein kinase PLK, which interacted with 16 differential proteins. In conclusion, poplar propolis inhibited SU-DHL-2 cells via ferroptosis pathway, accelerating cell death and down-regulated serine/threonine-protein kinase PLK1, affecting apoptosis of cell. This result provides a theoretical basis for the treatment of DLBCL using propolis.

Orelabrutinib and venetoclax synergistically induce cell death in double-hit lymphoma by interfering with the crosstalk between the PI3K/AKT and p38/MAPK signaling.

PURPOSE: Double-hit lymphoma (DHL) is a rare and aggressive mature B-cell malignancy with concurrent MYC and BCL2 rearrangements. When DHL becomes relapsed or refractory, it becomes resistant to the majority of therapeutic approaches and has subpar clinical results. Therefore, innovative therapeutics for this particular patient population are urgently needed. METHODS: Orelabrutinib, a new oral BTK inhibitor, combined with the Bcl-2 inhibitor venetoclax, was used to confirm the antitumor effect of DHL. Cell counting kit-8 and Annexin V-FITC/PI assays were used to examine the interaction of this combined regimen on DHL cell lines and primary lymphoma cells. RNA sequencing, EdU incorporation assay, mitochondrial membrane potential assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of orelabrutinib with or without venetoclax against DHL cell lines. RESULTS: In this study, orelabrutinib combined with venetoclax synergistically induced DHL cell death, as evidenced by the inhibition of cell proliferation, the induct of cell cycle arrest, and the promotion of cell apoptosis via the mitochondrial pathway. Orelabrutinib treatment alters genome-wide gene expression in DHL cells. The combined regimen decreases the expression of BTK and Mcl-1, potentially interfering with the activity and crosstalk of PI3K/AKT signaling and p38/MAPK signaling. In addition, the combination of orelabrutinib and venetoclax shows cytotoxic activity in primary B-lymphoma cells. CONCLUSION: In summary, these findings reveal a novel therapy targeting BCR signaling and the Bcl-2 family for DHL patients with a poor prognosis.

Cell of origin is not associated with outcomes of relapsed or refractory diffuse large B cell lymphoma.

Activated B cell (ABC) type diffuse large B cell lymphoma (DLBCL), double hit lymphoma (DHL) and double expressor lymphoma (DEL) have poor outcomes to frontline R-CHOP but impact of these molecular features on outcomes of relapsed/refractory (R/R) disease is not well-characterized. We evaluated the association of diagnostic cell of origin (COO), double hit and double expressor status with overall survival after first relapse in DLBCL patients who were enrolled into the Molecular Epidemiology Resource (MER) cohort. COO was available from immunohistochemistry (IHC) using Hans criteria or gene expression profiling (GEP) (Nanostring) on the diagnostic FFPE biopsy. Of 373 pts with R/R DLBCL, 278 had COO by IHC: 152 were GCB, 107 were non-GCB. One hundred and fourty had COO by GEP: 44 were ABC, 65 were GCB and 13 were unclassifiable. Nineteen out of 163 (12%) were DHL; 30 out of 135 (22%) had DEL. COO, either by IHC (2 years OS GCB: 45% [CI95 : 38-54] vs. non-GCB: 44% [CI95 :36-55], p > 0.05) or GEP (2 years OS ABC: 42% [CI95 : 29-59] vs. GCB: 40% [CI95 : 30-54], p > 0.05), was not associated with difference in OS. DHL (2 years OS 16 [CI95 :6-45] vs. 45% [CI95 : 34-59], p < 0.01) and DEL (2 years OS 33% [CI95 : 20-56], vs. 50% [CI95 : 41-60], p < 0.05) had lower OS than non-DHL and non-DEL/non-DHL counterparts, respectively. COO by IHC or GEP was not associated with OS in R/R DLBCL while DHL and DEL were adverse prognostic markers in DLBCL at first relapse.

Therapeutic efficacy of an injectable formulation of purinostat mesylate in SU-DHL-6 tumour model.

