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BackgroundOvarian cancer remains a formidable challenge in oncology, necessitating innovative therapeutic approaches. Claudin-6 (CLDN6), a member of the tight junction molecule CLDN family, exhibits negligible expression in healthy tissues but displays aberrant upregulation in various malignancies, including ovarian cancer. Although several therapeutic modalities targeting CLDN6 are currently under investigation, there is still a need for more potent therapeutic options. While T-cell engagers (TCEs) hold substantial promise as potent immunotherapeutic agents, their current efficacy and safety in terms of target antigen selection and T-cell exhaustion due to only CD3 stimulation without co-stimulation must be improved, particularly against solid tumors. To provide an efficacious treatment option for ovarian cancer, we generated SAIL66, a tri-specific antibody against CLDN6/CD3/CD137.MethodsUsing our proprietary next-generation TCE technology (Dual-Ig), SAIL66 was designed to bind to CLDN6 with one Fab and CD3/CD137 with the other, thereby activating T cells through CD3 activation and CD137 co-stimulation. The preclinical characterization of SAIL66 was performed in a series of in vitro and in vivo studies which included comparisons to a conventional TCE targeting CLDN6 and CD3.ResultsDespite the high similarity between CLDN6 and other CLDN family members, SAIL66 demonstrated high specificity for CLDN6, reducing the risk of off-target toxicity. In an in vitro co-culture assay with CLDN6-positive cancer cells, we confirmed that SAIL66 strongly activated the CD137 signal in the Jurkat reporter system, and preferentially induced activation of both CD4+ and CD8+ T cells isolated from human peripheral blood mononuclear cells compared to conventional TCEs. In vivo studies demonstrated that SAIL66 led to a more pronounced increase in intratumor T-cell infiltration and a decrease in exhausted T cells compared with conventional CLDN6 TCE by contribution of CD137 co-stimulation, resulting in better antitumor efficacy in tumor-bearing mouse models.ConclusionOur data demonstrate that SAIL66, designed to engage CLDN6, CD3, and CD137, has the potential to enhance antitumor activity and provide a potent therapeutic option for patients with ovarian and other solid tumors expressing CLDN6. Clinical trials are currently underway to evaluate the safety and efficacy of SAIL66.

Background Fibrosis is a hallmark of organ failure observed after chronic epithelial injury and inflammation. The transforming growth factor beta (TGF-β) is the master regulator of fibrogenesis, so blockade of the TGF-β pathway is a potential treatment strategy for fibrosis; however, the therapeutic potential of pan-TGF-β blockade is limited by side effects. Methods We generated SOF10, a humanized antibody that targets latent TGF-β1 and selectively blocks protease- and integrin αvβ8-mediated latent TGF-β1 activation. We conducted gene expression and histological analyses in nonalcoholic steatohepatitis (NASH)/liver fibrosis and renal interstitial fibrosis models. We also evaluated the combination effect of SOF10 with an immune checkpoint inhibitor in a syngeneic mouse model and performed safety studies in mice and monkeys. Results Here we show that SOF10 reduces fibrosis in NASH/liver fibrosis and renal interstitial fibrosis models and improves renal function in a chronic kidney disease model. Furthermore, the combination of SOF10 with an anti-PD-L1 antibody decreases tumor growth in a syngeneic mouse model. SOF10 demonstrates safety in both mice and monkeys. Conclusions Selective blockade of latent TGF-β1 activation represents a promising approach for treating a broad range of fibrotic diseases and cancers. By specifically targeting TGF-β1, SOF10 may offer a safer and more effective therapeutic option compared to non-selective TGF-β inhibitors. This strategy has the potential to transform the treatment paradigm for fibrosis-related conditions. Plain language summary Fibrosis, the excessive scarring of tissues, contributes to organ failure in many diseases. While increased amounts of a protein called TGF-β can encourage development of fibrosis, complete removal of its activity causes harmful side effects. We developed a protein called SOF10 that selectively blocks only some of the activities of TGF-β1. In our studies, SOF10 reduced scarring in models of liver and kidney disease, improved kidney function, and enhanced cancer treatment when combined with immunotherapy treatments. Importantly, SOF10 proved safe in both mice and monkeys. This selective approach to blocking TGF-β1 activity could be a promising strategy for treating various fibrotic diseases and cancers with fewer side effects than complete TGF-β blockade. Our findings could lead to new treatment options for patients suffering from chronic organ damage and certain cancers. Kanamori, Sato et al. develop SOF10, a humanized antibody that selectively blocks protease- and integrin αvβ8-mediated latent TGF-β1 activation. This selective blockade reduces fibrosis in multiple disease models, improves renal function, enhances anti-tumor immunity, and demonstrates safety in preclinical studies.

