Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires.

The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors. When sequentially immunized with modified gp120 glycoproteins designed to engage VRC01 germline and intermediate antibodies, IGHV1-2(∗)02-rearranging mice, which also express a VRC01-antibody precursor light chain, can support the affinity maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages.

Structural basis of malaria RIFIN binding by LILRB1-containing antibodies.

Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)-variant surface antigens that are expressed on infected erythrocytes1-bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies2,3. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to ß2 microglobulin and RIFINs through their apical domains4,5. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable-constant (VH-CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN-LILRB1 D3 interaction that is similar to that of RIFIN-LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH-CH1 elbow without affecting VH-VL or CH1-CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH-CH1 elbow.

Southward propagation of Nazca subduction along the Andes.

The Andean margin is the plate-tectonic paradigm for long-lived, continuous subduction, yet its geology since the late Mesozoic era (the past 100 million years or so) has been far from steady state. The episodic deformation and magmatism have been attributed to cyclic changes in the dip angle of the subducting slab, slab break-off and the penetration of the slab into the lower mantle; the role of plate tectonics remains unclear, owing to the extensive subduction of the Nazca-Farallon plate (which has resulted in more than 5,500 kilometres of lithosphere being lost to the mantle). Here, using tomographic data, we recreate the plate-tectonic geometry of the subducted Nazca slab, which enables us to reconstruct Andean plate tectonics since the late Mesozoic. Our model suggests that the current phase of Nazca subduction began at the northern Andes (5° S) during the late Cretaceous period (around 80 million years ago) and propagated southwards, reaching the southern Andes (40° S) by the early Cenozoic era (around 55 million year ago). Thus, contrary to the current paradigm, Nazca subduction has not been fully continuous since the Mesozoic but instead included episodic divergent phases. In addition, we find that foredeep sedimentation and the initiation of Andean compression are both linked to interactions between the Nazca slab and the lower mantle, consistent with previous modelling.

The use of multicomponent reactions in the development of bis-boronic acids for the detection of ß-sialic acid.

Sialic acid (SA) is a naturally occurring monosaccharide found in glycoproteins and glycolipids. Changes in the expression of SA are associated with several diseases; thus, the detection of SA is of great significance for biological research, cancer diagnosis, and treatment. Boronic acid analogs have emerged as a promising tool for detecting sugars such as SA due to its reversible covalent bonding ability. In this study, 11 bis-boronic acid compounds and 2 mono-boronic acid compounds were synthesized via a highly efficient Ugi-4CR strategy. The synthesized compounds were subjected to affinity fluorescence binding experiments to evaluate their binding capability to SA. Compound A1 was shown to have a promising binding constant of 2602 ± 100 M-1 at pH = 6.0. Density Functional Theory (DFT) calculations examining the binding modes between A1 and SA indicated that the position of the boronic acid functional group was strongly correlated with its interaction with SA's α-hydroxy acid unit. The DFT calculations were consistent with the observations from the fluorescence experiments, demonstrating that the number and relative positions of the boronic acid functional groups are critical factors in enhancing the binding affinity to SA. DFT calculations of both S and R configuration of A1 indicated that the effect of the S/R configuration of A1 on its binding with ß-sialic acid was insignificant as the Ugi-4CR generated racemic products. A fluorine atom was incorporated into the R2 substituent of A1 as an electron-withdrawing group to produce A5, which possessed a significantly higher capability to bind to SA (Keq = 7015 ± 5 M-1 at pH = 6.0). Finally, A1 and A5 were shown to possess exceptional binding selectivity toward ß-sialic acid under pH of 6.0 and 6.5 while preferring to bind with glucose, fructose, and galactose under pH of 7.0 and 7.5.

An in vivo method for diversifying the functions of therapeutic antibodies.

