Discovery of a SARS-CoV-2 Broadly-Acting Neutralizing Antibody with Activity against Omicron and Omicron + R346K Variants

The continual emergence of SARS-CoV-2 variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant, has rendered ineffective a number of previously EUA approved SARS-CoV-2 neutralizing antibody therapies. Furthermore, even those approved antibodies with neutralizing activity against Omicron are reportedly ineffective against the subset of Omicron variants that contain a R346K substitution, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. Following a campaign of antibody discovery based on the vaccination of Harbour H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of Spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against the Omicron and Omicron + R346K variants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for use in human clinical trials.

Protein-based RBD-C-tag COVID-19 Vaccination Candidate Elicits Protection Activity against SARS-COV-2 Variant Infection

The identification of a vaccination candidate against COVID-19 providing protecting activity against emerging SARS-COV-2 variants remains challenging. Here, we report protection activity against a spectrum of SARS-COV-2 and variants by immunization with protein-based recombinant RBD-C-tag administered with aluminum-phosphate adjuvant intramuscularly. Immunization of C57BL/6 mice with RBD-C-tag resulted in the in vivo production of IgG antibodies recognizing the immune-critical spike protein of the SARS-COV-2 virus as well as the SARS-COV-2 variants alpha ("United Kingdom"), beta ("South Africa"), gamma ("Brazil/Japan"), and delta ("India") as well as wt-spike protein. RBD-C-tag immunization led to a desired Th1 polarization of CD4 T cells producing IFN{gamma}. Importantly, RBD-C-tag immunization educated IgG production delivers antibodies that exert neutralizing activity against the highly transmissible SARS-COV-2 virus strains "Washington", "South Africa" (beta), and "India" (delta) as determined by conservative infection protection experiments in vitro. Hence, the protein-based recombinant RBD-C-tag is considered a promising vaccination candidate against COVID-19 and a broad range of emerging SARS-COV-2 virus variants.

Progress of biological functions and molecular mechanisms of long non-coding RNA Foxf1 adjacent non-coding developmental regulatory RNA in malignant tumors / 肿瘤研究与临床

In recent years, the morbidity and mortality of malignant tumors in China have been increased year by year, which has caused a serious economic burden on families and society. Therefore, researches of the mechanism of cancer development and new methods of diagnosis and treatment are desperately needed. Foxf1 adjacent non-coding developmental regulatory RNA (FENDRR) is a long non-coding RNA (LncRNA) discovered in recent years. Its abnormal expression can regulate cell proliferation, migration and invasion through different mechanisms, and participate in the development of various malignant tumors. This article reviews the progress of biological functions and molecular mechanisms of FENDRR in different malignancies.

Discovery and Development of Human SARS-CoV-2 Neutralizing Antibodies using an Unbiased Phage Display Library Approach

SARS-CoV-2 neutralizing antibodies represent an important component of the ongoing search for effective treatment of and protection against COVID-19. We report here on the use of a naive phage display antibody library to identify a panel of fully human SARS-CoV-2 neutralizing antibodies. Following functional profiling in vitro against an early pandemic isolate as well as a recently emerged isolate bearing the D614G Spike mutation, the clinical candidate antibody, STI-1499, and the affinity-engineered variant, STI-2020, were evaluated for in vivo efficacy in the Syrian golden hamster model of COVID-19. Both antibodies demonstrated potent protection against the pathogenic effects of the disease and a dose-dependent reduction of virus load in the lungs, reaching undetectable levels following a single dose of 500 micrograms of STI-2020. These data support continued development of these antibodies as therapeutics against COVID-19 and future use of this approach to address novel emerging pandemic disease threats.

A Targeted Vaccine against COVID-19: S1-Fc Vaccine Targeting the Antigen-Presenting Cell Compartment Elicits Protection against SARS-CoV-2 Infection

