Reduced-rank clustered coefficient regression for addressing multicollinearity in heterogeneous coefficient estimation.

Clustered coefficient regression (CCR) extends the classical regression model by allowing regression coefficients varying across observations and forming clusters of observations. It has become an increasingly useful tool for modeling the heterogeneous relationship between the predictor and response variables. A typical issue of existing CCR methods is that the estimation and clustering results can be unstable in the presence of multicollinearity. To address the instability issue, this paper introduces a low-rank structure of the CCR coefficient matrix and proposes a penalized non-convex optimization problem with an adaptive group fusion-type penalty tailor-made for this structure. An iterative algorithm is developed to solve this non-convex optimization problem with guaranteed convergence. An upper bound for the coefficient estimation error is also obtained to show the statistical property of the estimator. Empirical studies on both simulated datasets and a COVID-19 mortality rate dataset demonstrate the superiority of the proposed method to existing methods.

A randomized trial of the inflammatory cytokines levels and the blood transfusion rate between miniaturized tubing group and conventional tubing group in congenital heart disease open heart surgeries.

INTRODUCTION: We aimed to compare the inflammatory cytokines levels of the miniaturized and conventional extracorporeal circuit system. The miniaturized extracorporeal circuit system may be fewer possible inflammation-induced or blood transfusion-related complications. METHODS: We performed a prospective randomized controlled trial (RCT) of 101 patients undergoing congenital heart surgery with CPB (cardiopulmonary bypass, weight ≤15 kg, age ≤2 years). Patients were divided into two different CPB groups randomly by random data form. Blood samples at five different time points and the ultrafiltration fluid before and after CPB were collected in all patients. IL-6, IL-8, and TNF alpha were respectively tested with Abcam ELISA kit. RESULTS: The IL-6 level of blood serum in two groups had no statistical differences between the two groups at all time points. The IL-8 level of blood serum in two groups had no statistical differences right after anesthesia and 5 min after CPB. However, IL-8 level was significantly higher in conventional extracorporeal circuit group than that in miniaturized extracorporeal circuit group at 6 h, 12 h and 24 h after CPB. Blood serum TNF alpha in conventional extracorporeal circuit group was significantly higher at 6 h after CPB than that in miniaturized extracorporeal circuit group. No statistical differences in TNF alpha were found between two groups right after anesthesia and at 5 min after CPB, 12 h and 24 h after CPB. In ultrafiltration fluid, no statistical differences were found in IL-6, IL-8 nor TNF alpha between two groups in all time. No statistical differences were found in ICU (intensive care unit) stay and mechanical ventilation time between the two groups. The blood transfusion rate was significantly lower in miniaturized extracorporeal circuit group. CONCLUSION: Implementing the miniaturized extracorporeal circuit system could decrease the inflammatory cytokines at a certain level. The blood transfusion rate is significantly lower in miniaturized extracorporeal circuit group This indicates the miniaturized extracorporeal circuit system might be a safer CPB strategy with fewer possible inflammation-induced or blood transfusion-related complications.

A protecting group-free approach for synthesizing C-glycosides through glycosyl dithiocarbamates.

The first protection/deprotection-free process for radical C-glycosylation has been achieved through one-step preparable glycosyl dithiocarbamates (GDTCs). The Giese-type reaction and radical allylation of unprotected GDTCs were successfully performed to obtain the corresponding α-C-glycosides stereoselectively under mild reaction conditions.

Multispectral photodetectors based on 2D material/Cs3Bi2I9heterostructures with high detectivity.