V(D)J recombination generates mature B cells that express huge repertoires of primary antibodies as diverse immunoglobulin (Ig) heavy chain (IgH) and light chain (IgL) of their B cell antigen receptors (BCRs). Cognate antigen binding to BCR variable region domains activates B cells into the germinal center (GC) reaction in which somatic hypermutation (SHM) modifies primary variable region-encoding sequences, with subsequent selection for mutations that improve antigen-binding affinity, ultimately leading to antibody affinity maturation. Based on these principles, we developed a humanized mouse model approach to diversify an anti-PD1 therapeutic antibody and allow isolation of variants with novel properties. In this approach, component Ig gene segments of the anti-PD1 antibody underwent de novo V(D)J recombination to diversify the anti-PD1 antibody in the primary antibody repertoire in the mouse models. Immunization of these mouse models further modified the anti-PD1 antibodies through SHM. Known anti-PD1 antibodies block interaction of PD1 with its ligands to alleviate PD1-mediated T cell suppression, thereby boosting antitumor T cell responses. By diversifying one such anti-PD1 antibody, we derived many anti-PD1 antibodies, including anti-PD1 antibodies with the opposite activity of enhancing PD1/ligand interaction. Such antibodies theoretically might suppress deleterious T cell activities in autoimmune diseases. The approach we describe should be generally applicable for diversifying other therapeutic antibodies.

Genetic and molecular determinants of polymicrobial interactions in Fusobacterium nucleatum.

A gram-negative colonizer of the oral cavity, Fusobacterium nucleatum not only interacts with many pathogens in the oral microbiome but also has the ability to spread to extraoral sites including placenta and amniotic fluid, promoting preterm birth. To date, however, the molecular mechanism of interspecies interactions-termed coaggregation-by F. nucleatum and how coaggregation affects bacterial virulence remain poorly defined. Here, we employed genome-wide transposon mutagenesis to uncover fusobacterial coaggregation factors, revealing the intertwined function of a two-component signal transduction system (TCS), named CarRS, and a lysine metabolic pathway in regulating the critical coaggregation factor RadD. Transcriptome analysis shows that CarR modulates a large regulon including radD and lysine metabolic genes, such as kamA and kamD, the expression of which are highly up-regulated in the ΔcarR mutant. Significantly, the native culture medium of ΔkamA or ΔkamD mutants builds up abundant amounts of free lysine, which blocks fusobacterial coaggregation with streptococci. Our demonstration that lysine-conjugated beads trap RadD from the membrane lysates suggests that lysine utilizes RadD as its receptor to act as a metabolic inhibitor of coaggregation. Lastly, using a mouse model of preterm birth, we show that fusobacterial virulence is significantly attenuated with the ΔkamA and ΔcarR mutants, in contrast to the enhanced virulence phenotype observed upon diminishing RadD (ΔradD or ΔcarS mutant). Evidently, F. nucleatum employs the TCS CarRS and environmental lysine to modulate RadD-mediated interspecies interaction, virulence, and nutrient acquisition to thrive in the adverse environment of oral biofilms and extraoral sites.

Calreticulin, a potential coregulator of immune checkpoints and biomarker associated with tumor microenvironment and clinical prognostic significance in breast invasive carcinoma.

As a promising immune checkpoint of immunogenic cell death (ICD) and multifunctional calcium-binding molecular chaperone, calreticulin (CALR) has been attracting increasing attention. CALR mainly locates in cellular endoplasmic reticulum and significantly affects cell proliferation, invasion, induction of apoptosis, and angiogenesis in breast invasive carcinoma (BRCA). CALR overexpression might be correlated with a worse outcome. Nonetheless, it remains obscure how CALR correlates with immune infiltration and survival prognosis of BRCA. In this study, we investigated CALR expression utilizing RNAseq data from the cancer genome atlas (TCGA) and genotype-tissue expression (GTEx) database. The prognostic value of CALR was analyzed using clinical survival data. Enrichment analysis was conducted using the R package "clusterProfiler." We downloaded the immune cell infiltration score of TCGA samples from published articles and online databases and performed a correlation analysis between immune cell infiltration levels and CALR expression. We further assessed the association between CALR and immunomodulators. Moreover, we also evaluated the expression of CALR in 100 formalin-fixed and paraffin-embedded breast cancer and adjacent normal breast tissue specimens. Our results found that CALR was highly expressed in BRCA, and CALR expression levels differed in pathological stages, T stages, and N stages. Besides, these results suggested that CALR overexpression may have adverse effects on the progression-free interval (PFI) and disease-free interval (DFI), which may be related to tumor proliferation, invasion, and metastasis, leading to tumor deterioration. Meanwhile, immune cell infiltration analysis revealed a correlation between the expression of CALR and the number of neutrophils and dendritic cells, suggesting that CALR was highly correlated with many immunomodulators in BRCA. Our results provide potential biomarkers of CALR in BRCA. CALR may interact synergistically with other immunomodulators to regulate the immune microenvironment, which could be utilized to develop new immunotherapy drugs.

