Aggressive Type Research Articles

Clinical Outcomes of Patients With Variant Histology of Urothelial Carcinoma After Radical Cystectomy

Purpose: The efficacy of standard chemotherapy or radical cystectomy in patients who have urothelial tumors with variant histology (VH) is very limited in terms of their prognosis. This study aimed to investigate the prognosis of bladder cancer (BC) patients with VH who underwent radical cystectomy (RC).Materials and Methods: We retrospectively evaluated 327 BC patients who underwent RC at Pusan National University Yangsan Hospital between February 2010 and June 2021. VH was categorized into less and more aggressive types according to the patient’s mortality risk relative to pure urothelial carcinoma (PUC). More aggressive types included micropapillary, plasmacytoid, and sarcomatoid variants. Less aggressive types comprised other variant types, including squamous differentiation, glandular differentiation, lipoid, and nested. Small cell carcinoma, pure adenocarcinoma, pure squamous cell carcinoma, and lymphoma BC were excluded from analysis. The progression-free survival (PFS) and overall survival (OS) rates were evaluated using Kaplan-Meier analysis and Cox regression.Results: After the exclusion of nonurothelial tumors, data from 299 patients were available for analysis. We identified 244 (74.6%) and 55 patients (16.8%) with PUC and urothelial carcinoma with VH, respectively. VH patients were categorized as having less aggressive (n=35) and more aggressive (n=20) types. Univariate analysis identified significant differences in PFS (p=0.031) between patients with PUC (n=244) and more aggressive VH (n=20). Multivariate analysis showed that more aggressive VH was significantly associated with OS and PFS. In the Kaplan-Meier analysis, a statistically significant difference was observed between PUC and more aggressive VH in OS and PFS.Conclusions: VH patients with more aggressive types showed more advanced TNM stages at presentation than PUC patients. Pathological upstaging after RC was more common in VH patients. Among VH patients, the presence of a more aggressive VH type can be an independent predictor of progression after RC, with a worse prognosis than that of PUC patients.

Effect of NFATc2- and Sp1-mediated TNFalpha Regulation on the Proliferation and Migration Behavior of Pancreatic Cancer Cells.

One in two people will develop a tumor during their lifetime. Adenocarcinoma of the pancreas is one of the most aggressive types of cancer in humans with very poor long-term survival. A central role in the carcinogenesis of pancreatic cancer has been attributed to NFAT transcription factors. Previous studies have identified the transcription factor Sp1 as a binding partner of NFATc2 in pancreatic cancer. Using expression profile analysis, our group was able to identify the tumor necrosis factor TNFalpha as a target gene of the interaction between NFATc2 and Sp1. The present study investigated the effect of TNFalpha over-expression via the transcription factors NFATc2 and Sp1 on the pancreatic cancer cell lines PaTu 8988t and PANC-1. Transient transfection of NFATc2, Sp1, and TNFalpha siRNAs and their effects on the expression were investigated with immunoblot. Cell proliferation was measured with the ELISA BrdU assay. Cell migration was assayed with a Cell Migration Assay Kit using a Boyden chamber. Inhibition of the transfection factors NFATc2, Sp1, or TNFalpha by siRNA significantly inhibited proliferation, which was exacerbated when using the combination of NFATc2 and Sp1. TNFalpha was able to counterbalance this effect. In contrast to proliferation, migration of pancreatic cancer cells was increased by inhibiting these transfection factors. Tumor progression is strongly influenced by transcriptional changes in signaling cascades and oncogene mutations as well as by changes in tumor suppressor genes. Further studies are needed to understand the underlying mechanisms of these processes.

Active natural compounds perturb the melanoma risk-gene network.

Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. This study aimed at providing an in silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association study signals accounting for a total of 232 unique melanoma risk genes. A protein-protein interaction network was constructed using the melanoma risk genes as seeds and evaluated to describe the functional landscape in which the melanoma genes operate within the cellular milieu. Not only were the majority of the melanoma risk genes able to interact with each other at the protein level within the core of the network, but this showed significant enrichment for genes whose expression is altered in human melanoma specimens. Functional annotation showed the melanoma risk network to be significantly associated with processes related to DNA metabolism and telomeres, DNA damage and repair, cellular ageing, and response to radiation. We further explored whether the melanoma risk network could be used as an in silico tool to predict the efficacy of anti-melanoma phytochemicals, that are considered active molecules with potentially less systemic toxicity than classical cytotoxic drugs. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride. This reinforced our hypothesis that the network modeling approach not only provides an alternative way to identify molecular pathways relevant to disease but it may also represent an alternative screening approach to prioritize potentially active compounds.

DIFFERENCES BETWEEN BOYS AND GIRLS INVOLVED IN COMPUTER GAMES
 IN MANIFESTATION OF AGGRESSION IN ADOLESCENCE

This article examines the differences between boys and girls in the manifestation of different types of aggression.
 The author presents the data obtained in the course of an empirical study. Based on the results of the study, a significant
 difference was revealed between boys and girls in the severity of indirect verbal aggression. The study contributes to the
 prevention of aggressive behavior among adolescents.

