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Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours.

Individuals with germline mutations in the tumour-suppressor gene CYLD are at high risk of developing disfiguring cutaneous appendageal tumours, the defining tumour being the highly organised cylindroma. Here, we analysed CYLD mutant tumour genomes by array comparative genomic hybridisation and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overex

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… Cells were plated in equal numbers and transfected with empty vector, wild type CYLD and red fluorescent protein, and selected with puromycin. At Day 5 post selection, cells were trypsinised and viable cells counted. (a) Expression of CYLD was assessed using immunoblotting. … Cells were plated in equal numbers and transfected with empty vector, wild type CYLD and red fluorescent protein, and selected with puromycin. At Day 5 post selection, cells were trypsinised and viable cells counted. (a) Expression of CYLD was assessed using immunoblotting. …

Преодоление сопротивления CD44-overexpressing миэлома через комбинированную терапию с клетками ATRA, борцезомиба и NK.

CD44 — гликпротеин, часто переоцениваемый раком и связанный с плохим прогнозом. Мы проанализировали прогнозируемую значимость CD44 в перевыражении в миеломе (MM) и изучили терапевтическую эффективность сочетания естественной клеточной терапии убийцы (NK) с транс-ретиновой кислотой (ATRA) и борцезомибом (Bor) против CD44-overexpressing Мм. Для оценки результатов выживаемости по отношению к выражению CD44 были проанализированы клинические данные из базы данных CoMMpass. Ячейки NK были расширены за счет здоровых доноров с использованием K562-OX40L-mbIL-18/21 кормовые клетки, дополненные интерлейк

Notch3 signaling between myeloma cells and osteocytes in the tumor niche promotes tumor growth and bone destruction.

In multiple myeloma (MM), communication via Notch signaling in the tumor niche stimulates tumor progression and bone destruction. We previously showed that osteocytes activate Notch, increase Notch3 expression, and stimulate proliferation in MM cells. We show here that Notch3 inhibition in MM cells reduced MM proliferation, decreased Rankl expression, and abrogated the ability of MM cells to promote osteoclastogenesis. Further, Notch3 inhibition in MM cells partially prevented the Notch activation and increased proliferation induced by osteocytes, demonstrating that Notch3 mediates MM-osteocyt

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… Lentiviral-mediated gene knock-down in MM cells Murine 5TGMI MM cells were transduced with lentiviral particles (MOI=10; GenTarget Inc, San Diego, CA, USA) containing sequences for Red Fluorescent Protein (RFP) and validated shRNA against Notch3 or Notch2 . 5TGM1 MM cells transduced with shRNA-scramble …

ISEV2019 Abstract Book

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A Novel Bispecific T-Cell Engager (CD1a x CD3ε) BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3ε (CD1a x CD3ε) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical

Understanding Rare Anemias: Emerging Frontiers for Diagnosis and Treatment.

Background-This review provides a comprehensive overview of rare anemias, emphasizing their hereditary and acquired causes, diagnostic advancements, and evolving treatment strategies. It outlines the significance of rare anemias within public health, historical challenges in recognition and treatment, and the role of European initiatives like ENERCA and EuroBloodNet in advancing care. Content-This document discusses diagnostic technologies like next-generation sequencing and the impact of artificial intelligence, alongside the promising avenues of gene therapy, targeted drug treatments, and st

Dietary influences on chemotherapy sensitivity and cardiotoxicity modulated by IRE1 targeting in triple-negative breast cancer in female mice.

Triple-negative breast cancer (TNBC) predominantly affects young and minority women, with cytotoxic chemotherapy regimens causing severe side effects, including chronic cardiac dysfunction. Obesity worsens TNBC survival. Inositol-requiring enzyme-1 (IRE1), a key arm of the unfolded protein response (UPR), influences tumor progression. Using a TNBC mouse model with control and Western diets, we tested IRE1-targeting antisense morpholino and doxorubicin. Targeting IRE1 alone reduced tumor growth and, combined with doxorubicin, did not interfere with the oncologic efficacy of this drug. We observ

Сипонимод поддерживает воспоминание в неподдерживающей среде.

