Real-world study on the efficacy and prognostic predictive biomarker of patients with metastatic non-small cell lung cancer treated with programmed death-1/programmed death ligand 1 inhibitors / 中华肿瘤杂志

Objective: To describe the actual efficacy of programmed death-1 (PD-1)/ programmed-death ligand 1 (PD-L1) inhibitors in patients with metastatic non-small cell lung cancer (NSCLC) and explore potential prognostic predictive biomarkers. Methods: Patients with metastatic NSCLC who were treated with PD-1/PD-L1 inhibitors at Cancer Hospital, Chinese Academy of Medical Sciences from January 2016 to December 2019, either as monotherapy or in combination with other agents, were consecutively enrolled into this study. We retrospectively collected the data of demographics, clinical information and pathologic assessment to evaluate the therapeutic efficacy and conduct the survival analysis. Major endpoint of our study is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: The ORR of 174 patients who underwent PD-1/PD-L1 inhibitor was 28.7%, and the DCR was 79.3%. Immune-related adverse events (irAEs) occurred in 23 patients (13.2%). Brain metastasis, line of treatment, and treatment patterns were associated with the ORR of metastatic NSCLC patients who underwent immunotherapy (P<0.05). After a median follow-up duration of 18.8 months, the median PFS was 10.5 months (ranged from 1.5 to 40.8 months) while the median OS was not reached. The 2-year survival rate was estimated to be 63.0%. The pathologic type was related with the PFS of metastatic NSCLC patients who underwent immunotherapy (P=0.028). Sex, age, brain metastasis and autoimmune diseases were associated with OS (P<0.05). Analysis of the receptor characteristic curve (ROC) of neutrophil/lymphocyte ratio (NLR) predicting ORR of immunotherapy in metastatic NSCLC showed that the areas under the curve of NLR before immunotherapy (NLR(C0)), NLR after one cycle of immunotherapy (NLR(C1)) and ΔNLR were 0.600, 0.706 and 0.628, respectively. Multivariate logistic regression analysis showed that NLR(C1) was an independent factor of the ORR of metastatic NSCLC patients who underwent immunotherapy (OR=0.161, 95% CI: 0.062-0.422), and the efficacy of combination therapy was better than that of single agent (OR=0.395, 95% CI: 0.174-0.896). The immunotherapy efficacy in patients without brain metastasis was better than those with metastasis (OR=0.291, 95% CI: 0.095-0.887). Multivariate Cox regression analysis showed that NLR(C1) was an independent influencing factor of PFS of metastatic NSCLC patients after immunotherapy (HR=0.480, 95% CI: 0.303-0.759). Sex (HR=0.399, 95% CI: 0.161-0.991, P=0.048), age (HR=0.356, 95% CI: 0.170-0.745, P=0.006) were independent influencing factors of OS of metastatic NSCLC patients after immunotherapy. Conclusions: PD-1/PD-L1 inhibitors are proved to be efficacious and have tolerable toxicities for patients with metastatic NSCLC. Patients at advanced age could still benefit from immunotherapy. Brain metastasis is related to compromised response. Earlier application of immunotherapy in combination with other modalities enhances the efficacy without elevating risk of irAEs. NLR(C1) is an early predictor of clinical outcome. The OS of patients younger than 75 years may be improved when treated with immunotherapy.

Transcriptome Profiling of Potential Non-coding RNAs in Meningitis-causing Escherichia coli K1 / 中国生物化学与分子生物学报

Bacterial non-coding RNAs (ncRNAs) are pivotal transcriptional regulators during bacterial proliferation and infection processes.Bacterial ncRNAs play important roles in responding to environmental changes and regulating bacterial gene expression to resist environmental stress.Transcriptome profiling of neonatal meningitis-causing Escherichia coli K1 RS218 (NMEC) reveals abundant ncRNAs.Bioinformatic analyses identified 45 potential ncRNAs.Comparative genome analyses of non-pathogenic E.coli K12 and NMEC identified 300 NMEC-specific sequences (above 100 bp), which contain 9 NMEC-specific ncRNAs (Nsr).Moreover, deletion of one ncRNA, Nsr21, enhanced NMEC survival and proliferation in mouse blood (P< 0.01) , compared to the wild-type RS218 control, in a mouse tail vein injection model.qRT-PCR analysis further revealed expression of Nsr21 decreased in NMEC collected from mouse blood compared to that in NMEC collected from in vitro medium (P<0.001) , indicating that NMEC downregulates Nsr21 expression to benefit its survival and proliferation in blood.This study suggests that the NMEC genome contains a number of ncRNAs, which may be involved in regulating NMEC pathogenicity.During infection process in the blood, NMEC enhances its proliferation ability in blood by downregulating the expression of Nsr21.

