Reconstructing Solvation Structure by Steric Hindrance-Coordination Push-Pull of Dipolymer-H2O-Zn2+ toward Long-life Aqueous Zinc-Metal Batteries.

Aqueous zinc-metal batteries are prospective energy storge devices due to their intrinsically high safety and cost effectiveness. Yet, uneven deposition of zinc ions in electrochemical reduction and side reactions at the anode interface significantly hinder their development and application. Here, we propose a solvation-interface attenuation strategy enabled by a frustrated tertiary amine amphiphilic dipolymer electrolyte additive. The configuration of superhydrophilic segments with covalently bonded lipophilic spacers enables coupled steric hindrance/coordination, which establishes a balanced push-pull dynamic of dipolymer-H2O-Zn2+. Such interplay reconstructs the solvation structure of Zn2+ and allows the formation of a stable dipolymer-inorganic hybrid solid electrolyte interface (SEI) layer. This SEI layer effectively shields the zinc-metal anode from water and anions, significantly reducing side reactions. In addition, the dipolymer adsorbed at the zinc-metal anode interface regulates the interfacial electrochemical reduction kinetics and ensures uniform zinc deposition. As a result, the Zn-Zn symmetric cells with dipolymer-containing electrolyte exhibit remarkable cycling stability exceeding 5800 h (242 days). The Zn-NVO batteries and Zn-AC hybrid ion supercapacitors also deliver stable cycling for up to 1440 h (60 days) with high-capacity retention over 80%. This research demonstrates the potential to facilitate the development and commercialization of zinc-based energy storage devices.

A neural network-based algorithm for the reconstruction and filtering of single particle trajectory in magnetic particle tracking.

Magnetic particle tracking (MPT) is a recently developed non-invasive measurement technique that has gained popularity for studying dense particulate or granular flows. This method involves tracking the trajectory of a magnetically labeled particle, the field of which is modeled as a dipole. The nature of this method allows it to be used in opaque environments, which can be highly beneficial for the measurement of dense particle dynamics. However, since the magnetic field of the particle used is weak, the signal-to-noise ratio is usually low. The noise from the measuring devices contaminates the reconstruction of the magnetic tracer's trajectory. A filter is then needed to reduce the noise in the final trajectory results. In this work, we present a neural network-based framework for MPT trajectory reconstruction and filtering, which yields accurate results and operates at very high speed. The reconstruction derived from this framework is compared to the state-of-the-art extended Kalman filter-based reconstruction.

The FOXO1/G6PC axis promotes gastric cancer progression and mediates 5-fluorouracil resistance by targeting the PI3K/AKT/mTOR signaling pathway.

Gastric cancer (GC) is a prevalent malignancy of the digestive system. Distant metastasis and chemotherapy resistance are the crucial obstacles to prognosis in GC. Recent research has discovered that the glucose-6-phosphatase catalytic subunit (G6PC) plays an important role in tumor malignant development. However, little evidence has highlighted its role in GC. Herein, through a comprehensive analysis including profiling of tissue samples and functional validation in vivo and in vitro, we identify G6PC as a crucial factor in GC tumorigenesis. Importantly, we found that the FOXO1/G6PC axis could accelerate GC cell proliferation, metastasis, and 5-Fluorouracil (5-FU) resistance by targeting the PI3K/AKT/mTOR signaling pathway, implicating that as a prospective therapeutic approach in GC.

Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non-organ-confined Upper Tract Urothelial Carcinoma.

