Self-adjuvanted L-arginine-modified dextran-based nanogels for sustained local antigenic protein delivery to antigen-presenting cells and enhanced cellular and humoral immune responses.

In the development of cancer vaccines, antigens are delivered to elicit potent and specific T-cell responses to eradicate tumour cells. Nonetheless, successful vaccines are often hampered by the poor immunogenicity of tumour antigens, rapid clearance by the innate immunity, and limited cross-presentation on MHC-I to activate CD8+ T-cells arm. To address these issues, we developed dextran-based nanogels to promote antigen uptake, storage, and cross-presentation on MHC-I, while directing immunogenic maturation of the antigen-presenting cells (APCs). To promote the nanocarriers interaction with cells, we modified DX with L-arginine (Arg), whose immunomodulatory activities have been well documented. The ArgDX nanogel performance was compared with the nanogel modified with L-histidine (His) and L-glutamate (Glut). Moreover, we introduced pH-sensitive hydrazone crosslinking during the nanogel formation for the conjugation and controlled release of antigen ovalbumin (OVA). The OVA-laden nanogels have an average size of 325 nm. We demonstrated that the nanogels could rapidly release cargoes upon a pH change from 7 to 5 within 8 days, indicating the controlled release of antigens in the acidic cellular compartments upon internalization. Our results revealed that the ArgDX nanogel could promote greater antigen uptake and storage in DCs in vitro and promoted a stronger immunogenic maturation of DCs and M1 polarization of the macrophages. The OVA signals were co-localized with lysosomal compartments up till 96 hours post-treatment and washing, suggesting the nanogels could facilitate prolonged antigen storage and supply from endo-lysosomal compartments. Furthermore, all the tested nanogel formulations retained antigens at the skin injection sites until day 21. Such delayed clearance could be due to the formation of micron-sized aggregates of OVA-laden nanogels, extending the interactions with the resident DCs. Amongst the amino acid modifications, ArgDX nanogels promoted the highest level of lymph node homing signal CCR7 on DCs. The nanogels also showed higher antigen presentation on both MHC-I and II than DX in vitro. In the in vivo immune studies, ArgDX nanogels were more superior in inducing cellular and humoral immunity than the other treatment groups on day 21 post-treatment. These results suggested that ArgDX nanogel is a promising self-adjuvanted nanocarrier for vaccine delivery.

Effects of open and closed skill exercise interventions on executive function in typical children: a meta-analysis.

BACKGROUND: The effects of open and closed skill exercise interventions for executive function in children and adolescents have received widespread attention. Open skill refers to the skill of performing motor tasks in an unpredictable environment; closed skill refers to the skill of performing motor tasks in a stable environment. However, the results of related studies are currently controversial and Meta-analysis is urgently needed. METHODS: After computer searches of CNKI, Wan-Fang, VIP, WOS, PubMed, and EBSCO databases, two researchers independently screened articles, extracted information, and evaluated the quality of the articles. This study was statistical analyzed using Stata 16.0 software. RESULTS: A total of 31 articles were included, including 2988 typical children. Open, closed, continuous and sequential skills all improved executive function in typical children to varying degrees, but open and sequential skills were more effective in improving executive function, particularly in the former in the working memory (SMD=-0.833, P < 0.001) and in the latter in the inhibitory control (SMD=-0.834, P < 0.001) and cognitive flexibility (SMD=-0.903, P < 0.001). Long-term, moderate- intensity interventions were better than acute, vigorous-intensity interventions for executive function, with long-term interventions reflected in working memory (SMD=-0.579, P < 0.001) and moderate-intensity interventions reflected in all three dimensions of executive function (P < 0.01). Intervention periods, intervention intensity and continuous and sequential skills classified by action structure play a significant moderating role. Better results for long-term, sequential structural action interventions based on open skills (P < 0.001); better results for acute, moderate intensity, sequential structural action interventions based on closed (P < 0.05). Whereas intervention intensity had a non-significant moderating effect in the open skills intervention, both moderate and vigorous intensity had a significant effect on executive function (P < 0.001). CONCLUSION: Open and closed skills have different levels of facilitation effects on executive function in typical children, but open skills are more effective. The facilitation effects of open and closed skills were moderated by the qualitative characteristics and action structure of the intervention.

