Project description:Mitochondria are dynamic organelles that have essential metabolic activity and are regarded as signalling hubs with biosynthetic, bioenergetics and signalling functions that orchestrate key biological pathways. However, mitochondria can influence all processes linked to oncogenesis, starting from malignant transformation to metastatic dissemination. In this review, we describe how alterations in the mitochondrial metabolic status contribute to the acquisition of typical malignant traits, discussing the most recent discoveries and the many unanswered questions. We also highlight that expanding our understanding of mitochondrial regulation and function mechanisms in the context of cancer cell metabolism could be an important task in biomedical research, thus offering the possibility of targeting mitochondria for the treatment of cancer.
Project description:Severe acute respiratory syndrome coronavirus 2 infection affects not only the lungs, but also the cardiovascular system, having a major impact on patients' outcomes. Myocardial injury (MI) occurs in the context of coronavirus infectious disease 2019 (COVID-19) and is associated with a higher risk of severe clinical outcome and mortality. COVID-19-related MI can have various clinical manifestations, of which the main ones are myocarditis, stress cardiomyopathy, acute coronary syndrome, and pulmonary embolism. The exact mechanisms of how MI occurs in these patients are not yet fully known. Direct injury, through direct viral myocardial invasion, and indirect injury, through interaction with angiotensin I converting enzyme 2, increased inflammation, and thrombocyte and endothelial dysfunction, could be involved in acute MI in patients with COVID-19. A better understanding of these multiple potential mechanisms may help to develop new targeted therapeutic strategies. The purpose of this review is to provide the current understanding of the potential mechanisms involved in MI induced by COVID-19 and to discuss the current progress in the therapeutic strategies.
Project description:Malignant peripheral nerve sheath tumor (MPNST) is a rare but aggressive soft-tissue sarcoma characterized by poor response to therapy. The primary treatment remains surgical resection with negative margins. Nonetheless, in the setting of neurofibromatosis type 1 (NF1), the five-year survival rate is at 20-50%, with recurrence occurring in up to 50% of individuals. For patients with metastatic and unresectable disease, current treatment options include cytotoxic chemotherapy, which offers minimal benefit, and most patients die within five years of diagnosis. Despite advances in targeted therapy focusing on inhibiting Ras signaling and its downstream effectors, clinical trials report minimal clinical benefit, highlighting the need to explore alternative pathways in MPNST pathogenesis. Here, we discuss the role of the E3 ubiquitin ligase, UBR5, in cancer progression and immune modulation across various malignancies, including breast, lung, and ovarian cancer. We focus on mechanisms by which UBR5 contributes to tumorigenesis, focusing on its influence on tumor microenvironment and immune modulation. Additionally, we explore UBR5's roles in normal tissue function, DNA damage response, metastasis, and therapeutic resistance, illustrating its multifaceted contribution to cancer biology. We discuss evidence implicating UBR5 in immune evasion and highlight its potential as a therapeutic target to enhance the efficacy of immune checkpoint blockade (ICB) therapy in MPNST, a tumor typically characterized by an immune cold microenvironment. We outline current immune-based strategies and challenges in MPNST management, ongoing efforts to shift the immune landscape in MPNST, and ultimately, we suggest that targeting UBR5 could be a novel strategy to potentiate ICB therapy-mediated anti-tumor immune response and clinical outcomes, particularly in MPNST patients with inoperable or metastatic disease.
Project description:ObjectiveTo screen cDNA for NLGN3 and NLGN4 from lymphoblastoid cells from autistic subjects.Methods and results10 young autistic females and 30 non-autistic subjects were studied for alterations in two X linked genes, NLGN3 and NLGN4. A novel NLGN4 isoform lacking exon 4, which occurred de novo on the paternal allele, was identified in one of the autistic females. Monoallelic expression of NLGN4 was seen in this subject and in 11 of 14 informative autistic and non-autistic females using a single nucleotide polymorphism found at 3' UTR. Additionally, the NLGN3 transcript was present in two isoforms (with and without exon 7) in nine of 10 autistic females and in 30 non-autistic subjects, including parents of the autistic female having only the complete transcript with exon 7, and from the whole brain of a control. The novel truncated NLGN3 product may have a regulatory role, as reported in other proteins (for example, vasopressin receptor) by attenuating the function of the full length isoform, resulting in a reduction of the mature protein. Three dimensional protein structures were characterised using comparative modelling, and significant changes were suggested in the protein cores for these two neuroligin isoforms.ConclusionsSplice variants may lead to potentially abnormal neuroligins in the causation of autism spectrum disorders.
Project description:RNA was isolated from adults using the TRIzol (Invitrogen) reagent by following the company manual. Poly(A) mRNA was isolated from 20 µl total RNA using Oligo (dT) magnetic beads and then was broken into short fragments (about 200bp) in the presence of fragmentation buffer at 94 °C for 5 min. The mRNA samples were used to construct the cDNA libray with mRNA-Seq assay.The libraries were sequenced using HiSeq4000 (Illumina) in paired-end mode, creating reads with a length of 150 bp.