Epidemiological Insights into Large Granular Lymphocyte Leukemia: A Nationwide SEER Database Study

Background: Large granular lymphocytic (LGL) leukemia is a rare hematological malignancy that arises from cytotoxic T lymphocytes (T-LGL) or natural killer (NK) cells. LGL leukemia accounts for 2% to 5% of chronic lymphoproliferative disorders in the United States of America. LGL leukemia can either present as an indolent type or an aggressive type. Most patients remain asymptomatic and often have associated autoimmune diseases, such as rheumatoid arthritis and hematologic dyscrasias. We analyzed the demographic characteristics of LGL leukemia patients and investigated the influence of social determinants on their survival. Methods: We performed a retrospective cohort study of the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with LGL leukemia between years 2000 and 2020. Patient demographics, year of diagnosis, and timeline of treatment were analyzed by descriptive statistics. Cox proportional hazards regression analysis was performed to identify the factors influencing the survival of these patients. Results: A total of 2589 patients were diagnosed with LGL leukemia. Median age of diagnosis was 67 years. 59.4% were aged more than 65 years of age at the time of diagnosis, 52.7% were males, 81.5% were Caucasians, 64% had an annual income of more than $65,000, and 84.2% lived in metropolitan areas. 91.8% were diagnosed in the past decade after 2010. It is worth noting that 64.5% of the patients received treatment more than six months after diagnosis of LGL leukemia. 81.5% of patients were Caucasians, 9.6% were African Americans, 5.3% were Asians/Pacific Islanders, followed by 2% Hispanics and 1.5% American Indians. At the time of the last follow-up, 65.5% of patients were alive, with an overall median survival of forty months. 70% of patients had LGL leukemia as the only primary malignancy. Age less than 65 years had better outcomes than the older age group (HR 0.32). Female gender was protective (HR 0.69). Poor outcomes were seen in patients with an annual income of less than $65,000 (HR 1.21). The year of diagnosis and residence had no significant effect on survival. Marriage improved the outcomes of patients (HR 0.78) (Table 1). Patients receiving treatment within six months of diagnosis had higher mortality (HR 1.43) than the rest of the population. Caucasians comprised majority of the patient population and had better prognoses (HR 0.11) than Asians/Pacific Islanders (HR 0.49), Hispanics (HR 0.82), and African Americans (HR 0.97) (Figure 1). Conclusion: We present a population-based analysis and the determinants of survival in patients with LGL leukemia, a rare malignancy. The number of cases has increased in the past decade. Significant patient factors influencing survival in LGL leukemia patients include younger age at diagnosis, female gender, marriage and higher annual income.

Mechanistic Elucidation of the Tumor-Promoting Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in B-Cell Receptor Signaling in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a highly aggressive and incurable type of B-cell non-Hodgkin's lymphoma. B cell receptor (BCR) signaling plays an important role in the pathogenesis of MCL; however, the underlying mechanisms are unknown. Our genome-wide screens identified that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1/CC1) is a central component of BCR signaling and is essential for MCL survival in vitro and in vivo. Among the twelve alternatively spliced human CC1 isoforms, we found that CC1-4L, the longest CC1 isoform is overexpressed in MCL. Structurally, it has the N-terminal domain and three type 2 constant ectodomains, a transmembrane sequence and a signaling cytoplasmic domain with two immunoreceptor tyrosine-based inhibitory motifs (ITIMs or Y493/520). These ITIMs of CC1 can inhibit signals in T cells, NK cells, neutrophils and granulocytes. However, its role in B cells and BCR signaling is not clear. In this study, we have elucidated a novel mechanistic function of CC1 in promoting oncogenic BCR signaling in MCL. First, we studied the role of CC1 in lipid raft formation, which is one of the early events during BCR signaling activation. To study this, we used three panels of MCL lines, Jeko-1-NTC (non-template control), Jeko-1-gCC1 (CC1-knockout) and Jeko-1-gCC1-4L (CC1-knockout restored with CC1-4L isoform). Using high-resolution confocal microscopy, we observed that CC1-expressing Jeko-1 MCL cell line showed significantly increased lipid raft formation when compared to CC1-knockout cells. However, CC1-deficient cells restored with the CC1-4L isoform exhibited increased lipid raft assembly. Further, we also observed that CC1-expressing MCL lines showed increased cytoskeletal assembly, which was observed via increased F-actin and filamin A staining in CC1-expressing MCL lines when compared to CC1-knockout cells. Second, we analyzed the phosphorylation levels of proteins involved in the BCR signaling cascade in a panel of genetically engineered MCL lines, i.e., Jeko-1-NTC, Jeko-1-gCC1, Jeko-1-gCC1-4L, Jeko-1-gCC1-4S (CC1-knockout restored with CC1-4S or short cytoplasmic tail isoform) and Jeko-1-gCC1-mutants (CC1-knockout cells restored with N-terminal domain deletion mutant and ITIM-mutant or YY/FF 493/520). We observed that Jeko-1-NTC and Jeko-1-gCC1-4L cell lines showed significantly increased phosphorylation levels of BCR signaling components such as phospho-SRC (Y416), phospho-SYK (Y319), phospho-AKT (S473) and phospho-BTK (Y223) when compared to Jeko-1-gCC1, Jeko-1-gCC1-4S and Jeko-1-gCC1 mutant MCL lines. This shows that CC1 positively regulates or activates oncogenic BCR signaling in MCL and the N-terminal domain and cytoplasmic tail are required for this function. Next, we analyzed whether CC1 could interact with the BCR signaling components such as CD79B, LYN and SYK using immunoprecipitation (IP) and proximity ligation assay (PLA) in MCL lines. Further, we analyzed the kinetics of BCR activation in order to infer the role of SHP-1 binding to the ITIMs of CC1. Our IP and PLA experiments demonstrated that in Jeko-1 and Mino MCL lines, at the peak (i.e., at 5 and 15 min) of BCR activation, there was significantly increased interaction between CC1 and the BCR-pathway components (CD79B, LYN and SYK), and this interaction subsided by 30 min of IgM activation. However, in the case of CC1 and SHP-1, the interaction was stable throughout the time points and increased by 30 min of IgM activation. These interactions were disrupted in the CC1-N-terminal domain deletion and ITIM mutant MCL lines when compared to the CC-4L expressing MCL line. Finally, we analyzed the interaction between CD79B and SYK in CC1-4L, CC1-ITIM mutant and N-domain deletion mutant expressing MCL lines. Using PLA, we observed increased interaction between CD79B and SYK in CC1-4L expressing cell line compared to other cell lines indicating that functional CC1 is required for the recruitment of SYK to CD79B. In summary, CC1 stabilizes lipid rafts following BCR engagement by anchoring to F-actin and Filamin A. CC1 recruits and activates LYN and SYK at the BCR complex at the peak of BCR activation and subsequently recruits SHP-1 for signal downregulation. These activities of CC1 require intact ITIMs and the N-terminal ligand-binding domain. Hence, CC1 drives oncogenic BCR signaling in MCL and forms an important candidate for MCL immunotherapy.