Antibody responses following the surge of SARS-CoV-2 Omicron infection among patients with systemic autoimmune rheumatic diseases.

Objectives: The surge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant Omicron infections has affected most Chinese residents at the end of 2022, including a number of patients with systemic autoimmune rheumatic diseases (SARDs). Methods: To investigate the antibody level of the Omicron variant in SARD patients after SARS-CoV-2 Omicron infection, we tested BA.5.2 and BF.7 Omicron variant IgG antibody levels using ELISA on blood samples collected from 102 SARD patients and 19 healthy controls (HCs). The type of SARD, demographics, concurrent treatment, doses of SARS-CoV-2 vaccines and outcomes were also recorded. Results: A total of 102 SARD patients (mean age: 40.3 years; 89.2% female), including 60 SLE, 32 RA and 10 other SARDs, were identified. Of these, 87 (85.3%) were infected with SARS-CoV-2. We found that the BA.5.2 and BF.7 antibody levels of infected SARD patients were lower than those of HCs (P < 0.05). Sixty-five (63.7%) patients had at least one dose of a SARS-CoV-2 vaccine. SARD patients with at least two doses of SARS-CoV-2 vaccine had a higher level of BA.5.2 and BF.7 antibodies than the unvaccinated group (P < 0.05). There was no evidence for a significant inhibitory effect of glucocorticoids (GCs) on the BA.5.2 and BF.7 Omicron variant antibody levels in SARD patients. SLE patients using biologic DMARDs had a lower BA.5.2 Omicron variant antibody level than patients using GCs and/or HCQ. Conclusion: These data suggest that patients with SARDs had a lower antibody response than HCs after Omicron infection.

Total Synthesis of (+)-Haperforin G.

(+)-Haperforin G was synthesized in 20 steps from commercially available starting materials. A Co-catalyzed intramolecular Pauson-Khand reaction was used for stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position. Light-initiated photocatalysis was used for convergent and asymmetric cross-coupling of the unstabilized C(sp3) radical with an enone. The developed chemistry paves the way to the synthesis of structurally diverse analogs of haperforin G (6).

Vaccine delivery by zwitterionic polysaccharide-based hydrogel microparticles showing enhanced immunogenicity and suppressed foreign body responses.

The controlled release of antigens from injectable depots has been actively pursued to achieve long-lasting immune responses in vaccine development. Nonetheless, subcutaneous depots are often susceptible to foreign body responses (FBRs) dominated by macrophage clearance and fibrotic encapsulation, resulting in limited antigen delivery to target dendritic cells (DCs) that bridge innate and adaptive immunity. Here, we aim to develop a long-term antigen depot that can bypass FBR and engage DCs to mature and migrate to lymph nodes to activate antigen-specific T-cells. Leveraging the immunomodulatory properties of exogenous polysaccharides and the anti-fouling characteristics of zwitterionic phosphorylcholine (PC) polymers, we developed a PC functionalized dextran (PCDX) hydrogel for long-term antigen delivery. We observed that PCDX in both injectable scaffold and microparticle (MP) forms could effectively evade FBR as the anionic carboxymethyl DX (CMDX) in vitro and in vivo. Meanwhile, PCDX provided slower and longer release of antigens than CMDX, resulting in local enrichment of CD11c+ DCs at the MP injection sites. DC cultured on PCDX exhibited stronger immunogenic activation with higher CD86, CD40, and MHC-I/peptide complex than CMDX. PCDX also generated DC with greater propensity in migration to lymph nodes, as well as antigen presentations to trigger both CD4+ and CD8+ arms of T-cell responses, as compared to other charge derivatives of DX. Besides cellular responses, PCDX could also induce more durable and potent humoral responses, with higher levels of antigen specific IgG1 and IgG2a by day 28, as compared to other treatment groups. In conclusion, PCDX can incorporate the benefits of both immunogenic DX and anti-fouling properties of zwitterionic PC and thus, shows great promise in providing long-term delivery of antigens for vaccine development.