Воспаление, характерное для множественных повреждений склероза (MS), приводит к функциональным повреждениям и постепенной потере аксона с течением времени. Хотя, как считается, ремилеляция защищает аксоны, внутренние регенерационные процессы часто являются неполными или полностью неэффективными у многих пациентов с синдромом MS. Хотя точные причины провала воспоминаний остаются неясными, неоднократное обезвоживание в ранее затронутых районах с белыми телами является признанным фактором, способствующим этому. В одном из предыдущих исследований мы продемонстрировали, что модификатор Siпонimod с

The novel role of circular RNA ST3GAL6 on blocking gastric cancer malignant behaviours through autophagy regulated by the FOXP2/MET/mTOR axis.

Gastric cancer (GC) ranks third in mortality among all cancers worldwide. Circular RNAs (circRNAs) play an important role in the occurrence and development of gastric cancer. Forkhead box P2 (FOXP2), as a transcription factor, is closely associated with the development of many types of tumours. However, the regulatory network between FOXP2 and circRNAs remains to be explored. In our study, circST3GAL6 was significantly downregulated in GC and was associated with poor prognosis in GC patients. Overexpression of circST3GAL6 inhibited the malignant behaviours of GC cells, which was mediated by in

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… Confocal microscopy Cells were transfected with Green Fluorescent Protein‐Red Fluorescent Protein‐LC3 lentivirus (GeneChem, China) and inoculated into specific small Petri dishes for confocal microscopy. The nuclei were stained with DAPI. …

Potential Targeting Mechanisms for Bone-Directed Therapies.

Bone development is characterized by complex regulation mechanisms, including signal transduction and transcription factor-related pathways, glycobiological processes, cellular interactions, transportation mechanisms, and, importantly, chemical formation resulting from hydroxyapatite. Any abnormal regulation in the bone development processes causes skeletal system-related problems. To some extent, the avascularity of cartilage and bone makes drug delivery more challenging than that of soft tissues. Recent studies have implemented many novel bone-targeting approaches to overcome drawbacks. Howe

Porphyromonas gingivalis поощряет передачу Т-клеток через канал сигнала NF-_B/CXCR3 в экспериментальном аутоиммунном энцефаломиелите.

Множественный склероз (MS) является хроническим аутоиммунным заболеванием центральной нервной системы (CNS); его моделью является экспериментальный аутоиммунный энцефаломиелит (EAE). Периодонтит с участием Porphyromonas gingivalis (P. gingivalis) был связан с MS и продемонстрировал, что он усугубляет EAE, однако механизмы остаются неясными. МЕТОДЫ: Мыши были случайны four группы (n = 8): контроль, только периодонтит, только EAE и EAE с периодонитом. Ежедневно проводилась оценка неврологического дефицита. Спинальный CD4+ и CD4+CXCR3+ T-фильтрация и активация NF-_B были оценены иммунофлюоресценц

Novel Short PEG Chain-Substituted Porphyrins: Synthesis, Photochemistry, and In Vitro Photodynamic Activity against Cancer Cells.

This work presents the synthesis and characterization of metal-free, zinc (II), and cobalt (II) porphyrins substituted with short PEG chains. The synthesized compounds were characterized by UV-Vis, 1H and 13C NMR spectroscopy, and MALDI-TOF mass spectrometry. The origin of the absorption bands for tested compounds in the UV-Vis range was determined using a computational model based on the electron density functional theory (DFT) and its time-dependent variant (TD-DFT). The photosensitizing activity was evaluated by measuring the ability to generate singlet oxygen (ΦΔ), which reached values up

Bortezomib alters sour taste sensitivity in mice.

Chemotherapy-induced taste disorder is one of the critical issues in cancer therapy. Bortezomib, a proteasome inhibitor, is a key agent in multiple myeloma therapy, but it induces a taste disorder. In this study, we investigated the characteristics of bortezomib-induced taste disorder and the underlying mechanism in mice. Among the five basic tastes, the sour taste sensitivity of mice was significantly increased by bortezomib administration. In bortezomib-administered mice, protein expression of PKD2L1 was increased. The increased sour taste sensitivity induced by bortezomib returned to the co

Shengma Biejia Decoction Inhibits Cell Growth in Multiple Myeloma by Inducing Autophagy-Mediated Apoptosis Through the ERK/mTOR Pathway.