BACKGROUND: Optimal patient selection for neoadjuvant chemotherapy prior to surgical extirpation is limited by the inaccuracy of contemporary clinical staging methods in high-risk upper tract urothelial carcinoma (UTUC). OBJECTIVE: To investigate whether the detection of plasma circulating tumor DNA (ctDNA) can predict muscle-invasive (MI) and non-organ-confined (NOC) UTUC. DESIGN, SETTING, AND PARTICIPANTS: Plasma cell-free DNA was prospectively collected from chemotherapy-naïve, high-risk UTUC patients undergoing surgical extirpation and sequenced using a 152-gene panel and low-pass whole-genome sequencing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To test for concordance, whole-exome sequencing was performed on matching tumor samples. The performance of ctDNA for predicting MI/NOC UTUC was summarized using the area under a receiver-operating curve, and a variant count threshold for predicting MI/NOC disease was determined by maximizing Youden's J statistic. Kaplan-Meier methods estimated survival, and Mantel-Cox log-rank testing assessed the association between preoperative ctDNA positivity and clinical outcomes. RESULTS AND LIMITATIONS: Of 30 patients enrolled prospectively, 14 were found to have MI/NOC UTUC. At least one ctDNA variant was detected from 21/30 (70%) patients, with 52% concordance with matching tumor samples. Detection of at least two panel-based molecular alterations yielded 71% sensitivity at 94% specificity to predict MI/NOC UTUC. Imposing this threshold in combination with a plasma copy number burden score of >6.5 increased sensitivity to 79% at 94% specificity. Furthermore, the presence of ctDNA was strongly prognostic for progression-free survival (PFS; 1-yr PFS 69% vs 100%, p < 0.001) and cancer-specific survival (CSS; 1-yr CSS 56% vs 100%, p = 0.016). CONCLUSIONS: The detection of plasma ctDNA prior to extirpative surgery was highly predictive of MI/NOC UTUC and strongly prognostic of PFS and CSS. Preoperative ctDNA demonstrates promise as a biomarker for selecting patients to undergo neoadjuvant chemotherapy prior to nephroureterectomy. PATIENT SUMMARY: Here, we show that DNA from upper tract urothelial tumors can be detected in the blood prior to surgical removal of the kidney or ureter. This circulating tumor DNA can be used to predict that upper tract urothelial carcinoma is invasive into the muscular lining of the urinary tract and may help identify those patients who could benefit from chemotherapy prior to surgery.

Eschar dissolution and the immunoregulator effect of keratinase on burn wounds.

At present, enzyme debridement preparation has shown a good curative effect on eschar removal of burn wounds. Keratinase has shown great potential in enzymatic debridement because of its good fibrin-degrading ability. In this study, the debridement of keratinase was examined by using a third degree burn wound model in rats. We observed the wound, and keratinase shortened the time of eschar dissolution after debridement. Histopathology and immunofluorescence staining showed that the eschar in the keratinase group became thinner, inflammatory cell infiltration in the wound increased, the fluorescence intensity of the macrophage surface marker CD68 increased, and the CD163/CD86 ratio increased. In bone marrow-derived macrophages (BMDMs), there was no significant difference in the activity of CCK-8 in cells in the keratinase group compared with the control group. The fluorescence intensity of the keratinase group was higher than that of the control group. At 12 h, the cell scratches were obviously closed. The number of migrated Transwell cells increased. Flow cytometry and immunofluorescence analysis showed increased expression of CD206 and Arg-1 and decreased expression of CD86 and iNOS. The gene expression of the Arg-1, iNOS and IL-10 was increased, as shown by qPCR. The secretion of IL-10 was increased and TNF-α was decreased, as shown by ELISA. We concluded that keratinase dissolution of eschar not only has a hydrolytic effect on eschar but may also affect immune regulation to enhance the migration and phagocytosis of macrophages, promote the polarization of macrophages, and further enhance the effect of eschar dissolution. Therefore, keratinase may have good prospects for the debridement of burn wounds.

Integrated longitudinal circulating tumor DNA profiling predicts immunotherapy response of metastatic urothelial carcinoma in the POLARIS-03 trial.