Vaccination efficacy is enhanced by targeting the antigen-presenting cell compartment. Here, we show that S1-Fc antigen delivery targeting the Fc{gamma}R+ antigen-presenting cell compartment elicits anti-SARS-CoV-2 S1-antigen specific IgG production in vivo exerting biologically functional and protective activity against live virus infection, assessed in a stringent experimental virus challenge assay in vitro. The S1-domain of the SARS-CoV-2 spike protein was genetically fused to a human immunoglobulin Fc moiety, which contributes to mediate S1-Fc cellular internalization by Fc{gamma}R+ antigen-presenting cells. Immediately upon administration intramuscularly, our novel vaccine candidate recombinant rS1-Fc homes to lymph nodes in vivo where Fc{gamma}R+ antigen-presenting cells reside. Seroconversion is achieved as early as day 7, mounting considerably increased levels of anti-S1 IgGs in vivo. Interestingly, immunization at elevated doses with non-expiring S1-Fc encoding dsDNA favors the education of a desired antigen-specific adaptive T cell response. However, low-dose immunization, safeguarding patient safety, using recombinant rS1-Fc, elicits a considerably elevated protection amplitude against live SARS-CoV-2 infection. Our promising findings on rS1-Fc protein immunization prompted us to further develop an affordable and safe product for delivery to our communities in need for COVID-19 vaccinations.

Analysis of genomic copy number variations in two sisters with primary amenorrhea and hyperandrogenism / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze genomic copy number variations (CNVs) in two sisters with primary amenorrhea and hyperandrogenism.</p><p><b>METHODS</b>G-banding was performed for karyotype analysis. The whole genome of the two sisters were scanned and analyzed by array-based comparative genomic hybridization (array-CGH). The results were confirmed with real-time quantitative PCR (RT-qPCR).</p><p><b>RESULTS</b>No abnormality was found by conventional G-banded chromosome analysis. Array-CGH has identified 11 identical CNVs from the sisters which, however, overlapped with CNVs reported by the Database of Genomic Variants (http://projects.tcag.ca/variation/). Therefore, they are likely to be benign. In addition, a -8.44 Mb 9p11.1-p13.1 duplication (38,561,587-47,002,387 bp, hg18) and a -80.9 kb 4q13.2 deletion (70,183,990-70,264,889 bp, hg18) were also detected in the elder and younger sister, respectively. The relationship between such CNVs and primary amenorrhea and hyperandrogenism was however uncertain. RT-qPCR results were in accordance with array-CGH.</p><p><b>CONCLUSION</b>Two CNVs were detected in two sisters by array-CGH, for which further studies are needed to clarify their correlation with primary amenorrhea and hyperandrogenism.</p>

Research progress on lipid markers for atherosclerotic cardiovascular disease / 中华检验医学杂志

Detection of lipids ,lipoprotein and lipid metabolism related indicators is important in the risk assessment and prevention of atherosclerotic cardiovascular disease ( ASCVD ) .Along with the research progress,there are still defects within the established lipid biomarkers and methods ,which need continuous optimization.The ASCVD risk assessment is expected to be further improved as the new biomarkers are coming up.

Cranial nerve impairment in cryptococcal meningitis: predictors and prognosis / 中华传染病杂志

Objective To understand the predictors and prognostic significance of cranial nerve impairment in non-acquired immune deficiency syndrome (AIDS) patients with cryptococcal meningitis.Methods A total of 145 non-AIDS patients with cryptococcal meningitis admitted to Huashan Hospital,Fudan University from Jan 2000 to Dec 2010 were reviewed retrospectively.Clinical characteristics,initial antifungal therapies and outcome of these patients were analyzed.Continuous variables were analyzed using t test and categorical variables were compared by x2 test or Fisher's exact test.Multivariate analysis was performed by binary Logistic regressions.Results Out of 145 patients,52 (35.9％) patients had cranial nerve impairment at enrollment.Optic (25/52,48.1％) and oculomotor (22/52,42.3％) nerves were the most commonly involved,followed by auditory (12/52,23.1％),abducens (6/52,11.5％),olfactory (4/52,7.7％) and facial (3/52,5.8％) nerves.The best predictive factor of cranial nerve injury was duration of diagnosis (OR =1.056,95％ CI:1.002-1.111).The risk of cranial injury would increase by 5.6％ with one-week delay of diagnosis.Intracranial hypertension and low cerebrospinal fluid cell count were also the independent predictive factors (both P＜0.05).In the follow-up period,73.3％ patients who had cranial nerve injuries were fully recovered,with a median time of 3 (0.5-24.0) months.The independent predictors of recovery were numbers of nerve involved (OR =0.230,95 ％ CI:0.066-0.800,P=0.021) and amphotericin B (AmB) plus 5-fluorocytosine,triazole antifungal agent therapy (OR=10.317,95％CI:2.086-51.025,P=0.004).Conclusions Cranial nerve impairment occurs in one-third of non-AIDS patients with cryptococcal meningitis.Delay in diagnosis,intracranial hypertension and low cerebrospinal fluid cell count are independent predictive factors.Less cranial nerve involvement and AmB plus triazole therapy predict recovery.

