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Human Genome Variation Mar 2024A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis....
A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis. Whole-genome array comparative genomic hybridization (aCGH) revealed germline deletions at chromosome 5q22.1-22.2 encompassing the entire APC gene. The patient and her son exhibited mild intellectual disability without developmental delay. This case highlights the need for further exploration of the characteristics associated with whole APC deletions. aCGH is a valuable tool for studying FAP and provides a detailed analysis of large deletions.
PubMed: 38548799
DOI: 10.1038/s41439-024-00270-3 -
Molecular Cancer Research : MCR Jun 2024The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This...
UNLABELLED
The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA.
IMPLICATIONS
PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.
Topics: Humans; Glycosylphosphatidylinositols; Duodenal Neoplasms; Mutation; Adenomatous Polyposis Coli; Membrane Proteins; Carcinogenesis; Male; Female
PubMed: 38546397
DOI: 10.1158/1541-7786.MCR-23-0810 -
Genes Feb 2024E3 ubiquitin ligases play a pivotal role in ubiquitination, a crucial post-translational modification process. Anaphase-promoting complex (APC), a large cullin-RING E3...
E3 ubiquitin ligases play a pivotal role in ubiquitination, a crucial post-translational modification process. Anaphase-promoting complex (APC), a large cullin-RING E3 ubiquitin ligase, regulates the unidirectional progression of the cell cycle by ubiquitinating specific target proteins and triggering plant immune responses. Several E3 ubiquitin ligases have been identified owing to advancements in sequencing and annotation of the wheat genome. However, the types and functions of APC E3 ubiquitin ligases in wheat have not been reported. This study identified 14 members of the APC gene family in the wheat genome and divided them into three subgroups (CCS52B, CCS52A, and CDC20) to better understand their functions. Promoter sequence analysis revealed the presence of several cis-acting elements related to hormone and stress responses in the APC E3 ubiquitin ligases in wheat. All identified APC E3 ubiquitin ligase family members were highly expressed in the leaves, and the expression of most genes was induced by the application of methyl jasmonate (MeJA). In addition, the APC gene family in wheat may play a role in plant defense mechanisms. This study comprehensively analyzes APC genes in wheat, laying the groundwork for future research on the function of APC genes in response to viral infections and expanding our understanding of wheat immunity mechanisms.
Topics: Anaphase-Promoting Complex-Cyclosome; Triticum; Ubiquitin-Protein Ligases; Ubiquitination; Ubiquitin
PubMed: 38540330
DOI: 10.3390/genes15030271 -
Biomedicines Mar 2024Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian... (Review)
Review
Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes and . In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline mutations. Deleterious variants in the genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic mutations is less clear. Somatic -mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic mutations. The aim of this review is to summarize the predictive role of somatic mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.
PubMed: 38540206
DOI: 10.3390/biomedicines12030593 -
BMC Microbiology Mar 2024Vancomycin-resistant enterococci (VRE) are major opportunistic pathogens and the causative agents of serious diseases, such as urinary tract infections and endocarditis.... (Review)
Review
Vancomycin-resistant enterococci (VRE) are major opportunistic pathogens and the causative agents of serious diseases, such as urinary tract infections and endocarditis. VRE strains mainly include species of Enterococcus faecium and E. faecalis which can colonise the gastrointestinal tract (GIT) of patients and, following growth and persistence in the gut, can transfer to blood resulting in systemic dissemination in the body. Advancements in genomics have revealed that hospital-associated VRE strains are characterised by increased numbers of mobile genetic elements, higher numbers of antibiotic resistance genes and often lack active CRISPR-Cas systems. Additionally, comparative genomics have increased our understanding of dissemination routes among patients and healthcare workers. Since the efficiency of currently available antibiotics is rapidly declining, new measures to control infection and dissemination of these persistent pathogens are urgently needed. These approaches include combinatory administration of antibiotics, strengthening colonisation resistance of the gut microbiota to reduce VRE proliferation through commensals or probiotic bacteria, or switching to non-antibiotic bacterial killers, such as bacteriophages or bacteriocins. In this review, we discuss the current knowledge of the genomics of VRE isolates and state-of-the-art therapeutic advances against VRE infections.
