LECT2, a Ligand for Tie1, Plays a Crucial Role in Liver Fibrogenesis.

Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. In vivo studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in Lect2-KO mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.

Multimodeling approach to evaluating the efficacy of layering pharmaceutical and nonpharmaceutical interventions for influenza pandemics.

When an influenza pandemic emerges, temporary school closures and antiviral treatment may slow virus spread, reduce the overall disease burden, and provide time for vaccine development, distribution, and administration while keeping a larger portion of the general population infection free. The impact of such measures will depend on the transmissibility and severity of the virus and the timing and extent of their implementation. To provide robust assessments of layered pandemic intervention strategies, the Centers for Disease Control and Prevention (CDC) funded a network of academic groups to build a framework for the development and comparison of multiple pandemic influenza models. Research teams from Columbia University, Imperial College London/Princeton University, Northeastern University, the University of Texas at Austin/Yale University, and the University of Virginia independently modeled three prescribed sets of pandemic influenza scenarios developed collaboratively by the CDC and network members. Results provided by the groups were aggregated into a mean-based ensemble. The ensemble and most component models agreed on the ranking of the most and least effective intervention strategies by impact but not on the magnitude of those impacts. In the scenarios evaluated, vaccination alone, due to the time needed for development, approval, and deployment, would not be expected to substantially reduce the numbers of illnesses, hospitalizations, and deaths that would occur. Only strategies that included early implementation of school closure were found to substantially mitigate early spread and allow time for vaccines to be developed and administered, especially under a highly transmissible pandemic scenario.

Identification and characterization of novel genetic variants in the first Chinese family of mucopolysaccharidosis IIIC (Sanfilippo C syndrome).

Mucopolysaccharidosis type IIIC (MPS IIIC) is one of inherited lysosomal storage disorders, caused by deficiencies in lysosomal hydrolases degrading acidic mucopolysaccharides. The gene responsible for MPS IIIC is HGSNAT, which encodes an enzyme that catalyses the acetylation of the terminal glucosamine residues of heparan sulfate. So far, few studies have focused on the genetic landscape of MPS IIIC in China, where IIIA and IIIB were the major subtypes. In this study, we utilized whole-exome sequencing (WES) to identify novel compound heterozygous variants in the HGSNAT gene from a Chinese patient with typical MPS IIIC symptoms: c.743G>A; p.Gly248Glu and c.1030C>T; p.Arg344Cys. We performed in silico analysis and experimental validation, which confirmed the deleterious pathogenic nature of both variants, as evidenced by the loss of HGSNAT activity and failure of lysosomal localization. To the best of our knowledge, the MPS IIIC is first confirmed by clinical, biochemical and molecular genetic findings in China. Our study thus expands the spectrum of MPS IIIC pathogenic variants, which is of importance to dissect the pathogenesis and to carry out clinical diagnosis of MPS IIIC. Moreover, this study helps to depict the natural history of Chinese MPS IIIC populations.

SAP deletion promotes malignant insulinoma progression by inducing CXCL12 secretion from CAFs via the CXCR4/p38/ERK signalling pathway.

Malignant insulinoma is an extremely rare type of functioning pancreatic neuroendocrine tumour with a high degree of malignancy and a high incidence of metastasis. However, it is still unclear how malignant insulinomas develop and metastasize. Serum amyloid P component (SAP), a member of the pentraxin protein family, is an acute-phase protein secreted by liver cells. The role of SAP in insulinoma and the related mechanism are still unknown. To determine the effect of SAP on insulinoma, we crossed Rip1-Tag2 mice, which spontaneously develop insulinoma, and SAP knockout (KO) mice to generate Rip1-Tag2;SAP-/- mice. We found that SAP deletion significantly promoted the growth, invasion and metastasis of malignant insulinoma through C-X-C motif chemokine ligand 12 (CXCL12) secreted by cancer-associated fibroblasts (CAFs). Further study showed that SAP deletion promoted CXCL12 secretion by CAFs through the CXCR4/p38/ERK signalling pathway. These findings reveal a novel role and mechanism of SAP in malignant insulinoma and provide direct evidence that SAP may be a therapeutic agent for this disease.