Effect of high-flow nasal cannula on patients' recovery after inhalation general anesthesia.

Objective: To investigate the effect of high-flow nasal cannula (HFNC) and Oxygen Nebuliser mask (ONM) on patients recovering from inhalation anesthesia. Methods: A retrospective analysis was performed on 128 patients after inhalation of general anesthesia in the recovery room of the Anesthesiology Department of The Fourth Hospital of Hebei Medical University from September 2019 to September 2021. All patients received the same anesthesia induction and analgesia methods, inhalation anesthesia or intravenous-inhalation anesthesia maintenance, recovered spontaneous breathing and removed endotracheal intubation after surgery, then were divided into HFNC group and ONM group for oxygen therapy. HFNC setting mode: flow rate: 20-60 L/minutes, humidification temperature: 37°C, the oxygen concentration was adjusted to maintain finger pulse oxygen saturation SPO2>90%; ONM group, the oxygen flow rate was adjusted to maintain finger pulse oxygen saturation SPO2>90%. All patients in the two groups were compared immediately after they entered the recovery room for 0 minutes,, 10 minutes, and 20 minutes,, including tidal volume, blood gas, Richmond Agitation-Sedation Scale (RASS) score and time from sedation to awakening. Results: The changes in tidal volume, oxygenation index and RASS score over time in the HFNC group were higher than those in the ONM group (p<0.05), and the awakening time in the HFNC group was faster than that in the ONM group (p<0.01), with significant statistical differences. Conclusions: Compared with ONM, HFNC can shorten postoperative recovery time, reduce the incidence of agitation and improve lung function and oxygenation state during recovery from anesthesia.

Low-intensity low-frequency ultrasound mediates riboflavin delivery during corneal crosslinking.

We employed the mechanical effect from 40 kHz ultrasound (US) to improve the delivery of riboflavin into corneal stroma for collagen crosslinking, which can benefit the treatment of keratoconus and other corneal ectasias. Experiments were conducted, first with porcine corneas ex vivo and then with New Zealand white rabbits in vivo, at varying mechanical index (MI) and sonication time. Results showed that 15 min of US applied on the cornea at MI = 0.8 in the presence of 0.5% of riboflavin solution enabled its delivery to deeper corneal stroma. Excessive heat was removed by a cooling setup to negate the thermal effect. The corneal absorption amount and penetration of riboflavin through cornea as detected by fluorotron, as well as the enhancement of corneal stiffness as measured by Young's modulus, were comparable to the conventional approach that requires complete corneal epithelium debridement. Histological analysis revealed minor exfoliation of superficial cell layers of corneal epithelium and loss of ZO-1 tight junctions immediately after US. Full recovery of the corneal epithelium and restoration of tight junctions occurred in 3-4 days. The study shows that low-intensity low-frequency ultrasound (LILF US) is a less invasive alternative to the conventional epithelium-off method for delivering riboflavin into the corneal stroma.

Harnessing Reconstructed Macrophage Modulation of Infiltration-Excluded Immune Microenvironments To Delineate Glioma Infiltrative Region.

High invasiveness of glioma produces residual glioma cells in the brain parenchyma after surgery and ultimately causes recurrence. Precise delineation of glioma infiltrative region is critical for an accurate complete resection, which is challenging. The glioma-infiltrating area constitutes infiltration-excluded immune microenvironments (I-E TIMEs), which recruits endogenous or adoptive macrophages to the invasive edge of glioma. Thus, combined with immune cell tracing technology, we provided a novel strategy for the preoperative precise definition of the glioma infiltration boundary, even satellite-like infiltration stoves. Herein, the biomimetic probe was constructed by internalizing fluorophore labeled PEGylated KMnF3 nanoparticles into bone-marrow-derived macrophages using magnetic resonance imaging (MRI)/fluorescence imaging (FI). The biomimetic probe was able to cross the blood-brain barrier and home to the orthotopic glioma infiltrates including satellite stove under MRI and FI tracing, which was validated using hematoxylin and eosin staining, indicating its excellent performance in distinguishing the margins between the glioma cell and normal tissues. This study guides the precise definition of glioma infiltration boundaries at the cellular level, including the observation of any residual glioma cells after surgery. Thus, it has the potential to guide surgery to maximize resection and predict recurrence in the clinic.