Organocatalytic Si-CAryl Bond Functionalization-Enabled Atroposelective Synthesis of Axially Chiral Biaryl Siloxanes.

Chiral organosilanes are valuable chemical entities in the development of functional organic materials, asymmetric catalysis, and medicinal chemistry. As an important strategy for constructing chiral organosilanes, the asymmetric functionalization of the Si-CAryl bond typically relies on transition-metal catalysis. Herein, we present an efficient method for atroposelective synthesis of biaryl siloxane atropisomers via organocatalytic Si-C bond functionalization of dinaphthosiloles with silanol nucleophiles. The reaction proceeds through an asymmetric protonation and simultaneous Si-C bond cleavage/silanolysis sequence in the presence of a newly developed chiral Brønsted acid catalyst. The versatile nature of the Si-C bond streamlines the derivatization of axially chiral products into other functional atropisomers, thereby expanding the applicability of this method.

Molecular characterization, biological function, tumor microenvironment association and clinical significance of m6A regulators in lung adenocarcinoma.

N6-methyladenosine (m6A) modification can regulate a variety of biological processes. However, the implications of m6A modification in lung adenocarcinoma (LUAD) remain largely unknown. Here, we systematically evaluated the m6A modification features in more than 2400 LUAD samples by analyzing the multi-omics features of 23 m6A regulators. We depicted the genetic variation features of m6A regulators, and found mutations of FTO and YTHDF3 were linked to worse overall survival. Many m6A regulators were aberrantly expressed in tumors, among which FTO, IGF2BP3, YTHDF1 and RBM15 showed consistent alteration features across 11 independent cohorts. Besides, the regulator-pathway interaction network demonstrated that m6A modification was associated with various biological pathways, including immune-related pathways. The correlation between m6A regulators and tumor microenvironment was also assessed. We found that LRPPRC was negatively correlated with most tumor-infiltrating immune cells. On the other hand, we established a scoring tool named m6Sig, which was positively correlated with PD-L1 expression and could reflect both the tumor microenvironment characterization and prognosis of LUAD patients. Comparison of CNV between high and low m6Sig groups revealed differences on chromosome 7. Application of m6Sig on an anti-PD-L1 immunotherapy cohort confirmed that the high m6Sig group demonstrated therapeutic advantages and clinical benefits. Our study indicated that m6A modification is involved in many aspects of LUAD and contributes to tumor microenvironment formation. A better understanding of m6A modification will provide more insights into the molecular mechanisms of LUAD and facilitate developing more effective personalized treatment strategies. A web application was built along with this study (http://www.bioinfo-zs.com/luadexpress/).

Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort.

OBJECTIVE: Obesity is a risk factor for knee osteoarthritis (KOA) development and progression. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are indicated for type 2 diabetes mellitus (T2DM) and obesity. However, whether KOA patients can benefit from GLP-1RA therapies has not been sufficiently investigated, especially in the long term. METHODS: The Shanghai Osteoarthritis Cohort study is a prospective, observational, multicentre study of >40 000 adults with clinically diagnosed osteoarthritis aged >45 years in Shanghai. We identified all KOA participants with comorbid T2DM enrolled from 1 January 2011 to 1 January 2017. Primary outcome was incidence of knee surgery after enrolment. Secondary outcomes included pain-relieving medication use, number of intra-articular therapies, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and medial femorotibial joint cartilage thickness. To evaluate the effects of GLP-1RA, we performed before-and-after comparison and comparison with participants who had no GLP-1RA exposure. RESULTS: For an intergroup comparison (non-GLP-1RA vs GLP-1RA), more weight loss (adjusted mean difference in weight change from baseline -7.29 kg (95% CI -8.07 to -6.50 kg), p<0.001) and lower incidence of knee surgery (93/1574 (5.9%) vs 4/233 (1.7%), adjusted p=0.014) were observed in the GLP-1RA group. Statistically significant differences in mean change from baseline for the WOMAC total and pain subscale scores were observed (adjusted mean difference in WOMAC total score -1.46 (95% CI -2.84 to -0.08), p=0.038; adjusted mean difference in WOMAC pain subscore -3.37 (95% CI -5.79 to -0.94), p=0.007). Cartilage-loss velocity of the medial femorotibial joint was significantly lower in the GLP-1RA group postadjustment for baseline characteristics (adjusted mean difference -0.02 mm (95% CI -0.03 to -0.002 mm), p=0.004). For the before-and-after comparison within the GLP-1RA group, we observed a significant decrease of symptom-relieving medication consumption and cartilage loss velocity of medial femorotibial joint (after-treatment vs before-treatment: -0.03±0.05 vs -0.05±0.07 mm/year, p<0.001). The association between GLP-1RA exposure and decreased incidence of knee surgery was mediated by weight reduction (mediation proportion: 32.1%), instead of glycaemic control (too small to calculate). CONCLUSION: With sufficient treatment duration, GLP-1RA therapies might be disease-modifying for KOA patients with comorbid T2DM, possibly mediated by weight loss. Further investigation is needed to elucidate effects of GLP-1RA on disease process, joint structure and patient-reported outcomes of osteoarthritis.