Rapid Initiation of Antiretroviral Therapy with Coformulated Bictegravir, Emtricitabine, Tenofovir Alafenamide Versus Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in HIV-positive Men Who Have Sex with Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with HIV-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400-mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among HIV-positive men who have sex with men (MSM). METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV(400-mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/ml) at 48 weeks per FDA Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression; and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (p < 0.001), respectively, discontinued treatment due to adverse effects, death, or loss to follow-up. The median increase of CD4 count was 181 and 223 cells/µL (p = 0.020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < 0.001). CONCLUSION: BIC/FTC/TAF was more efficacious and safer than EFV(400-mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.

From Sheep Track to Motorway: Supramolecular-Mediated 2D Nanofluidic Channels for Ultrafast Water Transport.

Atomic thick 2D materials hold great potential as building blocks to construct highly permeable membranes, yet the permeability of laminar 2D material membranes is still limited by their irregularity sheep track-like interlayer channels. Herein, a supramolecular-mediated strategy to induce the regular assembly of high-throughput 2D nanofluidic channels based on host-guest interactions is proposed. Inspired by the characteristics of motorways, supramolecular-mediated ultrathin 2D membranes with broad and continuous regular water transport channels are successfully constructed using graphene oxide (GO) as an example. The prepared membrane achieves an ultrahigh water permeability (369.94 LMH bar-1) more than six times higher than that of the original membranes while maintaining dye rejection above 98.5%, which outperforms the reported 2D membranes. Characterization and simulation results show that the introduction of hyaluronate-grafted ß-cyclodextrin not only expands the interlayer channels of GO membranes but also enables the membranes to operate stably under harsh conditions with the help of host-guest interactions. This universal supramolecular assembly strategy provides new opportunities for the preparation of 2D membranes with high separation performance and reliable and stable nanofluidic channels.

Omicron BA.4/5 neutralization and cell-mediated immune responses in relation to baseline immune status and breakthrough infection among PLWH: A follow-up cohort study.

There is a paucity of data on hybrid immunity (vaccination plus breakthrough infection [BI]), especially cell-mediated responses to Omicron among immunosuppressed patients. We aim to investigate humoral and cellular responses to Omicron BA.4/5 among people living with HIV (PLWH) with/without BIs, the most prevalent variant of concern after the reopening of China. Based on our previous study, we enrolled 77 PLWH with baseline immune status of severe acute respiratory syndrome coronavirus 2 specific antibodies after inactivated vaccination. "Correlates of protection," including serological immunoassays, T cell phenotypes and memory B cells (MBC) were determined in PLWH without and with BI, together with 16 PLWH with reinfections. Higher inhibition rate of neutralizing antibodies (NAb) against BA.4/5 was elicited among PLWH with BI than those without. Omicron-reactive IL4+ CD8+ T cells were significantly elevated in PLWH experienced postvaccine infection contrasting with those did not. NAb towards wild type at baseline was associated with prolonged negative conversion time for PLWH whereas intermediate MBCs serve as protecting effectors. We uncovered that hybrid immunity intensified more protection on BA.4/5 than vaccination did. Strengthened surveillance on immunological parameters and timely clinical intervention on PLWH deficient in protection would reduce the severity and mortality in the context of coexistence with new Omicron subvariants.

Near-full-length genome analysis of two novel HIV second recombinant forms in Hebei, China.

The number of individuals infected with HIV-1 among men who have sex with men (MSM) has risen rapidly in recent years in China, and the subtypes CRF01_AE, CRF07_BC, and B, as well as many novel unique recombinant forms (URFs) are prevalent among them. Co-circulation of strains among MSM populations allows the generation of circulating recombinant forms (CRFs) and URFs. In this study, we identified two new URFs from two HIV-1-positive subjects who were infected through homosexual contact in Hebei, China. Analysis of near-full-length genome sequences, using phylogenetic and recombination analysis showed that the two URFs originated from CRF01_AE, CRF07_BC, and B, and CRF01_AE segments in the backbone of the URFs were derived from cluster 4 of CRF01_AE. The CRF07_BC segments of two URFs were clustered with 07BC_N in a phylogenetic tree. The identification of novel URFs with complex genomic structures shows that it is necessary to strengthen surveillance of HIV-1 variants in MSM populations in this region.

Micropollutant rejection by nanofiltration membranes: A mini review dedicated to the critical factors and modelling prediction.