A Multicenter, Open-Label, Single-Arm, Phase Ib Clinical Trial of HH2853 in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-Cell Lymphoma

Introduction Peripheral T cell lymphoma (PTCL) is an aggressive tumor type with poor survival, whereas treatment options for relapsed and/or refractory (r/r) disease are very limited. Standard treatments have a median progression free survival (PFS) of only 3-4 months. HH2853, the novel, potent and selective dual inhibitor of Enhancer of Zeste Homolog 1 and 2 (EZH1/2), has demonstrated a clinical benefit with a favorable safety profile in Phase 1 and Phase 2 trials in solid tumors and R/R non-Hodgkin's lymphoma (NHL) previously. Here we report the efficacy and safety data from phase 1b trial of HH2853 in r/r PTCL. Methods The Phase 1b clinical trial in PTCL (CTR20221416) was conducted from July, 2022 to June 15, 2023 at 15 sites in China. This study consisted of two parts. In part 1, 3+3 dose-escalation design with three dose levels of HH2853 (300mg, 400mg, 600mg BID) was used to identify the MTD and recommended Phase II dosage (RP2D) of HH2853. Part 2 was dose expansion at two dose groups (300mg and 400mg BID). HH2853 was orally dosed until disease progression, intolerable toxicity or withdrawal from the study. Safety was evaluated according to CTCAE v5.0. Tumor assessments were performed according to LUGANO 2014 every 2 treatment cycles (28-day/cycle). A final data cut off (DCO) on June 15, 2023 was conducted for safety and efficacy assessments. To that date, there were still 25 pts (73.5%) remained on HH2853 treatment. Results In this study in r/r PTCL, 34 pts enrolled with different PTCL histology types, including AITL (14 pts, 41.2%), PTCL-NOS (11 pts, 32.4%), ALK -ALCL (4 pts,11.8%), NKT (2 pts, 5.9%), TFH (2 pts, 5.9%), SKIN-PTCL (1 pt, 2.9%). Pts were a median age of 58 years (range: 34 to 79), ECOG 0-1 (ECOG 0, 9 pts, 26.5%, ECOG 1, 25 pts, 73.5%), had a median of 2 lines (range 1 to 5) prior systemic therapies, 6 pts (17.6%) had bone marrow involvement at the baseline. With 30 pts (88.2%) having prior CHOP or CHOP-like therapy，with 14 pts (41.2%) were refractory to their last treatment. 1pts (2.9%) had undergone hematopoietic stem cell transplantation. 32 patients (92.1%) had experienced a treatment related adverse event (TRAE), 7 pts (20.6%) experienced grade ≥3 TRAE. The most common TRAEs (≥10%) were PLT decreased (14 pts, 41.2%) , anaemia (13 pts, 38.2%)，and diarrhoea (11 pts, 32.4%). The frequently reported TRAEs of grade ≥3 with an incidence of ≥10% were PLT decreased (5 pts, 14.7%) and neutrophil count decreased (4 pts, 11.8%). 8 pts (23.5%) had dose interrupted due to TRAE. 3 pts (8.8%) had dose reductions due to TRAE from 600 to 400 mg BID, 1 pts (6.3%) had dose reductions from 400 to 200 mg BID, and 1 pts (2.9%) discontinued from the study due to TRAEs. The safety profile was consistent to that had been observed in HH2853 studies. 1 pt (2.9%) at 600mg BID experienced dose limiting toxicity (DLT)due to grade 4 PLT decreased. The majority of TRAEs were reversible or clinically manageable. Among the 34 enrolled pts, 28 patients had the evaluated response, the Overall Response Rate (ORR) was 60.7% (17 pts), including 21.4% (6 pts) Complete Responses (CR), 39.3% (11 pts) Partial Responses (PR) and 14.3% (4 pts) Stable Disease (SD), contributing to an 75.0% (21 pts) Disease Control Rate (DCR). The median time to response (mTTR) was 1.87 months (95% CI: 1.77, 2.17). At DCO the median follow up of the pts in the study was 2.79 month (IQR: 1.94, 5.88). The median Duration of Response (mDOR), the median Progression Free Survival (mPFS) and the median OS (mOS) had not reached. The 3-month PFS rate was 74.44% (95%CI:53.62%,86.95%). The 6-month OS rates was 91.97% (95%CI: 71.50%, 97.93%). Conclusions The selective EZH1/2 dual inhibitor HH2853 demonstrated good safety and promising efficacy in r/r PTCL patients, indicating its potential as a therapeutic option for this difficult to treat patient population.