Non-invasive biomarkers for immunotherapy response remain a compelling unmet medical need. POLARIS-03 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-programmed cell death 1) in refractory metastatic urothelial carcinoma (mUC). We assessed the predictive utility of longitudinal circulating tumor DNA (ctDNA) analysis from a single-institution biomarker cohort. Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled. Serial plasma specimens were obtained at baseline and then every two cycles during treatment. The 600-gene panel (PredicineATLAS™) liquid biopsy assay was applied to probe somatic variants and cancer cell fraction (CCF). Low-pass whole genome sequencing was used to determine the copy number abnormality (CNA) score. Across the entire cohort, we observed different degrees of concordance between somatic aberrations detected by ctDNA and those inferred by matched tumor samples. Although the baseline CCF or CNA had limited predictive value, early ctDNA response at week 8 was associated with toripalimab efficacy and prolonged patient survival. Integrating CCF and CNA decrease achieved a superior accuracy of 90.5% in classifying responders and non-responders and predicted long-term benefit from toripalimab. Dynamic changes in the CCF and CNA in blood exquisitely reflected radiographic assessment of malignant lesions, including those with FGFR3-TACC3 gene fusion or microsatellite instability. This study demonstrates the feasibility and effectiveness of integrated longitudinal ctDNA profiling as a potential biomarker in mUC patients undergoing immunotherapy and supports further clinical evaluation of minimally invasive liquid biopsy assays for treatment stratification and therapy monitoring. © 2023 The Pathological Society of Great Britain and Ireland.

Urinary Tumor DNA MRD Analysis to Identify Responders to Neoadjuvant Immunotherapy in Muscle-invasive Bladder Cancer.

PURPOSE: Bladder preservation is a viable option for some patients with muscle-invasive bladder cancer (MIBC), but an effective noninvasive biomarker test to accurately identify promising candidates is lacking. Here we present the clinical application of a novel tissue-agnostic, urine-based minimal residual disease (MRD) assay in the neoadjuvant setting for personalized disease surveillance and actionable target identification to facilitate bladder-sparing treatment approaches. PATIENTS AND METHODS: The urinary tumor DNA (utDNA) analysis was evaluated in an investigator-initiated phase I trial RJBLC-I2N003 in which 20 patients diagnosed with resectable MIBC were treated presurgically with the PD-1 inhibitor toripalimab followed by radical cystectomy (RC). RESULTS: We showed that neoadjuvant toripalimab therapy was feasible, safe, and induced a 40% rate (8/20) of pathologic complete response. Longitudinal utDNA profiling outperformed radiographic assessment and conventional biomarkers to predict the pathologic outcome of immune checkpoint blockade. In addition to detecting 3 exceptional responders with molecular MRD-negative status, we identified 7 other individuals characterized for utDNA response and 4 harboring FGFR3 mutants, all of whom (60%, 12/20) could have postponed or avoided RC. CONCLUSIONS: These findings demonstrate the safety and efficacy of neoadjuvant toripalimab, and suggest the immense potential of noninvasive utDNA MRD testing to guide tailored decision-making with regard to bladder preservation and change the current treatment paradigm for patients with MIBC.

BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype.

BACKGROUND: Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes. METHODS: Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2. FINDINGS: At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9-6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1-4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months). INTERPRETATION: These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials. FUNDING: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

Multi-Omic Integration of Blood-Based Tumor-Associated Genomic and Lipidomic Profiles Using Machine Learning Models in Metastatic Prostate Cancer.

PURPOSE: To determine prognostic and predictive clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castrate-resistant prostate cancer (mCRPC) on the basis of a combination of plasma-derived genomic alterations and lipid features in a longitudinal cohort of patients with advanced prostate cancer. METHODS: A multifeature classifier was constructed to predict clinical outcomes using plasma-based genomic alterations detected in 120 genes and 772 lipidomic species as informative features in a cohort of 71 patients with mHSPC and 144 patients with mCRPC. Outcomes of interest were collected over 11 years of follow-up. These included in mHSPC state early failure of androgen-deprivation therapy (ADT) and exceptional responders to ADT; early death (poor prognosis) and long-term survivors in mCRPC state. The approach was to build binary classification models that identified discriminative candidates with optimal weights to predict outcomes. To achieve this, we built multi-omic feature-based classifiers using traditional machine learning (ML) methods, including logistic regression with sparse regularization, multi-kernel Gaussian process regression, and support vector machines. RESULTS: The levels of specific ceramides (d18:1/14:0 and d18:1/17:0), and the presence of CHEK2 mutations, AR amplification, and RB1 deletion were identified as the most crucial factors associated with clinical outcomes. Using ML models, the optimal multi-omics feature combination determined resulted in AUC scores of 0.751 for predicting mHSPC survival and 0.638 for predicting ADT failure; and in mCRPC state, 0.687 for prognostication and 0.727 for exceptional survival. The models were observed to be superior than using a limited candidate number of features for developing multi-omic prognostic and predictive signatures. CONCLUSION: Using a ML approach that incorporates multiple omic features improves the prediction accuracy for metastatic prostate cancer outcomes significantly. Validation of these models will be needed in independent data sets in future.

