Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms ...underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups.
A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation.
Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-β signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01).
This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.
We introduce the antibody landscape, a method for the quantitative analysis of antibodymediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among ...pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.
Despite the apparent natural grouping of “picorna-like” viruses, the taxonomical significance of this putative “supergroup” was never addressed adequately. We recently proposed to the ICTV that an ...order should be created and named Picornavirales, to include viruses infecting eukaryotes that share similar properties: (i) a positive-sense RNA genome, usually with a 5'-bound VPg and 3'-polyadenylated, (ii) genome translation into autoproteolytically processed polyprotein(s), (iii) capsid proteins organized in a module containing three related jelly-roll domains which form small icosahedral, non-enveloped particles with a pseudo-T = 3 symmetry, and (iv) a three-domain module containing a superfamily III helicase, a (cysteine) proteinase with a chymotrypsin-like fold and an RNA-dependent RNA polymerase. According to the above criteria, the order Picornavirales includes the families Picornaviridae, Comoviridae, Dicistroviridae, Marnaviridae, Sequiviridae and the unassigned genera Cheravirus, Iflavirus and Sadwavirus. Other taxa of “picorna-like” viruses, e.g. Potyviridae, Caliciviridae, Hypoviridae, do not conform to several of the above criteria and are more remotely related: therefore they are not being proposed as members of the new order. Newly described viruses, not yet assigned to an existing taxon by ICTV, may belong to the proposed order.
The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and ...amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.
Magnetic reconnection is a fundamental process in collisionless space plasma environment, and plasma waves relevant to the kinetic interactions can have a significant impact on the multiscale ...behavior of reconnection. Here, we present Magnetospheric Multiscale (MMS) observations during an encounter of an X line of symmetric magnetic reconnection in the magnetotail. The X line is characterized by reversals of ion and electron jets and electromagnetic fields, agyrotropic electron velocity distribution functions (VDFs), and an electron‐scale current sheet. MMS observe large‐amplitude nonlinear upper‐hybrid (UH) waves on both sides of the neutral line, and the wave amplitudes have highly localized distribution along the normal direction. The inbound meandering electrons drive the UH waves, releasing the free energy stored from the reconnection electric field along the meandering trajectories. The interaction between the meandering electrons and the UH waves may modify the balance of the reconnection electric field around the X line.
Plain Language Summary
The electron‐scale kinetic physics in the electron diffusion region (EDR) controls how magnetic field lines break and reconnect. Electron crescent, an indicator of EDR, can drive high‐frequency electrostatic waves around EDR. For the first time, the upper‐hybrid (UH) waves are observed on both sides of the X line and we show the direct association between the UH waves and the reconnection electric field. The strong wave‐electron interaction can change the electron‐scale dynamics and may modify the reconnection electric field. This study demonstrates that the UH waves may play an important role in controlling the reconnection rate.
Key Points
Large amplitude nonlinear upper‐hybrid (UH) waves are observed on both inflow sides of an X line
The UH waves are driven by the inbound meandering electrons
The UH waves may dissipate a significant part of the meandering electron energy gained from the reconnection electric field
The nonlocal strain gradient and classical shell theories are used to derive the governing equations of functionally graded cylindrical nanopanels (open cylindrical shells). The properties of the ...nanopanel are graded as a power-law distribution through the thickness direction. The linearization stability equations are obtained using an adjacent equilibrium criterion. Governing equations are solved by Galerkin method to investigate the effects of the material length scale parameter, the nonlocal parameter, the geometric parameters, and the material properties on the buckling behavior of functionally graded cylindrical nanopanels. Numerical results are compared and discussed with available data. The solution of the closed cylindrical shell is recovered when the span angle is taken as 360 degrees.
We report a novel process for surface modified single-walled carbon nanotubes (SWCNTs) as drug nanocarriers by using facile and green synthetic methods. Firstly, polyampholytic alternating polymers ...having furfuryl amine and 3-(dimethylamino)-1-propylamine as functional groups were prepared via one-pot thiol-ene chemistry in sustainable conditions. The obtained polymers were then used to a direct functionalization onto the surface of SWCNTs through Diels-Alder click reaction conducted in aqueous media under ultrasonication. The resulting hybrid was characterized by 1H NMR, FT-IR, TGA and UV–vis measurements. The hybrid improved the drug loading content up to 150 wt%, indicating that they are potential doxorubicin (DOX) delivery nano-vehicles. Furthermore, the in-vitro drug release profiles showed that there was a burst release of DOX at pH 5.5 under an acidic condition in microenvironment of tumor cells, in contrast with a lower release rate at pH 7.4 in the physiological condition. Cell viability assays demonstrated the low cytotoxicity against the normal HEK293 cell of SWCNT hybrids, while they exhibited a high cytotoxic activity towards HeLa cancer cells. These evidences revealed the promising SWCNT-based drug carrier for tumor-targeting chemotherapy release in the cancer therapy.
a) Graphical illustration of PMT polymers grafted onto SWCNT for DOX loading and b) preparation of polyampholytic PMT polymers and PMT/SWCNTs. Display omitted
•A novel polyampholytes with functional groups was synthesized by thiol-ene chemistry by one-pot two step reaction.•The polyampholytes was grafted on SWCNT with furfuryl amine by Diels–Alder click reaction under ultrasound support.•Doxorubicin was loaded in the polyampholytes grafted SWCNT with a high drug loading capacity.•The drug release profile indicated pH-responsive characteristics.•The drug loaded hybrid showed a high cytotoxicity against HeLa cancer cells and a little toxic against normal cells.
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