Unbiased transcriptomic analyses reveal distinct effects of immune deficiency in CNS function with and without injury

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

Correction to: Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity

In the original publication, the label of Fig. 2C should be read as "GFAP/lectin/DAPI" not "DMP1/GFAP/lectin/DAPI".

Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations

Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells (NSC/NPCs) activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside. Moreover, brain NSC/NPCs themselves are not a homogenous population, making it even more difficult to uncover NSC/NPC sub-type specific aging mechanisms. Here, using both population-based and single cell transcriptome analyses of young and aged mouse forebrain ependymal and subependymal regions and comprehensive "big-data" processing, we report that NSC/NPCs reside in a rather inflammatory environment in aged brain, which likely contributes to the differentiation bias towards astrocytes versus neurons. Moreover, single cell transcriptome analyses revealed that different aged NSC/NPC subpopulations, while all have reduced cell proliferation, use different gene transcription programs to regulate age-dependent decline in cell cycle. Interestingly, changes in cell proliferation capacity are not influenced by inflammatory cytokines, but likely result from cell intrinsic mechanisms. The Erk/Mapk pathway appears to be critically involved in regulating age-dependent changes in the capacity for NSC/NPCs to undergo clonal expansion. Together this study is the first example of using population and single cell based transcriptome analyses to unveil the molecular interplay between different NSC/NPCs and their microenvironment in the context of the aging brain.

Glycosylation of dentin matrix protein 1 is a novel key element for astrocyte maturation and BBB integrity

The blood-brain barrier (BBB) is a tight boundary formed between endothelial cells and astrocytes, which separates and protects brain from most pathogens as well as neural toxins in circulation. However, detailed molecular players involved in formation of BBB are not completely known. Dentin matrix protein 1 (DMP1)-proteoglycan (PG), which is known to be involved in mineralization of bones and dentin, is also expressed in soft tissues including brain with unknown functions. In the present study, we reported that DMP1-PG was expressed in brain astrocytes and enriched in BBB units. The only glycosylation site of DMP1 is serine89 (S89) in the N-terminal domain of the protein in mouse. Mutant mice with DMP1 point mutations changing S89 to glycine (S89G), which completely eradicated glycosylation of the protein, demonstrated severe BBB disruption. Another breed of DMP1 mutant mice, which lacked the C-terminal domain of DMP1, manifested normal BBB function. The polarity of S89G-DMP1 astrocytes was disrupted and cell-cell adhesion was loosened. Through a battery of analyses, we found that DMP1 glycosylation was critically required for astrocyte maturation both in vitro and in vivo. S89G-DMP1 mutant astrocytes failed to express aquaporin 4 and had reduced laminin and ZO1 expression, which resulted in disruption of BBB. Interestingly, overexpression of wild-type DMP1-PG in mouse brain driven by the nestin promoter elevated laminin and ZO1 expression beyond wild type levels and could effectively resisted intravenous mannitol-induced BBB reversible opening. Taken together, our study not only revealed a novel element, i.e., DMP1-PG, that regulated BBB formation, but also assigned a new function to DMP1-PG.

Retrospective analysis of the clinical features and prognostic factors of 370 patients with advanced-stage diffuse large B-cell lymphoma / 中华肿瘤杂志