Dosing interval regimen shapes potency and breadth of antibody repertoire after vaccination of SARS-CoV-2 RBD protein subunit vaccine.

Vaccination with different vaccines has been implemented globally to counter the continuous COVID-19 pandemic. However, the vaccine-elicited antibodies have reduced efficiency against the highly mutated Omicron sub-variants. Previously, we developed a protein subunit COVID-19 vaccine called ZF2001, based on the dimeric receptor-binding domain (RBD). This vaccine has been administered using different dosing intervals in real-world setting. Some individuals received three doses of ZF2001, with a one-month interval between each dose, due to urgent clinical requirements. Others had an extended dosing interval of up to five months between the second and third dose, a standard vaccination regimen for the protein subunit vaccine against hepatitis B. In this study, we profile B cell responses in individuals who received three doses of ZF2001, and compared those with long or short dosing intervals. We observed that the long-interval group exhibited higher and broader serologic antibody responses. These responses were associated with the increased size and evolution of vaccine-elicited B-cell receptor repertoires, characterized by the elevation of expanded clonotypes and somatic hypermutations. Both groups of individuals generated substantial amounts of broadly neutralizing antibodies (bnAbs) against various SARS-CoV-2 variants, including Omicron sub-variants such as XBB. These bnAbs target four antigenic sites within the RBD. To determine the vulnerable site of SARS-CoV-2, we employed cryo-electron microscopy to identify the epitopes of highly potent bnAbs that targeted two major sites. Our findings provide immunological insights into the B cell responses elicited by RBD-based vaccine, and suggest that a vaccination regimen of prolonging time interval should be used in practice.

Triple-negative Breast Carcinoma With Apocrine and Histiocytoid Features: A Clinicopathologic and Molecular Study of 18 Cases.

Triple-negative breast cancer (TNBC) is a heterogenous group of tumors. Most TNBCs are high-grade aggressive tumors, but a minority of TNBCs are not high grade, with relatively indolent behavior and specific morphologic and molecular features. We performed a clinicopathologic and molecular assessment of 18 non-high-grade TNBCs with apocrine and/or histiocytoid features. All were grade I or II with low Ki-67 (≤20%). Thirteen (72%) showed apocrine features, and 5 (28%) showed histiocytoid and lobular features. In all, 17/18 expressed the androgen receptor, and 13/13 expressed gross cystic disease fluid protein 15. Four (22.2%) patients were treated with neoadjuvant chemotherapy, but none achieved a pathologic complete response. In all, 2/18 patients (11%) had lymph node metastasis at the time of surgery. None of the cases had a recurrence or disease-specific death, with an average follow-up time of 38 months. Thirteen cases were profiled by targeted capture-based next-generation DNA sequencing. Genomic alterations (GAs) were most significant for PI3K-PKB/Akt pathway (69%) genes, including PIK3R1 (23%), PIK3CA (38%), and PTEN (23%), and RTK-RAS pathway (62%) including FGFR4 (46%) and ERBB2 (15%). TP53 GA was seen in only 31% of patients. Our findings support those on high-grade TNBCs with apocrine and/or histiocytoid features as a clinicopathologic and genetically distinct subgroup of TNBC. They can be defined by features including tubule formation, rare mitosis, low Ki-67 (≤20%), triple-negative status, expression of androgen receptor and/or gross cystic disease fluid protein 15, and GA in the PI3K-PKB/Akt and/or RTK-RAS pathway. These tumors are not sensitive to chemotherapy but have favorable clinical behavior. Tumor subtype definitions are the first step to implementing future trial designs to select these patients.

Immunogenicity and safety of heterologous immunisation with Ad5-nCOV in healthy adults aged 60 years and older primed with an inactivated SARS-CoV-2 vaccine (CoronaVac): a phase 4, randomised, observer-blind, non-inferiority trial.