Topics: Humans; Anti-Bacterial Agents; Vancomycin-Resistant Enterococci; Enterococcus faecium; Gastrointestinal Microbiome; Genomics; Gram-Positive Bacterial Infections; Microbial Sensitivity Tests
PubMed: 38539119
DOI: 10.1186/s12866-024-03243-2 -
Nature Communications Mar 2024To broaden the substrate scope of microbial cell factories towards renewable substrates, rational genetic interventions are often combined with adaptive laboratory...
To broaden the substrate scope of microbial cell factories towards renewable substrates, rational genetic interventions are often combined with adaptive laboratory evolution (ALE). However, comprehensive studies enabling a holistic understanding of adaptation processes primed by rational metabolic engineering remain scarce. The industrial workhorse Pseudomonas putida was engineered to utilize the non-native sugar D-xylose, but its assimilation into the bacterial biochemical network via the exogenous xylose isomerase pathway remained unresolved. Here, we elucidate the xylose metabolism and establish a foundation for further engineering followed by ALE. First, native glycolysis is derepressed by deleting the local transcriptional regulator gene hexR. We then enhance the pentose phosphate pathway by implanting exogenous transketolase and transaldolase into two lag-shortened strains and allow ALE to finetune the rewired metabolism. Subsequent multilevel analysis and reverse engineering provide detailed insights into the parallel paths of bacterial adaptation to the non-native carbon source, highlighting the enhanced expression of transaldolase and xylose isomerase along with derepressed glycolysis as key events during the process.
Topics: Xylose; Pseudomonas putida; Transaldolase; Metabolic Engineering; Pentose Phosphate Pathway
PubMed: 38531855
DOI: 10.1038/s41467-024-46812-9 -
Human α-synuclein overexpression upregulates SKOR1 in a rat model of simulated nigrostriatal ageing.Aging Cell Jun 2024Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is...
Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α-synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre-parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague-Dawley rats received a unilateral intranigral injection of adeno-associated viral (AAV) vector carrying wild-type human αSyn (AAV-αSyn) or control vector (AAV-Null). AAV-αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild-type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post-surgery. Microarray analysis revealed that the gene most-upregulated in the ipsilateral SN of the AAV-αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH-SY5Y cells. Furthermore, experiments in SH-SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP-SMAD-dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn-induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing-related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.
Topics: Animals; Female; Humans; Rats; Aging; alpha-Synuclein; Corpus Striatum; Disease Models, Animal; Dopaminergic Neurons; Parkinson Disease; Rats, Sprague-Dawley; Substantia Nigra; Up-Regulation
PubMed: 38529808
DOI: 10.1111/acel.14155 -
Journal of Research in Medical Sciences... 2024Stools from colorectal cancer patients are noninvasive samples that could be used to compare the frequency of hotspot mutations between two different ethnic cohorts.
BACKGROUND
Stools from colorectal cancer patients are noninvasive samples that could be used to compare the frequency of hotspot mutations between two different ethnic cohorts.
MATERIALS AND METHODS
We collected stool samples from the Iranian cohort (52 patients and 49 controls) and the Finnish cohort (40 patients and 14 controls). Following stool DNA extraction, we used the AmpliSeq Colon and Lung Cancer panel to prepare DNA libraries before sequencing.
RESULTS
The Iranian cohort exhibited 35 hotspot mutations in the , , , , , , , , , , , and genes. In the Finnish cohort, 13 hotspot mutations were found in the , , , , , , and genes. Mutations in and were observed only in the Iranian cohort, while mutations were exclusive for the Finnish cohort.
