Antibody-Mediated Suppression Regulates the Humoral Immune Response to Influenza Vaccination in Humans.

BACKGROUND: Preexisting immunity, including memory B cells and preexisting antibodies, can modulate antibody responses to influenza in vivo to antigenically related antigens. We investigated whether preexisting hemagglutination inhibition (HAI) antibodies targeting the K163 epitope on the hemagglutinin (K163 antibodies) could affect antibody responses following vaccination with A/California/07/2009-like A(H1N1)pdm09 influenza viruses in humans. METHODS: Pre- and postvaccination sera collected from 300 adults (birth years, 1961-1998) in 6 seasons (2010-2016) were analyzed by HAI assays with 2 reverse genetics viruses and A(H1N1) viruses circulated from 1977 to 2018. Antibody adsorption assays were used to verify the preexisting K163 antibody-mediated suppression effect. RESULTS: Preexisting K163 antibody titers ≥80 affected HAI antibody responses following influenza vaccination containing A/California/07/2009-like antigens. At high K163 antibody concentrations (HAI antibody titers ≥160), all HAI antibody responses were suppressed. However, at moderate K163 antibody concentrations (HAI antibody titer, 80), only K163 epitope-specific antibody responses were suppressed, and novel HAI antibody responses targeting the non-K163 epitopes were induced by vaccination. Novel antibodies targeting non-K163 epitopes cross-reacted with newly emerging A(H1N1)pdm09 strains with a K163Q mutation rather than historic 1977-2007 A(H1N1) viruses. CONCLUSIONS: K163 antibody-mediated suppression shapes antibody responses to A(H1N1)pdm09 vaccination. Understanding how preexisting antibodies suppress and redirect vaccine-induced antibody responses is of great importance to improve vaccine effectiveness.

Fabrication of Carbon Dots with Singlet Oxygen Generation and Their Potential Photodynamic Therapy Applications.

Due to the unique chemical and biomedical properties of carbon dots (CDs), they have increasingly obtained the attention in many research fields, for example, bioimaging, fluorescence sensing, and drug delivery, etc. Recently, it was found that, under light excitation, CDs can also be exploited as a novel photosensitizer to prepare reactive oxygen species (ROS), which expand their applications in the field of photodynamic therapy for cancer treatment. Nevertheless, the high cost and complex fabrication approach of CDs significantly limit their applications. To address this issue, bottom-up routes usually utilize sustainable and inexpensive carbon precursor as starting materials, employed N,N-dimethylformamide (DMF) or ethanol as an environmental-friendly solvent. Bottom-up approach was energy efficient, and the purification process was relatively simple by dialysis. Therefore, carbon dots (CDs) were facilely fabricated in a one-pot solvothermal process using 1-aminoanthraquinone as a precursor, and their application as photosensitizers for in vitro antitumor cells, especially photodynamic therapy (PDT) was established. Then the photophysical and nanoscale dimensions properties of the fabricated CDs were characterized via TEM, UV-visible, fluorescence, and FT-IR spectroscopy. The synthesized N-doped CDs can easily dissolve in water, possess very low biotoxicity, yellow-light emission (maximum peak at 587 nm). More importantly, PDT studies demonstrated that the obtained CDs possess a high singlet oxygen yield of 35%, and exhibit significant phototoxicity to cancer cells upon 635 nm laser irradiation. These studies highlight that N-doped CDs can be facilely synthesized from only one precursor, and are a potentially novel theranostic agent for in vivo PDT.

Practical NTRU Signcryption in the Standard Model.

Based on the NTRU trapdoor used in NIST's Falcon, a signcryption scheme following the sign-then-encrypt paradigm is constructed. The existing partitioning technique based on Waters hash over the lattice can not complete the security reduction in the standard model for the signature part due to the "partiality" of the pre-image generated with the NTRU trapdoor. To address this, a variant of Waters hash over small integers is proposed and, the probability of the successful reduction is analyzed. The resulting signcryption achieves existential unforgeability under the adaptive chosen-message attacks. By utilizing the uniqueness of the secret and the noise in an NTRU instance, the tag used in encryption is eliminated. Furthermore, a method to construct tamper-sensitive lattice public key encryption is proposed. This approach implants the ciphertext-sensitive information into the lattice public key encryption and binds it to the encrypted information. The malleability to the public key ciphertext triggers the change of the message-signature pair so that the IND-CCA2 security of the entire ciphertext can be guaranteed by the signature for the message. Thanks to the rational design and the efficiency of the NTRU trapdoor, the computational overhead of the proposed scheme is reduced significantly compared to the existing lattice-based signcryption scheme, reaching orders of magnitude improvement in efficiency. The experiment shows that the proposed scheme is efficient.