Background: Previous studies have proven that Purinostat Mesylate (PM) is a new HDAC inhibitor and exhibits significant antitumor efficacy. However, the clinical application of PM was greatly limited by its poor solubility in water and low bioavailability.Objective:To increase the solubility of PM through pharmaceutical research, and prepare it into an injection that meets the needs of intravenous use to promote its clinical application.MethodsThe prepared PM/HP-ß-CD inclusion complex was studied by computer simulation, fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (1H-NMR spectroscopy), and scanning electron microscopy (SEM). Then, the antitumor effects of PM/HP-ß-CD inclusion complex were studied by in vitro cytotoxicity assay, apoptosis assay, pharmacokinetic study and in vivo antitumor assay.Results:Phase Solubility Analysis revealed that PM and HP-ß-CD were compatible and the solubility of PM increased almost 220 times, to 2.02 mg/mL. The interaction mechanism studies revealed that PM could be embedded into the cavity of HP-ß-CD through the side of the aminobenzene ring. Cell viability and apoptosis assays showed that PM/HP-ß-CD complex maintained the good anti-cancer activity of PM, and PM/HP-ß-CD complex has a better anti-tumor effect and lower toxicity than LBH589 and Hyper-CVAD/RTX in vivo. All the results suggest that HP-ß-CD can solve the problem of PM administration and provide a way for clinical application of PM.Conclusions: In this study, an injectable formulation of PM in HP-ß-CD (10% w/v) was prepared to improve its water solubility. Our research provides a way for clinical administration of PM, which has been under phase I clinical trial for the treatment of relapsed or refractory B-cell-related hematologic malignancies in China and the USA.KEY MESSAGESWe developed a preparation of Purinostat Mesylate that can be administered intravenously, reducing the toxicity associated with oral administration.This preparation has an outstanding therapeutic effect on SU-DHL-6 xenograft tumour, indicating its clinical value, which has been under phase I clinical trial for the treatment of relapsed or refractory B-cell-related haematologic malignancies in China and the USA.

MiR-665 suppresses the progression of diffuse large B cell lymphoma (DLBCL) through targeting LIM and SH3 protein 1 (LASP1).

Diffuse large B cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma worldwide, is aggressive and highly heterogeneous. MiR-665 was found to be lowly expressed in serum exosomes of DLBCL patients and in DLBCL cell lines, but its function in DLBCL progression remains unclear. In this study, miR-665 was overexpressed in SU-DHL-4 cells via miR-665 mimics and knocked down in FARAGE cells via miR-665 inhibitor. Knockdown of miR-665 promoted DLBCL cell proliferation and invasion and decreased cell apoptosis, whereas miR-665 overexpression showed opposite effects on DLBCL cell malignant behaviors. Luciferase reporter assay confirmed LIM and SH3 protein 1 (LASP1) and MYC as target genes of miR-665. Moreover, the expression of LASP1 was negatively correlated with that of miR-665 in LDLBCL cells. LASP1 has tumor-promoting property and its inhibition abolished the effect of miR-665 knockdown on DLBCL cell proliferation, invasion, and apoptosis. SU-DHL-4 cells were inoculated into the flank of nude mice, followed by orthotopic injection with miR-665 agomir. MiR-665 overexpression restricted tumor growth in vivo. Thus, we demonstrates that miR-665 suppresses DLBCL cell malignant behaviors by inhibiting cell proliferation and invasion and inducing apoptosis via targeting LASP1 and MYC, suggesting the importance of miR-665 in DLBCL progression.

Dehydrocostuslactone attenuated oxygen and glucose deprivation/reperfusion-induced PC12 cell injury through inhibition of apoptosis and autophagy by activating the PI3K/AKT/mTOR pathway.