Project description:Previous studies on the association of insomnia with body mass index (BMI) have been controversial. Physiological hyperarousal, the key pathological mechanism of insomnia, may be an important reason for different findings. We explored whether insomnia with physiological hyperarousal measured by the multiple sleep latency test (MSLT) is associated with body-weight differences. A total of 185 normal sleepers and 440 insomniacs were included in this study. Insomnia was defined by standard diagnostic criteria with symptoms lasting ≥6 months. All subjects underwent one night of laboratory polysomnography followed by a standard MSLT. We used the median MSLT value (i.e., ≥14 min) to define physiological hyperarousal. BMI was based on measured height (cm) and weight (kg) during the subjects' sleep laboratory visit. BMI > 25 kg/m2 was defined as overweight, while BMI < 18.5 kg/m2 was defined as underweight. After controlling for confounders, the odds of lower weight rather than overweight were significantly increased among insomnia patients with increased MSLT: insomnia with MSLT 14-17 min and MSLT > 17 min increased the odds of lower weight by approximately 89% (OR = 1.89, 95% CI 1.00-4.85) and 273% (OR = 3.73, 95% CI 1.51-9.22) compared with normal sleepers, respectively. In contrast, insomnia in patients with MSLT 11-14 min and 8-11 min was not different from normal sleepers in terms of body weight. Insomnia associated with physiological hyperarousal, the most severe phenotype of chronic insomnia, is associated with higher odds of lower weight and underweight compared with normal sleepers. This is a novel finding consistent with previous physiologic data and has significant clinical implications.
Project description:Simple Summary Radiotherapy is an option for curing localized and locally advanced prostate cancer. However, radioresistance can occur, determining treatment failure and poor prognosis. Herein, we developed a model of radio-resistant prostate cancer cells by irradiating the bone metastasis-derived PC3 highly metastatic prostate cancer cell line and the brain-derived moderately metastatic DU-145 prostate cancer cell line, both castration-resistant. Ultra-hypo-fractionated radiotherapy was used, with doses and intervals similar to the ones used in clinical practice. These in vitro models were tested to gain information on the molecular mechanisms used by prostate cancer cells to survive radiation-induced death. Results from bioassays and molecular assays show that in the highly metastatic cells (PC3), the acquired radioresistance—though enhancing clonogenic efficiency, enrichment of cancer stem cells, proliferation rate and migration ability—interestingly results in significantly higher sensitivity to Docetaxel. This behaviour was not observed using the moderately metastatic DU-145 prostate cancer cells. It can be hypothesised that subgroups of patients with highly metastatic prostate cancer could benefit from chemotherapy immediately after the failure of radiotherapy, before a re-challenge with hormonal treatment or other strategies. Abstract The use of a higher dose per fraction to overcome the high radioresistance of prostate cancer cells has been unsuccessfully proposed. Herein, we present PC3 and DU-145, castration-resistant prostate cancer cell lines that survived a clinically used ultra-higher dose per fraction, namely, radioresistant PC3 and DU-145 cells (PC3RR and DU-145RR). Compared to PC3, PC3RR showed a higher level of aggressive behaviour, with enhanced clonogenic potential, DNA damage repair, migration ability and cancer stem cell features. Furthermore, compared to PC3, PC3RR more efficiently survived further radiation by increasing proliferation and down-regulating pro-apoptotic proteins. No significant changes of the above parameters were described in DU-145RR, suggesting that different prostate cancer cell lines that survive ultra-higher dose per fraction do not display the same grade of aggressive phenotype. Furthermore, both PC3RR and DU-145RR increased antioxidant enzymes and mesenchymal markers. Our data suggest that different molecular mechanisms could be potential targets for future treatments plans based on sequential strategies and synergistic effects of different modalities, possibly in a patient-tailored fashion. Moreover, PC3RR cells displayed an increase in specific markers involved in bone remodeling, indicating that radiotherapy selects a PC3 population capable of migrating to secondary metastatic sites. Finally, PC3RR cells showed a better sensitivity to Docetaxel as compared to native PC3 cells. This suggests that a subset of patients with castration-resistant metastatic disease could benefit from upfront Docetaxel treatment after the failure of radiotherapy.
Project description:Approximately one-third of our food globally comes from insect-pollinated crops. The dependence on pollinators has been linked to yield instability, which could potentially become worse in a changing climate. Insect-pollinated crops produced via hybrid breeding (20% of fruit and vegetable production globally) are especially at risk as they are even more reliant on pollinators than open-pollinated plants. We already observe a wide range of fruit and seed yields between different cultivars of the same crop species, and it is unknown how existing variation will be affected in a changing climate. In this study, we examined how three hybrid carrot varieties with differential performance in the field responded to three temperature regimes (cooler than the historical average, average, and warmer that the historical average). We tested how temperature affected the plants' ability to set seed (seed set, pollen viability) as well as attract pollinators (nectar composition, floral volatiles). We found that there were significant intrinsic differences in nectar phenolics, pollen viability, and seed set between the carrot varieties, and that higher temperatures did not exaggerate those differences. However, elevated temperature did negatively affect several characteristics relating to the attraction and reward of pollinators (lower volatile production and higher nectar sugar concentration) across all varieties, which may decrease the attractiveness of this already pollinator-limited crop. Given existing predictions of lower pollinator populations in a warmer climate, reduced attractiveness would add yet another challenge to future food production.
Project description:BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAF(V600K) melanoma cells. We further describe a new screening approach, a genome-wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N-terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution (BRAF(L505H) ), is the first resistance-conferring second-site mutation identified in BRAF mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF-PLX4032 interface with a larger polar residue. Moreover, we show that BRAF(L505H) , found in human prostate cancer, is itself a MAPK-activating, PLX4032-resistant oncogenic mutation. Lastly, we demonstrate that the PLX4032-resistant melanoma cells are sensitive to novel, next-generation BRAF inhibitors, especially the 'paradox-blocker' PLX8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF-mutations.