Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) ...represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A
dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell-cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A
DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.
The biochemistry of somatic hypermutation Peled, Jonathan U; Kuang, Fei Li; Iglesias-Ussel, Maria D ...
Annual review of immunology,
01/2008, Letnik:
26
Journal Article
Recenzirano
Affinity maturation of the humoral response is mediated by somatic hypermutation of the immunoglobulin (Ig) genes and selection of higher-affinity B cell clones. Activation-induced cytidine deaminase ...(AID) is the first of a complex series of proteins that introduce these point mutations into variable regions of the Ig genes. AID deaminates deoxycytidine residues in single-stranded DNA to deoxyuridines, which are then processed by DNA replication, base excision repair (BER), or mismatch repair (MMR). In germinal center B cells, MMR, BER, and other factors are diverted from their normal roles in preserving genomic integrity to increase diversity within the Ig locus. Both AID and these components of an emerging error-prone mutasome are regulated on many levels by complex mechanisms that are only beginning to be elucidated.
Polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) share some similarity in clinical imaging manifestations. However, their disease entity and treatment ...strategy as well as visual outcomes are very different. To distinguish these two vision-threatening diseases is somewhat challenging but necessary. In this study, we propose a new artificial intelligence model using an ensemble stacking technique, which combines a color fundus photograph-based deep learning (DL) model and optical coherence tomography-based biomarkers, for differentiation of PCV from nAMD. Furthermore, we introduced multiple correspondence analysis, a method of transforming categorical data into principal components, to handle the dichotomous data for combining with another image DL system. This model achieved a robust performance with an accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of 83.67%, 80.76%, 84.72%, and 88.57%, respectively, by training nearly 700 active cases with suitable imaging quality and transfer learning architecture. This work could offer an alternative method of developing a multimodal DL model, improve its efficiency for distinguishing different diseases, and facilitate the broad application of medical engineering in a DL model design.
CDC73/Parafibromin is a critical component of the Paf1 complex (PAF1C), which is involved in transcriptional elongation and histone modifications. Mutations of the human CDC73/HRPT2 gene are ...associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant disorder. CDC73/parafibromin was initially recognized as a tumor suppressor by inhibiting cell proliferation via repression of cyclin D1 and c-myc genes. In recent years, it has also shown oncogenic features by activating the canonical Wnt/β-catenin signal pathway. Here, through limited proteolysis analysis, we demonstrate that the evolutionarily conserved human CDC73 N-terminal 111 residues form a globularly folded domain (hCDC73-NTD). We have determined a crystal structure of hCDC73-NTD at 1.02 Å resolution, which reveals a novel protein fold. CDC73-NTD contains an extended hydrophobic groove on its surface that may be important for its function. Most pathogenic CDC73 missense mutations associated with the HPT-JT syndrome are located in the region encoding CDC73-NTD. Our crystal and biochemical data indicate that most CDC73 missense mutations disrupt the folding of the hydrophobic core of hCDC73-NTD, while others such as the K34Q mutant reduce its thermostability. Overall, our results provide a solid structural basis for understanding the structure and function of CDC73 and its association with the HPT-JT syndrome and other diseases.
DNA double-strand breaks (DSBs) are the most perilous and harmful type of DNA damage and can cause tumorigenesis or cell death if left repaired with an error or unrepaired. RadD, a member of the SF2 ...family, is a recently discovered DNA repair protein involved in the repair of DSBs after radiation or chemical damage. However, the function of RadD in DNA repair remains unclear. Here, we determined the crystal structures of RadD/ATPγS and RadD/ATP complexes and revealed the novel mechanism of RadD binding to DNA and ATP hydrolysis with biochemical data. In the RadD catalytic center, the Gly34 and Gly36 on the P-loop are key residues for ATP binding besides the conserved amino acids Lys37 and Arg343 in the SF2 family. If any of them mutate, then RadD loses ATPase activity. Asp117 polarizes the attacking water molecule, which then starts a nucleophilic reaction toward γ-phosphate, forming the transition state. Lys68 acts as a pocket switch to regulate substrate entry and product release. We revealed that the C-terminal peptide of single-stranded DNA-binding protein (SSB) binds the RadD C-terminal domain (CTD) and promotes the RadD ATPase activity. Our mutagenesis studies confirmed that the residues Arg428 on the zinc finger domain (ZFD) and Lys488 on the CTD of RadD are the key sites for binding branched DNA. Using the Coot software combined with molecular docking, we propose a RadD-binding DNA model for the DNA damage repair process.
