Most of the small-molecule drugs approved for the treatment of cancer over the past 40 years are based on natural compounds. Bacteria provide an extensive reservoir for the development of further anti-cancer therapeutics to meet the challenges posed by the diversity of these malignant diseases. While identifying cytotoxic compounds is often easy, achieving selective targeting of cancer cells is challenging. Here we describe a novel experimental approach (the Pioneer platform) for the identification and development of 'pioneering' bacterial variants that either show or are conduced to exhibit selective contact-independent anti-cancer cytotoxic activities. We engineered human cancer cells to secrete Colicin M that repress the growth of the bacterium Escherichia coli, while immortalised non-transformed cells were engineered to express Chloramphenicol Acetyltransferase capable of relieving the bacteriostatic effect of Chloramphenicol. Through co-culturing of E. coli with these two engineered human cell lines, we show bacterial outgrowth of DH5α E. coli is constrained by the combination of negative and positive selection pressures. This result supports the potential for this approach to screen or adaptively evolve 'pioneering' bacterial variants that can selectively eliminate the cancer cell population. Overall, the Pioneer platform demonstrates potential utility for drug discovery through multi-partner experimental evolution.
- MeSH
- antitumorózní látky * farmakologie MeSH
- buněčné linie MeSH
- Escherichia coli genetika MeSH
- kokultivační techniky MeSH
- lidé MeSH
- nádory * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
miRNA expression in triple-negative breast cancers (TNBC) has mainly been studied from a methodological viewpoint. However, it has not been considered that miRNA expression profile may be associated with a specific morphological entity inside every tumor. The verification of this hypothesis on a set of 25 TNBCs was the subject of our previous work, where we confirmed specific expression of the studied miRNAs in 82 samples of different morphologies including inflammatory infiltrate, spindle cell, clear cell, and metastases after RNA extraction and purification as well as microchip and biostatistical analysis. In the current work, we demonstrate a low suitability of in situ hybridization method for miRNA detection compared to RT-qPCR, and in detail discuss the biological role of 8 miRNAs with the most significant changes of expression.
- MeSH
- lidé MeSH
- mikro RNA * genetika metabolismus MeSH
- triple-negativní karcinom prsu * genetika patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Mature non-Hodgkin lymphomas (NHL) in the childhood, adolescent and young adult (CAYA) population are rare and exhibit unique clinical, immunophenotypic and genetic characteristics. Application of large-scale unbiased genomic and proteomic technologies such as gene expression profiling and next generation sequencing (NGS) have led to enhanced understanding of the genetic basis for many lymphomas in adults. However, studies to investigate the pathogenetic events in CAYA population are relatively sparse. Enhanced understanding of the pathobiologic mechanisms involved in non-Hodgkin lymphomas in this unique population will allow for improved recognition of these rare lymphomas. Elucidation of the pathobiologic differences between CAYA and adult lymphomas will also lead to the design of more rational and much needed, less toxic therapies for this population. In this review, we summarize recent insights gained from the proceedings of the recent 7th International CAYA NHL Symposium held in New York City, New York October 20-23, 2022.
Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.
- MeSH
- B-buněčný lymfom genetika patologie MeSH
- dítě MeSH
- genetické lokusy MeSH
- genová dávka MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mutace MeSH
- nádorový supresorový protein p53 genetika MeSH
- předškolní dítě MeSH
- progrese nemoci MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: The aim of this prospective observational study was to investigate the effects of a novel Wim Hof psychophysiological training program on stress responses and hormone release in healthy participants during an Antarctic expedition. METHODS: All members of an Antarctic expedition were included in the study. The participants were healthy volunteers allocated to an intervention group (n = 6) and a control group (n = 7). The intervention consisted of 8 weeks of Wim Hof training. The training program comprised three integrated parts: breathing exercises, cold exposure and meditation. Psychometric measures (the Beck Depression Inventory and the Trauma Symptom Checklist-40) and neuroendocrine measures (cortisol, melatonin) were assessed pre- and post-intervention. RESULTS: The results showed that the 8-week training program significantly reduced stress responses, as indicated by a reduction in depressive symptoms. A non-significant reduction in cortisol was also observed. CONCLUSIONS: These data constitute preliminary findings indicating that the Wim Hof Method may positively affect stress symptoms and adaptability of the hormonal system to respond adequately to the circadian rhythm in healthy volunteers who participated in an Antarctic expedition.
- MeSH
- cirkadiánní rytmus MeSH
- expedice * MeSH
- hydrokortison MeSH
- lidé MeSH
- meditace * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Geografické názvy
- Antarktida MeSH
BACKGROUND: Frequent truncation mutations of the histone lysine N-methyltransferase KMT2C have been detected by whole exome sequencing studies in various cancers, including malignancies of the prostate. However, the biological consequences of these alterations in prostate cancer have not yet been elucidated. METHODS: To investigate the functional effects of these mutations, we deleted the C-terminal catalytic core motif of Kmt2c specifically in mouse prostate epithelium. We analysed the effect of Kmt2c SET domain deletion in a Pten-deficient PCa mouse model in vivo and of truncation mutations of KMT2C in a large number of prostate cancer patients. RESULTS: We show here for the first time that impaired KMT2C methyltransferase activity drives proliferation and PIN formation and, when combined with loss of the tumour suppressor PTEN, triggers loss of senescence, metastatic dissemination and dramatically reduces life expectancy. In Kmt2c-mutated tumours we show enrichment of proliferative MYC gene signatures and loss of expression of the cell cycle repressor p16INK4A. In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer. CONCLUSIONS: We identified truncating events of KMT2C as drivers of proliferation and PIN formation. Loss of PTEN and KMT2C in prostate cancer results in loss of senescence, metastatic dissemination and reduced life expectancy. Our data demonstrate the prognostic significance of KMT2C mutation status in prostate cancer patients. Inhibition of the MYC signalling axis may be a viable treatment option for patients with KMT2C truncations and therefore poor prognosis.