Lacutamab in Patients with Relapsed and Refractory Sèzary Syndrome: Results from the Tellomak Phase 2 Trial

Introduction Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Sézary syndrome (SS) is a rare, aggressive and advanced type of CTCL. It has a unique biology, with high expression of KIR3DL2, a killer immunoglobulin-like receptor, reported in more than 85% of patients. SS is characterized by erythroderma, significant blood involvement with malignant SS cells, and lymphadenopathy. These patients suffer from debilitating itching and recurrent skin infections, often affecting quality of life (QoL). SS is distinguished by its poor prognosis, as the median survival of patients is approximately 5 years. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity and phagocytosis. Methods TELLOMAK is an international, open-label, Phase 2 trial with multiple cohorts (NCT03902184). We report here results from Cohort 1, designed to evaluate safety and efficacy of single agent lacutamab in patients with relapsed/refractory (R/R) SS after at least 2 prior systemic therapies including mogamulizumab. Patients had blood stage B2 (≥1000 circulating Sézary cells/mm 3) at screening based on central evaluation by flow cytometry. Patients with evidence of large cell transformation were excluded. Lacutamab 750 mg is administered as an intravenous infusion weekly × 5 weeks (w), every 2 w × 10, then every 4 w until progression or unacceptable toxicity. Primary endpoint was Objective Response Rate (ORR) by global response score based on the evaluation of 4 compartments: skin, blood, lymph nodes and viscera according to International Consensus criteria (Olsen 2011). Secondary endpoints included but not limited to additional efficacy endpoints, safety, QoL assessments. Results At the data cut-off of May 1, 2023, 56 SS patients were enrolled treated and evaluated in Cohort 1. Median age was 69 years (range: 42-86), the median prior lines of systemic therapies was 6.0 (range: 2-15), 60.7 % (n=34) had stage IVA1, 32.1 % (n=18) had stage IVA2 and 7.1% (n=4) had stage IVB disease at baseline, all patients (100%) had blood involvement (B2), 67.9% (n=38) had confluence of erythema covering ≥ 80% body surface area (T4), 35.7% (n=20) had lymph node lymphoma involvement (N3). Median follow-up was 14.4 months (95% CI 9.0-18.4). In the ITT population (n=56), Global confirmed ORR was 37.5% (n=21; 95% CI 26.0-50.6) including 2 CRs, with a median time to response of 2.8 months (range 1-9; Figure 1). Confirmed ORR in skin was 46.4% (n=26; 95% CI 34.0-59.3) including 5 CRs. Confirmed ORR in blood was 48.2% (n=27; 95% CI 35.7-61.0) including 15 CRs. Clinical Benefit Rate (CBR, defined as CR+PR+SD) was 87.5 % (n=49; 95% CI 76.4-93.8). Median PFS was 8.0 months (95% CI 4.7-21.2). Grade ≥ 3 Treatment-related (TR) Treatment-Emergent Adverse events (TEAEs) were observed in 10/56 (17.9%) pts, Serious TR TEAEs were observed in 4/56 (7.1%) and 3/56 (5.4%) pts discontinued study drug due to TR TEAE. Data from additional key endpoints will be presented. Conclusion In this SS cohort from the TELLOMAK study, our data confirm that lacutamab monotherapy shows promising clinical activity in a R/R population previously treated with 2 or more prior systemic therapies including mogamulizumab, and an overall favourable safety profile. Continued evaluation of this new targeted treatment option for patients with SS is warranted.

CNS Prophylaxis Among Patients with HIV-Associated Diffuse Large B-Cell Lymphoma - a Single Center Retrospective Study

Title: CNS Prophylaxis Among Patients with HIV-Associated Diffuse Large B-Cell Lymphoma - A Single Center Retrospective Study Introduction: Patients with Human Immunodeficiency Virus (HIV) are known to develop Lymphoma at a higher rate compared with the general population, with Diffuse Large B-Cell Lymphoma (DLBCL) being the most common subtype. Historically, before the advent of HIV treatment with antiretroviral therapy (ART), HIV-associated DLBCL was considered a more aggressive type of lymphoma and all patients were treated with central nervous system (CNS) prophylaxis. However, since ART has been widely adopted, there is some data to suggest that HIV-associated DLBCL among those taking ART more closely resembles de-novo DLBCL and may not need to be universally treated with CNS prophylaxis. There are no good prospective trials evaluating which patients who develop HIV-associated DLBCL while on ART should receive CNS prophylaxis. Furthermore, studies that tried to predict which DLBCL patients are at greater risk for CNS relapse explicitly excluded patients with HIV. Despite the absence of data, guidelines have shifted and current NCCN guidelines now recommend that HIV patients with DLBCL should be risk stratified as de-novo DLBCL patients with respect to CNS directed therapy. In this study, patients with HIV-associated DLBCL were retrospectively analyzed to understand the patterns of CNS prophylaxis and effects on relapse free survival. Methods: The Electronic Medical Record was queried at a large academic medical center in New York City for patients with HIV-associated DLBCL between the years of 2012 and 2021 using ICD-10 codes. Other subtypes of Lymphoma such as Burkitt's or Plasmablastic Lymphoma were excluded. Patients who did not receive their entire treatment course within the institution were also excluded. Clinical characteristics at diagnosis, treatment type, CNS prophylaxis, and survival data was collected and analyzed. Results: A total of 38 patients were identified according to the inclusion criteria. 26 patients (68%) underwent screening lumbar punctures (LPs) for CNS disease while 12 patients (32%) did not. The two groups were not statistically different within any categories except for LDH, where the LP group had a median LDH of 492 units/L and the non-LP group had a median LDH of 241 units/L (p-value: 0.031). The two groups were not statistically different in cell of origin subtypes, stage, bone marrow involvement, kidney/adrenal involvement, the use of ART prior to diagnosis, IPI or CNS-IPI scores. In addition, among the group that had an LP done with no CNS involvement (n=25), there was no statistical difference in relapse-free survival among those who received adequate CNS prophylaxis and those who did not (p-value 0.886). Conclusions: Among patients with HIV-associated DLBCL in a large academic medical center in New York City, there is no reliable indicator to predict which were offered screening lumbar punctures and which were not. Clinicians may be using additional measures of aggressiveness not accounted for in standard IPI and CNS-IPI scoring algorithms. Furthermore, there was no clear benefit in relapse free survival among high-risk patients who received adequate CNS prophylaxis versus those who did not in this limited sample size. Further research is needed to determine whether patients with HIV-associated DLBCL should be risk stratified similarly to de-novo DLBCL patients with respect to CNS prophylactic therapy.