CONCLUSION
Genes involved in MAPK and PI3K-MAPK pathways showed a higher frequency of mutations in Iranian patients which may have therapeutic implications.
PubMed: 38524743
DOI: 10.4103/jrms.jrms_208_23 -
Cell & Bioscience Mar 2024Bacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver...
BACKGROUND
Bacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of this is the short-term nature of RNA interference in vivo due to plasmid instability. To overcome this, we sought to develop tumour-targeting attenuated bacteria that stably express shRNA by virtue of integration of an expression cassette within the bacterial chromosome and demonstrate therapeutic efficacy in vitro and in vivo.
RESULTS
The attenuated tumour targeting Salmonella typhimurium SL7207 strain was modified to carry chromosomally integrated shRNA expression cassettes at the xylA locus. The colorectal cancer cell lines SW480, HCT116 and breast cancer cell line MCF7 were used to demonstrate the ability of these modified strains to perform intracellular infection and deliver effective RNA and protein knockdown of the target gene c-Myc. In vivo therapeutic efficacy was demonstrated using the Lgr5creERApc and BlgCreBrca2p53 orthotopic immunocompetent mouse models of colorectal and breast cancer, respectively. In vitro co-cultures of breast and colorectal cancer cell lines with modified SL7207 demonstrated a significant 50-95% (P < 0.01) reduction in RNA and protein expression with SL7207/c-Myc targeted strains. In vivo, following establishment of tumour tissue, a single intra-peritoneal administration of 1 × 10 CFU of SL7207/c-Myc was sufficient to permit tumour colonisation and significantly extend survival with no overt toxicity in control animals.
CONCLUSIONS
In summary we have demonstrated that tumour tropic bacteria can be modified to safely deliver therapeutic levels of gene knockdown. This technology has the potential to specifically target primary and secondary solid tumours with personalised therapeutic payloads, providing new multi-cancer detection and treatment options with minimal off-target effects. Further understanding of the tropism mechanisms and impact on host immunity and microbiome is required to progress to clinical translation.
PubMed: 38521952
DOI: 10.1186/s13578-024-01206-8 -
Oncogene May 2024Wnt/β-catenin signalling is aberrantly activated in most colorectal cancer (CRC) and is one key driver involved in the initiation and progression of CRC. However,...
Wnt/β-catenin signalling is aberrantly activated in most colorectal cancer (CRC) and is one key driver involved in the initiation and progression of CRC. However, mutations of APC gene in CRC patients retain certain activity of APC protein with decreased β-catenin signalling and DKK4 expression significantly upregulates and represses Wnt/β-catenin signalling in human CRC tissues, suggesting that a precisely modulated activation of the Wnt/β-catenin pathway is essential for CRC formation and progression. The underlying reasons why a specifically reduced degree, not a fully activating degree, of β-catenin signalling in CRC are unclear. Here, we showed that a soluble extracellular inhibitor of Wnt/β-catenin signalling, DKK4, is an independent factor for poor outcomes in CRC patients. DKK4 secreted from CRC cells inactivates β-catenin in fibroblasts to induce the formation of stress fibre-containing fibroblasts and myofibroblasts in culture conditions and in mouse CRC xenograft tissues, resulting in restricted expansion in tumour masses at primary sites and enhanced CRC metastasis in mouse models. Reduced β-catenin activity by a chemical inhibitor MSAB promoted the CRC metastasis. Our findings demonstrate why reduced β-catenin activity is needed for CRC progression and provide a mechanism by which interactions between CRC cells and stromal cells affect disease promotion.
Topics: Colorectal Neoplasms; Humans; Animals; Intercellular Signaling Peptides and Proteins; Mice; beta Catenin; Wnt Signaling Pathway; Neoplasm Metastasis; Fibroblasts; Cell Line, Tumor; Male; Female; Mice, Nude
PubMed: 38519641
DOI: 10.1038/s41388-024-03008-1