Group VA metal halide-based perovskites have emerged as intensively explored Pb-free perovskites, owing to their excellent environmental stability and low-toxicity. However, the relatively low carrier mobility and high photocarrier recombination rates restrict their applications in photodetectors. One promising approach to achieve higher performance is to integrate these Pb-free perovskites with 2D materials to form heterostructures. Here, we report on the high sensitivity photodetectors based on MoS2/Cs3Bi2I9and graphene/Cs3Bi2I9heterostructures for multispectral regions. The heterostructures combine the high carrier mobility of 2D materials with superior light-harvesting properties of perovskites, as well as the effective built-in electric filed at the junction area, leading to efficient photocarrier separation and extraction. The specific detectivity of MoS2/Cs3Bi2I9device reaches 1.15 × 1013Jones for the detection of ultraviolet (UV) light of 325 nm, which is four orders of magnitude higher than UV detectors built on GaN. As a result of the efficient dark current suppression, the specific detectivity of graphene/Cs3Bi2I9photodetector can be promoted to 5.24 × 1011Jones, 1.33 × 1011Jones, and 1.12 × 1011Jones for the detection of 325 nm, 447 nm, and 532 nm light, respectively.

Previous chronic symptomatic and asymptomatic cerebral hemorrhage in patients with acute ischemic stroke.

PURPOSE: Identifying previous chronic cerebral hemorrhage (PCH), especially asymptomatic cases in patients with ischemic stroke, is essential for proper antithrombotic management. The study aimed to further clarify the prevalence of PCH and the associated factors in patients with acute ischemic stroke using multi-modal neuroimaging including susceptibility-weighted MR imaging (SWI). METHODS: This was a retrospective cross-sectional study of 382 patients with acute ischemic stroke. All patients underwent 3.0-T MRI for cranial SWI, 1.5-T or 3.0-T conventional cranial MRI, and cranial CT. Patients found with PCH were matched 1:4 with patients without PCH. Clinical manifestation, computed tomography, conventional cranial MRI, and cranial SWI were used to determine PCH. Clinical and neuroimaging findings between the patients with symptomatic vs. asymptomatic PCH were compared. RESULTS: Thirty-six patients (36/382, 9.4%) were determined to have had a PCH. Of these 36 patients, 17 (17/36, 47.2%, or 17/382, 4.5%) had asymptomatic PCH. Multivariable analysis showed that serum total cholesterol (OR = 0.510, 95%CI 0.312-0.832, P = 0.007), cerebral microbleeds (OR = 6.251, 95%CI 2.220-17.601, P = 0.001), and antithrombotic drugs history (OR = 3.213, 95%CI 1.018-10.145, P = 0.047) were independently associated with PCH. Asymptomatic PCH had similar clinical and neuroimaging characteristics with symptomatic PCH. CONCLUSION: PCH is not uncommon in acute ischemic stroke patients. Total serum cholesterol, cerebral microbleeds on SWI, and history of antithrombotic drugs were independently associated with PCH in patients with acute ischemic stroke. Asymptomatic PCH, which is easier to be missed and has similar characteristics with symptomatic PCH, should draw much attention.

Plasma Levels of miR-125b-5p and miR-206 in Acute Ischemic Stroke Patients After Recanalization Treatment: A Prospective Observational Study.

INTRODUCTION: Multiple microRNAs (miRNAs) participate in the response to hypoxic/ischemic and ischemia-reperfusion events. However, the expression of these miRNAs in circulation from patients with acute ischemic stroke (AIS) receiving recanalization treatment has not been examined, and whether they are associated with the severity and outcome of stroke is still unknown. MATERIALS AND METHODS: In this prospective cohort study, plasma levels of miR-125b-5p, miR-15a-3p, miR-15a-5p, and miR-206 were measured at 24 hours after thrombolysis with or without endovascular treatment in 94 patients with AIS, as determined by qRT-PCR. Stroke severity was assessed based on National Institutes of Health Stroke Scale (NIHSS) score and infarct lesion. Intracranial haemorrhage (ICH) was recorded. An unfavorable outcome was defined as a modified Rankin Scale score greater than 2 at day 90 after stroke. RESULTS: miR-125b-5p and miR-206 levels were correlated with NIHSS scores (P = .014 and P = .002) and cerebral infarction volumes (P = .025 and P = .030). miR-125b-5p levels were significantly higher in patients with an unfavorable outcome than in patients with a favorable outcome (P = .002) and showed good diagnostic accuracy in discriminating the presence of an unfavorable outcome (area under the curve .735, 95% confidence interval .623-.829, P < .001). No association was found between different miRNAs and ICH. CONCLUSIONS: In AIS patients after thrombolysis with or without endovascular treatment, miR-125b-5p is a novel prognostic biomarker highly associated with an unfavorable outcome. miR-125b-5p and miR-206 levels are associated with stroke severity.