Objective@#The clinical features and prognosis of diffuse large B-cell lymphoma (DLBCL) were analyzed to optimize the treatment.@*Methods@#We retrospectively collected the clinical data of patients with advanced-stage DLBCL from January 2006 to December 2012 in National Cancer Center/Cancer Hospital. The demographic characteristics, clinical stage, histological diagnosis, treatment and prognostic characteristics of these patients were analyzed.@*Results@#A total of 370 patients with median age of 55 years old were recruited in the study. The male-to-female ratio was 1.3∶1. Among the 361 patients who underwent therapy, 280 cases received chemotherapy alone, 65 cases received chemoradiotherapy, and 16 cases received chemotherapy combined with autologous hematopoietic stem cell transplantation (AHSCT). The median follow-up period was 89 months, the 5-year overall survival (OS) rate of the entire cohort was 42.9%. The 5-year OS rate of chemotherapy alone, chemoradiotherapy and chemotherapy combined with AHSCT were 36.8%, 58.5%, 87.5%, respectively. The 5-year OS rate were significantly different between chemoradiotherapy and chemotherapy alone (P=0.001), and between chemotherapy combined with AHSCT and chemoradiotherapy (P=0.040). Univariate analysis showed that the age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, Ann Arbor stage, B symptom, bulky disease, number of extranodal sites, Ki-67 index, lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), international prognostic index (IPI), therapeutic manner and chemotherapy combined with rituximab were significantly associated with the prognosis of advanced DLBCL patients (all P<0.05). Multivariate analysis demonstrated that the age >60 years, Ann Arbor stage IV, with B symptom, with bulky disease, ECOG PS≥1, Ki-67 index > 90%, CD5 expression, up-regulation of serum LDH and β2-MG, and chemotherapy without rituximab were related with the poor prognosis of patients with advanced-stage DLBCL (all P<0.05).@*Conclusions@#Chemotherapy combined with rituximab can improve the outcome of patients with advanced-stage DLBCL. The age, stage, B symptom, bulky disease, ECOG PS score, Ki-67 index, CD5 expression, LDH, β2-MG and chemotherapy combined with rituximab are associated with the prognosis of these patients.

Theranostic research of radiolabeled prostate-specific membrane antigen ligands in metastatic castra-tion-resistant prostate cancer / 中华核医学与分子影像杂志

Prostate cancer is the most common cancer among males. Advanced prostate cancer could develop into metastatic castration-resistant prostate cancer (mCRPC), which is a challenge in the di-agnosis and treatment. The prognosis and quality of life of patients can be significantly improved by using ra-diolabeled prostate-specific membrane antigen ( PSMA) ligands for localization and targeted therapy of mCRPC. This review summarizes the research progress of radiolabeled PSMA ligands in theranostics of mCRPC including SPECT imaging, PET imaging, and brachytherapy.

Coupled electrophysiological recording and single cell transcriptome analyses revealed molecular mechanisms underlying neuronal maturation

The mammalian brain is heterogeneous, containing billions of neurons and trillions of synapses forming various neural circuitries, through which sense, movement, thought, and emotion arise. The cellular heterogeneity of the brain has made it difficult to study the molecular logic of neural circuitry wiring, pruning, activation, and plasticity, until recently, transcriptome analyses with single cell resolution makes decoding of gene regulatory networks underlying aforementioned circuitry properties possible. Here we report success in performing both electrophysiological and whole-genome transcriptome analyses on single human neurons in culture. Using Weighted Gene Coexpression Network Analyses (WGCNA), we identified gene clusters highly correlated with neuronal maturation judged by electrophysiological characteristics. A tight link between neuronal maturation and genes involved in ubiquitination and mitochondrial function was revealed. Moreover, we identified a list of candidate genes, which could potentially serve as biomarkers for neuronal maturation. Coupled electrophysiological recording and single cell transcriptome analysis will serve as powerful tools in the future to unveil molecular logics for neural circuitry functions.