Influence of Immune Priming and Egg Adaptation in the Vaccine on Antibody Responses to Circulating A(H1N1)pdm09 Viruses After Influenza Vaccination in Adults.

Background: Although ferret antisera used in influenza surveillance did not detect antigenic drift of A(H1N1)pdm09 viruses during the 2015-2016 season, low vaccine effectiveness was reported in adults. We investigated the immune basis of low responses to circulating A(H1N1)pdm09 viruses after vaccination. Methods: Prevaccination and postvaccination serum samples collected from >300 adults (aged 18-49 years) in 6 seasons (2010-2011 to 2015-2016) were analyzed using hemagglutination inhibition assays to evaluate the antibody responses to 13 A(H1N1) viruses circulated from 1977 to 2016. Microneutralization and serum adsorption assays were used to verify the 163K and 223R specificity of antibodies. Results: Individual antibody profiles to A(H1N1) viruses revealed 3 priming patterns: USSR/77, TW/86, or NC/99 priming. More than 20% of adults had reduced titers to cell-propagated circulating 6B.1 and 6B.2 A(H1N1)pdm09 viruses compared with the A/California/07/2009 vaccine virus X-179A. Significantly reduced antibody reactivity to circulating viruses bearing K163Q was observed only in the USSR/77-primed cohort, whereas significantly lower reactivity caused by egg-adapted Q223R change was detected across all 3 cohorts. Conclusion: Both 163K specificity driven by immune priming and 223R specificity from egg-adapted changes in the vaccine contributed to low responses to circulating A(H1N1)pdm09 viruses after vaccination. Our study highlights the need to incorporate human serology in influenza surveillance and vaccine strain selection.

Message Integration Authentication in the Internet-of-Things via Lattice-Based Batch Signatures.

The internet-of-things (also known as IoT) connects a large number of information-sensing devices to the Internet to collect all kinds of information needed in real time. The reliability of the source of a large number of accessed information tests the processing speed of signatures. Batch signature allows a signer to sign a group of messages at one time, and signatures' verification can be completed individually and independently. Therefore, batch signature is suitable for data integration authentication in IoT. An outstanding advantage of batch signature is that a signer is able to sign as many messages as possible at one time without worrying about the size of signed messages. To reduce complexity yielded by multiple message signing, a binary tree is usually leveraged in the construction of batch signature. However, this structure requires a batch residue, making the size of a batch signature (for a group of messages) even longer than the sum of single signatures. In this paper, we make use of the intersection method from lattice to propose a novel generic method for batch signature. We further combine our method with hash-and-sign paradigm and Fiat⁻Shamir transformation to propose new batch signature schemes. In our constructions, a batch signature does not need a batch residue, so that the size of the signature is relatively smaller. Our schemes are securely proved to be existential unforgeability against adaptive chosen message attacks under the small integer solution problem, which shows great potential resisting quantum computer attacks.

Effect of Priming With Seasonal Influenza A(H3N2) Virus on the Prevalence of Cross-Reactive Hemagglutination-Inhibition Antibodies to Swine-Origin A(H3N2) Variants.