The presence of pesticide residues in pears is a serious health concern. This study presents the results from a 2-year investigation （2013-2014） that used gas chromatography, GS/MS and UPLC/MS-MS to ...measure the levels of 104 pesti- cides in 310 pear samples. In 93.2% of the samples, 43 pesticides were detected, of which the maximum residue levels （MRLs） were exceeded in 2.6% of the samples. Multiple residues （two to eight compounds） were present in 69.7% of the samples; one sample contained nine pesticides and one sample contained 10. Only 6.8% of the samples did not contain residues. To assess the health risks, the pesticide residue data have been combined with daily pear consumption data for children and adult populations. A deterministic model was used to assess the chronic and acute exposures based on the Joint Meeting on Pesticide Residues （JMPR） method. A potential acute risk was demonstrated for children in the case of bifenthrin, which was found to be present at 105.36% of the acute reference dose （ARfD） value. The long- term exposure of the Chinese consumer to pesticide residues through the consumption of raw pears was far below the acceptable daily intake （ADI） criterion. Additionally, the matrix ranking scheme was used to classify risk subgroups of pesticides and pear samples. In general, 95.5% of samples were deemed to be safe and nine pesticides were classified as being of a relatively high risk. The findings indicated that the occurrence of pesticide residues in pears should not be considered a serious public health problem. Nevertheless, a more detailed study is required for vulnerable consumer groups, especially children. Continuous monitoring of pesticides in pears and tighter regulation of pesticide residue standards are recommended.
Hypereosinophilic syndromes (HES) are a heterogeneous group of rare disorders defined by the presence of marked peripheral or tissue eosinophilia resulting in end-organ damage. Although conventional ...therapies, including glucocorticoids, hydroxyurea, and IFN-α, are initially effective in reducing eosinophilia and symptoms in a majority of patients with platelet-derived growth factor mutation-negative HES, the development of resistance and treatment-related toxicity are common. In contrast, targeted therapy with the tyrosine kinase inhibitor, imatinib, is well tolerated but effective only in the subset of patients with HES with a primary myeloid disorder. Eosinophil-targeted biotherapeutics offer the potential of improved efficacy with few, if any, adverse effects. The aims of this review are to provide an overview of current approaches to the use of conventional HES therapies and a discussion of existing biotherapeutics that target eosinophils and their potential use in the treatment of HES. With the continuing expansion of eosinophil-targeted biotherapeutics, the future for patients with eosinophilic disorders is promising.
The determination of lumbopelvic alignment is essential for planning adult spinal deformity surgery and for ensuring favorable surgical outcomes. This prospective study investigated the correlation ...between the lumbar section of lumbar spine lordosis and increasing pelvic incidence in 324 Asian adults with a mean age of 55 ± 13 years (range: 20-80 years), comprising 115 male and 209 female volunteers. Participants were divided into three groups based on pelvic incidence (G1, G2, and G3 had pelvic incidence of < 45°, 45-55°, and ≥ 55°, respectively). We determined that distal and proximal lumbar lordosis contributed differentially to the increase in pelvic incidence, whereas the lordosis ratio of the L3-L4 and L4-L5 segments mostly remained constant. The mean contribution ratio of the segmental lordosis from L1 to S1 was as follows: L1-L2, 2.3%; L2-L3, 11.7%; L3-L4, 18.1%; L4-L5, 25.2%; and L5-S1, 42.7%. Pelvic incidence had a stronger correlation with proximal lumbar lordosis than did distal lumbar lordosis. The ratios of proximal lumbar lordosis to distal lumbar lordosis were 37.8% in G1, 45.8% in G2, and 55.9% in G3. These findings serve as a reference for future lumbar spine correction or fusion surgery for Asian adults.
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