- MeSH
- DNA vazebné proteiny fyziologie MeSH
- inhibitor p16 cyklin-dependentní kinasy genetika metabolismus MeSH
- lidé MeSH
- methyltransferasy * genetika MeSH
- mutace MeSH
- myši MeSH
- nádory prostaty * metabolismus MeSH
- sekvenování exomu MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: One of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls. DESIGN: We performed bulk TCR repertoire profiling of both the TCR alpha and beta chains using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. We further characterised specific T cell clonotypes via single-cell RNAseq. RESULTS: We identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn's disease (CD) and particularly expanded in the CD8+ T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs. CONCLUSIONS: We identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies.
Lymphomas of the breast are rare neoplasms that arise from breast lymphoid tissue and are characterised by neoplastic B or T cells. Breast lymphomas arising from B cells include, but are not limited to, diffuse large B cell lymphoma, follicular lymphoma, extra-nodal marginal zone lymphoma and Burkitt lymphoma. Anaplastic large cell lymphoma (ALCL) is of a T cell origin and both anaplastic lymphoma kinase (ALK)-positive and ALK-negative presentations have been noted in the breast. In addition, there is a more recently identified presentation of ALK-negative ALCL that arises around textured breast implants and is usually confined to a periprosthetic fibrous capsule. Here, we discuss the clinical presentations, histological and immunohistochemical features and treatment options for each type of primary breast lymphoma. We hope that this review will highlight the importance of the timely and accurate diagnosis of breast lymphoma in order to tailor the most appropriate treatment. We also wish to raise awareness of the breast implant-associated lymphomas, with the goal of stimulating work that will aid our understanding of their epidemiology and pathogenesis.
- Publikační typ
- časopisecké články MeSH
Cellular proteins begin to fold as they emerge from the ribosome. The folding landscape of nascent chains is not only shaped by their amino acid sequence but also by the interactions with the ribosome. Here, we combine biophysical methods with cryo-EM structure determination to show that folding of a β-barrel protein begins with formation of a dynamic α-helix inside the ribosome. As the growing peptide reaches the end of the tunnel, the N-terminal part of the nascent chain refolds to a β-hairpin structure that remains dynamic until its release from the ribosome. Contacts with the ribosome and structure of the peptidyl transferase center depend on nascent chain conformation. These results indicate that proteins may start out as α-helices inside the tunnel and switch into their native folds only as they emerge from the ribosome. Moreover, the correlation of nascent chain conformations with reorientation of key residues of the ribosomal peptidyl-transferase center suggest that protein folding could modulate ribosome activity.
- MeSH
- cirkulární dichroismus MeSH
- elektronová kryomikroskopie MeSH
- Escherichia coli genetika metabolismus MeSH
- konformace proteinů, alfa-helix MeSH
- konformace proteinů, beta-řetězec MeSH
- molekulární modely MeSH
- posttranslační úpravy proteinů MeSH
- proteiny a peptidy chladového šoku chemie genetika metabolismus MeSH
- proteiny z Escherichia coli chemie genetika metabolismus MeSH
- proteosyntéza MeSH
- ribozomy genetika metabolismus MeSH
- sbalování proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T cell Non-Hodgkin Lymphoma (NHL) associated with breast implants. Raising awareness of the possibility of BIA-ALCL in anyone with breast implants and new breast symptoms is crucial to early diagnosis. The tumour begins on the inner aspect of the peri-implant capsule causing an effusion, or less commonly a tissue mass to form within the capsule, which may spread locally or to more distant sites in the body. Diagnosis is usually made by cytological, immunohistochemical and immunophenotypic evaluation of the aspirated peri-implant fluid: pleomorphic lymphocytes are characteristically anaplastic lymphoma kinase (ALK) negative and strongly positive for CD30. BIA-ALCL is indolent in most patients but can progress rapidly. Surgical removal of the implant with the intact surrounding capsule (total en-bloc capsulectomy) is usually curative. Late diagnosis may require more radical surgery and systemic therapies and although these are usually successful, poor outcomes and deaths have been reported. By adopting a structured approach, as suggested in these guidelines, early diagnosis and successful treatment will minimize the need for systemic treatments, reduce morbidity and the risk of poor outcomes.
- MeSH
- anaplastický velkobuněčný lymfom diagnóza etiologie terapie MeSH
- lidé MeSH
- mamoplastika normy MeSH
- nádory prsu MeSH
- plastická chirurgie * MeSH
- počítačové zpracování obrazu MeSH
- prsní implantáty škodlivé účinky MeSH
- směrnice pro lékařskou praxi jako téma * MeSH
- společnosti lékařské * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Spojené království MeSH