The purpose of this study is to investigate the protective effect of dehydrocostuslactone (DHL) on PC12 cells injury induced by oxygen and glucose deprivation/reperfusion (OGD/R) and its possible mechanism on the PI3K/AKT/mTOR pathway. The maestro 11.1 software was used to predict the binding sites of DHL with LC3, Beclin-1, PI3K, AKT, mTOR, Bax, Bcl-2, Caspase-3, Caspase-9, and Caspase-7. We used a cellular model of 2 h of OGD and 24 h of reperfusion to mimic cerebral ischemia-reperfusion injury. Cells were treated with DHL during the reperfusion phase. The docking results showed that DHL had binding sites with LC3, Beclin-1, PI3K, AKT, mTOR, Bax, Bcl-2, Caspase-3, Caspase-9, and Caspase-7. The expression levels of autophagy-related proteins, LC3 and Beclin-1 increased while P-PI3K, P-AKT, and P-mTOR decreased. Apoptosis-related proteins, namely, Bax, Cyto-c, Caspase-3, Caspase-7, Caspase-9 increased, but the anti-apoptosis Bcl-2 protein decreased. However, DHL effectively inhibited these undesirable changes induced by OGD/R in PC12 cells. Our results suggested that DHL attenuated OGD/R-induced neuronal injury by inhibiting apoptosis and autophagy by activating PI3K/AKT/mTOR signaling. This inhibition can improve cell survival and offer evidence for the beneficial effects of DHL on the nervous system.

CS2164 and Venetoclax Show Synergistic Antitumoral Activities in High Grade B-Cell Lymphomas With MYC and BCL2 Rearrangements.

High-grade B-cell lymphoma with concurrent MYC and BCL2 rearrangements (HGBL-DHL) is a rare, aggressive mature B-cell malignancy with a high likelihood of treatment failure following front-line immunochemotherapies. Patients with HGBL-DHL who develop a relapsed or refractory disease have little effective therapeutic strategies and show very poor clinical outcomes, thus calling for development of novel therapies for this specific patient population. In this study, we investigated the preclinical anti-lymphoma efficacies and potential mechanism of action of a novel treatment approach, combining the BCL2 inhibitor venetoclax with CS2164, a new orally active multitarget inhibitor, in HGBL-DHL models. This combination therapy exhibited a robust synergistic cytotoxicity against HGBL-DHL cells, evidenced by cooperatively inducing loss of cell viability and promoting cell apoptosis. Moreover, coadministration of CS2164 and venetoclax resulted in significant superior suppression of HGBL-DHL cell growth and remarkably abrogated tumor burden in a HGBL-DHL-xenografted mouse model. The synergistic lethality of CS2164 and venetoclax in HGBL-DHL cells was associated with induction of DNA damage and impairment of DNA repair ability. Of importance, the combined treatment almost abolished the expression of both BCL2 and MYC, two hallmark proteins of HGBL-DHL, and substantially blunted the activity of PI3K/AKT/mTOR signaling cascade. In addition, MCL1 and BCL-XL, two well-characterized contributors for venetoclax resistance, were significantly lessened in the presence of CS2164 and venetoclax, thus leading to the accumulation of proapoptotic proteins BAX and PUMA and then initiating the intrinsic apoptosis pathway. Taken together, these findings suggest that the regimen of CS2164 and venetoclax is highly effective to eliminate HGBL-DHL cells in the preclinical setting, warranting further clinical investigations of this regimen for the treatment of unfavorable HGBL-DHL patients.

Complement C5a-triggered differentiated HL-60 stimulates migration of THP-1 monocytic leukocytes via secretion of CCL2.

Leukocytes play an important role in vascular inflammation prior to atherosclerosis. In particular, monocyte adhesion and migration to the endothelium contribute to the development of vascular inflammation. Previously, we showed the importance of neutrophils and complement C5a in the early phase of vascular inflammation in mice fed a high-fat diet. However, the relationship between monocytes and neutrophils is not well understood. In this study, we elucidated the involvement of neutrophils in the migration of monocytes. We observed that C5a induces CCL2 expression in neutrophil-like dHL-60 cells. To investigate the physiological significance of CCL2 secretion, we performed a chemotaxis assay. Interestingly, dHL-60 culture supernatant in the presence of C5a enhanced the migration of THP-1 in comparison with the absence of C5a. Furthermore, CCL2 expression and secretion significantly increased in C5a-stimulated dHL-60 through the phosphorylation of NF-κB p65. Actin polymerization on THP-1 was enhanced by the presence of C5a compared with the absence of C5a when stimulated by a dHL-60-cultured medium. These results suggest that crosstalk between neutrophils and monocytes via CCL2 may play an important role in vascular inflammation.