Nanofiltration (NF) membranes, extensively used in advanced wastewater treatment, have broad application prospects for the removal of emerging trace organic micropollutants (MPs). The treatment performance is affected by several factors, such as the properties of NF membranes, characteristics of target MPs, and operating conditions of the NF system concerning MP rejection. However, quantitative studies on different contributors in this context are limited. To fill the knowledge gap, this study aims to assess critical impact factors controlling MP rejection and develop a feasible model for MP removal prediction. The mini-review firstly summarized membrane pore size, membrane zeta potential, and the normalized molecular size (λ = rs/rp), showeing better individual relationships with MP rejection by NF membranes. The Lindeman-Merenda-Gold model was used to quantitatively assess the relative importance of all summarized impact factors. The results showed that membrane pore size and operating pressure were the high impact factors with the highest relative contribution rates to MP rejection of 32.11% and 25.57%, respectively. Moderate impact factors included membrane zeta potential, solution pH, and molecular radius with relative contribution rates of 10.15%, 8.17%, and 7.83%, respectively. The remaining low impact factors, including MP charge, molecular weight, logKow, pKa and crossflow rate, comprised all the remaining contribution rates of 16.19% through the model calculation. Furthermore, based on the results and data availabilities from references, the machine learning-based random forest regression model was trained with a relatively low root mean squared error and mean absolute error of 12.22% and 6.92%, respectively. The developed model was then successfully applied to predict MPs' rejections by NF membranes. These findings provide valuable insights that can be applied in the future to optimize NF membrane designs, operation, and prediction in terms of removing micropollutants.

Hippocampal neurons' cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep.

The hippocampus is essential for consolidating transient experiences into long-lasting memories. Memory consolidation is facilitated by postlearning sleep, although the underlying cellular mechanisms are largely unknown. We took an unbiased approach to this question by using a mouse model of hippocampally mediated, sleep-dependent memory consolidation (contextual fear memory). Because synaptic plasticity is associated with changes to both neuronal cell membranes (e.g., receptors) and cytosol (e.g., cytoskeletal elements), we characterized how these cell compartments are affected by learning and subsequent sleep or sleep deprivation (SD). Translating ribosome affinity purification was used to profile ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different cell populations (whole hippocampus, Camk2a+ neurons, or highly active neurons with phosphorylated ribosomal subunit S6 [pS6+]). We examined how transcript profiles change as a function of sleep versus SD and prior learning (contextual fear conditioning; CFC). While sleep loss altered many cytosolic ribosomal transcripts, CFC altered almost none, and CFC-driven changes were occluded by subsequent SD. In striking contrast, SD altered few transcripts on membrane-bound (MB) ribosomes, while learning altered many more (including long non-coding RNAs [lncRNAs]). The cellular pathways most affected by CFC were involved in structural remodeling. Comparisons of post-CFC MB transcript profiles between sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons and protein synthesis in highly active pS6+ (putative "engram") neurons as biological processes disrupted by SD. These findings provide insights into how learning affects hippocampal neurons and suggest that the effects of SD on memory consolidation are cell type and subcellular compartment specific.

Sleep loss drives acetylcholine- and somatostatin interneuron-mediated gating of hippocampal activity to inhibit memory consolidation.

Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type-specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type-specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss-driven inhibitory gate on hippocampal information processing.

Analysis of complete hydatidiform mole in one twin using traditional and molecular techniques.

A pregnant woman with hydatidiform mole in one twin was misdiagnosed as one of the twins with embryonic arrest. She chose to terminate the pregnancy and developed distant lung metastasis. After chemotherapy, she eventually recovered. This article systematically analyzes the diagnosis and treatment of hydatidiform mole in one twin to increase the awareness and reduce misdiagnosis of the disease.

Carbon Dots Derived from Non-Biomass Waste: Methods, Applications, and Future Perspectives.

Carbon dots (CDs) are luminescent carbon nanoparticles with significant potential in analytical sensing, biomedicine, and energy regeneration due to their remarkable optical, physical, biological, and catalytic properties. In light of the enduring ecological impact of non-biomass waste that persists in the environment, efforts have been made toward converting non-biomass waste, such as ash, waste plastics, textiles, and papers into CDs. This review introduces non-biomass waste carbon sources and classifies them in accordance with the 2022 Australian National Waste Report. The synthesis approaches, including pre-treatment methods, and the properties of the CDs derived from non-biomass waste are comprehensively discussed. Subsequently, we summarize the diverse applications of CDs from non-biomass waste in sensing, information encryption, LEDs, solar cells, and plant growth promotion. In the final section, we delve into the future challenges and perspectives of CDs derived from non-biomass waste, shedding light on the exciting possibilities in this emerging area of research.