Butein, a potential drug for the treatment of bone cancer pain through bioinformatic and network pharmacology.

Bone cancer pain is a difficult-to-treat pathologic condition that impairs the patient's quality of life. The effective therapy options for BCP are restricted due to the unknown pathophysiology. Transcriptome data were obtained from the Gene Expression Omnibus database and differentially expressed gene extraction was performed. DEGs integrated with pathological targets found 68 genes in the study. Butein was discovered as a possible medication for BCP after the 68 genes were submitted to the Connectivity Map 2.0 database for drug prediction. Moreover, butein has good drug-likeness properties. To collect the butein targets, we used the CTD, SEA, TargetNet, and Super-PRED databases. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed butein's pharmacological effects, indicating that butein may aid in treating BCP by altering the hypoxia-inducible factor, NF-kappa B, angiogenesis, and sphingolipid signaling pathways. Moreover, the pathological targets integrated with drug targets were obtained as the shared gene set A, which was analyzed by ClueGO and MCODE. Biological process analysis and MCODE algorithm further analyzed that BCP related targets were mainly involved in signal transduction process and ion channel-related pathways. Next, we integrated targets related to network topology parameters and targets of core pathways, identified PTGS2, EGFR, JUN, ESR1, TRPV1, AKT1 and VEGFA as butein regulated hub genes by molecular docking, which play a critical role in its analgesic effect. This study lays the scientific groundwork for elucidating the mechanism underlying butein's success in the treatment of BCP.

Synthesizing multi-frame high-resolution fluorescein angiography images from retinal fundus images using generative adversarial networks.

BACKGROUND: Fundus fluorescein angiography (FA) can be used to diagnose fundus diseases by observing dynamic fluorescein changes that reflect vascular circulation in the fundus. As FA may pose a risk to patients, generative adversarial networks have been used to convert retinal fundus images into fluorescein angiography images. However, the available methods focus on generating FA images of a single phase, and the resolution of the generated FA images is low, being unsuitable for accurately diagnosing fundus diseases. METHODS: We propose a network that generates multi-frame high-resolution FA images. This network consists of a low-resolution GAN (LrGAN) and a high-resolution GAN (HrGAN), where LrGAN generates low-resolution and full-size FA images with global intensity information, HrGAN takes the FA images generated by LrGAN as input to generate multi-frame high-resolution FA patches. Finally, the FA patches are merged into full-size FA images. RESULTS: Our approach combines supervised and unsupervised learning methods and achieves better quantitative and qualitative results than using either method alone. Structural similarity (SSIM), normalized cross-correlation (NCC) and peak signal-to-noise ratio (PSNR) were used as quantitative metrics to evaluate the performance of the proposed method. The experimental results show that our method achieves better quantitative results with structural similarity of 0.7126, normalized cross-correlation of 0.6799, and peak signal-to-noise ratio of 15.77. In addition, ablation experiments also demonstrate that using a shared encoder and residual channel attention module in HrGAN is helpful for the generation of high-resolution images. CONCLUSIONS: Overall, our method has higher performance for generating retinal vessel details and leaky structures in multiple critical phases, showing a promising clinical diagnostic value.

Public antibodies to malaria antigens generated by two LAIR1 insertion modalities.

