Efficacy and safety comparison between axillary lymph node dissection with no axillary surgery in patients with sentinel node-positive breast cancer: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to study the evidence on the efficacy and safety of omitting axillary lymph node dissection (ALND) for patients with clinically node-negative but sentinel lymph node (SLN)-positive breast cancer using all the available evidence. METHODS: The Embase, Medline, and Cochrane Library databases were searched through February 25, 2023. Original trials that compared only the sentinel lymph node biopsy (SLNB) with ALND as the control group for patients with clinically node-negative but SLN-positive breast cancer were included. The primary outcomes were axillary recurrence rate, total recurrence rate, disease-free survival (DFS), and overall survival (OS). Meta-analyses were performed to compare the odds ratio (OR) in rates and the hazard ratios (HR) in time-to-event outcomes between both interventions. Based on different study designs, tools in the revised Cochrane risk of bias tool were used for randomized trials and the risk of bias in nonrandomized studies of interventions to assess the risk of bias for each included article. Funnel plots and Egger's test were used for the publication's bias assessment. RESULTS: In total, 30 reports from 26 studies were included in the systematic review (9 reports of RCTs, 21 reports of retrospective cohort studies). According to our analysis, omitting ALND in patients with clinically node-negative but SLN-positive breast cancer had a similar axillary recurrence rate (OR = 0.95, 95% confidence interval (CI): 0.76-1.20), DFS (HR = 1.02, 95% CI: 0.89-1.16), and OS (HR = 0.97, 95% CI: 0.92-1.03), but caused a significantly lower incidence of adverse events and benefited in locoregional recurrence rate (OR = 0.76, 95% CI: 0.59-0.97) compared with ALND. CONCLUSION: For patients with clinically node-negative but SLN-positive breast cancer (no matter the number of the positive SLN), this review showed that SLNB alone had a similar axillary recurrence rate, DFS, and OS, but caused a significantly lower incidence of adverse events and showed a benefit for the locoregional recurrence compared with ALND. An OS benefit was found in the Macro subset that used SLNB alone versus complete ALND. Therefore, omitting ALND is feasible in this setting. TRIAL REGISTRATION: CRD 42023397963.

Mitochondrial DNA haplogroup D4b is a protective factor for ischemic stroke in Chinese Han population.

Mitochondrial DNA (mtDNA) haplogroups affect the assembly and stability of the mitochondrial respiratory chain, which is potentially related to susceptibility to ischemic stroke (IS). However, the role of mtDNA in IS has not been comprehensively studied. The purpose of this study was to explore whether mtDNA polymorphisms and haplogroups are involved in the etiology of IS in the Chinese Han population. We recruited 200 patients with IS and 200 matched controls and genotyped them for 18 mtDNA single nucleotide polymorphisms defining the major Eastern Asian haplogroups by SNaPshot minisequencing. We also sequenced the hypervariable segment I (HVS-I), position 16051-16400. The prevalence of haplogroup D4b was significantly lower in IS patients than in healthy controls (0 and 8 %, respectively, corrected P = 2 × 10(-5), odds ratio = 0.028, 95 % confidence interval = 0.002-0.468).The positive association between haplogroup D4b and IS may be related to the protective effect of haplogroup D4b against oxidative damage, which decreases the risk of IS. Our study provides the first evidence that haplogroup D4b is a potential genetic protective factor for IS in the Chinese Han population.

Dynamic role of CUL4B in radiation-induced intestinal injury-regeneration.

CUL4B, a crucial scaffolding protein in the largest E3 ubiquitin ligase complex CRL4B, is involved in a broad range of physiological and pathological processes. While previous research has shown that CUL4B participates in maintaining intestinal homeostasis and function, its involvement in facilitating intestinal recovery following ionizing radiation (IR) damage has not been fully elucidated. Here, we utilized in vivo and in vitro models to decipher the role of CUL4B in intestinal repair after IR-injury. Our findings demonstrated that prior to radiation exposure, CUL4B inhibited the ubiquitination modification of PSME3, which led to the accumulation of PSME3 and subsequent negative regulation of p53-mediated apoptosis. In contrast, after radiation, CUL4B dissociated from PSME3 and translocated into the nucleus at phosphorylated histones H2A (γH2AX) foci, thereby impeding DNA damage repair and augmenting p53-mediated apoptosis through inhibition of BRCA1 phosphorylation and RAD51. Our study elucidated the dynamic role of CUL4B in the repair of radiation-induced intestinal damage and uncovered novel molecular mechanisms underlying the repair process, suggesting a potential therapeutic strategy of intestinal damage after radiation therapy for cancers.