Targeting Super-Enhancers Driving EVI1 Expression in Leukemia By Inhibition of p300/CBP

Introduction One of the most aggressive types of acute myeloid leukemia (AML) is caused by aberrant activation of EVI1 as a result of the hijacking of enhancers repositioned by structural rearrangements. One of these enhancers, the MYC-blood enhancer cluster ( MYC-BENC) (Bahr et al. 2018) activates EVI1 in AML patients with t(3;8). MYC-BENC consists of several enhancer modules, of which only one is essential for activating EVI1: deletion of this element abrogates MYC-BENC to EVI1 promoter interaction as well as transcription of EVI1 (Ottema et al. 2021). Approach Given the central role of acetyltransferases p300 and CBP in enhancer activation, in particular super-enhancers such as MYC-BENC, we wondered whether we could specifically inhibit MYC-BENC driven EVI1 transcription using p300/CBP inhibitors. We studied this in a previously reported t(3;8) K562 model (Ottema et al. 2021), in which we introduced GFP 3' of EVI1 as a readout for MYC-BENC-driven EVI1 expression. Results ChIP-seq in t(3;8) cells showed that p300 binds to the promoter of EVI1 and to MYC-BENC, whereas CBP only binds to MYC-BENC (Fig. A). Following rapid p300/CBP degradation (3 hours) with the heterobifunctional p300/CBP degrader dCBP-1 (Vannam et al. 2021), we found a severe reduction of nascent EVI1 (and MYC) transcripts (SLAM-seq), as well as of EVI1 protein levels, i.e. by EVI1-eGFP, intracellular anti-EVI1-PE staining (Fig. B) and western blot.. Importantly, p300/CBP degradation was accompanied by loss of H3K27ac at MYC-BENC, but not at the promoter of EVI1 (Fig. A). Thus, the activation of EVI1 in t(3;8) AML appears strongly dependent on the presence of p300/CBP at MYC-BENC super-enhancer. Importantly, in healthy HSPCs, we observed that EVI1 expression was not strongly downregulated upon p300/CBP degradation (Fig. B). These data suggest that MYC-BENC driven EVI1 transcription in AML can be targeted, while leaving EVI1 transcription in normal HSPCs unaffected. We next studied whether loss of enhancer activity was dependent on functional domains within p300/CBP using specific inhibitors of either the acetyltransferase domain (A485) or bromodomain (GNE781). Treatment of t(3;8) EVI1-GFP cells with single inhibitors had a mild effect on EVI1 expression, but simultaneous A485/GNE781 treatment showed strong synergy in reducing EVI1 levels (Fig. B). Dual inhibition also led to a profound loss of H3K27ac signal at the MYC-BENC locus, but not at the EVI1 promoter (Fig. A). Thus, both domains in CBP/p300 are required to activate EVI1 expression via the hijacked MYC-BENC enhancer. As with dCBP-1, we found that EVI1 expression levels in healthy HSPCs were not affected by A485 and GNE781 treatment (Fig. B). We hypothesized that A485/GNE781 treatment would only cause loss of p300/CBP activity, but p300 ChIP-sequencing showed that A485/GNE781 treatment caused strong loss of p300 binding at the enhancer while the total protein levels of p300 and CBP were not affected. p300 binding at the EVI1 promoter was not decreased by A485/GNE781 treatment. In line with this, we observed that genome-wide p300 binding at enhancers was reduced at 15939 out of 41160 (39%) putative enhancers upon A485/GNE781 exposure, whereas dual inhibitor treatment only affected p300 binding at 429 out of 12452 promoters (3.5%) (Fig. A), suggesting a high selectivity of p300 inhibitors for long distant regulatory elements. Conclusion In summary, EVI1 is sensitive to pharmacological p300/CBP inhibition when activated by the hijacked MYC-BENC enhancer, but not in normal HSPCs. Globally, the sensitivity of genomic regions to bromo- or acetyltransferase inhibition is highly locus-dependent and is mainly restricted to enhancers. Our findings demonstrate that aberrantly controlled expression of oncogenes by hijacked enhancers in leukemia can be pharmacologically targeted, pointing to a potential therapeutic avenue for patients who are refractory to current treatment regimens.

Selinexor in Combination with Salvage Regimen for Refractory Peripheral T-Cell Lymphoma (PTCL) Patients