Background: People over 60 have been found to develop less protection after two doses of inactivated COVID-19 vaccines than younger people. Heterologous immunisation could potentially induce more robust immune responses compared to homologous immunisation. We aimed to assess the immunogenicity and safety of a heterologous immunisation with an adenovirus type 5-vectored vaccine (Ad5-nCOV, Convidecia) among elderly who were primed with an inactivated vaccine (CoronaVac) previously. Methods: We did a randomised, observer-blinded, non-inferiority trial in healthy adults aged 60 years and older in Lianshui County (Jiangsu, China) between August 26, 2021 and May 15, 2022. 199 eligible participants who had received two doses of CoronaVac in the past 3-6 months were randomised (1:1) to receive a third dose of Convidecia (group A, n = 99) or CoronaVac (group B, n = 100), while 100 participants primed with one dose of CoronaVac in the past 1-2 months were randomised equally to receive a second dose of Convidecia (group C, n = 50) or CoronaVac (group D, n = 50). Participants and investigators were masked to the vaccine received. Primary outcomes were the geometric mean titers (GMTs) of neutralising antibodies against live SARS-CoV-2 virus 14 days after boosting and 28-day adverse reactions. This study was registered with ClinicalTrials.govNCT04952727. Findings: A heterologous third dose of Convidecia resulted in a 6.2-fold (GMTs: 286.4 vs 48.2), 6.3-fold (45.9 vs 7.3) and 7.5-fold (32.9 vs 4.4) increase in neutralising antibodies against SARS-CoV-2 wild-type, delta (B.1.617.2) and omicron (BA.1.1) 14 days post boosting, respectively, compared with the homologous boost. The heterologous booster with Convidecia induced significantly higher neutralsing activities, with up to 91% inhibition in binding of Spike to ACE2 for BA.4 and BA.5 variants, compared with 35% inhibition induced by three doses of CoronaVac. For participants primed with one dose of CoronaVac, a heterologous dose of Convidecia induced higher neutralising antibodies against wild-type than two doses of CoronaVac (GMTs: 70.9 vs 9.3, p < 0.0001), but not for that against variants of concern (GMTs against delta: 5.0 vs 4.0, p = 0.4876; GMTs against omicron: 4.8 vs 3.7, p = 0.4707). Adverse reactions were reported by 8 (8.1%) participants in group A and 4 (4.0%) in group B (p ＞ 0.05), and 8 (16.0%) in group C and 1 (2.0%) in group D (p = 0.031). Interpretation: In elderly individuals primed with two doses of CoronaVac, the heterologous immunisation with Convidecia induced strong antibodies against SARS-CoV-2 wildtype and variants of concern, which could be an alternative regimen for enhancing protection in this vulnerable population. Funding: National Natural Science Foundation of China, Jiangsu Provincial Key Research and Development Program, and Jiangsu Science Fund for Distinguished Young Scholars Program.

Clinicopathologic features, genomic profiles and outcomes of younger vs. older Chinese hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer patients.

Background: Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We have evaluated the clinicopathologic characteristics and genomic profiles of real-world hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) patients to examine the determinants of outcome for younger vs. older patients in a single clinical subtype undergoing treatment in the same clinic. Patients and methods: This study included patients presenting at the Peking University Cancer Hospital with primary stage IV or first-line metastatic HR+/HER2- breast cancer who consented to an additional blood draw for genomic profiling prior to treatment. Plasma samples were analyzed with a targeted 152-gene NGS panel to assess somatic circulating tumor DNA (ctDNA) alterations. Genomic DNA (gDNA) extracted from peripheral blood mononuclear cells was analyzed for germline variants using a targeted 600-gene NGS panel. Kaplan-Meier survival analysis was performed to analyze disease free survival (DFS), progression free survival (PFS) and overall survival (OS) in association with clinicopathologic and genomic variables. Results: Sixty-three patients presenting with HR+/HER2- MBC were enrolled in this study. Fourteen patients were < 40 years, 19 were 40-50 years, and 30 were > 50 years at the time of primary cancer diagnosis. No significant associations were observed between age and DFS, PFS or OS. Shorter OS was associated with de novo Stage IV disease (p = 0.002), Luminal B subtype (p = 0.006), high Ki67 index (p = 0.036), resistance to adjuvant endocrine therapy (p = 0.0001) and clinical stage (p = 0.015). Reduced OS was also observed in association with somatic alterations in FGFR1 (p = 0.008), CCND2 (p = 0.012), RB1 (p = 0.029) or TP53 (p = 0.029) genes, but not in association with germline variants. Conclusion: In this group of real-world HR+/HER2- MBC breast cancer patients younger age was not associated with poor outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients.