Structural changes of cerebellum and brainstem in migraine without aura.

BACKGROUND: Increasing evidence has suggested that the cerebellum is associated with pain and migraine. In addition, the descending pain system of the brainstem is the major site of trigeminal pain processing and modulation and has been discussed as a main player in the pathophysiology of migraine. Cerebellar and brainstem structural changes associated with migraineurs remain to be further investigated. METHODS: Voxel-based morphometry (VBM) (50 controls, 50 migraineurs without aura (MWoAs)) and diffusion tensor imaging (DTI) (46 controls, 46 MWoAs) were used to assess cerebellum and brainstem anatomical alterations associated with MWoAs. We utilized a spatially unbiased infratentorial template toolbox (SUIT) to perform cerebellum and brainstem optimized VBM and DTI analysis. We extracted the average diffusion values from a probabilistic cerebellar white matter atlas to investigate whether MWoAs exhibited microstructure alterations in the cerebellar peduncle tracts. RESULTS: MWoAs showed decreased fractional anisotropy (FA) in the vermis VI extending to the bilateral lobules V and VI of the cerebellum. We also found higher axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in the right inferior cerebellum peduncle tract in MWoAs. MWoAs exhibited both reduced gray matter volume and increased AD, MD and RD in the spinal trigeminal nucleus (SpV). CONCLUSION: MWoAs exhibited microstructural changes in the cerebellum and the local brainstem. These structural differences might contribute to dysfunction of the transmission and modulation of noxious information, trigeminal nociception, and conduction and integration of multimodal information in MWoAs. These findings further suggest involvement of the cerebellum and the brainstem in the pathology of migraine without aura.

Chemistry of 1,2-Anhydro Sugars.

The 1,2-anhydro sugars are a class of valuable and versatile intermediates in carbohydrate chemistry. In the first part of this article, a review is given on preparation methods of 1,2-anhydro sugars that are suitably protected. Protected 1,2-anhydro sugars have been widely used as glycosyl donors for the synthesis of glycosyl compounds such as oligosaccharides and nucleosides. In the second part, a brief history and the chemistry of unprotected 1,2-anhydro sugars is described. In the past few years, our research group has developed protection-free methods for synthesis of glycosyl compounds through unprotected 1,2-anhydro sugars as reactive intermediates based on the concept of 'direct anomeric activation'. In this article, the one-step preparation of glycosyl compounds such as thioglycoside derivatives and glycosyl azides by using formamidinium-type dehydrating agents is presented. Furthermore, the initial results on the first detection of unprotected 1,2-anhydro sugar intermediates by NMR measurements are shown along with their full structure characterizations.

Relationship between intracranial internal carotid artery calcification and enlarged cerebral perivascular space.

PURPOSE: The association between intracranial internal carotid artery (IICA) calcification and lacunes, white matter hyperintensity (WMH), and cerebral microbleeds (CMBs) has been well researched. However, enlarged cerebral perivascular space (PVS) has not yet been reported to correlate with intracranial internal carotid artery calcification. Therefore, the primary aim of this study was to investigate the relationship between IICA calcification and enlarged PVS. METHODS: A total of 189 patients with ischemic stroke in the middle cerebral artery territory who presented within 7 days of ictus from 2012 to 2015 were enrolled respectively. All patients were required to have undergone head computed tomography, magnetic resonance imaging, susceptibility-weighted magnetic resonance imaging, magnetic resonance angiography, or computed tomography angiography. Clinical characteristics were recorded. IICA calcification and enlarged PVS were semi-quantitatively evaluated, and the presence of lacunes, WMH, and CMBs was recorded. RESULTS: Of the 189 patients, 63.5% were male. Mean age of the patients was 68.6 ± 12.2 years. There were 104 patients with IICA calcification. Age, diabetes mellitus, lacunes, and white matter hyperintensity were significantly associated with IICA calcification (P < 0.05). Multivariate logistic regression analysis showed that age, diabetes mellitus, and lacunes were independent predictors of IICA calcification (P < 0.05). A lower risk of IICA calcification was found in patients with a higher enlarged PVS score (P = 0.004). CONCLUSION: Higher enlarged PVS scores were associated with a lesser degree of IICA calcification. There appears to be a relationship between reduced risk of IICA calcification and enlarged PVS.