In two previously described donors, the extracellular domain of LAIR1, a collagen-binding inhibitory receptor encoded on chromosome 19 (ref. 1), was inserted between the V and DJ segments of an antibody. This insertion generated, through somatic mutations, broadly reactive antibodies against RIFINs, a type of variant antigen expressed on the surface of Plasmodium falciparum-infected erythrocytes. To investigate how frequently such antibodies are produced in response to malaria infection, we screened plasma from two large cohorts of individuals living in malaria-endemic regions. Here we report that 5-10% of malaria-exposed individuals, but none of the European blood donors tested, have high levels of LAIR1-containing antibodies that dominate the response to infected erythrocytes without conferring enhanced protection against febrile malaria. By analysing the antibody-producing B cell clones at the protein, cDNA and gDNA levels, we characterized additional LAIR1 insertions between the V and DJ segments and discovered a second insertion modality whereby the LAIR1 exon encoding the extracellular domain and flanking intronic sequences are inserted into the switch region. By exon shuffling, this mechanism leads to the production of bispecific antibodies in which the LAIR1 domain is precisely positioned at the elbow between the VH and CH1 domains. Additionally, in one donor the genomic DNA encoding the VH and CH1 domains was deleted, leading to the production of a camel-like LAIR1-containing antibody. Sequencing of the switch regions of memory B cells from European blood donors revealed frequent templated inserts originating from transcribed genes that, in rare cases, comprised exons with orientations and frames compatible with expression. These results reveal different modalities of LAIR1 insertion that lead to public and dominant antibodies against infected erythrocytes and suggest that insertion of templated DNA represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering.

Elevated Serum Aspergillus Fumigatus-Specific Immunoglobulin G in Type 2 Chronic Rhinosinusitis.

Background: Aspergillus fumigatus-specific immunoglobulin G (Af-sIgG) has been applied to diagnose allergic bronchopulmonary aspergillosis, a hypersensitivity reaction to the colonization of the fungus in the lower airways. In the upper airways, it has been reported to be involved in allergic fungal rhinosinusitis and local fungal rhinosinusitis. However, in primary chronic rhinosinusitis (CRS), a more common upper airway disease, the role of Af-sIgG remains unclear. Objective: The aim of our study was to investigate the role of serum Af-sIgG levels in primary CRS patients. Methods: We prospectively recruited patients diagnosed with bilateral primary CRS and patients with nasal septal deviation as the non-CRS group. Patients in the primary CRS group were further classified into two endotypes, including type 2 (T2) and non-T2 groups. Serum samples collected were sent for Af-sIgG analysis. Potential factors and surgical outcomes were analyzed. Results: Forty-eight patients with a diagnosis of primary CRS (including 28 with T2 and 20 with non-T2 CRS) and 22 patients in the non-CRS group were recruited. The T2 CRS group had significantly higher serum Af-sIgG levels than the non-T2 CRS group (odds ratio 10.2 with Af-sIgG more than 27.6 mg/L; p < 0.001). Further multivariate logistic regression showed that the serum Af-sIgG level was the independent factor for early disease recurrence within one year in primary CRS patients. The optimal cutoff value of the serum Af-sIgG level to predict postoperative recurrence was 27.1 mg/L (odds ratio 15.1, p = 0.013). Conclusions: We suggest that the serum Af-sIgG level is a practical marker to detect T2 inflammation and the surgical outcome of primary CRS. By applying this feasible test, we may be able to achieve optimal treatment for every individual with primary CRS. This study may provide physicians with a reference for future clinical applications in dealing with primary CRS.

Salvage boron neutron capture therapy for pediatric patients with recurrent diffuse midline glioma.

PURPOSE: Pediatric diffuse malignant glioma located in the brainstem was officially named "diffuse midline glioma" (DMG) by the World Health Organization in 2016. For this disease, radical surgery is not beneficial, and the only major treatment strategy is radiotherapy. However, the dose limitations to brainstem tissue mean that treatment by radiotherapy can only control and not eradicate the tumors, and there is no effective treatment for recurrence, resulting in short overall survival of 6-12 months. This paper reports our experience with boron neutron capture therapy (BNCT), a new treatment process, and its efficacy in treating children with recurrent DMG. METHODS: From September 2019 to July 2022, we treated 6 children affected by recurrent DMG. With the collaboration of Taipei Veteran General Hospital (TVGH) and National Tsing-Hua University (NTHU), each patient received two sessions of BNCT within 1 month. RESULTS: Among the six patients, three showed partial response and the rest had stable disease after the treatment. The overall survival and recurrence-free survival duration after treatment were 6.39 and 4.35 months, respectively. None of the patients developed severe side effects, and only one patient developed brain necrosis, which was most likely resulted from previous hypofractionated radiotherapy received. CONCLUSION: BNCT elicited sufficient tumor response with low normal tissue toxicity; it may benefit vulnerable pediatric patients with DMG.