Testing a school-based program to promote digital health literacy and healthy lifestyle behaviours in intermediate elementary students: The Learning for Life program.

Promoting digital health literacy and healthy lifestyle behaviours in children can lead to positive long-term health outcomes and prevent chronic diseases. However, there are few school-based interventions promoting this education to intermediate elementary students. The objective of this study was to test the effectiveness of a novel intervention to increase students' digital health literacy and health knowledge. Learning for Life is a classroom-based education program, developed for grade 4-7 students and delivered by teachers over six weeks. Three Canadian schools were recruited to deliver the intervention in 2018. This study had a pre-post design and no control group. Students' self-reported digital health literacy and healthy lifestyle behaviours were measured at pre-intervention (n = 126), post-intervention (n = 119), and two-month follow-up (n = 104). Students at pre-intervention had a mean (SD) age of 10.98 (0.56) years (57.1% females). Almost all (97%) students had unsupervised access to the Internet through a computer or smartphone. From pre- to post-intervention, students' digital health literacy increased (p = 0.009), but decreased from post-intervention to follow-up (p < 0.001). Post-intervention, the majority of students could identify at least one healthy behaviour (e.g., exercising one hour/day) and reported making at least one healthy change in their lives (e.g., eating more fruits/vegetables). This study demonstrated that the Learning for Life intervention can improve intermediate elementary students' digital health literacy over the short-term and help them learn and retain healthy lifestyle knowledge and behaviours. These findings affirm the need for interventions promoting digital healthy literacy and healthy lifestyle behaviours for this age group.

Rational targeted therapeutics for double-hit lymphoma.

"Double-hit lymphomas with MYC and BCL2 translocations can be effectively treated by combined targeting of the driver oncogenes".

Efficacy of dose-adjusted EPOCH plus rituximab/R-CHOP regimens and the prognosis analysis in patients with MYC, BCL2/BCL6 gene copy number gain lymphoma and double-hit lymphoma: results from a single institution retrospective clinical study.

PURPOSE: To compare the efficacy of rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-DA-EPOCH) with traditional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimens in double-hit lymphoma (DHL) and gene copy number gain (CNG) lymphoma and to contrast the prognosis of these two disease types. METHODS: We retrospectively examined 127 cases of newly diagnosed diffuse large B-cell lymphoma (DLBCL), and used fluorescence in situ hybridization (FISH) to detect genetic abnormalities in MYC, BCL2, and BCL6. RESULTS: In the two schemes, the 2-year progression-free survival (PFS) was higher for R-DA-EPOCH group than for R-CHOP (79.8% vs 57.5%, P=0.002), this advantage was also reflected in 2-year overall survival (OS) (81.6% vs 58.5%, P=0.002). In double CNG patients, R-DA-EPOCH regimen was significantly better than R-CHOP (P=0.007 for PFS, P=0.010 for OS), and R-DA-EPOCH has the same advantage in DHL patients (P=0.001 for PFS, P=0.047 for OS). For the two disease types, the PFS for DHL was inferior to that for double CNG (52.9% vs 72.4%, P=0.008), while the OS was not significantly different (P=0.050). Subgroup analysis showed that the PFS for double CNG with MYC and BCL2 was superior to that for DHL with MYC and BCL2 (P=0.043), this trend is also seen in double CNG and DHL with MYC and BCL6 (P=0.036). However, the OS was not significantly different between the two subgroups. Multivariate analyses showed that in DLBCL patients with genetic abnormality detected by FISH, the treatment and disease types were independent prognostic factors. The adverse reaction rates were similar in R-DA-EPOCH and R-CHOP (P>0.05). CONCLUSION: Our retrospective study shows that DHL has a poorer prognosis than double CNG. Based on its improved lifetime and good tolerance, R-DA-EPOCH is a promising regimen for DHL or double CNG, which is expected to become the first-line treatment for high-risk DLBCL types based on more clinical research.