Blockage of Glyoxalase I Inhibits Colorectal Tumorigenesis and Tumor Growth via Upregulation of STAT1, p53, and Bax and Downregulation of c-Myc and Bcl-2.

GlyoxalaseI (GLOI) is an enzyme that catalyzes methylglyoxal metabolism. Overexpression of GLOI has been documented in numerous tumor tissues, including colorectal cancer (CRC). The antitumor effects of GLOI depletion have been demonstrated in some types of cancer, but its role in CRC and the mechanisms underlying this activity remain largely unknown. Our purpose was to investigate the antitumor effects of depleted GLOI on CRC in vitro and in vivo. RNA interference was used to deplete GLOI activity in four CRC cell lines. The cells' proliferation, apoptosis, migration, and invasion were assessed by using the Cell Counting Kit-8, plate colony formation assay, flow cytometry, and transwell assays. Protein and mRNA levels were analyzed by western blot and quantitative real-time PCR (qRT-PCR), respectively. The antitumor effect of GLOI depletion in vivo was investigated in a SW620 xenograft tumor model in BALB/c nude mice. Our results show that GLOI is over-expressed in the CRC cell lines. GLOI depletion inhibited the proliferation, colony formation, migration, and invasion and induced apoptosis of all CRC cells compared with the controls. The levels of signal transducer and activator of transcription 1 (STAT1), p53, and Bcl-2 assaciated X protein (Bax) were upregulated by GLOI depletion, while cellular homologue of avian myelocytomatosis virus oncogene (c-Myc) and B cell lymphoma/lewkmia-2 (Bcl-2) were downregulated. Moreover, the growth of SW620-induced CRC tumors in BALB/c nude mice was significantly attenuated by GLOI depletion. The expression levels of STAT1, p53, and Bax were increased and those of c-Myc and Bcl-2 were decreased in the GLOI-depleted tumors. Our findings demonstrate that GLOI depletion has an antitumor effect through the STAT1 or p53 signaling pathways in CRC, suggesting that GLOI is a potential therapeutic target.

Assessment of gray and white matter structural alterations in migraineurs without aura.

BACKGROUND: Migraine constitute a disorder characterized by recurrent headaches, and have a high prevalence, a high socio-economic burden and severe effects on quality of life. Our previous fMRI study demonstrated that some brain regions are functional alterations in migraineurs. As the function of the human brain is related to its structure, we further investigated white and gray matter structural alterations in migraineurs. METHODS: In current study, we used surface-based morphometry, voxel-based morphometry and diffusion tensor imaging analyses to detect structural alterations of the white matter and gray matter in 32 migraineurs without aura compared with 32 age- and gender-matched healthy controls. RESULTS: We found that migraineurs without aura exhibited significantly increased gray matter volume in the bilateral cerebellar culmen, increased cortical thickness in the lateral occipital-temporal cortex, decreased cortical thickness in the right insula, increased gyrification index in left postcentral gyrus, superior parietal lobule and right lateral occipital cortex, and decreased gyrification index in the left rostral middle frontal gyrus compared with controls. No significant change in white matter microstructure was found in DTI analyses. CONCLUSION: The significantly altered gray matter brain regions were known to be associated with sensory discrimination of pain, multi-sensory integration and nociceptive information processing and were consistent with our previous fMRI study, and may be involved in the pathological mechanism of migraine without aura.

Increased default mode network connectivity and increased regional homogeneity in migraineurs without aura.