Background: Recent outbreaks of swine-origin influenza A(H3N2) variant (H3N2v) viruses have raised public health concerns. Previous studies indicated that older children and young adults had the highest levels of hemagglutination-inhibition (HI) antibodies to 2010-2011 H3N2v viruses. However, newly emerging 2013 H3N2v have acquired antigenic mutations in the hemagglutinin at amino acid position 145 (N145K/R). We estimated the levels of serologic cross-reactivity among humans primed with seasonal influenza A(H3N2) (sH3N2), using postinfection ferret antisera. We also explored age-related HI antibody responses to 2012-2013 H3N2v viruses. Methods: Human and ferret antisera were tested in HI assays against 1 representative 2012 H3N2v (145N) and 2 2013 H3N2v (145K/R) viruses, together with 9 sH3N2 viruses circulating since 1968. Results: Low levels of cross-reactivity between the H3N2v and sH3N2 viruses from the 1970s-1990s were observed using postinfection ferret antisera. The overall seroprevalence among the sH3N2-primed population against 2012-2013 H3N2v viruses was >50%, and age-related seroprevalence was observed. Seroprevalence was significantly higher to 2013 H3N2v than to 2012 H3N2v viruses among some children likely to have been primed with A/Sydney/5/97-like (145K) or A/Wuhan/359/95-like viruses (145K). Conclusions: A single substitution (N145K/R) was sufficient to affect seropositivity to H3N2v viruses in some individuals. Insight into age-related antibody responses to newly emerging H3N2v viruses is critical for risk assessment and pandemic preparedness.

A marine algicidal Thalassospira and its active substance against the harmful algal bloom species Karenia mikimotoi.

The aim of the present study was to obtain a marine bacterium active against Karenia mikimotoi from the East China Sea and to characterize its extracellular algicidal substances. Using preparative high-performance liquid chromatography (prep-HPLC) and electrospray ionization/quadrupole-time of flight mass spectrometer coupled with a high-performance liquid chromatography (LC/MS-Q-TOF) system, we purified the alga-lysing substance produced by strain ZR-2 and determined its molecular structure. Based on morphology and l6S ribosomal DNA (rDNA) sequence analysis, the ZR-2 strain was highly homologous to Thalassospira species. Algicidal activity against K. mikimotoi was detected in the cell-free filtrate but not in bacterial cells. The alga-lysing substance produced by ZR-2 was ethanol-soluble and thermostable, with a retention time of 6.3 min and a measured elemental composition of C7H5O2 ([M-H](-) ion at m/z 121.0295). The alga-lysing substance produced by ZR-2 was determined to be benzoic acid. Compared with the negative control, both purified ZR-2 bacteria-free filtrate and standard benzoic acid promoted K. mikimotoi cell disruption and induced K. mikimotoi cell content leakage. Our study is the first to report benzoic acid activity against K. mikimotoi as well as production of benzoic acid by a Thalassospira species.

Mechanisms of Surfactin from Bacillus subtilis SF1 against Fusarium foetens: A Novel Pathogen Inducing Potato Wilt.

Fusarium wilt is a severe and worldwide disease in potato cultivation. In this study, Fusarium foetens was first identified as the pathogen of potato wilt. Bacillus subtilis SF1 has the potential for controlling potato wilt induced by F. foetens, resulting in a mycelium growth inhibition of 52.50 ± 2.59% in vitro and a significant decrease in incidence rate by 45.56% in vivo. This research highlighted the antifungal activity of surfactin from B. subtilis SF1 and attempted to reveal the unknown antifungal mechanisms. Surfactin inhibited F. foetens mycelium growth beyond the concentration of 20 µg/µL. Surfactin-treated mycelium appeared to have morphological malformation. Surfactin enhanced reduced glutathione production and caused the increase in values of the extracellular fluids in OD260 and OD280. Surfactin induced differential protein expression and changed the genes' transcription levels. Surfactin binds to fungal DNA via groove-binding mode, with a binding constant of Kb 2.97 × 104 M-1. Moreover, B. subtilis SF1 harbored genes encoding plant-promoting determinants, making potato seedlings grow vigorously. The results will help provide a comprehensive understanding of the mechanisms of surfactin against filamentous fungi and the application of surfactin-producing microbial in the biocontrol of plant pathogenic fungi.

Use of Biolayer Interferometry to Identify Dominant Binding Epitopes of Influenza Hemagglutinin Protein of A(H1N1)pdm09 in the Antibody Response to 2010-2011 Influenza Seasonal Vaccine.