Enhanced ApcMin/+ adenoma formation after epithelial CUL4B deletion by recruitment of myeloid-derived suppressor cells.

Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing ApcMin/+ mice with Cul4bΔIEC mice to achieve specific deletion of Cul4b in the gut epithelium against an ApcMin/+ background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited ApcMin/+ adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted ApcMin/+ adenomas. Furthermore, the addition of MDSCs to in vitro cultured ApcMin/+; Cul4bΔIEC adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating ApcMin/+ adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.

IOX1 epigenetically enhanced photothermal therapy of 3D-printing silicene scaffolds against osteosarcoma with favorable bone regeneration.

Osteosarcoma (OS) is the third most common malignancy in adolescence. Currently, the treatments of OS confront great obstacles of tumor recurrence and critical bone defects after surgery, severely affecting the survival rates and living qualities of patients. Hence, it is urged to develop distinct biomaterials with both efficient tumor therapeutic and osteogenic functions. Although photothermal therapy (PTT) has aroused expanding interest, characterizing negligible invasiveness and high spatiotemporal adjustment, few studies discussed its drawbacks, such as thermal injury to adjacent normal tissue and exceeded laser power density, implying that focusing on sensitizing OS to PTT instead of simply elevating the laser power density may be a fresh way to enhance the PTT efficacy and attenuate the side/adverse effects. Herein, we successfully constructed 3D-printing silicene bioactive glass scaffolds with preferable PTT efficacy at the second near-infrared (NIR-II) biowindow and outstanding osteogenic biofunctions owing to the release of bioactive elements during degradation. Impressively, a histone demethylase inhibitor, IOX1, was introduced before PTT to sensitize OS to thermal therapy and minimize the side/adverse effects. This work offered a distinctive paradigm for optimizing the PTT efficacy of osteogenic scaffolds against OS with epigenetic modulation agents.

Cullin 4b-RING ubiquitin ligase targets IRGM1 to regulate Wnt signaling and intestinal homeostasis.

Hierarchical organization of intestine relies on the self-renewal and tightly regulated differentiation of intestinal stem cells (ISCs). Although signals like Wnt are known to sustain the continued intestinal renewal by maintaining ISCs activity and lineage commitment, molecular mechanisms underlying ISCs 'stemness' and supportive niche have not been well understood. Here, we found that CUL4B-RING ubiquitin ligase (CRL4B) regulates intestinal homeostasis by targeting immunity-related GTPase family M member 1 (IRGM1) for proteasomal degradation. CUL4B was mainly expressed at ISCs zone. Deletion of Cul4b led to reduced self-renewal of ISCs and a decreased lineage differentiation towards secretory progenitors through downregulated Wnt signals. Besides, Cul4b-null mice exhibited impaired Paneth cells number and structure. Mechanistically, CRL4B complex were associated with WD40 proteins and targeted IRGM1 at K270 for ubiquitination and proteosomal degradation. Impaired intestinal function caused by CUL4B deletion was rescued by down-regulation of its substrate IRGM1. Our results identified CUL4B as a novel regulator of ISCs and revealed a new 26 S proteasome degradation mechanism in intestine self-renewal and lineage commitment.

Pinocembrin Inhibits the Proliferation and Metastasis of Breast Cancer via Suppression of the PI3K/AKT Signaling Pathway.

The survival rate of breast cancer (BC) patients remains poor, thus the identification of safe and effective new drugs is crucial to improve therapeutic outcomes and overall survival. Pinocembrin (PCB), a pharmacologically active ingredient of Pinus heartwood, Eucalyptus, Euphorbia, Populus, and Sparattosperma leucanthum, has been widely applied for the treatment of various diseases and possesses anticancer activities. In vitro assays were performed to investigate the antiproliferation and antimetastasis activities of PCB in BC cells. A tumorigenesis assay with the use of murine BC models was performed to assess the antiproliferation activities of PCB in vivo. Moreover, the molecular mechanisms underlying the anticancer activities of PCB in BC cells were explored. The results showed that the anti-inhibitory and antiproliferation activities of PCB in BC might involve cell cycle (G2/M phase) arrest and apoptosis. PCB downregulated the expression levels of proteins involved in cell cycle progression and apoptosis, including cyclinB1, Cdc2, PARP1, Bcl-2, and survivin, and upregulated protein levels of cleaved PARP1, cleaved caspase3, cleaved caspase9, and BAX. In a murine subcutaneous tumor model, PCB suppressed the growth of MCF-7 cells in vivo. Low concentrations of PCB also significantly inhibited the migration and invasion abilities of BC cells. Mechanistically, PCB administration was correlated to suppression of the PI3K/AKT signaling pathway. Inhibition of the proliferation of BC cells by PCB involved cell cycle (G2/M phase) arrest and apoptosis in vitro and in vivo. Low concentrations of PCB also significantly inhibited the migration and invasion abilities of BC cells. These findings suggest that PCB might be an effective agent for treatment of BC patients.

