Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
Objective Human Lyme arthritis caused by Borrelia burgdorferi is characterized by an inflammatory infiltrate that consists mainly of neutrophils and T cells. This study was undertaken to evaluate the role of the innate and acquired immune responses elicited by the neutrophil‐activating protein A (NapA) of B burgdorferi in patients with Lyme arthritis. Methods Serum anti‐NapA antibodies were measured in 27 patients with Lyme arthritis and 30 healthy control subjects. The cytokine profile of synovial fluid T cells specific for NapA was investigated in 5 patients with Lyme arthritis. The cytokine profile induced by NapA in neutrophils and monocytes was also investigated. Results Serum anti‐NapA antibodies were found in 48% of the patients with Lyme arthritis but were undetectable in the healthy controls. T cells from the synovial fluid of patients with Lyme arthritis produced interleukin‐17 (IL‐17) in response to NapA. Moreover, NapA was able to induce the expression of IL‐23 in neutrophils and monocytes, as well as the expression of IL‐6, IL‐1β, and transforming growth factor β (TGFβ) in monocytes, via Toll‐like receptor 2. Conclusion These findings indicate that NapA of B burgdorferi is able to drive the expression of IL‐6, IL‐1β, IL‐23, and TGFβ by cells of the innate immune system and to elicit a synovial fluid Th17 cell response that might play a crucial role in the pathogenesis of Lyme arthritis.
We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.
Summary: Purpose: To assess the magnetic resonance imaging (MRI), positron emission tomography (PET), pathology, and clinical findings of patients with the MRI feature of whitematter change (WMC) in the anterior temporal lobe.Methods: Fifty-six patients with pathologically proven mesial temporal sclerosis were included in this study. MRI and F-2-deoxyglucose-(FDG) PET images were obtained before in surgery in all patients. The patients were divided into two groups according to the presence of WMC on their MRI. WMC consists of an indistinct gray-white matter demarcation and an increased signal intensity of the anterior temporal lobe on T,-weighted images. The two groups were then compared in terms of MRI, PET, pathology, and clinical features.Results: The MRI feature of WMC was observed in 18 (32%) of the 56 patients. PET images of those patients revealed more severe hypometabolism of the ipsilateral temporal lobes (p < 0.05). In terms of histologic findings, larger numbers of heterotopic neurons were observed in the anterior temporal lobe white matter of these patients who also shared the following clinical features: earlier seizure onset, frequent history of febrile convulsions, and favorable surgical outcomes.Conclusions: The MRI feature of WMC is an additive sign for correct seizure lateralization and may be related to a favorable surgical outcome in patients with temporal lobe epilepsy. Key Words: Mesial temporal sclerosis-Epilepsy-Magnetic resonance imaging-Positron emission tomography-White matter change.Atrophy and signal changes of the hippocampus have been known as the most reliable magnetic resonance imaging (MRI) criteria of mesial temporal sclerosis ( 1 4 ) . One MRI feature of mesial temporal sclerosis is whitematter change (WMC) in the anterior temporal lobe. This change consists of an indistinct gray-white matter demarcation with increased signal intensity on T,-weighted images (1,2,5-13). Previous pathologic studies (2,9,10, 12-17) conducted on tissue obtained after temporal lobectomies revealed abnormal histologic changes in the white matter of the ipsilateral temporal lobe in patients with intractable temporal lobe epilepsy (TLE). However, the pathologic documentation of WMC on MRIs has not been fully performed, and the clinical significance has not been established.The purpose of this study was to assess the MRI, pos- hsbyun@smc.samsung.co.kr itron emission tomography (PET), pathology, and clinical findings of patients with WMC. We also attempted to determine the value of this MRI feature for the presurgical lateralizaton of the epileptic focus and the surgical outcome in patients with mesial temporal sclerosis. METHODSFrom January 1995 to February 1997, 58 consecutive patients with TLE were surgically proven to have mesial temporal sclerosis. Two cases that were concomitant with focal cortical dysplasia were excluded from this study, with the remained 56 included. The study group consisted of 31 men and 25 women with a mean age of 28 years (range, 13-44 years). All patients underwent an ante...
Bilateral patchy areas of opacity depicted radiographically and good clinical response to treatment may differentiate NIP from other interstitial pneumonias.
Of the genetic changes in primary central nervous system lymphoma (PCNSL), little is known. To detect copy number alterations and differentially expressed genes in PCNSL, we analyzed a total of 12 PC-NSL samples with high-resolution arraybased comparative genomic hybridization and performed expression profiling in 7 of the 12 samples. The most frequent deletion found in 8 patients (66.7%) occurred in 9p21.3 containing CDKN2A. We compiled the top 96 genes (family-wise error rate, P < .05) showing the greatest differential expression between PCNSL and normal lymph node tissues. From these, we selected 8 candidate genes (NPFFR2, C4orf7, OSMR, EMCN, TPO, FNDC1, COL12A1, and MSC) in which expression changes were associated with copy number aberrations. All 8 genes showed both down-regulation in expression microarray and deletion in arraybased comparative genomic hybridization analyses. These genes participate in cell signaling or cell adhesion. In addition, low mRNA expression of C4orf7 was significantly associated with poor survival (P ؍ .0425). Using gene set enrichment analysis, we identified several signal transduction pathways, such as Janus kinase-signal transducers and activators of transcription pathway and adhesionrelated pathways, which may be involved in pathogenesis of PCNSL. In conclusion, this study identified novel tumor suppressor genes that may serve as therapeutic targets of PCNSL. (Blood. 2011;117(4): 1291-1300)
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