BACKGROUND: The precuneus/posterior cingulate cortex, which has been associated with pain sensitivity, plays a pivotal role in the default mode network. However, information regarding migraine-related alterations in resting-state brain functional connectivity in the default mode network and in local regional spontaneous neuronal activity is not adequate. METHODS: This study used functional magnetic resonance imaging to acquire resting-state scans in 22 migraineurs without aura and in 22 healthy matched controls. Independent component analysis, a data-driven method, was used to calculate the resting-state functional connectivity of the default mode network in the patient and healthy control groups. Regional homogeneity (ReHo) was used to analyse the local features of spontaneous resting-state brain activity in the migraineurs without aura. RESULTS: Compared with the healthy controls, migraineurs without aura showed increased functional connectivity in the left precuneus/posterior cingulate cortex within the default mode network and significant increase in ReHo values in the bilateral precuneus/posterior cingulate cortex, left pons and trigeminal nerve entry zone. In addition, functional connectivity was decreased between the areas with abnormal ReHo (using the peaks in the precuneus/posterior cingulate cortex) and other brain areas. CONCLUSIONS: The abnormalities in the precuneus/posterior cingulate cortex suggest that migraineurs without aura may exhibit information transfer and multimodal integration dysfunction and that pain sensitivity and pian processing may also be affected.

Correlation between fasting blood glucose level and risk of breast cancer in women: a single-center, prospective cohort study.

Purpose: We prospectively analyzed the correlation between fasting plasma glucose (FPG) and the risk of breast cancer in women; explored the independent risk factors for breast cancer in women, and compared the effect of FPG level on the risk of young and non-young breast cancer. Our study provides new evidence and ideas for research into breast cancer etiology in China, improves the accuracy of secondary prevention of breast cancer, and provides options for the clinical diagnosis and treatment of breast cancer patients with diabetes. Materials and methods: Three cohorts of women participating in the first health examination of the Kailuan Group in 2006, 2008 and 2010 were assembled to conduct a descriptive analysis of the baseline data on FPG. The cumulative incidence of breast cancer in different groups over 13 years was calculated using the Kaplan-Meier method and groups were compared using the log-rank test. A Cox proportional hazards regression model was used to analyze the association between FPG level and the risk of breast cancer. Results: The cumulative incidence of breast cancer increased in people with FPG higher than 5.29 mmol/L, but there was no significant difference in the effect of different levels of FPG on the risk of young breast cancer in the population. Different degrees of fasting glucose can affect the risk of non-young breast cancer in the population. Conclusion: The results of this study suggest that the risk of breast cancer can be reversed by early intervention to control levels of FPG. Regular monitoring of FPG may reduce the misdiagnosis rate of breast cancer in the population.

Eukaryotes may play an important ecological role in the gut microbiome of Graves' disease.

The prevalence of autoimmune diseases worldwide has risen rapidly over the past few decades. Increasing evidence has linked gut dysbiosis to the onset of various autoimmune diseases. Thanks to the significant advancements in high-throughput sequencing technology, the number of gut microbiome studies has increased. However, they have primarily focused on bacteria, so our understanding of the role and significance of eukaryotic microbes in the human gut microbial ecosystem remains quite limited. Here, we selected Graves' disease (GD) as an autoimmune disease model and investigated the gut multi-kingdom (bacteria, fungi, and protists) microbial communities from the health control, diseased, and medication-treated recovered patients. The results showed that physiological changes in GD increased homogenizing dispersal processes for bacterial community assembly and increased homogeneous selection processes for eukaryotic community assembly. The recovered patients vs. healthy controls had similar bacterial and protistan, but not fungal, community assembly processes. Additionally, eukaryotes (fungi and protists) may play a more significant role in gut ecosystem functions than bacteria. Overall, this study gives brief insights into the potential contributions of eukaryotes to gut and immune homeostasis in humans and their potential influence in relation to therapeutic interventions.

Prognostic value of pathological nodal burden after neoadjuvant chemotherapy in initially cN0-1 breast cancer patients: a dual-center, 10-year survival analysis.