A analysis of the outcome and prognostic factors in 415 patients with Hodgkin lymphoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>The aim of this study was to investigate the effectiveness of treatment, survival and prognostic factors in Chinese patients with Hodgkin lymphoma.</p><p><b>METHODS</b>A total of previously untreated 415 patients with histologically confirmed Hodgkin lymphoma admitted in the Cancer Hospital, Chinese Academy of Medical Sciences from February 1999 to February 2011 were included in this study. Their short-term and long-term survivals, as well as prognostic factors were analyzed.</p><p><b>RESULTS</b>For the whole group, 371 cases (89.4%) had complete remission (CR), 33 cases (8.0%) had partial remission (PR) and 11 cases (2.7%) experienced disease progression. The CR rates for stage I, II, III and IV patients were 96.6% (56/58), 92.0% (219/238), 83.6% (51/61) and 77.6% (45/58), respectively (P < 0.001). The 5-year disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) were 90.6%, 84.1% and 92.5%. The stage I-II patients were significantly better than stage III-IV patients in terms of 5-year DFS rate (94.5% vs. 79.2%, P < 0.001), 5-year PFS rate (91.2% vs. 66.4%, P < 0.001) and 5-year OS rate (97.0% vs. 81.5%, P < 0.001). For stage I-II patients, combined modality therapy was related to better DFS, PFS and OS as compared with radiotherapy alone, and was associated with a better PFS compared with chemotherapy alone. There was a trend that consolidative radiotherapy could improve the long-term survival for stage III-IV patients who achieved disease remission after chemotherapy. What's more, consolidative radiotherapy could significantly improve PFS for those stage II-IV patients who achieved PR after chemotherapy. Multivariate analysis showed that clinical stage and pathological type were independent prognostic factors for the 5-year DFS rate (both P < 0.05), and the stage, elevated serum β2-microglobulin and none-ABVD/BEACOP chemotherapy regimen were independent prognostic factors for 5-year PFS rate and 5-year overall survival rate (P < 0.05 for all).</p><p><b>CONCLUSIONS</b>Patients with HL treated in China have a good prognosis. Combined modality therapy is the preferred treatment for stage I-II patients. Consolidative radiotherapy is recommended to those of stage III-IV patients who experienced PR after chemotherapy. Stage, serum β2-microglobulin and first-line chemotherapy regimen significantly affect the prognosis for patients with Hodgkin lymphoma.</p>

Clinical features and prognostic analysis of mantle cell lymphoma patients / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To analyze the clinical features, therapeutic outcome and prognostic factors of mantle cell lymphoma (MCL).</p><p><b>METHODS</b>Clinical data of a total of 68 patients with MCL admitted from August 2003 to June 2013 in our department were retrospectively analyzed.</p><p><b>RESULTS</b>Of all the patients, the median age was 58.5 years, with marked male predominance (2.8:1), 59 patients (86.8%) were in Ann Arbor stage III/IV. 56 cases (82.4%) primarily showed lymph node involvement, 49 cased showed extranodal involvement and 19 cases (38.8%) had bone marrow involvement. Patients were followed up for 4 to 122 months with a median follow up time of 35 months. The 3- and 5-year overall survival (OS) rates were 78.5% and 64.1%, respectively. The 2- and 3-year progression-free survival (PFS) rates were 41.3% and 23.7%, respectively, and the median time to progression was 20.0 months. The overall response rate (ORR) of CHOP regimen was superior to that of intense regimens (P = 0.036). Univariate analysis showed that stage III/IV,IPI score of 3-5, expression of Ki-67 higher than 30%, elevated LDH, elevated β2-MG, blastic variant, more than 5 lymph nodes involved, and failure to chemotherapy were the negative factors. Multivariate analysis showed that Ki-67 index, LDH and the response to chemotherapy were independent factors affecting survival.</p><p><b>CONCLUSIONS</b>Most patients with MCL were elderly males with advanced stage and usually had bone marrow involvement. Although ORR of CHOP regimen is superior to intense regimens, the prognosis of MCL remains poor.</p>

Efficacy analysis of different follow-up methods in detecting first recurrence of lymphoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>This study aimed to evaluate the value of different follow-up methods for the detection of first recurrence in lymphoma patients in first complete remission (CR), and to find reasonable long-term follow-up strategies.</p><p><b>METHODS</b>We retrospectively analyzed 277 lymphoma patients who achieved CR after first-line therapies and subsequently relapsed. All patients were divided into routine surveillance imaging group (group A) and irregular imaging follow-up visit group (group B). To compare the two groups of patients with tumor burden (tumor diameter and number of tumor invasion areas) at the time of relapse, and the number of imaging scans before the relapse. To analyze the main ways of finding lymphoma relapse in the two groups.</p><p><b>RESULTS</b>Among a total of 277 patients, there were 187 patients in the group A and 90 patients in the group B. The tumor recurrence occurred in 120 cases (43.3%) within the first year, and 76 patients (27.4%) in the second year. At the time of diagnosis of recurrence, the average maximum diameter of tumors in the groups A and B were (3.2 ± 2.2) cm and (3.8 ± 2.9) cm, respectively (P = 0.123). The two groups showed slight difference in number of tumor invasion areas (P = 0.050). At the time of diagnosis of recurrence, there were 3 of 121 patients (2.5%) with maximum diameter of tumors more than 8 cm in the group A and 6 of 49 cases (12.2%) in the group B (P = 0.018). In the group A, the patients had in average 4.9 times of imaging scans before recurrence, significantly more than the 0.22 times in the group B (P < 0.001). Among all patients, the diagnosis of recurrence was based on imaging scans only in 59 patients (21.3%).</p><p><b>CONCLUSIONS</b>Most lymphoma patients do not benefit from routine surveillance imaging to detect the tumor recurrence. It indicates that we should not rely solely on imaging examinations at follow-up visits, and should pay more attention on clinical signs and symptoms.</p>