Three-dimensional image-guided topical photodynamic therapy system with light dosimetry dynamic planning and monitoring.

Photodynamic therapy (PDT) has shown significant potential for skin disease treatment. As a key element, light is critical to influencing its treatment outcome, and light dosimetry is an issue of much concern for researchers. However, because of three-dimensional irregularity in shape and patient's movement during the therapy, irradiance hardly keeps uniform on the lesion and flux measurement remains a challenge. In this work, we report the development of a three-dimensional image-guided PDT system, and the method of dynamic irradiance planning and flux monitoring for lesions in different poses. This system comprises a three-dimensional camera for monitoring patients' movement during therapy, a computer for data analysis and processing, and a homemade LED array for forming uniform irradiance on lesions. Simulations on lesions of the face and arm show that the proposed system significantly increases effective therapy area, enhances irradiance uniformity, is able to visualize flux on the lesion, and reduces risks of burns during PDT. The developed PDT system is promising for optimizing procedures of PDT and providing better treatment outcomes by delivering controllable irradiance and flux on lesions even when a patient is moving.

Case report: Difference in outcomes between two cases of Hailey-Hailey disease treated with apremilast.

Hailey-Hailey disease (HHD) is a rare autosomal dominant acantholytic dermatosis clinically characterized by recurrent erythematous plaques and erosions mainly on the intertriginous regions. Although HHD seriously affects quality of life, conventional treatments often fail to provide long-term relief for most patients. The effectiveness of apremilast, a phosphodiesterase-4 inhibitor, against severe HHD was first reported in 2018, and after further testing, this agent is currently expected to be established as an efficacious and safe therapeutic option. Here we report two cases of HHD treated with apremilast which showed opposite outcomes. Although the case with extremely severe symptoms showed remarkable and long-lasting improvement with apremilast used after acute treatment with oral corticosteroid, the other case, with milder symptoms treated only with apremilast, showed no improvement. Our transcriptome analysis using skin samples collected prior to apremilast administration revealed the involvement of the NF-κB signaling pathway, which is related to the responses to bacteria and other organisms. However, this pathway was more strongly activated in case 2 than in case 1, suggesting that the steroid treatment preceding apremilast may have been effective and supportive in the apremilast-responding case. One of the two cases highlights the potential of apremilast as a treatment option for HHD, but the other underlines the difficulties in managing HHD and the complexity of the disease background. The accumulation of cases and larger clinical studies are expected to precisely evaluate the safety and efficacy of apremilast, and the potential for therapies in combination with conventional treatments.

Activation of peripheral group III metabotropic glutamate receptors suppressed formalin-induced nociception.

Intraplantar injection of formalin produces persistent spontaneous nociception and hyperalgesia. The underlying mechanism, however, remains unclear. The present study was, therefore, designed to determine the roles of peripheral group III metabotropic glutamate receptors (mGluRs) in formalin-evoked spontaneous nociception. Pre-treatment with intraplantar injections of L-serine-O-phosphate (L-SOP), a group III mGluRs agonist, significantly inhibited formalin-induced nociceptive behaviours and decreased Fos production in the spinal dorsal horn. The inhibitory effects of L-SOP were abolished completely by pre-treatment with the group III mGluR antagonist (RS)-a-methylserine-O-phosphate (M-SOP). These data suggest that the activation of group III mGluRs in the periphery may play a differential role in formalin-induced nociception. In addition, L-SOP decreased the formalin-induced upregulation of tumour necrosis factor-α (TNF-α) as well as interleukine-1ß (IL-1ß) expression in the spinal cord, suggesting that activation of peripheral group III mGluRs reduces formalin-induced nociception through inhibition of the pro-inflammatory cytokines in the spinal cord. Therefore, the agonists acting peripheral group III mGluRs possess therapeutic effectiveness in chronic pain.