The globular head domain of influenza virus surface protein hemagglutinin (HA1) is the major target of neutralizing antibodies elicited by vaccines. As little as one amino acid substitution in the HA1 can result in an antigenic drift of influenza viruses, indicating the dominance of some epitopes in the binding of HA to polyclonal serum antibodies. Therefore, identifying dominant binding epitopes of HA is critical for selecting seasonal influenza vaccine viruses. In this study, we have developed a biolayer interferometry (BLI)-based assay to determine dominant binding epitopes of the HA1 in antibody response to influenza vaccines using a panel of recombinant HA1 proteins of A(H1N1)pdm09 virus with each carrying a single amino acid substitution. Sera from individuals vaccinated with the 2010-2011 influenza trivalent vaccines were analyzed for their binding to the HA1 panel and hemagglutination inhibition (HI) activity against influenza viruses with cognate mutations. Results revealed an over 50% reduction in the BLI binding of several mutated HA1 compared to the wild type and a strong correlation between dominant residues identified by the BLI and HI assays. Our study demonstrates a method to systemically analyze antibody immunodominance in the humoral response to influenza vaccines.

Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus.

BACKGROUND: A new pandemic influenza A (H1N1) virus has emerged, causing illness globally, primarily in younger age groups. To assess the level of preexisting immunity in humans and to evaluate seasonal vaccine strategies, we measured the antibody response to the pandemic virus resulting from previous influenza infection or vaccination in different age groups. METHODS: Using a microneutralization assay, we measured cross-reactive antibodies to pandemic H1N1 virus (2009 H1N1) in stored serum samples from persons who either donated blood or were vaccinated with recent seasonal or 1976 swine influenza vaccines. RESULTS: A total of 4 of 107 persons (4%) who were born after 1980 had preexisting cross-reactive antibody titers of 40 or more against 2009 H1N1, whereas 39 of 115 persons (34%) born before 1950 had titers of 80 or more. Vaccination with seasonal trivalent inactivated influenza vaccines resulted in an increase in the level of cross-reactive antibody to 2009 H1N1 by a factor of four or more in none of 55 children between the ages of 6 months and 9 years, in 12 to 22% of 231 adults between the ages of 18 and 64 years, and in 5% or less of 113 adults 60 years of age or older. Seasonal vaccines that were formulated with adjuvant did not further enhance cross-reactive antibody responses. Vaccination with the A/New Jersey/1976 swine influenza vaccine substantially boosted cross-reactive antibodies to 2009 H1N1 in adults. CONCLUSIONS: Vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1 in any age group. Persons under the age of 30 years had little evidence of cross-reactive antibodies to the pandemic virus. However, a proportion of older adults had preexisting cross-reactive antibodies.

[The evaluation of combined CT pulmonary and bronchial arteriography for the diagnosis of hemoptysis].

OBJECTIVE: To establish the method of multi-slice spiral CT pulmonary angiography (CTPA)combined with bronchial angiography (CTBA) and to evaluate its value for diagnosis and treatment in hemoptysis. METHODS: After contrast material was administered intravenously, a 16-detector row helical CT scanner (Light Speed Ultra 16; GE Medical Systems) was used to complete CTPA first with a scan delay time of 12 - 16 s. Then CTBA was carried out, with a scan delay time of 26 - 28 s. The images were reformatted to evaluate the pulmonary artery and bronchial artery (BA). RESULTS: In 36 cases of hemoptysis, CTPA showed 7 pulmonary arterial abnormalities (3 cases with pulmonary embolism, 4 cases with one of pulmonary artery abnormity, primary pulmonary artery leiomyosarcoma, loss of sharpness of pulmonary artery or occlusion of right-inferior lung artery). In the 36 cases, CTBA showed 37 right BAs (11 tortuosity and thickening), 40 left right BAs (10 tortuosity and thickening) and 3 non-bronchial systemic arteries (1 from abdominal aorta tortuosity and thickening). Abnormal vessels had a close relation with pulmonary diseases. CONCLUSIONS: With this method CTPA and CTBA can be completed in a single procedure and abnormal pulmonary arteries and bronchial arteries can be shown clearly. This procedure maybe of important value for the diagnosis and treatment of hemoptysis.

A pre-pandemic outbreak of triple-reassortant swine influenza virus infection among university students, South Dakota, 2008.