Background: There is an interest in performing de-escalating axillary surgery after neoadjuvant chemotherapy (NAC). However, the significance of residual axillary node disease after NAC has not been well studied. Objectives: To investigate the pathological residual axillary lymph node tumor burden (ypN) of patients with initial clinical nodal stage cN0-1 breast cancer after NAC and determine its prognostic value. Design: Initial cN0-1 breast cancer patients who received NAC followed by axillary surgery at the First Hospital of Jilin University and the First Affiliated Hospital of Xi'an Jiaotong University between January 2011 and December 2019 were included. Methods: Survival outcomes were compared according to different clinical and pathological stage and nodal response to NAC. The main outcomes were disease-free survival (DFS) and overall survival (OS). Factors associated with survival were defined by Cox regression analysis. Results: A total of 911 patients were included, among whom 260 had cN0 and 651 had cN1 tumors. After NAC, 410 patients were ypN0, and another 501 were ypN+. The median follow-up time was 63 months. There was no significant difference in DFS or OS between the cN0 and cN1 groups in hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+) and HR-/HER2- subtypes; instead, ypN status was significantly related to DFS and OS. In HR+/HER2- subtype, both cN and ypN stages did not show significant survival differences, but the ypN number and the nodal response to NAC showed significant prognostic value (p < 0.05). Among HR-/HER2+ patients, all cN status, ypN status, ypN number, and nodal response were significantly associated with survival (p < 0.05). Furthermore, tumor biology, axillary surgery, ypN status, pathological tumor size, and radiotherapy were independent prognostic factors for DFS and OS. Conclusion: The ypN status after NAC provide more prognostic information than the initial cN stage in cN0-1 patients, and the surgical axillary staging after NAC may have high clinical value.

Identification of the core genes in Randall's plaque of kidney stone and immune infiltration with WGCNA network.

Background: Randall's plaque is regarded as the precursor lesion of lithiasis. However, traditional bioinformatic analysis is limited and ignores the relationship with immune response. To investigate the underlying calculi formation mechanism, we introduced innovative algorithms to expand our understanding of kidney stone disease. Methods: We downloaded the GSE73680 series matrix from the Gene Expression Omnibus (GEO) related to CaOx formation and excluded one patient, GSE116860. In the RStudio (R version 4.1.1) platform, the differentially expressed genes (DEGs) were identified with the limma package for GO/KEGG/GSEA analysis in the clusterProfiler package. Furthermore, high-correlated gene co-expression modules were confirmed by the WGCNA package to establish a protein-protein interaction (PPI) network. Finally, the CaOx samples were processed by the CIBERSORT algorithm to anchor the key immune cells group and verified in the validation series matrix GSE117518. Results: The study identified 840 upregulated and 1065 downregulated genes. The GO/KEGG results revealed fiber-related or adhesion-related terms and several pathways in addition to various diseases identified from the DO analysis. Moreover, WGCNA selected highly correlated modules to construct a PPI network. Finally, 16 types of immune cells are thought to participate in urolithiasis pathology and are related to hub genes in the PPI network that are proven significant in the validation series matrix GSE117518. Conclusion: Randall's plaque may relate to genes DCN, LUM, and P4HA2 and M2 macrophages and resting mast immune cells. These findings could serve as potential biomarkers and provide new research directions.

Phyllanthi Fructus: A modal medicinal and food homologous item in quality evaluation.

Phyllanthi Fructus is a highly unique medicine and food homologous item, which exhibits distinctive flavor, notable nutritional value, and abundant pharmacological activity. It has enormous potential in the creation of health products and pharmaceuticals. However, due to the unique laws of quality formation and transfer of Phyllanthi Fructus, its appearance, shape, chemical compositions, nutrients, and sensory flavors are frequently greatly influenced by botanical resources, the processing and storage conditions. As a result, the current quality evaluation model is difficult to meet the needs of Phyllanthi Fructus as a medicine and food homologous item in the development of diversified products. This paper constructs the hierarchical utilization mode of Phyllanthi Fructus based on its unique quality formation and transmission laws, explores the quality evaluation model for food-oriented use and medicinal-oriented use, respectively, and systematically describes the quality evaluation idea under diversified application scenarios. This paper aims to serve as a reference for the construction of a quality evaluation model suitable for the medicine and food homologous item of Phyllanthi Fructus.