The first cases of human infection with the avian influenza A(H7N9) virus were identified in China in early 2013. This report describes findings for 139 persons with confirmed H7N9 virus infection through December 1, 2013. The first identified cases of human infection with a novel influenza A(H7N9) virus occurred in eastern China during February and March 2013 and were characterized by rapidly progressive pneumonia, respiratory failure, the acute respiratory distress syndrome (ARDS), and fatal outcomes. 1 We analyzed available data from field investigations to characterize the descriptive epidemiology of laboratory-confirmed cases of avian influenza A(H7N9) virus infection in humans that were reported to the Chinese Center for Disease Control and Prevention (China CDC) as of December 1, 2013. In this report, we summarize the epidemiologic findings of case investigations and follow-up monitoring of close contacts of . . .

ObjectiveWe investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS).MethodsN-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses.ResultsAmong 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker.ConclusionMR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS.

Biomass-derived cellulose hybrid composite materials are promising for application in the field of photocatalysis due to their excellent properties. The excellent properties between biomass-derived cellulose and photocatalyst materials was induced by biocompatibility and high hydrophilicity of the cellulose components. Biomass-derived cellulose exhibited huge amount of electron-rich hydroxyl group which could promote superior interaction with the photocatalyst. Hence, the original sources and types of cellulose, synthesizing methods, and fabrication cellulose composites together with applications are reviewed in this paper. Different types of biomasses such as biochar, activated carbon (AC), cellulose, chitosan, and chitin were discussed. Cellulose is categorized as plant cellulose, bacterial cellulose, algae cellulose, and tunicate cellulose. The extraction and purification steps of cellulose were explained in detail. Next, the common photocatalyst nanomaterials including titanium dioxide (TiO2), zinc oxide (ZnO), graphitic carbon nitride (g-C3N4), and graphene, were introduced based on their distinct structures, advantages, and limitations in water treatment applications. The synthesizing method of TiO2-based photocatalyst includes hydrothermal synthesis, sol-gel synthesis, and chemical vapor deposition synthesis. Different synthesizing methods contribute toward different TiO2 forms in terms of structural phases and surface morphology. The fabrication and performance of cellulose composite catalysts give readers a better understanding of the incorporation of cellulose in the development of sustainable and robust photocatalysts. The modifications including metal doping, non-metal doping, and metal–organic frameworks (MOFs) showed improvements on the degradation performance of cellulose composite catalysts. The information and evidence on the fabrication techniques of biomass-derived cellulose hybrid photocatalyst and its recent application in the field of water treatment were reviewed thoroughly in this review paper.

This study produced a novel polysulfone (PSF) membrane for dye removal using lemon-derived carbon quantum dots-grafted silver nanoparticles (Ag/CQDs) as membrane nanofiller. The preparation of CQDs was completed by undergoing hydrothermal treatment to carbonize the pulp-free lemon juice into CQD solution. The CQD solution was then coupled with Ag nanoparticles to form Ag/CQDs nanohybrid. The synthesized powders were characterized in terms of morphologies, functional groups and surface charges. A set of membranes was fabricated with different loadings of Ag/CQDs powder using the nonsolvent-induced phase separation (NIPS) method. The modified membranes were studied in terms of morphology, elemental composition, hydrophilicity and pore size. In addition, pure water flux, rejection test and fouling analysis of the membranes were evaluated using tartrazine dye. From the results, 0.5 wt % of Ag/CQD was identified as the optimum loading to be incorporated with the pristine PSF membrane. The modified membrane exhibited an excellent pure water permeability and dye rejection with improvements of 169% and 92%, respectively. In addition, the composite membrane also experienced lower flux decline, higher reversible fouling and lower irreversible fouling. This study has proven that the addition of CQD additives into membrane greatly improves the polymeric membrane’s properties and filtration performance.