BACKGROUND: After identifying a student with triple-reassortant swine influenza virus (SIV) infection and pig exposure at a livestock event, we investigated whether others were infected and if human-to-human transmission occurred. METHODS: We conducted a cohort study and serosurvey among persons exposed to (1) event pigs, (2) other pigs, (3) the index case, and (4) persons without pig or index case exposure. Confirmed cases had respiratory specimens positive for SIV within 2 weeks of the index case's illness. Probable and suspected cases had illness and (1) exposure to any pig or (2) contact with a confirmed case preceding illness. Probable cases were seropositive. Suspected cases did not give serum samples. RESULTS: Of 99 event pig-exposed students, 72 (73%) participated in the investigation, and 42 (42%) provided serum samples, of whom 17 (40%) were seropositive and 5 (12%) met case criteria. Of 9 students exposed to other pigs, 2 (22%) were seropositive. Of 8 index case-exposed persons and 10 without exposures, none were seropositive. Pig-exposed persons were more likely to be seropositive than persons without pig exposure (37% vs 0%, P < .01). CONCLUSIONS: We identified an outbreak of human SIV infection likely associated with a livestock event; there was no evidence of human-to-human transmission.

Samidorphan for the treatment of weight gain associated with olanzapine in patients with schizophrenia and bipolar disorder.

INTRODUCTION: Olanzapine (OLZ) is one of the most effective antipsychotic agents, however, its clinical utility has been limited by weight gain. Samidorphan (SAM) is a µ-opioid receptor antagonist and it can reduce the weight gain associated with OLZ. A combination of OLZ and SAM (OLZ/SAM) has been developed to provide the antipsychotic efficacy of OLZ, while mitigating OLZ-associated weight gain. AREAS COVERED: A comprehensive literature search was conducted in PubMed. Key search terms included SAM and weight gain associated with OLZ. The pharmacological action, clinical efficacy, and safety of SAM were reviewed. EXPERT OPINION: OLZ can lead to weight gain. SAM is a new drug that acts as an opioid receptor antagonist that can decrease weight gain. SAM mitigates OLZ-associated weight gain while preserving the antipsychotic efficacy of OLZ. Clinical trials have confirmed that OLZ/SAM significantly improved psychotic symptoms, and resulted in significantly less weight gain than OLZ. OLZ/SAM was well tolerated. Therefore, it is a potential new treatment option for schizophrenia.

Microstructure and Mechanical Properties of the 6 wt% Mn-Doped Martensitic Steel Strengthened by Cu/NiAl Nanoparticles.

The microstructure and mechanical properties of 6 wt.% Mn-doped martensitic steel have been investigated through a combination of electron backscatter diffraction (EBSD), transmission electron microscopy (TEM), and small-angle neutron scattering (SANS). The 6 wt.% Mn-doped steel exhibits a yield strength of ~1.83 GPa and an elongation-to-failure of ~7% under peak aging, and the ~853 MPa of precipitation strengthening is much higher than that observed in the 1.5 wt.% and 3 wt.% Mn-doped steels. The steel is composed of α'-martensite and slightly equiaxed α-ferrite together with a high proportion (~62.3%) of low-angle grain boundaries, and 6 wt.% Mn doping and the aging treatment have an effect on the matrix's microstructure. However, 6 wt.% Mn doping can obviously increase the mean size of the Cu/NiAl nanoparticles by enhancing the chemical driving force of the Mn partitioning on the NiAl nanoparticles, which differs from the refining effect on the nanoparticles in 3 wt.% Mn-doped steels. Furthermore, larger Cu/NiAl nanoparticles can significantly improve the yield strength of martensitic steel through precipitation-strengthening mechanisms.

Low quality antibody responses in critically ill patients hospitalized with pandemic influenza A(H1N1)pdm09 virus infection.