The effect of polysaccharide-based hydrogels on the response of antigen-presenting cell lines to immunomodulators.

Hydrogel presents as foreign material to the host and participates in immune responses, which skew the biofunctions of immunologic loads (antigen and adjuvants) during in situ DC priming. This study aims to investigate the effect of the hydrogel made from different polysaccharides on macrophage (RAW264.7) activation and DC (JAWSII) modulation. We adopted polysaccharides of different sugar chemistry to fabricate hydrogels. Hyaluronate (HA), glycol chitosan (GC) and dextran (DX) were functionalized with vinyl sulfone and chemically cross-linked with dithiothreitol via thiol-click chemistry. We found that HA reduced macrophage adhesion and activation on the hydrogel surface. GC and DX promoted M1 polarization in terms of higher CCR7 expression and TNF-α, IL-6 production. In terms of DC engagement, GC promoted antigen uptake by JAWSII and all hydrogels promoted antigen presentation on MHC-I molecules. GC and DX favoured the generation of immunogenic DC while accommodating immunostimulatory functions of IFN-γ and polyI:C or LPS during co-incubation. Particularly, the co-incubation of IP with GC promoted CCR7 expression on JAWSII. Conversely, HA was more appropriate for the construction of a tolerogenic DC priming platform. We observed that HA did not induce co-stimulatory markers expression on DC but suppressed the action of LPS in inducing TNF-α generation. Moreover, when immunosuppressive cytokines, IL-10 and TGF-ß were added, cytokines' immunosuppressive action was amplified by hydrogel bedding, HA, GC and to a less extent DX in suppressing LPS-induced IL-6 generation from JAWSII. We concluded that HA is preferable for tolerogenic DC development while minimizing the macrophage response in conferring foreign body response, whereas DX and GC are more appropriate for immunogenic DC development. This study demonstrates the potential of polysaccharides in conferring in situ DC priming together with antigen and adjuvant loads while addressing the tradeoff between the foreign body responses and DC engagement by selecting appropriate polysaccharides for the hydrogel platform construction.

Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism.

Revertant mosaicism, or "natural gene therapy," refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.

Enhancement degree of brain metastases: correlation analysis between enhanced T2 FLAIR and vascular permeability parameters of dynamic contrast-enhanced MRI.

OBJECTIVES: To investigate the correlation between enhancement degrees of brain metastases on contrast-enhanced T2-fluid-attenuated inversion recovery (CE-T2 FLAIR) and vascular permeability parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: Thirty-nine patients with brain metastases were prospectively collected. They underwent non-enhanced T2 FLAIR, DCE-MRI, CE-T2 FLAIR, and contrast-enhanced three-dimensional brain volume imaging (CE-BRAVO). Quantitative parameters of DCE-MRI were evaluated for all lesions, which included volume transfer constant (Ktrans), rate constant (Kep), and fractional volume of the extracellular extravascular space (Ve). Contrast ratio (CR) and percentage increase (PI) values of all lesions on CE-T2 FLAIR were also measured. The tumor enhancement degree on CE-T2 FLAIR in relation to CE-BRAVO was visually classified as higher (group A), equal (group B), and lower (group C). RESULTS: A total of 82 brain metastases were evaluated, including 31 in group A, 19 in group B, and 32 in group C. The Ktrans and Kep were negatively correlated with the CR (ρ = - 0.551, p < 0.001 and ρ = - 0.708, p < 0.001, respectively) and PI (ρ = - 0.511, p < 0.001 and ρ = - 0.621, p < 0.001, respectively). The Ktrans and Kep of group A were significantly lower than those of group C (both p < 0.001). No significant difference was found in Ve among the groups (p = 0.327). CONCLUSIONS: The enhancement degree of brain metastases on CE-T2 FLAIR is negatively correlated with Ktrans and Kep values, which indicate that vascular permeability parameters may play an important role in explaining the difference in enhancement between CE-T2 FLAIR and CE-BRAVO. KEY POINTS: • The enhancement degree on CE-T2 FLAIR was negatively correlated with Ktrans and Kep values. • The vascular permeability of brain metastasis accounted for the difference in enhancement degree between CE-T2 FLAIR and CE-BRAVO. • CE-T2 FLAIR is useful for detecting brain metastases with mild disruption of the blood-brain barrier.