Ecological impacts of the expansion of offshore wind farms on trophic level species of marine food chain.

The global demand for renewable energy has resulted in a rapid expansion of offshore wind farms (OWFs) and increased attention to the ecological impacts of OWFs on the marine ecosystem. Previous reviews mainly focused on the OWFs' impacts on individual species like birds, bats, or mammals. This review collected numerous field-measured data and simulated results to summarize the ecological impacts on phytoplankton, zooplankton, zoobenthos, fishes, and mammals from each trophic level and also analyze their interactions in the marine food chain. Phytoplankton and zooplankton are positively or adversely affected by the 'wave effect', 'shading effect', oxygen depletion and predation pressure, leading to a ± 10% fluctuation of primary production. Although zoobenthos are threatened transiently by habitat destruction with a reduction of around 60% in biomass in the construction stage, their abundance exhibited an over 90% increase, dominated by sessile species, due to the 'reef effect' in the operation stage. Marine fishes and mammals are to endure the interferences of noise and electromagnetic, but they are also aggregated around OWFs by the 'reef effect' and 'reserve effect'. Furthermore, the complexity of marine ecosystem would increase with a promotion of the total system biomass by 40% through trophic cascade effects strengthen and resource partitioning alternation triggered by the proliferation of filter-feeders. The suitable site selection, long-term monitoring, and life-cycle-assessment of ecological impacts of OWFs that are lacking in current literature have been described in this review, as well as the carbon emission and deposition.

Disturbed hippocampal histidine metabolism contributes to cognitive impairment induced by recurrent nonsevere hypoglycemia in diabetes.

Hypoglycemia is a common adverse reaction to glucose-lowering treatment. Diabetes mellitus (DM) combined with recurrent nonsevere hypoglycemia (RH) can accelerate cognitive decline. Currently, the metabolic pattern changes in cognition-related brain regions caused by this combined effect of DM and RH (DR) remain unclear. In this study, we first characterized the metabolic profiles of the hippocampus in mice exposed to DR using non-targeted metabolomic platforms. Our results showed that DR induced a unique metabolic pattern in the hippocampus, and several significant differences in metabolite levels belonging to the histidine metabolism pathway were discovered. Based on these findings, in the follow-up experiment, we found that histidine treatment could attenuate the cognitive impairment and rescue the neuronal and synaptic damage induced by DR in the hippocampus, which are closely related to ameliorated mitochondrial injury. These findings provide new insights into the metabolic mechanisms of the hippocampus in the progression of DR, and l-histidine supplementation may be a potential metabolic therapy in the future.

NF-κB Activator 1 downregulation in macrophages activates STAT3 to promote adenoma-adenocarcinoma transition and immunosuppression in colorectal cancer.

BACKGROUND: Adenoma-adenocarcinoma transition is a key feature of colorectal cancer (CRC) occurrence and is closely regulated by tumor-associated macrophages (TAMs) and CD8+ T cells. Here, we investigated the effect of the NF-κB activator 1 (Act1) downregulation of macrophages in the adenoma-adenocarcinoma transition. METHODS: This study used spontaneous adenoma-developing ApcMin/+, macrophage-specific Act1-knockdown (anti-Act1), and ApcMin/+; anti-Act1 (AA) mice. Histological analysis was performed on CRC tissues of patients and mice. CRC patients' data retrieved from the TCGA dataset were analyzed. Primary cell isolation, co-culture system, RNA-seq, and fluorescence-activated cell sorting (FACS) were used. RESULTS: By TCGA and TISIDB analysis, the downregulation of Act1 expression in tumor tissues of CRC patients negatively correlated with accumulated CD68+ macrophages in the tumor. Relative expression of EMT markers in the tumor enriched ACT1lowCD68+ macrophages of CRC patients. AA mice showed adenoma-adenocarcinoma transition, TAMs recruitment, and CD8+ T cell infiltration in the tumor. Macrophages depletion in AA mice reversed adenocarcinoma, reduced tumor amounts, and suppressed CD8+ T cell infiltration. Besides, macrophage depletion or anti-CD8a effectively inhibited metastatic nodules in the lung metastasis mouse model of anti-Act1 mice. CRC cells induced activation of IL-6/STAT3 and IFN-γ/NF-κB signaling and the expressions of CXCL9/10, IL-6, and PD-L1 in anti-Act1 macrophages. Anti-Act1 macrophages facilitated epithelial-mesenchymal-transition and CRC cells' migration via CXCL9/10-CXCR3-axis. Furthermore, anti-Act1 macrophages promoted exhaustive PD1+ Tim3+ CD8+ T cell formation. Anti-PD-L1 treatment repressed adenoma-adenocarcinoma transition in AA mice. Silencing STAT3 in anti-Act1 macrophages reduced CXCL9/10 and PD-L1 expression and correspondingly inhibited epithelial-mesenchymal-transition and CRC cells' migration. CONCLUSIONS: Act1 downregulation in macrophages activates STAT3 that promotes adenoma-adenocarcinoma transition via CXCL9/10-CXCR3-axis in CRC cells and PD-1/PD-L1-axis in CD8+ T cells.