Comparison of clinical characteristics and prognoses between primary Waldeyer's ring diffuse large B-cell lymphoma and extranodal nasal-type NK/T-cell lymphoma / 中华放射肿瘤学杂志

ObjectiveThis study aimed to compare the clinical characteristics and prognoses of primary Waldeyer's ring diffuse large B-cell lymphoma (DLBCL) and extranodal nasal-type NK/T-cell lymphoma ( ENKTCL).MethodsFrom 2000 to 2008,122 patients with primary Waldeyer's ring DLBCL and 44 patients with primary Waldeyer' s ring ENKTCL consecutively diagnosed were retrospectively compared.Patients with DLBCL usually received 4-6 cycles of CHOP-based chemotherapy followed by involved-field radiotherapy.Patients with early stage ENKTCL usually received extended-field radiotherapy with or without subsequent chemotherapy,or short courses ( 1 - 3 cycles ) of chemotherapy followed by radiotherapy.Kaplan-Meier method was used for survival analysis.Logrank method was used for univariate analysis.ResultsThe follow-up rate was 82％.The number of patients followed 5 years were 32 and 15 in DLBCL and ENKTCL.DLBCL mainly presented with stage Ⅱ tonsillar disease with regional lymph node involvement.ENKTCL occurred predominately in young males,as nasopharyngeal stage I disease with B symptoms and involving adjacent structures.The 5-year overall survival (OS) and progression-free survival (PFS) rates were 74％ and 67％ in DLBCL,and 68％ and 59％ in ENKTCL (x2=0.53,1.06,P=0.468,0.303),respectively.In stage Ⅰ and Ⅱ diseases,the 5-year OS and PFS rates were 79％ and 76％ for DLBCL compared to 72％ and 62％ for ENKTCL (x2 =1.20,2.46,P=0.273,0.117).On univariate analysis,age ＞ 60 years,elevated lactate dehydrogenase,eastern cooperative oncology group performance status ＞ 1,international prognosis index ( IPI ) score ≥ 1,stage Ⅲ/Ⅳ diseases and bulky disease were associated with unfavorable survival for DLBCL (x2=9.40,12.72,6.15,10.36,12.48,5.53,P=0.002,0.000,0.013,0.001,0.000,0.019),and only age＞60 years and IPI score ≥ 1 were associated with poor survival for ENKTCL (x2 =3.98,8.41,P =0.046,0.004).ConclusionsThese results indicate that remarkable clinical disparities exist between DLBCL and ENKTCL in Waldeyer's ring. Different treatment strategies for each can result in similarly favorable prognoses.

Pharmacokinetics Study and Clinical Evaluation on Boanmycin / 中国药房

OBJECTIVE:To study the pharmacokinetics of boanmycin and to make a clinical evaluation on which.METHODS:36patients with malignant tumor were subjected to the first stage of clinical study after injected intramuscular injection.with0.5～7.5mg/m 2 boanmycin.Of which,8patients were chosen as the subjects for the pharmacokinetic study by microbioassay.RESULTS:Boanmycin had little influence on the functions of heart,liver,kidney and lungs and which had no inhibitory action on bone marrow.After intramuscular injection with5.29～7.65mg/m 2 boanmycin,parameters of pharma?cokinetics in the patients were determined as the following:t 1/2? was(14.036?4.409)min,t 1/2? was(39.160?5.599)min,AUC was(14.697?1.826)(?g?min)/ml and CLs was(0.781?0.102)L/min.CONCLUSION:Serum clearance of boanmycin shows two-compartment model.