Severe to profound sensorineural hearing loss seriously affects the communication and cognitive ability of the patients. Cochlear implantation (CI) is currently the most effective treatment, while it may damage the remaining inner ear function due to its poor biocompatibility and the resultant fibrosis. Herein, a porous methacrylated poly(dimethylsiloxane) (MA‐PDMS)‐coated cochlear electrode is presented for CI and hearing protection. The porous MA‐PDMS is filled with a hybrid hydrogel system made of dexamethasone sodium phosphate (Dex), Ti3C2Tx MXene (MXene), and methacrylate gelatin (GelMA). The coating shows good biocompatibility and drug loading and release capacity in vitro, protective effects on hair cells (HCs) and spiral ganglion neurons (SGNs) of the inner ear, as well as the residual hearing protection and the effective fibrosis reduction in vivo. It is anticipated that this porous electrode drug‐loading coating may provide a valuable reference strategy for the future cochlear electrode transplantation system. This study presents a novel porous drug‐loading coating for cochlear electrodes, utilizing MA‐PDMS infused with GelMA hydrogel containing dexamethasone and MXene nanoparticles. The coating enhances biocompatibility, enables sustained drug release, reduces fibrosis, and preserves residual hearing post‐CI. This approach offers a promising strategy for improving cochlear electrode design and clinical outcomes.

Background Retinal imaging features, and blood-based biomarkers may provide insights into cognitive neuropathology. However, the combined utility of retinal imaging features, and blood-based biomarkers for predicting cognitive decline remains under-investigated. Methods A cohort of memory-clinic subjects (age 71.86 ± 7.91 years, 48.4% male) were followed for 5 years, with annual Clinical Dementia Rating Scale Sum-of-Boxes(CDR-SB) assessments. Cognitive decline was defined as a CDR-SB ≥ 2 increment from baseline. Elastic net regression of 71 multimodal variables for predicting cognitive decline was performed comprising:8 clinical factors, 50 retinal fundoscopic features, and 13 blood-based biomarkers (Ergothioneine, pTau-181, NfL, insulin, leptin, IL-6, IL-8, TNF, NGF, thrombomodulin, GDF-15, hs-cTnT and NT-proBNP). This yielded a set of 13 variables(4 clinical factors, 5 blood-based biomarkers, and 4 retinal fundoscopic indices) which was used for model construction. Predictive models for cognitive decline were built using:1)Clinical variables, 2)Clinical+Retinal variables 3)Clinical+Blood variables, and 4)Clinical+Retinal+Blood variables. Predictive performance for cognitive decline was evaluated using cross-validated AUROC(area under receiver operating characteristic curve). Results Here we show, of 306 subjects followed-up for 60.0 months [Interquartile range 48.0–60.0], 104 (33.9%) display cognitive decline. The AUROC of the clinical model for cognitive decline is 0.691[0.629-0.754]. The addition of retinal features to the clinical model does not provide additive risk stratification(AUROC 0.680, [0.616-0.743],p = 0.486), but the addition of blood-based biomarkers improves the discriminative ability of the clinical model for cognitive decline(AUROC 0.748,[0.691-0.754],p = 0.016). A combination of clinical+retinal+blood variables yields the highest predictive ability for cognitive decline(AUROC 0.752 [0.695-0.809]). Conclusions A multimodal model comprising blood, retinal and clinical variables may represent an accessible, non-invasive tool for predicting cognitive decline. Plain language summary Combining clinical, retinal and blood-based biomarkers for the prediction of cognitive decline has not been previously explored. We examined this in a longitudinal Asian memory clinic cohort of 306 subjects, with 104 incident cases of cognitive decline, followed up for 5 years. Supervised machine learning was used to develop predictive models for cognitive decline, using 71 baseline predictor variables (8 clinical variables, 13 blood-based biomarkers, and 50 retinal fundoscopic features). We found that a predictive model combining retinal, blood-based and clinical variables yielded the greatest prediction for cognitive decline. However, a combination of clinical, and blood-based biomarkers achieved a desirable balance between predictive performance and resource utilisation. Our findings suggest future scalable models for the prediction of cognitive decline. Sim, Tham et al. explore the combined predictive ability of clinical, retinal, and blood biomarkers for the prediction of cognitive decline in Southeast Asian memory clinic participants. Authors find that combining blood tests, eye markers, and clinical data may be a potential noninvasive tool for early risk detection for cognitive decline.