The Role of Inactivated NF-κB in Premature Ovarian Failure.

Premature ovarian failure (POF) is defined as deployment of amenorrhea due to the cessation of ovarian function in a woman younger than 40 years old. The pathologic mechanism of POF is not yet well understood, although genetic aberrations, autoimmune damage, and environmental factors have been identified. The current study demonstrated that NF-κB inactivation is closely associated with the development of POF based on the data from literature and cyclophosphamide (Cytoxan)-induced POF mouse model. In the successfully established NF-κB-inactivated mouse model, the results showed the reduced expression of nuclear p65 and the increased expression of IκBα in ovarian granulosa cells; the reduced numbers of antral follicles; the reduction of Ki-67/proliferating cell nuclear antigen-labeled cell proliferation and enhanced Fas/FasL-dependent apoptosis in granulosa cells; the reduced level of E2 and anti-Müllerian hormone; the decreased expression of follicle-stimulating hormone receptor and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) in granulosa cells, which was reversed in the context of blocking NF-κB signaling with BAY 11-7082; and the decreased expressions of glucose-regulated protein 78 (GRP78), activating transcription factor 6, protein kinase R-like endoplasmic reticulum kinase, and inositol-requiring enzyme 1 in granulosa cells. Dual-luciferase reporter assay demonstrated that p50 stimulated the transcription of GRP78, and NF-κB affected the expression of follicle-stimulating hormone receptor and promoted granulosa cell proliferation through GRP78-mediated endoplasmic reticulum stress. Taken together, these data indicate, for the first time, that the inactivation of NF-κB signaling plays an important role in POF.

Booster shot of inactivated SARS-CoV-2 vaccine induces potent immune responses in people living with HIV.

This study aimed to investigate the immunogenicity to SARS-CoV-2 and evasive subvariants BA.4/5 in people living with HIV (PLWH) following a third booster shot of inactivated SARS-CoV-2 vaccine. We conducted a cross-sectional study in 318 PLWH and 241 healthy controls (HC) using SARS-CoV-2 immunoassays. Vaccine-induced immunological responses were compared before and after the third dose. Serum levels of IgG anti-RBD and inhibition rate of NAb were significantly elevated at the "post-third dose" sampling time compared with the pre-third dose in PLWH, but were relatively decreased in contrast with those of HCs. Induced humoral and cellular responses attenuated over time after triple-dose vaccination. The neutralizing capacity against BA.4/5 was also intensified but remained below the positive inhibition threshold. Seropositivity of SARS-CoV-2-specific antibodies in PLWH was prominently lower than that in HC. We also identified age, CD4 cell counts, time after the last vaccination, and WHO staging type of PLWH as independent factors associated with the seropositivity of antibodies. PLWH receiving booster shot of inactivated vaccines generate higher antibody responses than the second dose, but lower than that in HCs. Decreased anti-BA.4/5 responses than that of WT impede the protective effect of the third dose on Omicron prevalence.

CYD0281, a Bcl-2 BH4 domain antagonist, inhibits tumor angiogenesis and breast cancer tumor growth.