Development of neutralizing antibodies against SARS-CoV-2, using a high-throughput single-B-cell cloning method.

Background: Rapid and efficient strategies are needed to discover neutralizing antibodies (nAbs) from B cells derived from virus-infected patients. Methods: Here, we report a high-throughput single-B-cell cloning method for high-throughput isolation of nAbs targeting diverse epitopes on the SARS-CoV-2-RBD (receptor binding domain) from convalescent COVID-19 patients. This method is simple, fast and highly efficient in generating SARS-CoV-2-neutralizing antibodies from COVID-19 patients' B cells. Results: Using this method, we have developed multiple nAbs against distinct SARS-CoV-2-RBD epitopes. CryoEM and crystallography revealed precisely how they bind RBD. In live virus assay, these nAbs are effective in blocking viral entry to the host cells. Conclusion: This simple and efficient method may be useful in developing human therapeutic antibodies for other diseases and next pandemic.

In vivo and in vitro studies of a propolis-enriched silk fibroin-gelatin composite nanofiber wound dressing.

In this study, electrospun nanofibers (NFs) used in trauma dressings were prepared using silk fibroin (SF) and gelatin (GT) as materials and highly volatile formic acid as the solvent, with three different concentrations of propolis extracts (EP), which were loaded through a simple process. The resulting samples were characterized by surface morphology, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), contact angle meter, water absorption, degradation rate, and mechanical property tests. The incorporation of propolis improved its antibacterial properties against Escherichia coli, and Staphylococcus aureus, compared to those of the silk gelatin nanofiber material (SF/GT) alone. In vitro biocompatibility assays showed that SF/GT-1%EP had good cytocompatibility and hemocompatibility. In addition, it can also significantly promote the migration of L929 cells. SF/GT-1%EP was applied to a mouse model of full thickness skin defects, and it was found to significantly promote wound healing. These results indicate that the SF/GT-EP nanofiber material has good biocompatibility, migrating-promoting capability, antibacterial properties, and healing-promoting ability, providing a new idea for the treatment of full thickness skin defects.

Autoantibody repertoire characterization provides insight into the pathogenesis of monogenic and polygenic autoimmune diseases.

Autoimmune diseases vary in the magnitude and diversity of autoantibody profiles, and these differences may be a consequence of different types of breaks in tolerance. Here, we compared the disparate autoimmune diseases autoimmune polyendocrinopathy-candidiasis-ecto-dermal dystrophy (APECED), systemic lupus erythematosus (SLE), and Sjogren's syndrome (SjS) to gain insight into the etiology of breaks in tolerance triggering autoimmunity. APECED was chosen as a prototypical monogenic disease with organ-specific pathology while SjS and SLE represent polygenic autoimmunity with focal or systemic disease. Using protein microarrays for autoantibody profiling, we found that APECED patients develop a focused but highly reactive set of shared mostly anti-cytokine antibodies, while SLE patients develop broad and less expanded autoantibody repertoires against mostly intracellular autoantigens. SjS patients had few autoantibody specificities with the highest shared reactivities observed against Ro-52 and La. RNA-seq B-cell receptor analysis revealed that APECED samples have fewer, but highly expanded, clonotypes compared with SLE samples containing a diverse, but less clonally expanded, B-cell receptor repertoire. Based on these data, we propose a model whereby the presence of autoreactive T-cells in APECED allows T-dependent B-cell responses against autoantigens, while SLE is driven by breaks in peripheral B-cell tolerance and extrafollicular B-cell activation. These results highlight differences in the autoimmunity observed in several monogenic and polygenic disorders and may be generalizable to other autoimmune diseases.

Heparin-based sericin hydrogel-encapsulated basic fibroblast growth factor for in vitro and in vivo skin repair.