Background The association between platelet endothelial cell adhesion molecule‐1 (PECAM‐1) with cerebral small vessel disease (CSVD) and cognition in non‐demented subjects remains un‐investigated. Method A longitudinal, prospective cohort of subjects recruited from memory clinics was followed‐up for 5 years. Non‐demented subjects were included and classified as no cognitive impairment (NCI) or mild cognitive impairment (MCI). Annual neuropsychological assessments and 2‐yearly magnetic resonance imaging (MRI) scans were performed. The associations of baseline circulating plasma PECAM‐1 levels with neuroimaging markers of CSVD, cognitive decline (Montreal Cognitive Assessment [MoCA] scores and executive function Z‐scores), and conversion to dementia were evaluated. Result Of 213 subjects (age 70.2±7.7 years, 51.2% male, 122 (57.3%) NCI, and 91 (42.7%) MCI), median PECAM‐1 levels were 0.790 [IQR 0.645‐0.955] ng/ml). Compared with the highest tertile, subjects within the lowest PECAM‐1 tertile had higher age‐related white matter changes scores (first tertile: β 1.50, 95% C.I. 0.23‐2.77, p=0.02) and cerebral microbleeds (first tertile: Adjusted risk ratio [ARR] 2.59, 95% C.I. 1.81‐3.72, p<0.0001). PECAM‐1 levels were not associated with baseline MOCA and executive function. Of the 204 participants with follow‐up data (median 60.0 [IQR 60.0‐60.0] months), 24 (11.8) had incident dementia. Compared with the highest tertile, subjects within the lower tertiles of PECAM‐1 were independently associated with higher risk of incident dementia (first tertile: Adjusted Hazard Ratio [AHR] 4.18, 95% C.I. 1.26‐13.93, p=0.020; second tertile: AHR 3.45, 95% C.I. 1.07‐11.14, p=0.038, Figure 1). The lowest PECAM‐1 tertile was associated with greater 4‐year progression of cerebral microbleeds (Incident Relative Risk [IRR] 2.44, 95% C.I. 1.20‐4.98, p=0.014), and decline in executive function (β ‐0.43, 95% C.I. ‐0.73, ‐0.14, p=0.004), and MoCA (β ‐1.32, 95% C.I. ‐2.30, ‐0.35, p=0.008) scores. Conclusion In non‐demented subjects, lower circulating PECAM‐1 levels are associated with greater CSVD progression, cognitive decline, and incident dementia. PECAM‐1 may be a potential therapeutic target for CSVD and cognitive decline.

Tick species distribution and prevalence of spotted fever group Rickettsiae (SFGR) in ticks were investigated in Zhejiang Province, China in 2010 and 2011. PCR was used to detect SFGR and positive amplicons were sequenced, compared to published sequences and phylogenic analysis was performed using MEGA 4.0. A total of 292 adult ticks of ten species were captured and 7.5 % (22/292) of the ticks were PCR-positive for SFG Rickettsia. The PCR-positive rates were 5.5 % (6/110) for Haemaphysalis longicornis, 3.6 % (1/28) for Amblyomma testudinarium and 16 % (15/94) for Ixodes sinensis, respectively. Phylogenetic analyses of gltA genes detected in ticks indicated that there are two dominating groups of SFGR. Sequences of group one were closely related to Rickettsia monacensis, whereas sequences of group two were closest related to Rickettsia heilongjiangensis and Rickettsia japonica, which are human pathogens. Our findings underline the importance of these ticks in public health surveillance in Zhejiang Province, China.