BACKGROUND: B-cell lymphoma 2 (Bcl-2) family proteins are key regulators of apoptosis, which possess four conserved Bcl-2 homologies (BH) domains. Among the BH domains, the BH3 domain is considered as a potent 'death domain' while the BH4 domain is required for anti-apoptotic activity. Bcl-2 can be converted to a pro-apoptotic molecule through the removal or mutation of the BH4 domain. Bcl-2 is considered as an inducer of angiogenesis, which can promote tumor vascular network formation and further afford nutrients and oxygen to promote tumor progression. However, whether disrupting the function of the BH4 domain to convert Bcl-2 into a pro-apoptotic molecule could make Bcl-2 possess the potential for anti-angiogenic therapy remains to be defined. METHODS: CYD0281 was designed and synthesized according to the lead structure of BDA-366, and its function on inducing a conformational change of Bcl-2 was further evaluated via immunoprecipitation (IP) and immunofluorescence (IF) assays. Moreover, the function of CYD0281 on apoptosis of endothelial cells was analyzed via cell viability, flow cytometry, and western blotting assays. Additionally, the role of CYD0281 on angiogenesis in vitro was determined via endothelial cell migration and tube formation assays and rat aortic ring assay. Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, breast cancer cell xenograft tumor on CAM and in mouse models as well as the Matrigel plug angiogenesis assay were used to explore the effects of CYD0281 on angiogenesis in vivo. RESULTS: We identified a novel potent small-molecule Bcl-2-BH4 domain antagonist, CYD0281, which exhibited significant anti-angiogenic effects both in vitro and in vivo, and further inhibited breast cancer tumor growth. CYD0281 was found to induce conformational changes in Bcl-2 through the exposure of the BH3 domain and convert Bcl-2 from an anti-apoptotic molecule into a cell death inducer, thereby resulting in the apoptosis of vascular endothelial cells. CONCLUSIONS: This study has revealed CYD0281 as a novel Bcl-2-BH4 antagonist that induces conformational changes of Bcl-2 to convert to a pro-apoptotic molecule. Our findings indicate that CYD0281 plays a crucial role in anti-angiogenesis and may be further developed as a potential anti-tumor drug candidate for breast cancer. This work also provides a potential anti-angiogenic strategy for breast cancer treatment.

Risk Stratification and Overall Survival Prediction in Advanced Gastric Cancer Patients Based on Whole-Volume MRI Radiomics.

BACKGROUND: The prognosis of advanced gastric cancer (AGC) patients has attracted much attention, but there is a lack of evaluation method. MRI-based radiomics has the potential to evaluate AGC patients' prognosis. PURPOSE: To identify and validate the risk stratification and overall survival (OS) in AGC patients using MRI-based radiomics. STUDY TYPE: Retrospective. SUBJECTS: A total of 233 patients (168 males, 63.6 ± 11.1 years; 65 females, 59.7 ± 11.8 years) confirmed AGC were collected. The data were randomly divided into a training (164) and validation set (69). SEQUENCE: A 3.0 T, axial T2-weighted, diffusion-weighted imaging, and contrast-enhanced T1-weighted (CE-T1WI). ASSESSMENT: Radiologist 1 segmented 233 patients and radiologist 2 segmented randomly 50 patients on CE-T1WI. The risk score (RS) was summed by each sample based on the radiomics features and correlation coefficients. Patients were followed up for 7-67 months (median 41; 138 dead and 95 alive). STATISTICAL TESTS: The intraclass correlation coefficient (ICC) and Kappa value were calculated. Differences in survival analysis were assessed by Kaplan-Meier curves and log-rank test. Cox-regression analysis was performed to identify the radiomics features and clinical indicators associated with OS. The calibration curves were built to assess the model. A two-tailed P value < 0.05 was considered statistically significant. RESULTS: Integrated with age, lymphovascular invasion (LVI) and RS, a survival combined model was built. The area under the curve (AUC) for predicting 3-year and 5-year OS was 0.765 and 0.788 in the training set, 0.757 and 0.729 in the validation set. There was no significant difference between the radiomics model and survival combined model for 3-year (0.690 vs. 0.757, P = 0.425) and 5-year OS (0.687 vs. 729, P = 0.412) in the validation set. The calibration curves showed a high degree of fit for the survival combined model. DATA CONCLUSION: This study established a survival combined model that might help AGC patients in future clinical decision-making. EVIDENCE LEVEL: 33 TECHNICAL EFFICACY: Stage 5.