Background Peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS) are a diverse and aggressive type of non-Hodgkin lymphomas with a poor prognosis when treated with conventional chemotherapy. The standard CHOP chemotherapy regimen typically yields an overall response rate (ORR) of 60-80%, a complete response (CR) rate of 30-40%, and long-term survival, measured by 5-yr OS，in the range of 20-30% in non-ALCL (anaplastic large cell lymphoma) subtypes. Azacitidine plus CHOP has achievied a 75% CR in newly diagnosed PTCL, but patients with DNMT3A mutation showed adverse progression-free survival (PFS), indicating that genetic mutations may influence resistance to chemotherapy. Selinexor has shown promising results in refractory lymphoma patients by inhibiting oncogenes, therefore, the efficacy of selinexor combined salvage regimen in refractory PTCL remains great interest. Method Refractory PTCL patients were enrolled to be treated with selinexor plus GDP/ICE/Gemox since December 2021 at our center. Selinexor was administered orally (40 mg day 1, 8, 15) plus GDP (gemcitabine 1g/m2*d1, cisplatin 25mg/m2 d1-d3, dexamethasone 40mg d1-d4), ICE (ifosfamide 1.5g/m2*3d, carboplatin (AUC 5) and etoposide 100mg/m2*3d), Gemox (gemcitabine 1g/m2*d1, oxaliplatin 100mg/m2*d1) every 3 weeks as per physician's choice. Objective response rate (ORR) was evaluated every 3 cycles based on Lugano 2014 criteria and Adverse events (AE) were rated according to the NCI CTCAE 5.0. Results 10 patients were treated with selinexor plus salvage regimen in this study and received more than two cycles of the treatment, making them eligible for response evaluation in this poster. The median age of the 10 patients was 65 years (range from 42 to 79), 8 (80%) were male, 9 (90%) had disease stage III-IV at screening, and 60% of all patients had an IPI intermediate to high risk. All of the patients were refractory to the last line of treatment. Among 10 patients, 2 were angioimmunoblastic T-cell lymphoma (AITL), 3 with PTCL-NOS, 3 with ALK-ALCL, 2 with monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). As shown in Figure 1, 3 patients had TP53 alterations, 2 patients with DNMT3A mutation. Patients received a median of three cycles (range, 2-6) of selinexor 40mg once a week combined with salvage regimen（4 patients received Selinexor-GDP, 3 with selinexor-ICE, 3 with selinexor-Gemox）. The best overall and complete response rates were 70% and 50%, respectively. In terms of MEITL refractory to conventional CHOP treatment, 1 achieved PR but progressed and died after stop treatment for three months due to Covid19 and 1 in CR with selinexor maintenance. Conclusions There are limited options for the treatment of refractory PTCL. We identified a dosing schedule of selinexor (40mg qw) with GDP/ICE/Gemox that is efficiency inrefractory PTCL and is worthy of further study on its mechanism of action.

POINT STIMULATION WITH ESSENTIAL OILS IN COMPLEX TREATMENT OF LUMBOSACRAL DORSOPATHIES

The material is devoted to the analysis of the main mechanisms and comparative assessment of the effectiveness of various options for the cutaneous use of essential oils in dorsopathies.Materials and methods. 90 patients (women and men) with exacerbation of lumbosacral dorsopathy were selected. In the course of the study, along with neurological, psychological and electrophysiological analysis was carried out. The observed individuals were divided into three randomized groups, each of 30 people in which standard treatment was performed standard treatment. In addition to this, in the first two, main groups, a mixture of essential oils was used: in the 1st group by massaging the lumbosacral zone, in the 2nd – biopuncture, with its application to the area of segmental and distant acupuncture points In the 3rd, control group, sesame oil was applied to the area of the same points as a placebo.Results and conclusion. The results of the study confirmed the effectiveness of both types of use of essential oils, exceeding, at the level of reliability, the indicators of the control group. However, in the main groups, the rates of sustained analgesia varied, achieved on average after 7.2 procedures in the 1st and 5.5 in the 2nd group. In a similar proportion, the final intensity of pain also decreased – by 51.7 and 65%, respectively, compared with the initial one. According to the delayed assessment performed after six months, exacerbations of the process in the control group were noted in a third of patients, while in the main groups they were observed in a comparably smaller number. Nevertheless, there are differences in the severity of periodically occurring algia: in the 2nd group they increased slightly, while in others they increased to a significantly greater extent. At the same time, the data of rheovasograms testified in favor of greater stability of the results in the 2nd group. The noted advantage of biopuncture with essential oils can be explained by the cumulative effect inherent in the methods of reflexology. In addition, this technique, given the physiology, can be an addition to more aggressive types (classical acupuncture, electrical stimulation) of physical exposure.

Simultaneous detection of CA-125 and mesothelin by gold nanoparticles in surface plasmon resonance

The early-stage diagnosis and monitoring of disease evolution is still one of the most challenging tasks in the field of cancer research. Several research have been driven toward the discovery of new cancer biomarkers as well as to the development of biosensors able to detect these biomarkers with high specificity and sensitivity. Many types of cancer have been detected at an advanced stage and, in particular, epithelial ovarian cancer (EOC) has a high incidence of diagnosis in the metastatic stage. This cancer is considered as the most aggressive type of gynecological cancer with a 5-year survival and until now, no specific biomarkers have been identified. Nevertheless, some studies have indicated that mesothelin, a protein overexpressed by tumour cells in the ovary, interacts with the CA-125 biomarker present in the blood system accelerating the metastatic process. Therefore, the simultaneous presence of CA-125 and mesothelin in the blood during the evolution of EOC could be used to diagnose this disease before the metastasis. Therefore, with this motivation, this work aimed at the development of a biosensor capable of simultaneously detecting mesothelin and CA-125 at low concentrations. A biosensor based on the surface plasmon resonance imaging (SPRi) technique was developed and gold nanoparticles (AuNPs) were used in order to enhance the sensitivity. The study analysed successive injections of the biomarkers CA-125 and mesothelin, both in solution (analytical range of 9–120 nM). The limits of detection were obtained for CA-125 and mesothelin, being of 3.03 nM and 13.62 nM, respectively. The biosensor detected mesothelin at a concentration close to the cutoff point for EOC (3 nM) and was able to detect the biomarker CA-125 at 9 nM. Furthermore, the biosensor interacted preferentially and simultaneously with the biomarkers CA-125 and mesothelin incubated in fetal bovine serum. Finally, the use of AuNPs increased the sensor signal for CA-125 detection compared to its direct detection and showed greater selectivity for both biomarkers. Therefore, the biosensor has important characteristics that allow testing with real samples. In a future project, it could be applied in the research of diagnosis and prognosis of EOC.