Although some adults infected with influenza 2009 A(H1N1)pdm09 viruses mounted high hemagglutination inhibition (HAI) antibody response, they still suffered from severe disease, or even death. Here, we analyzed antibody profiles in patients (n = 31, 17-65 years) admitted to intensive care units (ICUs) with lung failure and invasive mechanical ventilation use due to infection with A(H1N1)pdm09 viruses during 2009-2011. We performed a comprehensive analysis of the quality and quantity of antibody responses using HAI, virus neutralization, biolayer interferometry, enzyme-linked-lectin and enzyme-linked immunosorbent assays. At time of the ICU admission, 45% (14/31) of the patients had HAI antibody titers ≥ 80 in the first serum (S1), most (13/14) exhibited narrowly-focused HAI and/or anti-HA-head binding antibodies targeting single epitopes in or around the receptor binding site. In contrast, 42% (13/31) of the patients with HAI titers ≤ 10 in S1 had non-neutralizing anti-HA-stem antibodies against A(H1N1)pdm09 viruses. Only 19% (6/31) of the patients showed HA-specific IgG1-dominant antibody responses. Three of 5 fatal patients possessed highly focused cross-type HAI antibodies targeting the (K130 + Q223)-epitopes with extremely low avidity. Our findings suggest that narrowly-focused low-quality antibody responses targeting specific HA-epitopes may have contributed to severe infection of the lower respiratory tract.

Serologically confirmed household transmission of 2009 pandemic influenza A (H1N1) virus during the first pandemic wave--New York City, April-May 2009.

BACKGROUND: Understanding transmissibility of influenza viruses within households is critical for guiding public health response to pandemics. We studied serologically confirmed infection and disease among household contacts of index case patients with 2009 pandemic influenza A (H1N1) virus (pH1N1) infection in a setting of minimal community pH1N1 transmission. METHODS: We defined index case patients as students and staff of a New York City high school with laboratory-confirmed pH1N1 infection during the earliest phase of the pH1N1 outbreak in April 2009. We visited households of index case patients twice, once in early May and again in June/July 2009. At each visit, household members (both index case patents and household contacts) provided serum samples and completed questionnaires about illness and possible risk factors. Serologic testing was performed using microneutralization and hemagglutination-inhibition assays. RESULTS: Of 79 eligible household contacts in 28 households, 19% had serologically confirmed pH1N1 infection, and 28% of those infected were asymptomatic. Serologically confirmed infection varied by age among household contacts: 36% of contacts younger than 10 years were infected, compared with 46% of contacts age 10-18 years, 8% of contacts aged 19-54 years, and 22% of contacts aged 55 years and older. CONCLUSIONS: Infection rates were high for household contacts of persons with confirmed pH1N1, particularly for contacts aged 10-18 years, and asymptomatic infection was common. Efforts to reduce household transmission during influenza pandemics are important adjuncts to strategies to reduce community illness.

Sensitivity and specificity of serologic assays for detection of human infection with 2009 pandemic H1N1 virus in U.S. populations.

Swine origin 2009 H1N1 influenza virus has spread globally to cause the first influenza pandemic of the 21st century. Serological studies can improve our understanding of the extent of human infection and risk factors associated with the transmission of this pandemic virus. The "gold standard" for serodiagnosis of human influenza virus infection is the detection of seroconversion between acute- and convalescent-stage samples. However, the timing of seroepidemiological investigations often precludes the collection of truly acute-phase sera, requiring development of serological criteria for evaluating convalescent-phase sera that optimize detection of true positives and true negatives. To guide seroepidemiological investigations into the spread of the novel 2009 pandemic H1N1 virus, we characterized serum antibody responses to 2009 H1N1 virus in 87 individuals with confirmed viral infection and 227 nonexposed U.S. individuals using microneutralization (MN) and hemagglutination inhibition (HI) assays. Sensitivity and specificity were determined for each assay alone and in combination for detection of 2009 H1N1 virus-specific antibodies in convalescent-phase sera. Although the HI assay was more specific for detecting antibody to 2009 H1N1, the MN assay was more sensitive, particularly for detecting low-titer seroconversions. A combination of titers (MN ≥ 40 and HI ≥ 20) provided the highest sensitivity (90%) and specificity (96%) for individuals aged <60 years and 92% specificity for adults aged ≥ 60 years for detection of serologically confirmed 2009 H1N1 infections in U.S. populations during the first pandemic waves. These studies provide an approach to optimize timely serological investigations for future pandemics or outbreaks of novel influenza viruses among humans.