Autoinhibitory mechanism controls binding of centrosomin motif 1 to γ-tubulin ring complex.

The γ-tubulin ring complex (γTuRC) is the principal nucleator of cellular microtubules, and the microtubule-nucleating activity of the complex is stimulated by binding to the γTuRC-mediated nucleation activator (γTuNA) motif. The γTuNA is part of the centrosomin motif 1 (CM1), which is widely found in γTuRC stimulators, including CDK5RAP2. Here, we show that a conserved segment within CM1 binds to the γTuNA and blocks its association with γTuRCs; therefore, we refer to this segment as the γTuNA inhibitor (γTuNA-In). Mutational disruption of the interaction between the γTuNA and the γTuNA-In results in a loss of autoinhibition, which consequently augments microtubule nucleation on centrosomes and the Golgi complex, the two major microtubule-organizing centers. This also causes centrosome repositioning, leads to defects in Golgi assembly and organization, and affects cell polarization. Remarkably, phosphorylation of the γTuNA-In, probably by Nek2, counteracts the autoinhibition by disrupting the γTuNA‒γTuNA-In interaction. Together, our data reveal an on-site mechanism for controlling γTuNA function.

Tumor-Associated Extracellular Microvesicles with Fluorine-Modified Carbohydrate Antigens Trigger a Stronger Antitumor Immune Response.

Abnormal glycosylation is a hallmark of tumor development, and tumor-associated carbohydrate antigens are potential immune targets for tumor therapy. Tumor-associated extracellular microvesicles are subcellular vesicles released from cell membranes that have immunogenicity similar to that of precursor cells. However, unmodified tumor-derived microvesicles have weaknesses, such as low immunogenicity, poor biostability, and short half-life in vivo. For the first time, we herein generated extracellular microvesicles containing modified tumor-associated carbohydrate antigens by constructing a cell line with highly expressed antigen-processing enzymes utilizing fluorine-modified monosaccharide substrates via a metabolic oligosaccharide engineering strategy. The microvesicles were applied to tumor immunity, achieving enhanced immunoprophylaxis and immunotherapy effects. Furthermore, the mechanisms of antitumor immunity were explored. Our findings may provide new insights into the adhibition of suitably modified extracellular microvesicles and the development of more effective carbohydrate-based anticancer vaccines.

Effect of HER2-low-positive status on neoadjuvant chemotherapy and survival outcome of breast cancer: a 10-year dual-center retrospective study.

Various novel HER2-targeted antibody-conjugated drugs (ADCs) have shown satisfactory antitumor activity in HER2-low-positive breast cancer (BC). It is urgent to clarify whether HER2-low-positive tumors have unique biological behavior and should be considered a new molecular subtype. We screened eligible BC patients and collected relevant information at the First Hospital of Jilin University and the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to December 2020. A total of 1027 patients were included in our study cohort, and 66.0% (678/1027) had HER2-low-positive tumors. Compared to HER2-zero patients, HER2-low-positive patients tended to have more lymph node metastasis, a larger proportion of hormone receptor (HR)-positive tumors, and a lower proliferation rate (Ki-67). The pathologic complete response (pCR) rate of HER2-low-positive patients was lower than that of HER2-zero patients (19.3% vs 26.1%), especially in the HR-positive subgroup (12.00% vs 20.29%). However, multivariate logistic regression analysis showed that HER2 status was not an independent factor for predicting pCR. HER2-low-positive patients had a higher overall survival (OS) rate in the HR-positive subgroup. The Cox regression model analysis suggested that HER2-low-positive status did not statistically significantly affect the survival outcomes, regardless of disease-free survival (DFS) (P=0.308) or OS (P=0.066). In conclusion, HER2-low-positive tumors have unique clinical and pathological characteristics, with a lower pCR rate in the HR-positive subgroup and better survival in the HR-negative subgroup compared to HER2-zero tumors. However, the effect of HER2-low-positive status on pCR or survival outcomes was not statistically significant.