The utility of DHL-HisZnNa, a novel antioxidant, against anticancer agent-induced alopecia in breast cancer patients: a multicenter phase II clinical trial.

PURPOSE: Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of anticancer drugs; however, there are currently no mechanisms to completely prevent CIA. In this study, we performed a clinical trial to examine whether sodium N-(dihydrolipoyl)-l-histidinate zinc complex (DHL-HisZnNa), an alpha-lipoic acid derivative, prevents CIA in patients with breast cancer. METHODS: Between July 2014 and May 2015, we performed a multi-center, single arm, clinical trial involving 103 breast cancer patients who received adjuvant chemotherapy at three medical institutions in Japan. During chemotherapy, a lotion containing 1% DHL-HisZnNa was applied daily to the patients' scalps. The primary endpoint was the incidence of grade 2 alopecia; the secondary endpoints were the duration of grade 2 alopecia, alopecia-related symptoms, and drug-related adverse events. Alopecia was evaluated by three independent reviewers using head photographs taken from four angles. RESULTS: Safety analysis was performed for 101 patients who started the protocol therapy. After excluding one patient who experienced disease progression during treatment, 100 patients who received at least two courses of chemotherapy underwent efficacy analysis. All original 101 patients developed grade 2 alopecia, the median durations of which were 119 days (112-133 days) and 203 days (196-212 days) in the groups treated with four and eight courses of chemotherapy, respectively. Mild or moderate adverse events potentially related to DHL-HisZnNa were observed in 11 patients. Alopecia-related symptoms were observed in 53 patients (52%). CONCLUSIONS: The application of 1% DHL-HisZnNa to the scalp did not prevent CIA. However, this drug may promote recovery from CIA. TRIAL REGISTRATION NUMBER: UMIN000014840.

Advances in pathological understanding of high-grade B cell lymphomas.

INTRODUCTION: The designation high-grade B-cell lymphoma (HGBL) has been incorporated into the 2016 Revision of the WHO classification of lymphoid neoplasms and includes two types: (1) HGBL, not otherwise specified; and (2) HGBL with MYC and BCL2 and/or BCL6 rearrangements, also known as double or triple hit lymphoma (DHL/THL). These categories of lymphomas represent 1-2% of non-Hodgkin lymphomas and a considerable portion of DLBCL patients who are primary refractory to R-CHOP therapy. It corresponds to the designation 'B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma' in the 2008 WHO classification. Areas covered: This paper provides an update of HGBL, focusing on their pathologic features, prognosis, and diagnostic workup. It highlights advances in our understanding of DHL/THL. Expert commentary: The diagnosis relies on FISH testing and the major controversial question is when to perform it to diagnose virtually all DHL/THL cases, but also being cost effective. Currently there is no consensus. Considering the high refractory rate of these patients to standard R-CHOP induction, the authors recommend FISH testing in all newly diagnosed large B-cell lymphoma by using our stepwise test strategy. With the progress of molecular genetics, the prognosis will be further stratified and HGBL-NOS maybe further evolve too.

Uric acid disrupts hypochlorous acid production and the bactericidal activity of HL-60 cells.