Risk factors and prognostic analysis of cranial nerve impairment in 121 patients with tuberculous meningitis / 中华传染病杂志

Objective To investigate the risk factors associated with cranial nerve impairment in patients with tuberculous meningitis.Methods A total of 121 patients with tuberculous meningitis who were admitted to Huashan Hospital from 2000 to 2011 were reviewed retrospectively.Demographic data (gender,age),course of disease,initial results of cerebral spinal fluid (CSF) tests,occurrence of cranial nerve impairment and prognosis of these patients were collected.All the patients were followed up for at least 3 months,and for those with cranial nerve impairment,the minimum follow-up period was 1 year in order to judge the recovery of cranial nerve impairment.Multivariate analysis was performed to study the associated risk factors.Results Out of 121 patients,22 (18.2 ％)developed cranial nerve impairment.Nerves involved were abducens nerve,oculomotor nerve,optic nerve and auditory nerve,and impairment of single nerve occurred in 9 (40.9 ％),8 (36.4 ％),7(31.8％) and 1(4.5％) patient,respectively.Three cases had more than one group of cranial nerves involved,accounting for 13.6％ of the 22 patients with cranial nerve impairment.The incidence of conscious disturbance was significantly higher in patients with cranial nerve impairment than those without impairment (77 ％ vs 45 ％,P=0.020).Delay in diagnosis (OR =1.017,95 ％ CI:1.001-1.033,P=0.040) and occurrence of conscious disturbance (OR =3.242,95 ％ CI:1.142-9.205,P=0.027) were independent predictive factors of cranial nerve injury.During one-year follow-up,90.9％ of patients were fully recovered from cranial nerve impairment,with a median duration of 1 month (range 0.5-6.0 months).Conclusions Cranial nerve impairment is a common complication in patients with tuberculous meningitis.Delay in diagnosis and occurrence of conscious disturbance were independent predictive factors.Most cranial nerve impairment were reversible,and timely diagnosis and treatment are important ways to reduce complications.

Four noninvasive score systems for diagnosis of liver fibrosis in patients with chronic hepatitis B / 中华临床感染病杂志

Objective To assess the value of S index and FIB-4 for diagnosis of liver fibrosis in patients with chronic hepatitis B (CHB) by comparing with traditional indexes APRI and Forns.Methods A total of 361 patients with confirmed CHB from the First Hospital of Nanjing Medical University and Huashan Hospital Affiliated to Fudan University during January 2006 and December 2011 were enrolled in the study.The clinical,laboratory and pathological data of patients were collected.Four noninvasive score systems APRI,Forns,S index and FIB-4 were computed.With liver biopsy as the gold standard,the area under the ROC curve (AUROC) was used to assess the value of above 4 score systems in diagnosis of liver fibrosis,and Z test was performed to evaluate the effectiveness of above systems.Results The areas under ROC curve (AUCs) of APRI,Forns,S index and FIB-4 for significant fibrosis (≥S2) were (0.737 ±0.027),(0.716 ± 0.028),(0.745 ± 0.026) and (0.781 ± 0.025),respectively.When the cut off value of FIB-4 was set at 1.62,the sensitivity,specificity,positive predictive value (PPV) and negative predictive value (NPV) for diagnosis of significant fibrosis were 59.3％,85.8％,89.4％ and 51.2％,respectively,which were better than Forn index (Z =3.28,P =0.001).While for S4 (cirrhosis) the AUCs of APRI,Foms,S index and FIB-4 were (0.687 ± 0.035),(0.792 ± 0.028),(0.863 ± 0.024) and (0.832 ± 0.025),respectively.When the cut off value of S index was set at 1.06,the sensitivity,specificity,PPV and NPV for diagnosis of cirrhosis were 77.9％,85.5％,59.4％ and 93.5％,respectively,which were better than APRI and Forns (Z =6.74 and 3.21,P ＜ 0.01).Conclusions APRI,Forns,S index and FIB-4 are simple and accurate methods for assessing liver fibrosis.FIB-4 and S index are better than APRI and Forns in diagnosis of significant fibrosis and cirrhosis,which may replace liver biopsy in certain extend.