Shengma Biejia decoction (SMBJD), a traditional Chinese formula recorded in the Golden Chamber, has been widely used for the treatment of malignant tumors. However, its underlying molecular targets and mechanisms are still unclear. This study showed that SMBJD inhibited tumor growth and stimulated hemogram recovery significantly in a multiple myeloma xenograft model. Western blot and immunohistochemistry assays of tumor tissues showed that SMBJD reduced the ratio of autophagy-related proteins LC3-II/LC3-I, while P62 and apoptosis-related proteins cleaved caspase-3/caspase-3 and Bax/Bcl-2 were

Inhibition of CARM1 suppresses proliferation of multiple myeloma cells through activation of p53 signaling pathway.

BackgroundMultiple myeloma (MM) is a malignant proliferative disease of plasma cells, the incidence of which is increasing every year and remains incurable. The enzyme co-activator-associated arginine methyltransferase 1 (CARM1) is highly expressed in a variety of cancers, such as Hodgkin's lymphoma and acute myeloid leukemia, and CARM1 is closely associated with tumor cell proliferation. However, the role of CARM1 in MM has not been elucidated.Methods and resultsIn this study, we found that CARM1 is overexpressed in MM and closely associated with poor prognosis in MM. CCK-8 and colony formati

USP14 inhibition by degrasyn induces YAP1 degradation and suppresses the progression of radioresistant esophageal cancer.

BACKGROUND: Radiotherapy is a major modality for esophageal cancer (ESCA) treatment, yet radioresistance severely hampers its therapeutic efficacy. Ubiquitin-specific peptidase 14 (USP14) is a novel deubiquitinase and can mediate cancer cells' response to irradiation, although the underlying mechanism remains unclear, including in ESCA. METHODS: To evaluate the expression of USP14 in ESCA tissues or cells, we used RNA-Seq, immunoblotting, co-immunoprecipitation (Co-IP), ubiquitination, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence assays in this investigat

A Rare Case of Epidural Myeloma Presenting as Recurrent Subdural Bleeding.

Multiple myeloma (MM) is an incurable clonal B-cell malignancy that usually presents with neoplastic monoclonal plasma cells in either bone or soft tissues. Central nervous system involvement of the myeloma (CNS-MM), such as dural myeloma or intraparenchymal infiltration, or diffuse leptomeningeal involvement, is uncommon. Dural involvement of myeloma without parenchymal or leptomeningeal disease is even rarer, with only seven cases reported previously. We present a case of epidural myeloma in a 50-year-old man with known kappa light chain MM, presenting with multiple episodes of subdural hemo

CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo.

BackgroundChemotherapy in cancer patients can be associated with serious short- and long-term adverse neurological effects, such as leukoencephalopathy and cognitive impairment, even when therapy is delivered systemically. The underlying cellular basis for these adverse effects is poorly understood.ResultsWe found that three mainstream chemotherapeutic agents--carmustine (BCNU), cisplatin, and cytosine arabinoside (cytarabine), representing two DNA cross-linking agents and an antimetabolite, respectively--applied at clinically relevant exposure levels to cultured cells are more toxic for the p

Transferrin-Bound Doxorubicin Enhances Apoptosis and DNA Damage through the Generation of Pro-Inflammatory Responses in Human Leukemia Cells.

Doxorubicin (DOX) is an effective antineoplastic drug against many solid tumors and hematological malignancies. However, the clinical use of DOX is limited, because of its unspecific mode of action. Since leukemia cells overexpress transferrin (Tf) receptors on their surface, we proposed doxorubicin-transferrin (DOX-Tf) conjugate as a new vehicle to increase drug concentration directly in cancer cells. The data obtained after experiments performed on K562 and CCRF-CEM human leukemia cell lines clearly indicate severe cytotoxic and genotoxic properties of the conjugate drug. On the other hand,

Mechanistic study of pre-eclampsia and macrophage-associated molecular networks: bioinformatics insights from multiple datasets.

BACKGROUND: Pre-eclampsia is a pregnancy-related disorder characterized by hypertension and proteinuria, severely affecting the health and quality of life of patients. However, the molecular mechanism of macrophages in pre-eclampsia is not well understood. METHODS: In this study, the key biomarkers during the development of pre-eclampsia were identified using bioinformatics analysis. The GSE75010 and GSE74341 datasets from the GEO database were obtained and merged for differential analysis. A weighted gene co-expression network analysis (WGCNA) was constructed based on macrophage content, and