Droplet-Based Microfluidic Synthesis of Hydrogel Microparticles via Click Chemistry-Based Cross-Linking for the Controlled Release of Proteins.

Hydrogel microparticles (HMPs) have been widely applied in biological, pharmacologic, and biomedical industries due to their versatility. Particle size is a paramount factor for controlling drug release profiles from HMPs. Conventional fabrication methods such as bulk emulsion, coacervation, and spray drying do not offer a precise size control and high reproducibility, which may compromise the utility of HMPs for controlled release. Here, we report a droplet-based microfluidic synthesis method for the precise fabrication of HMPs. Functionalized polysaccharides/protein fluid mixtures were emulsified into monodisperse droplets in light mineral oil using a flow-focusing device and well mixed in precursor droplets through a serpentine mixing channel before the solidification of HMPs. The homogenized precursor polymers cross-link in the droplets by catalyst-free Michael addition. As a demonstration of the controlled release of a model drug from the HMPs, fluorescein-labeled immunoglobulin G (F-IgG) and bevacizumab were encapsulated in the HMPs of different diameters for measuring its release dynamics over time. The release kinetics of F-IgG from the HMPs was shown to be controllable by altering the particle size while keeping other parameters unchanged. Around 70% of bevacizumab released from DX HMPs was functional. Both HA and DX HMPs showed no cytotoxicity in the HEK293 cell line. We anticipate that this approach could be used as a general method to fabricate HMPs made of hydrophilic polymers for the controlled release of biotherapeutics.

Deep Learning for Detecting Cerebral Aneurysms with CT Angiography.

Background Cerebral aneurysm detection is a challenging task. Deep learning may become a supportive tool for more accurate interpretation. Purpose To develop a highly sensitive deep learning-based algorithm that assists in the detection of cerebral aneurysms on CT angiography images. Materials and Methods Head CT angiography images were retrospectively retrieved from two hospital databases acquired across four different scanners between January 2015 and June 2019. The data were divided into training and validation sets; 400 additional independent CT angiograms acquired between July and December 2019 were used for external validation. A deep learning-based algorithm was constructed and assessed. Both internal and external validation were performed. Jackknife alternative free-response receiver operating characteristic analysis was performed. Results A total of 1068 patients (mean age, 57 years ± 11 [standard deviation]; 660 women) were evaluated for a total of 1068 CT angiograms encompassing 1337 cerebral aneurysms. Of these, 534 CT angiograms (688 aneurysms) were assigned to the training set, and the remaining 534 CT angiograms (649 aneurysms) constituted the validation set. The sensitivity of the proposed algorithm for detecting cerebral aneurysms was 97.5% (633 of 649; 95% CI: 96.0, 98.6). Moreover, eight new aneurysms that had been overlooked in the initial reports were detected (1.2%, eight of 649). With the aid of the algorithm, the overall performance of radiologists in terms of area under the weighted alternative free-response receiver operating characteristic curve was higher by 0.01 (95% CI: 0.00, 0.03). Conclusion The proposed deep learning algorithm assisted radiologists in detecting cerebral aneurysms on CT angiography images, resulting in a higher detection rate. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kallmes and Erickson in this issue.

Optimization of Contrast Agent Dosage on Contrast-Enhanced T2 Fluid-Attenuated Inversion Recovery: An In Vitro and In Vivo Study.