Antibacterial Effect of Aqueous and Alcoholic Ginger Extracts on Periodontal Pathogen Aggregatibacter Actinomycetem Comitans [An in Vitro Study] (Part 1)

Among natural food sources with antimicrobial activities, ginger rhizome has been used as widely grown food spices and medicinal crops for centuries. Furthermore, it possess antifungal and antioxidant properties due to the phenols – related constituents (gingerols) that constrain the growth of many Gram positive and Gram negative bacteria including some periodontal bacteria. The Actinomycetem comitans is a portion of the normal microbiota in numerous healthy individuals but is also a major etiological agent in some aggressive and chronic types of periodontitis. The present study was conducted to test the effect of aqueous and alcoholic ginger extracts on the growth of Aggregatibacter actinomycetem comitans in comparision to 0.2% chlorohexidine gluconate mouth wash and distilled water in vitro, determination of ginger extracts minimum inhibitory concentration and minimum bactericidal concentration and detection of active ingredients of ginger extracts by using the high-performance liquid chromatography as well as chemical elements.

Application of Small Cell Lung Cancer Molecular Subtyping Markers to Small Cell Neuroendocrine Carcinoma of the Cervix: NEUROD1 as a Poor Prognostic Factor.

Cervical small cell neuroendocrine carcinoma (CSCNEC) is a rare, aggressive type of cervical cancer. The treatment for CSCNEC follows the chemotherapeutic regimens used for small cell lung cancer (SCLC), with which it shares similar clinical and histologic features. For the first time, we applied neuroendocrine (NE) and SCLC molecular subtyping immunohistochemical markers [achaete-scute homolog 1 (ASCL1), neurogenic differentiation factor 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1] in 45 patients with CSCNEC. For the combined NE score, 51.1% of NE-high and 48.9% of NE-low subtypes were identified. The NE-high subtype tended to show worse progression-free survival and overall survival (OS) than the NE-low subtype ( P =0.059 and P =0.07, respectively). Applying the SCLC molecular subtyping, 53.3% of cases were identified as NEUROD1-dominant, 17.8% as ASCL1-dominant, 13.3% as YAP-dominant, and 4.4% as POU2F3-dominant, while 11.1% of cases showed negative expression for all markers; the distribution was different from that of SCLC. The NEUROD1-dominant subtype exhibited the worst OS, while the POU2F3 subtype exhibited the best OS ( P =0.003), similar to SCLC. In addition, the ASCL1-dominant and NEUROD1-dominant subtypes showed high NE scores, while yes-associated protein 1-dominant and POU2F3-dominant subtypes showed low NE scores ( P =0.008). In multivariate analysis, the NEUROD1 expression was further identified as the independent prognostic factor for worse OS, together with the high FIGO stage. CSCNEC was revealed to be a heterogeneous disease with different biological phenotypes and to share some similarities and differences with SCLC. Regarding the ongoing development of tailored treatments based on biomarkers in SCLC, the application of biomarker-driven individualized therapy would improve clinical outcomes in patients with CSCNEC.

High overall copy number variation burden by genome-wide methylation profiling holds negative prognostic value in surgically treated pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer with an overall 5-year survival of around 10 %. New prognostic tools to stratify patients are needed. Our main aim was to evaluate the prognostic value of overall copy number variation (CNV) burden in surgically treated PDAC. DNA extracted from 108 surgical PDAC specimens was examined to collect data on the genome-wide DNA methylation status of >850,000 CpG sites in promoter, gene body, and enhancer regions (Illumina Infinium Methylation EPIC BeadChip Kit). CNV profiles were obtained and all PDACs were stratified into one of three groups: Low, moderate, or high overall CNV burden. Tumors histologically showing a dominant conventional and/or tubulopapillary pattern in 60 %–100 % and 0–59 % were categorized as Group A and Group B as per Kalimuthu. We also performed targeted next-generation sequencing (NGS) and immunohistochemistry. High overall CNV burden held independent negative prognostic value with poor survival (HR 4.01 (95%CI 1.96–8.19), p = 0.00014) and was more frequent in Group B (p = 0.0003). Most frequent chromosomal arm-level aberrations were gains of 8q (29 %) and 1q (19 %) and losses of 17p (55 %), 18q (43 %), 6q (37 %), 9p (36 %), 6p (26 %), 19p (26 %), and 8p (25 %). Most frequent mutations found were in KRAS (95 %), TP53 (62 %), CDKN2A (24 %), SMAD4 (23 %), ATM (9 %), ARID1A (7 %), RNF43 (7 %), GNAS (6 %), and KDM6A (6 %). Group A PDACs showed more frequently KRAS variants other than Gly12Val and Gly12Asp (p = 0.012). Our data indicate that overall CNV burden using genome-wide methylation profiling may be a useful prognostic tool in surgically treated PDAC. Importantly, our approach, using data from genome-wide methylation profiling for analysis of overall CNV burden, can be performed on formalin-fixed and paraffin embedded PDAC tissues. Future studies should examine the prognostic value of overall CNV burden in unresectable PDAC.

The Role of Parent-Child Attachment, Hostile Attribution Bias in Aggression: A Meta-Analytic Review.