Surufatinib for the treatment of advanced extrapancreatic neuroendocrine tumors.

Introduction: Surufatinib (also known as HMPL-012, sulfatinib) is a novel oral tyrosine kinase inhibitor (TKI), which has the dual activity of anti-angiogenesis and immune regulation. In December 2020, surufatinib was approved as a monotherapy for unresectable locally advanced or metastatic, progressive nonfunctioning, well differentiated (grade 1 or 2) extrapancreatic neuroendocrine tumors (epNETs) in China.Areas covered: In this paper, the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy, safety, and tolerability of surufatinib for treatment of advanced extrapancreatic NETs are introduced in detail. We performed a systematic review of the literature in PubMed and the following keywords were used: 'surufatinib,' 'sulfatinib' and 'HMPL-012.'Expert opinion: Surufatinib is a potent, selective, and small-molecule TKI that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor 1 (FGFR1) and colony stimulating factor 1 receptor (CSF1R). Surufatinib showed an acceptable safety profile and encouraging antitumor activity in patients with advanced epNETs. The most frequently observed adverse events (AEs) were hypertension and proteinuria. Surufatinib provides a new treatment option for patients with advanced epNETs. More clinical trials of surufatinib are ongoing to develop a combination of therapy strategies and new indications for malignancies.

Intranasal vaccination with 1918 influenza virus-like particles protects mice and ferrets from lethal 1918 and H5N1 influenza virus challenge.

Influenza vaccines capable of inducing cross-reactive or heterotypic immunity could be an important first line of prevention against a novel subtype virus. Influenza virus-like particles (VLPs) displaying functional viral proteins are effective vaccines against replication-competent homologous virus, but their ability to induce heterotypic immunity has not been adequately tested. To measure VLP vaccine efficacy against a known influenza pandemic virus, recombinant VLPs were generated from structural proteins of the 1918 H1N1 virus. Mucosal and traditional parenteral administrations of H1N1 VLPs were compared for the ability to protect against the reconstructed 1918 virus and a highly pathogenic avian H5N1 virus isolated from a fatal human case. Mice that received two intranasal immunizations of H1N1 VLPs were largely protected against a lethal challenge with both the 1918 virus and the H5N1 virus. In contrast, mice that received two intramuscular immunizations of 1918 VLPs were only protected against a homologous virus challenge. Mucosal vaccination of mice with 1918 VLPs induced higher levels of cross-reactive immunoglobulin G (IgG) and IgA antibodies than did parenteral vaccination. Similarly, ferrets mucosally vaccinated with 1918 VLPs completely survived a lethal challenge with the H5N1 virus, while only a 50% survival rate was observed in parenterally vaccinated animals. These results suggest a strategy of VLP vaccination against a pandemic virus and one that stimulates heterotypic immunity against an influenza virus strain with threatening pandemic potential.

A live attenuated H1N1 M1 mutant provides broad cross-protection against influenza A viruses, including highly pathogenic A/Vietnam/1203/2004, in mice.

The emergence of novel influenza A H1N1 and highly pathogenic avian influenza (HPAI) H5N1 viruses underscores the urgency of developing efficient vaccines against an imminent pandemic. M(NLS-88R) (H1N1), an A/WSN/33 mutant with modifications in the multibasic motif 101RKLKR105 of the matrix (M1) protein and its adjacent region, was generated by reverse genetics. The M(NLS-88R) mutant had in vitro growth characteristics similar to those of wild-type A/WSN/33 (wt-WSN), but it was attenuated in mice. Vaccination with M(NLS-88R) not only fully protected mice from lethal homologous challenges but also prevented mortality caused by antigenically distinct H3N2 and H5N1 viruses. M(NLS-88R)-induced homologous protection was mainly antibody dependent, but cellular immunity was also beneficial in protecting against sublethal wt-WSN infection. Adoptive transfer studies indicated that both humoral and cellular immune responses were crucial for M(NLS-88R)-induced heterologous protection. Our study suggests an alternative approach to attenuate wt influenza viruses for the development of a pandemic vaccine with broad cross-protection.