mRNA-1273 efficacy in a severe COVID-19 model: attenuated activation of pulmonary immune cells after challenge

The mRNA-1273 vaccine was recently determined to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from interim Phase 3 results. Human studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibit more severe SARS-CoV-2 disease similar to hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and non-human primates, mRNA-1273- mediated immunity was non-sterilizing and coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high resolution analysis which is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a two-dose schedule and provides insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.

SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study

BackgroundThe risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subsequent infection among seropositive young adults was studied prospectively. MethodsThe study population comprised 3,249 predominantly male, 18-20-year-old Marine recruits. Upon arrival at a Marine-supervised two-week quarantine, participants were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a 1:150 dilution or greater on receptor binding domain and full-length spike protein enzyme-linked immunosorbent (ELISA) assays. SARS-CoV-2 infection was assessed by PCR at initiation, middle and end of the quarantine. After appropriate exclusions, including participants with a positive PCR during quarantine, we performed three biweekly PCR tests in both seropositive and in seronegative groups once recruits left quarantine and entered basic training and baseline neutralizing antibody titers on all subsequently infected seropositive and selected seropositive uninfected participants. FindingsAmong 189 seropositive participants, 19 (10.1%) had at least one positive PCR test for SARS-CoV-2 during the six-week follow-up (1.1 cases per person-year). In contrast, 1,079 (48.0%) of the 2,247 seronegative participants tested positive (6.2 cases per person-year). The incidence rate ratio was 0.18 (95% CI 0.11-0.28, p<0.00001). Among seropositive recruits, infection was associated with lower baseline full-length spike protein IgG titers (p<0.0001). Compared with seronegative recruits, seropositive recruits had about 10-fold lower viral loads (ORF1ab gene, p<0.005), and trended towards shorter duration of PCR positivity (p=0.18) and more frequent asymptomatic infections (p=0.13). Among seropositive participants, baseline neutralizing titers were detected in 45 of 54 (83.3%) uninfected and in 6 of 19 (31.6%) infected participants during the 6 weeks of observation (ID50 difference p<.0001). InterpretationSeropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection. These findings may be relevant for optimization of mass vaccination strategies. FundingDefense Health Agency and Defense Advanced Research Projects Agency

Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia.

Somatic PTPN11 mutations cause juvenile myelomonocytic leukemia (JMML). Germline PTPN11 defects cause Noonan syndrome (NS), and specific inherited mutations cause NS/JMML. Here, we report that hematopoietic cells differentiated from human induced pluripotent stem cells (hiPSCs) harboring NS/JMML-causing PTPN11 mutations recapitulated JMML features. hiPSC-derived NS/JMML myeloid cells exhibited increased signaling through STAT5 and upregulation of miR-223 and miR-15a. Similarly, miR-223 and miR-15a were upregulated in 11/19 JMML bone marrow mononuclear cells harboring PTPN11 mutations, but not those without PTPN11 defects. Reducing miR-223's function in NS/JMML hiPSCs normalized myelogenesis. MicroRNA target gene expression levels were reduced in hiPSC-derived myeloid cells as well as in JMML cells with PTPN11 mutations. Thus, studying an inherited human cancer syndrome with hiPSCs illuminated early oncogenesis prior to the accumulation of secondary genomic alterations, enabling us to discover microRNA dysregulation, establishing a genotype-phenotype association for JMML and providing therapeutic targets.

Modified total cystectomy and neobladder: experience in 21 cases of invasive bladder cancer / 中国综合临床

Objective To summarize our experience in the modified total cystectomy and neobladder in patients with invasive bladder cancer.Methods Twenty one male patients with invasive bladder cancer were treated with modified total cystectomy and neobladder.Reconstruction of the lower urinary tract using modifiled ileal neobladder(in 17 patients)and sigmoid neobladder(in 4 patients)were performed.The median age of the patients was 62 years.The patients were followed up for 1-4 years.Clinical outcomes of these patients was evaluated,including the function of the neobladder,urinary function,renal function,serum electrolytes and QOL.Results There was no surgical mortality.The operating time was 3.5-6.5 h(mean,4.5 h).Blood transfusion was required in 4 cases.Fifteen patients(97 ％ had voluntary control of urination at daytime and 6 at night.They were functional to control urination 3-6 months after operation.Hydronephrosis to certain extent occurred in 5 patients,but was recovered after 6-8 months.There were one case of intestinal obstruction and one case of metabolic acidosis.Residual urinary volume was 30 ml in 1 cases and 40 ml in another.Conclusions Modified total cystectomy and neobladder is an ideal technique to treat invasive bladder cancer with good clinical outcomes of tumor control,high life quality,few severe complications and good urination control.