The treatment of full-thickness cutaneous wounds remains a significant challenge in clinical therapeutics. Exogenous growth factor (GF) has been applied in clinics to promote wound healing. However, the retention of GF on the wound bed after its direct application to the wound surface is difficult. Moreover, growth factors (GFs) are always inactivated in the complex wound healing microenvironment due to various factors, which significantly decrease the therapeutic effect. Sericin hydrogel (S) can be used as an effective carrier for GFs owing to its low immunogenicity, good biocompatibility, and good healing-promoting ability. Here, we designed a heparin-based sericin hydrogel (HS) -encapsulated basic fibroblast growth factor (bFGF-HS) to facilitate wound healing and skin regeneration. The hydrogel exhibited a three-dimensional (3D) microporous structure, excellent biodegradability, good adhesiveness, and low cytotoxicity. In vitro release of bFGF from bFGF-HS coacervates revealed that bFGF-HS might control the release of bFGF within 25 days through heparin regulation. bFGF-HS significantly promoted vascularization and re-epithelialization and improved collagen deposition, ultimately accelerating wound healing in vivo in mice. bFGF-HS treated wounds were also found to have more hair follicles and milder inflammatory reactions. Overall, this study provides a new therapeutic approach for full-thickness skin defect wounds using bFGF-HS.

6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress.

Poor outcomes in advanced gastric cancer necessitate alternative therapeutic strategies. 6-Phosphogluconate dehydrogenase (6-PGDH), an enzyme that catalyzes the decarboxylation step in the oxidative pentose phosphate pathway, has been identified as a promising therapeutic target in many cancers. In this study, we systematically investigated the expression and function of 6-PGDH in gastric cancer. We found that 6-PGDH expression and activity were aberrantly elevated in gastric cancer tissues compared to their adjacent normal tissues. 6-PGDH knockdown using two independent shRNAs resulted in minimal 6-PGDH levels and activity, decreased growth, and enhanced gastric cancer cell sensitivity to 5-flurorouracil. However, 6-PGDH knockdown did not affect the cancer cells. Mechanistic studies showed that 6-PGDH inhibition disrupted lipid biosynthesis and redox homeostasis in gastric cancer, inhibited growth, and induced apoptosis. Notably, the in vitro findings were validated using an in vivo gastric cancer xenograft mouse model. This study established that 6-PGDH is broadly elevated in gastric cancer patients and that 6-PGDH inhibition can sensitize gastric cancer cells in response to chemotherapy.

Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor-Positive (HR+)/HER2-Negative Metastatic Breast Cancer.

PURPOSE: Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance. EXPERIMENTAL DESIGN: ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole-exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy-number burden (bCNB). RESULTS: High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared with patients with low bTMB or low bCNB (all P < 0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) versus low bTMB (0/37, 0%; P = 0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P = 0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R = 0.98). During serial monitoring, an increase in bCNB score preceded radiographic progression in 12 of 18 (66.7%) patients. CONCLUSIONS: Genomic complexity detected by noninvasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population.

Contrastive Active Learning Under Class Distribution Mismatch.

Active learning(AL) has been successful based on the premise that labeled and unlabeled data come from the same class distribution. However, its performance undergoes a severe deterioration under class distribution mismatch, wherein the unlabeled data contain numerous instances out of the class distribution of labeled data. In this article, we solve this practical yet rarely studied problem by minimizing the AL error, which is formally defined and decomposed as the valid query error and invalid query error. Specifically, the invalid query error is associated with the queries from unknown categories, and the valid query error is attributed to less informative queries from target categories. In light of this discovery, we propose a contrastive AL framework, named ConAL, to simultaneously learn the semantics and distinctiveness of the instances by contrastive techniques, thereby reducing the invalid query error and valid query error, respectively. Theoretically, we prove that the AL error of ConAL has a tight upper bound. Experimentally, ConAL achieves superior performance on two benchmark datasets, CIFAR10 and CIFAR100, and a cross-dataset with class distribution across multi-datasets. Furthermore, we validate that the ConAL technique performs admirably even on the realistic dataset. To the best of our knowledge, ConAL is the first AL work for class distribution mismatch.