Parent-Child Attachment (PCA) and Hostile Attribution Bias (HAB) are closely related to aggression, but findings regarding their relationships are inconsistent. There is a lack of understanding of the underlying mechanism between PCA and aggression. This review employed meta-analysis approaches to investigate the associations between PCA and aggression, as well as between HAB and aggression, and the mechanism for the PCA-aggression association. An article search was conducted in CNKI, PubMed, PsycINFO, Web of Science, ProQuest, and Google Scholar. Totally, 118 studies involving general populations and those at high risk for aggression were included. Results revealed negative associations between Parent-Child Attachment Security (PCAS) and aggression (ρ = -.267, p < .001) and positive associations between Parent-Child Attachment Insecurity (PCAI) and aggression (ρ = .240, p < .05). HAB and aggression were found to be positively associated (ρ = .303, p < .001). As for the PCAS-aggression association, a larger effect size was found in females than in males. The HAB-reactive aggression association was stronger than the HAB-proactive aggression association. In Eastern culture, the association between HAB and aggression was stronger than in Western culture. HAB mediated the association between PCAS and aggression. Our findings contribute to the understanding of the occurrence and development of aggression by establishing an association between attachment theory and the social information processing model. The practical implications include interventions targeting cultivating PCAS and alleviating HAB, which might serve as effective ways to reduce aggression, yet aggression type, gender, and cultural background should be taken into consideration.

Depressive symptoms and anger and aggression in Russian adolescents

Research among adolescents exploring the association between depressive symptoms and aggression has produced inconsistent findings. This study investigated the prevalence of clinically significant (current major depressive episode) and subthreshold depressive symptoms in a general population sample of adolescents from Northern Russia and explored their association with aggression and anger, while controlling for comorbid mental health problems. The sample consisted of 2600 participants, aged 13–17 years (59.5% female; 95.7% ethnic Russian). Symptoms of a current major depressive episode, types of anger and aggression (anger rumination, trait anger, physical, verbal and social aggression) and comorbid problems (posttraumatic stress, alcohol use, anxiety, and hyperactivity/impulsivity) were assessed by means of self-reports. The prevalence of a clinically significant depressive episode in the past month was 3.5%, while for subthreshold depression it was 21.6%. All anger and aggression variables, as well as comorbid problems increased together with increasing levels of depression. The association between overt aggressive behavior and depression was primarily explained by comorbid mental health problems, whereas anger rumination and social aggression had more direct associations with depression, independent of comorbidity. Among adolescents with depression, boys reported higher levels of social and verbal aggression and of anger rumination than girls. The results of this study suggest that interventions aiming to reduce aggressive behavior in adolescents should consider depression and its comorbid conditions.

Registered nurses’ exposure to workplace aggression in Norway: 12-month prevalence rates, perpetrators, and current turnover intention

BackgroundIdentifying occupational health hazards among Registered Nurses (RNs) and other health personnel and implementing effective preventive measures are crucial to the long-term sustainability of health services. The objectives of this study were (1) to assess the 12-month prevalence rates of exposure to workplace aggression, including physical violence, threats of violence, sexual harassment, and bullying; (2) to identify whether the perpetrators were colleagues, managers, subordinates, or patients and their relatives; (3) to determine whether previous exposure to these hazards was associated with RNs’ current turnover intention; and (4) to frame workplace aggression from an occupational health and safety perspective.MethodsThe third version of the Copenhagen Psychosocial Questionnaire (COPSOQ III) was used to assess RNs’ exposure to workplace aggression and turnover intention. A national sample of 8,800 RNs in Norway, representative of the entire population of registered nurses in terms of gender and geography, was analysed. Binary and ordinal logistic regression analyses were conducted, and odds for exposure and intention to leave are presented, with and without controls for RNs’ gender, age, and the type of health service they work in.ResultsThe 12-month prevalence rates for exposure were 17.0% for physical violence, 32.5% for threats of violence, 12.6% for sexual harassment, and 10.5% for bullying. In total, 42.6% of the RNs had experienced at least one of these types of exposure during the past 12 months, and exposure to more than one of these hazards was common. Most perpetrators who committed physical acts and sexual harassment were patients, while bullying was usually committed by colleagues. There was a strong statistical association between exposure to all types of workplace aggression and RNs’ intention to leave. The strongest association was for bullying, which greatly increased the odds of looking for work elsewhere.ConclusionsEfforts to prevent exposure to workplace aggression should be emphasised to retain health personnel and to secure the supply of skilled healthcare workers. The results indicate a need for improvements. To ensure the sustainability of health services, labour and health authorities should join forces to develop effective workplace measures to strengthen prevention, mitigation, and preparedness regarding incidents of workplace aggression in health services and the response and recovery regarding incidents that could not be prevented.

Downregulation of TAB182 promotes cancer stem-like cell properties and therapeutic resistance in triple-negative breast cancer cells

TAB182 participates in DNA damage repair and radio-/chemosensitivity regulation in various tumors, but its role in tumorigenesis and therapeutic resistance in breast cancer remains unclear. In the current paper, we observed that triple-negative Breast Cancer (TNBC), a highly aggressive type of breast cancer, exhibits a lower expression of TAB182. TAB182 knockdown stimulates the proliferation, migration, and invasion of TNBC cells. Our study first obtained RNA-seq data to explore the cellular functions mediated by TAB182 at the genome level in TNBC cells. A transcriptome analysis and in vitro experiments enabled us to identify that TAB182 downregulation drives the enhanced properties of cancer stem-like cells (CSCs) in TNBC cells. Furthermore, TAB182 deletion contributes to the resistance of cells to olaparib or cisplatin, which can be rescued by silencing GLI2, a gene downstream of cancer stemness-related signaling pathways. Our results reveal a novel function of TAB182 as a potential negative regulator of cancer stem-like properties and drug sensitivity in TNBC cells, suggesting that TAB182 may be a tumor suppressor gene and is associated with increased therapeutic benefits for TNBC patients.