Combination of kidney transplantation with hematopoietic stem cell infusion / 中华全科医师杂志

Ninety six female patients with chronic renal failure were randomly allocated into combination group (n =48) and control group (n =48).In combination group patients received both kidney transplantation and hematopoietic stem cell infusion,in control group patients underwent kidney transplantation only.The results showed that chronic rejection in the combination group was lower than that in the control group [2％(1/48)vs.17％ (8/48),P＜0.05)].The 1-,3-,5-and 10 y-survival rates of kidney in the combination group were 98％ (47/48),94％ (45/48),83％ (34/41) and 9/17,respectively,those in control group were 98％ (47/48),90％ (43/48),76％ (31/41) and 7/17,respectively.Infusion of donor hematopoietic stem cells can augment chimerism in early postoperative period and significantly reduce the rate of graft rejection,which is beneficial for the quality of life of the recipients.

Expressions of cyclooxgenase 2 and vascular endothelial growth factor in human clear cell renal cell carcinoma and their relationships with occurrence and development of tumor / 肿瘤研究与临床

Objective To investigate the expression of cyclooxgenase 2 (COX-2) and vascular endothelial growth factor (VEGF) in clear cell renal cell carcinoma (CCRCC) and their correlation with Prognosis. Methods EnVision immunohistochemistry was used to determine the expression of COX-2 and VEGF in 80 CCRCC tissues and 20 normal kidney tissues .The relationship between the above marks and prognosis were analyzed. Results The positive rates of COX-2[65.00 % (52/80) vs 10.00 % (2/20), x2= 7.760, P= 0.021]and VEGF[61.25 % (49/20) vs 20.00 (4/80),x2 = 8.870, P= 0.012]were much higher in CCRCC than those in normal kidney. The expression of COX-2 was correlated with TNM stage (x2 = 8.200,P =0.005), histological grade (x2 = 13.860, P = 0.000) and lymph node metastasis (x2 = 6.050, P = 0.001) in CCRCC, but not with age (x2 = 0.560, P = 0.663) and diameter of tumor (x2 = 0.700, P = 0.528). Both COX-2 expression and VEGF expression were associated significantly with prognosis in CCRCC (x2 = 18.280,P = 0.038;x2 = 6.420, P= 0.042, respectively). There was a positive correlation between COX-2 and VEGF in CCRCC (r =0.485, P < 0.01). Conclusion COX-2 is related to prognosis in CCRCC and can be used as prognostic indicators in patients.

Induction of immune tolerance using kidney-bone marrow transplantation: Does it promote chimerism formation? / 中国组织工程研究

BACKGROUND: Infusion of hemopoietic stem cell from donors can promote the chimeric formation and induce specific immunologic tolerance in the allograft recipients. However, the pretreatment for cell transplantation has great toxicity to recipients. So immunosuppressant combined bone marrow infusion is introduced to anti graft versus host reaction. OBJECTIVE: Based on microchimerism, to study the security and associativity of chimera formation induced by kidney-bone marrow transplantation and immunologic tolerance.DESIGN, TIME AND SETTING: The contrast observation was performed at the department of urinary surgery, The Third People's Hospital of Zhengzhou City from January 1998 to December 2005.PARTICIPANTS: According to ABO/Rh blood type and HLA matching, 96 female patients with chronic renal failure and waiting for kidney transplantation were divided into 2 groups, In the combination group, patients received kidney combined bone marrow transplantation; the other uremia patients received the other kidney of cadavers were served as control group. The donors were 48 healthy males. METHODS: Bone marrow of donors was collected simultaneously with kidney obtain and preserved with cryoprotectant at -198 ℃ in nitrogen canister. After kidney transplantation, large dose of anti-human lymphocyte immune globulin were used for 2 weeks, then (0.9-2.5)×10~8/kg mononuclearcell was reinfused. PCR-SRY was used to identify donor derived cell-chimerism. Lymphocyte subgroup of recipients was determined by blood test; and interleukin 10 was measured by enzyme linked immunosorbent assay; in addition, the mass concentration of tumor necrosis factor α and tumor necrosis factor β was detected. MAIN OUTCOME MEASURES: Chimerism, lymphocyte subsets and cytokines were detected at various time points following transplantation. Simultaneously, the transplantation results and complication status of recipients were observed. RESULTS: The positive rate of chimera in the combination group was greater than that of the control group (P < 0.05). The 3-year follow-up showed that incidence differences of acute rejection between recipients with positive chimera and recipients with negative chimera had significance (13%, 35%, P < 0.05). There was no graft versus host disease occurred in the combination group. CONCLUSION: Kidney-bone marrow transplantation can augment chimerism in early postoperative period, and significantly reduce the rate of acute rejection, which is safe and beneficia1to induce specific immunologic tolerance in the renal allograft recipients.

Studies on the Chemical Constituents Bigflower Rhodiola (Rhodiola crenulata) / 中草药

Five compounds were isolated from the rhizome and roots of Rhodiola crenulata S.H.Fu.They werc identified as rhodionin (Ⅰ), rhodiosin(Ⅱ), tyrosol(Ⅲ), salidroside(Ⅳ) and gallic acid (Ⅴ), respectively, by UV, MS, 1H and 13CNMR spectroscopic and chemical reactions.