Brain and Spinal Tumors Originating from the Germ Line Cells.

Primary central nervous system germ cell tumors (CNS GCTs) are part of the GCTs in children and adults. This tumor entity presents with geographic variation, age, and sex predilection. There are two age peaks of incidence distribution at the first few months of life and in adolescence. CNS GCTs are heterogeneous in histopathological subtypes, locations, and tumor marker (AFP, ß-hCG) secretions. In the WHO CNS tumor classification, GCTS are classified as germinoma and nongerminomatous GCT (NGGCT) with different subtypes (including teratoma). Excluding mature teratoma, the remaining NGGCTs are malignant (NGMGCT). In teratoma, growing teratoma syndrome and teratoma with somatic-type malignancy should be highlighted. The common intracranial locations are pineal region, neurohypophysis (NH), bifocal pineal-NH, basal ganglia, and cerebral ventricle. Above 50% of intracranial GCTs (IGCTs) present obstructive hydrocephalus. Spinal tumors are rare. Age, locations, hydrocephalus, and serum/CSF titer of ß-hCG correlate with clinical manifestations. Delayed diagnosis is common in tumors arising in neurohypophysis, bifocal, and basal ganglia resulting in the increasing of physical dysfunction and hormonal deficits. Staging work-up includes CSF cytology for tumor cells and contrast-enhanced MRI of brain and spine for macroscopic metastasis before treatment commences. The therapeutic approach of CNS GCTs integrates locations, histopathology, staging, tumor marker level, and therapeutic classification. Treatment strategies include surgical biopsy/excision, chemotherapy, radiotherapy (single or combination). Secreting tumors with consistent imaging may not require histopathological diagnosis. Primary germinomas are highly radiosensitive and the therapeutic aim is to maintain high survival rate using optimal radiotherapy regimen with/without chemotherapy combination. Primary NGNGCTs are less radiosensitive. The therapeutic aim is to increase survival utilizing more intensive chemotherapy and radiotherapy. The negative prognostic factors are residue disease at the end of treatment and serum or CSF AFP level >1000 ng/mL at diagnosis. In refractory or recurrent NMGGCTs, besides high-dose chemotherapy, new therapy is necessary. Molecular profiling and analysis help for translational research. Survivors of pediatric brain tumors frequently experience cancer-related cognitive dysfunction, physical disability, pituitary hormone deficiency, and other CNS complications after cranial radiotherapy. Continuous surveillance and assessment may lead to improvements in treatment protocols, transdisciplinary interventions, after-treatment rehabilitation, and quality of life.

Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models.

HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1-infected individuals, bnAbs evolved from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar antibody maturation process. One way to test a vaccine is to immunize mouse models that express human bnAb precursors and assess whether the vaccine can convert precursor antibodies into bnAbs. A major problem with such mouse models is that bnAb expression often hinders B cell development. Such developmental blocks may be attributed to the unusual properties of bnAb variable regions, such as poly-reactivity and long antigen-binding loops, which are usually under negative selection during primary B cell development. To address this problem, we devised a method to circumvent such B cell developmental blocks by expressing bnAbs conditionally in mature B cells. We validated this method by expressing the unmutated common ancestor (UCA) of the human VRC26 bnAb in transgenic mice. Constitutive expression of the VRC26UCA led to developmental arrest of B cell progenitors in bone marrow; poly-reactivity of the VRC26UCA and poor pairing of the VRC26UCA heavy chain with the mouse surrogate light chain may contribute to this phenotype. The conditional expression strategy bypassed the impediment to VRC26UCA B cell development, enabling the expression of VRC26UCA in mature B cells. This approach should be generally applicable for expressing other bnAbs that are under negative selection during B cell development.

Acculturation and depressive symptoms among older Chinese immigrants in the United States: the roles of positive and negative social interactions.