Uric acid is the end product of purine metabolism in humans and is an alternative physiological substrate for myeloperoxidase. Oxidation of uric acid by this enzyme generates uric acid free radical and urate hydroperoxide, a strong oxidant and potentially bactericide agent. In this study, we investigated whether the oxidation of uric acid and production of urate hydroperoxide would affect the killing activity of HL-60 cells differentiated into neutrophil-like cells (dHL-60) against a highly virulent strain (PA14) of the opportunistic pathogen Pseudomonas aeruginosa. While bacterial cell counts decrease due to dHL-60 killing, incubation with uric acid inhibits this activity, also decreasing the release of the inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF- α). In a myeloperoxidase/Cl-/H2O2 cell-free system, uric acid inhibited the production of HOCl and bacterial killing. Fluorescence microscopy showed that uric acid also decreased the levels of HOCl produced by dHL-60 cells, while significantly increased superoxide production. Uric acid did not alter the overall oxidative status of dHL-60 cells as measured by the ratio of reduced (GSH) and oxidized (GSSG) glutathione. Our data show that uric acid impairs the killing activity of dHL-60 cells likely by competing with chloride by myeloperoxidase catalysis, decreasing HOCl production. Despite diminishing HOCl, uric acid probably stimulates the formation of other oxidants, maintaining the overall oxidative status of the cells. Altogether, our results demonstrated that HOCl is, indeed, the main relevant oxidant against bacteria and deviation of myeloperoxidase activity to produce other oxidants hampers dHL-60 killing activity.

A Great Mimicker in Thoracic Spine: Spinal Double Expressor Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is one of the most common causes of non-Hodgkin's lymphoma (NHL). Some of these DLBCLs can have genetic mutations as well as protein overexpression. The genes involved are MYC, BCL-2 and BCL-6. These are very aggressive and do not respond well to standard chemotherapy regiment. Lymphomas usually show classic signs and symptoms but rarely can present with little or no symptoms or even mimic other disease processes. Here we will present a case where a spinal lymphoma mimicked a hematoma and the patient developed signs and symptoms only after mechanical fall and hitting his back.

Effects of 17-DMAG on diffuse large B-cell lymphoma cell apoptosis.

17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) is a water soluble, semisynthetic derivative of endotoxin that has anticancer effects. The aim of the present study was to determine whether 17-DMAG enhances the apoptosis of lymphoma cells in diffuse large B-cell lymphoma. Apoptosis was induced in SU-DHL-4 diffuse large B-cell lymphoma cells treated with 17-DMAG, as evaluated by MTT assay and flow cytometry analysis. Apoptosis-associated protein levels were assessed using western blotting, and the results indicated that B-cell lymphoma 2 (Bcl-2)-associated protein X (Bax) was upregulated, whereas heat shock protein family A member 5 (HSPA5) and Bcl-2 were downregulated. Additionally, staining with 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide revealed that treatment with 17-DMAG decreased mitochondrial membrane potential in SU-DHL-4 diffuse large B-cell lymphoma cells. These results suggested that 17-DMAG is able to inhibit proliferation in diffuse large B-cell lymphoma cells in a concentration-dependent manner. The underlying mechanism may be that 17-DMAG induces oxidative stress, which inhibits the expression of HSPA5 and Bcl-2 and promotes the expression of Bax, leading to the apoptosis of SU-DHL-4 cells. Taken together, these results indicated that 17-DMAG may be an effective novel agent for the treatment of diffuse large B-cell lymphoma.

[Diffuse large B-cell lymphoma with concomitant c-MYC and BCL6 gene rearrangements with primary skin involvement: A case report and a review of literature]. / Diffuznaia V-krupnokletochnaia limfoma s sochetannoi rearanzhirovkoi genov c-MYC i BCL6 s pervichnym porazheniem kozhi: sobstvennoe nabliudenie i obzor literatury.

Double-hit lymphoma (DHL) is a rare aggressive B-cell lymphoma with concomitant c-MYC, BCL2 or BCL6 gene rearrangements, which is characterized by the high frequency of extranodal lesions and by resistance to chemotherapy. The median survival does not exceed 18 months in patients with this disease. The majority of DHL is represented by с-MYC/BCL2 cases. The combination of c-MYC/BCL6 occurs rarely (5-8%). The paper describes a case of DHL with concomitant c-MYC and BCL6 gene rearrangements, which mimics diffuse large B-cell lymphoma, leg-type.