Application of iTRAQ multiple labeling and tandem mass spectrometry in proteomic research of human peripheral blood mononuclear cells / 生物医学工程学杂志

This paper is aimed to establish and optimize proteomic research platform using isobaric tags for relative and absolute quantitation (iTRAQ) so as to facilitate further proteomic research of human peripheral blood mononuclear cells (hPBMC). We collected hPBMC, after protein extraction and trypsin digestion, we labeled the samples with iTRAQ reagents and then subjected to mass spectrometry. In triplicates, thirty precursors were randomly selected and detected; as a result, 26, 28 and 29 peptides were respectively tagged with ITRAQ reporter ions. The labeling efficiencies ranged between 86.7%-96.7%, with no significant difference among the groups (P>0.05). The coefficient of variance for the relative ratios of peptides from different proteins was ranged from 7.6% to 25.5% and there were no significant differences across the groups (P>0.05). The coefficient of variance for the relative ratios of different peptides from the same protein was varied from 9.3% to 19.1% and the differences across groups were not significant (P>0.05). The labeling of iTRAQ combined with tandem mass spectrometry in PBMC was successful with favourable reproducibility and accuracy, which could lay a foundation for further proteomic study of hPBMC in autoimmune disorders.

Detection and analysis of genomic copy number variations in a 46,X0, +der(?) fetus by array-based comparative genomic hybridization / 基础医学与临床

Objective To understand genomic copy number variations (CNVs) and ascertain karyotype for a 46,X0, + der(?) fetus, and investigate possibility and superiority of array-based comparative genomic hybridization (array-CGH ) in clinical cytogenetic diagnosis. Methods G-banded chromosome analysis was carried out. The whole genome of the fetus was scanned and analysed by array-CGH. The results of array-CGH were confirmed by RT-qPCR. Results G-banded chromosome analysis showed that the fetal karyotype was 46,X0, +der(?). Array-CGH revealed the derivative chromosome as Y chromosome without CNVs. A total number of 118 submicroscopic CNVs were identified. Comparable results between array-CGH and RT-qPCR were obtained for 9 novel CNVs. Conclusion Comparing with conventional cytogenetic analysis, array-CGH is of high resolution, high-throughput and high accuracy, which provides a technical platform for accurate detection of submicroscopic chromosomal aberrations.

Quality of life following radical gastrectomy in patients with gastric carcinoma / 中国现代普通外科进展

Objective:To compare the quality of life following total gastrectomy(TG) with that folliwng subtotal gastrectomy(SG) in patients with gastric carcinoma.Methods:Sixty-six patients underwent gastrectomy between 2003 and 2005 at the Department of General Surgery of the Qilu Hospital were enrolled into this study.Among them,15 underwent TG,42 accepted distal end subtotal gastrectomy(DSG) and 9 underwent proximal end(PSG) .The EORTC quality of life questionnaire QLQ-STO20 was used in the present retrospective study to assess follow quality of life of thes patients.The food-intake,local symptom and quality of life of the 3 groups were compared.Results:Patients recovered worse in short term after TG compared with PSG,but there was no statistical difference in the near future.But both of them were not as good as DSG.The contraflow was common and serious after PSG.The incidence rate of abdominal distension was high.Conclusion:The indication of TG for carcinoma of the superior part of stomach can be extented properly.Evidence-Based Medicine should be used to screen better reconstruction mode.On the base of radical cure,quality of life should be improved as far as possible.

The study of histone H3 lysine 4 trimethylation in peripheral blood mononuclear cells of systemic lupus erythematosus patients / 中华风湿病学杂志

Objective To study histone H3 lysine 4 trimethylation (H3K4me3) in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus(SLE) patients.Methods PBMCs were isolated by density gradient centrifugation from 10 active SLE patients,7 inactive SLE patients and 8 healthy volunteers.Chromatin immunopreeipitation linked to mieroarrays (ChIP-chip) was used to profile the variations in H3K4me3 in CpG island regions in PBMCs of SLE patients and controls.ChIP-qPCR was used to validate the mieroarray results.To confirm correlations between H3K4me3 and gene expression,expression analysis by qRT-PCR was performed on three randomly selected H3K4me3 candidates.Results 413 (137 increased and 276 decreased H3K4me3) and 393 genes (112 increased and 281 decreased H3K4me3) displayed significant differences in H3K4me3 between active and inactive SLE when compared with healthy SUhjeets.The results of ChiP-qPCR were consistent with microarray.ConclusiOn There are significant differences in H3K4me3 profiling between SLE and healthy subjects.These novel candidate genes may be potential biomarkers for future therapeutic targets.The ChIP-chip technology can help further reveal SLE molecular mechanisms and discover new therapeutic targets.