Objectives: Immigration is a stressful experience. Social interactions with family members and friends play an important role in the health and well-being of immigrant older adults. This study examined the association between different domains of acculturation and depressive symptoms among older Chinese immigrants in the United States and investigated the roles of positive and negative interactions with family and friends in such associations.Method: We used data from the Population Study of Chinese Elderly (PINE), a population-based survey of community-dwelling Chinese older adults in the Greater Chicago area (N = 3,158). Depressive symptoms were measured by the PHQ-9. Acculturation, positive and negative social interactions with partner/family/friends were all measured by standard scales. Binary logistic regression models were used to examine the relationship between acculturation and the probability of having depressive symptoms.Results: Results showed that only social acculturation was correlated with a higher likelihood of having depressive symptoms after controlling for relevant sociodemographic variables. Results also demonstrated that 'high positive & high negative', as well as 'high positive & low negative' social interactions had significant moderating effects on the association between media acculturation and depressive symptoms.Conclusion: The study findings suggest that although older Chinese immigrants in the United States with high levels of social acculturation are vulnerable to depressive symptoms, high positive social interactions with partner/family/friends buffer the relationship between media acculturation and depressive symptoms. Community services can help with social acculturation and more positive interactions from partner/family/friends to alleviate depressive symptoms among older Chinese immigrants.

Risk Factors for Poor Prognosis in Acute Coronary Syndrome Admitted in the Emergency Department: A Retrospective Cohort Study.

BACKGROUND: In the present study, we aimed to identify risk factors of poor prognosis for patients with acute coronary syndrome in the emergency department. METHODS: The study included 2667 patients, who were admitted to the Emergency Department of Chest Pain Center, Fujian Provincial Hospital, due to chest pain from January 1, 2017 to March 31, 2020. Logistic regression was used to identify factors of poor prognosis for patients with ACS in the ED. Receiver operating characteristic (ROC) curve was plotted to assess the performance of the multivariate logistic regression model. Subgroup analysis was used to analyze the difference of SBP in ACS patients with different characteristics. RESULTS: The final analysis included 2667 patients, of whom 2,057 patients (77.8%) had poor prognosis. STEMI (compared with UA) (OR=20.139; 95% CI:12.448-32.581; P < 0.001), NSTEMI (compared with UA) (OR=7.430; 95% CI:5.159-10.700; P < 0.001), respiratory rate ≥20 bpm (compared with <20 bpm) (OR=1.334; 95% CI: 1.060-1.679; P = 0.014), and use of antiplatelets (OR=1.557; 95% CI:1.181-2.053; P = 0.002) was associated with increased likelihood of poor prognosis for ACS patients in ED. SBP ≥140 mmHg (compared with<140mmHg) (OR=0.574; 95% CI: 0.477-0.690; P < 0.001) was associated with decreased likelihood of poor prognosis for ACS patients in the ED. The area under curve (AUC) of the predictive efficacy of logistic regression model was 0.825 (95% CI: 0.795-0.833, P < 0.001). CONCLUSION: This study found that STEMI, NSTEMI, respiratory rate ≥20 bpm, and use of antiplatelets were associated with increased likelihood of poor prognosis for ACS patients in the ED. It also found that SBP≥140 was associated with decreased likelihood of poor prognosis. Our study may be useful for doctors to make clinical decisions for ACS patients.

Advances in Boron Neutron Capture Therapy (BNCT) for Recurrent Intracranial Meningioma.

Meningiomas are the most frequently diagnosed primary intracranial tumors in adults. Surgical resection is preferred if the meningioma is accessible; for those that are not suitable for surgical resection, radiotherapy should be considered to improve local tumor control. However, recurrent meningiomas are challenging to treat, as the recurrent tumor might be located in the previously irradiated area. Boron Neutron Capture Therapy (BNCT) is a highly selective radiotherapy modality in which the cytotoxic effect focuses mainly on cells with increased uptake of boron-containing drugs. In this article, we describe four patients with recurrent meningiomas treated with BNCT in Taiwan. The mean boron-containing drug tumor-to-normal tissue uptake ratio was 4.125, and the tumor mean dose was 29.414 GyE, received via BNCT. The treatment response showed two stable diseases, one partial response, and one complete response. We also introduce and support the effectiveness and safety of BNCT as an alternative salvage treatment for recurrent meningiomas.