Nerve growth factor for the treatment of spinocerebellar ataxia type 3: an open-label study / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA worldwide, and runs a slowly progressive and unremitting disease course. There is currently no curable treatment available. Growing evidence has suggested that nerve growth factor (NGF) may have therapeutic effects in neurodegenerative diseases, and possibly also in SCA3. The objective of this study was to test the efficacy of NGF in SCA3 patients.</p><p><b>METHODS</b>We performed an open-label prospective study in genetically confirmed adult (>18 years old) SCA3 patients. NGF was administered by intramuscular injection (18 μg once daily) for 28 days consecutively. All the patients were evaluated at baseline and 2 and 4 weeks after treatment using the Chinese version of the scale for assessment and rating of ataxia (SARA).</p><p><b>RESULTS</b>Twenty-one SCA3 patients (10 men and 11 women, mean age 39.14 ± 7.81 years, mean disease duration 4.14 ± 1.90 years, mean CAG repeats number 77.57 ± 2.27) were enrolled. After 28 days of NGF treatment, the mean total SARA score decreased significantly from a baseline of 8.48 ± 2.40 to 6.30 ± 1.87 (P < 0.001). Subsections SARA scores also showed significant improvements in stance (P = 0.003), speech (P = 0.023), finger chase (P = 0.015), fast alternating hand movements (P = 0.009), and heel-shin slide (P = 0.001).</p><p><b>CONCLUSIONS</b>Our preliminary data suggest that NGF may be effective in treating patients with SCA3.</p>

SiRNA targeting ICP4 attenuates HSV-1 replication / 病毒学报

HSV-1, a neurotropic virus, always leads to severe nervous symptoms. It is hard to completely eradicate the latent viruses after conventional therapy so that recurrence is inevitable. ICP is a key regulator for HSV replication and transcription that determines the cytolytic infection or latent state. In search of new anti-virus strategy targeting HSV-1ICP4, two pairs of siRNA were designed, and a recombinant eukaryotic lentiviral expression plasmid pLKO-puro(r)-hU6-siRNA was constructed. Vero cells were transfected with the designed siRNAs by Lipofectamine 2000 and four stable monoclonal cell lines were established by puromycin screening method. The ICP4 expression at mRNA level was detected with real-time PCR, and the HSV-1 replication was measured with TCID50 assay. SiRNA was shown as an effective way to inhibit the expression of ICP4 in monoclonal cell lines. Meanwhile, HSV-1 replication was significantly inhibited when ICP4 was shut down by siRNA. We conclude that siRNA targeting ICP4 attenuates HSV-1 replication. Further more, multi-site siRNAs show stronger inhibitory effect on viral replication, which may be an effective and feasible approach for biological anti-viral drugs.

Classification and regression tree analysis of 154 patients with cancer of unknown primary / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the prognostic factors and their impact on survival of patients with cancer of unknown primary (CUP).</p><p><b>METHODS</b>The clinical and follow up data of 154 CUP patients referred to the Cancer Hospital & Institute, Chinese Academy of Medical Sciences from January 1, 2003 to December 31, 2007 were analyzed. Multivariate analysis of survival was performed using recursive partitioning referred to as classification and regression tree (CART) analysis.</p><p><b>RESULTS</b>The median survival for 154 eligible consecutive CUP patients was 18.2 months, and the 5-year survival rate was 1.3%. CART was performed with an initial split on age of 34, and 5 terminal subgroups were formed. The median survival of the 5 subsets ranged from 5.5 months (younger than 34 years old subgroup) to 61.8 months for patients at age of 34 to 60, with one or two organ sites involved, and non-adenocarcinoma histology subsets.</p><p><b>CONCLUSIONS</b>CART can be used to identify previously unappreciated patient subsets and is a useful method for dissecting complex clinical situations and identifying homogeneous patient populations in clinical practice and future clinical trials.</p>