OBJECTIVE: This study aimed to ascertain the minimum gadolinium dosage on contrast-enhanced (CE) T2 fluid-attenuated inversion recovery (FLAIR) at appropriate imaging time. METHODS: Different dosages of gadodiamide were imaged with a 3.0-T magnetic resonance scanner for T2-FLAIR and T1WI. Twenty glioma-induced rat models were randomly assigned into 4 groups (1/2, 1/4, 1/6, 1/8 of routine dosage) and imaged for T2-FLAIR and T1WI preinjection and postinjection of gadodiamide. Contrast-enhanced T2-FLAIR was acquired for 8 repetitions postinjection. Enhancement effects were assessed by calculating contrast-noise ratio and contrast ratio using Kruskal-Wallis and Mann-Whitney rank sum test. RESULTS: The in vitro experiment showed that gadodiamide at 1/4 of the T1WI dosage presented the best contrast on CE-T2-FLAIR. For in vivo study, the best enhancement effect on CE-T2-FLAIR was achieved at 1/2 of the routine dosage at 8 to 12 minutes of delayed scanning. Compared with CE-T1WI at routine dosage, CE-T2-FLAIR at 1/2 gadodiamide dosage presented similar enhancement effects with no statistical difference (P = 0.244 and 0.090 for contrast-noise ratio and contrast ratio, respectively). CONCLUSIONS: Contrast-enhanced T2-FLAIR imaging with half of T1WI routine gadodiamide dosage can produce similar enhancement effects to CE-T1WI when characterizing brain gliomas. The cut-down of contrast agent dosage may help reduce gadolinium accumulation in certain tissues.

Successful Conservative Treatment of Massive Infective Endocarditis with Severe Mitral Valve Regurgitation and Septic Emboli

@#Management of complicated massive infective endocarditis (IE) in patients who are contraindicated for surgical valve replacement has long been a dilemma for many clinicians. Studies have shown that massive IE patients who were treated conservatively generally result in poorer prognosis. We report two cases of massive native valve infective endocarditis with severe mitral valve regurgitation and septic emboli that has been successfully treated conservatively. Interestingly, despite having a large vegetation and multiple septic emboli complications, none of these two cases had any positive culture or serology. Managing culture negative IE without surgical intervention pose an even greater challenge to the choice and duration of antibiotics with further long-term plans. We hope to share these case series to aid in the management dilemma of similar cases in the future.

Total Synthesis of (+)-Haperforin G.

A concise chemical synthesis of (+)-haperforin G in 20 steps from commercially available starting materials is achieved with the integration of the Co-catalyzed intramolecular Pauson-Khand reaction for the stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position and the light-initiated photocatalysis for convergent and asymmetric cross-coupling of the unstabilized C(sp3)-radical with an enone. The developed chemistry paves the way to synthesizing structurally diverse analogs of haperforin G (6).

Tumor Immune Microenvironments (TIMEs): Responsive Nanoplatforms for Antitumor Immunotherapy.

Interest in cancer immunotherapy has rapidly risen since it offers many advantages over traditional approaches, such as high efficiency and prevention of metastasis. Efforts have primarily focused on two major strategies for regulating the body's antitumor immune response mechanisms: "enhanced immunotherapy" that aims to amplify the immune activation, and "normalized immunotherapy" that corrects the defective immune mechanism in the tumor immune microenvironments (TIMEs), which returns to the normal immune trajectory. However, due to the complexity and heterogeneity of the TIMEs, and lack of visualization research on the immunotherapy process, cancer immunotherapy has not been widely used in clinical setting. Recently, through the design and modification of nanomaterials, intelligent TIME-responsive nanoplatforms were developed from which encouraging results in many aspects of immunotherapy have been achieved. In this mini review, the status of designed nanomaterials for nanoplatform-based immune regulation of TIMEs has been emphasized, particularly with respect to the aforementioned approaches. It is envisaged that future prospects will focus on a combination of multiple immunotherapies for more efficient cancer inhibition and elimination.