Polypropylene/Polyvinyl Alcohol/Metal-Organic Framework-Based Melt-Blown Electrospun Composite Membranes for Highly Efficient Filtration of PM2.5.

Particulate matter 2.5 (PM2.5) has become a public hazard to people's lives and health. Traditional melt-blown membranes cannot filter dangerous particles due to their limited diameter, and ultra-fine electrospinning fibers are vulnerable to external forces. Therefore, creating highly efficient air filters by using an innovative technique and structure has become necessary. In this study, a combination of polypropylene (PP) melt-blown and polyvinyl alcohol (PVA)/zeolite imidazole frameworks-8 (ZIF-8) electrospinning technique is employed to construct a PP/PVA/ZIF-8 membrane with a hierarchical fibrous structure. The synergistic effect of hierarchical fibrous structure and ZIF-8 effectively captures PM2.5. The PP/PVA composite membrane loaded with 2.5% loading ZIF-8 has an average filtration efficacy reaching as high as 96.5% for PM2.5 and quality factor (Qf) of 0.099 Pa-1. The resultant membrane resists 33.34 N tensile strength and has a low pressure drop, excellent filtration efficiency, and mechanical strength. This work presents a facile preparation method that is suitable for mass production and the application of membranes to be used as air filters for highly efficient filtration of PM2.5.

CUL4B contributes to cancer stemness by repressing tumor suppressor miR34a in colorectal cancer.

Given that colorectal cancer stem cells (CCSCs) play key roles in the tumor dormancy, metastasis, and relapse, targeting CCSCs is a promising strategy in cancer therapy. Here, we aimed to identify the new regulators of CCSCs and found that Cullin 4B (CUL4B), which possesses oncogenic properties in multiple solid tumors, drives the development and metastasis of colon cancer by sustaining cancer stem-like features. Elevated expression of CUL4B was confirmed in colon tumors and was associated with poor overall survival. Inhibition of CUL4B in cancer cell lines and patient-derived tumor organoids led to reduced sphere formation, proliferation and metastasis capacity. Mechanistically, CUL4B coordinates with PRC2 complex to repress miR34a expression, thus upregulates oncogenes including MYCN and NOTCH1, which are targeted by miR34a. Furthermore, we found that elevated CUL4B expression is associated with miR34a downregulation and upregulation of miR34a target genes in colon cancer specimens. Collectively, our findings demonstrate that CUL4B functions to repress miR34a in maintaining cancer stemness in CRC and provides a potential therapeutic target.

A promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP gene is associated with decreased risk of ischemic stroke in two independent Chinese populations.

No coding sequence variants of the gene encoding 5-lipoxygenase-activating protein (ALOX5AP) leading to amino acid substitutions have been identified. Therefore, variants in the ALOX5AP promoter region have received attention recently. The purpose of this study was to explore whether the promoter polymorphism rs17222919 is involved in the etiology of ischemic stroke (IS) in the Chinese Han population. We investigated the rs17222919 polymorphism by TaqMan genotyping in two independent Chinese Han samples: the first comprised 910 IS patients and 925 healthy inhabitants from the northern Henan Province, while the second included 1003 IS patients and 889 healthy controls from the southern Henan Province. Functional characterization of rs17222919 was performed by an in vitro luciferase assay. After adjusting for conventional risk factors, the G allele frequencies in the IS groups were significantly lower than that in the control groups of the two independent Chinese cohorts (19.0% vs. 22.9%, P = 0.004, odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.675-0.929; 18.8% vs. 22.9%, P = 0.002, OR = 0.782, 95% CI = 0.668-0.915, respectively). This was also observed in the large-artery atherosclerosis (LAA) and stroke of other undetermined etiology (SUE) subtypes (P = 0.019, OR = 0.815, 95% CI = 0.687-0.967; P = 0.021, OR = 0.815, 95% CI = 0.685-0.970, respectively). Additionally, the TG genotype and G allele frequencies were significantly lower in the IS compared with the control group in two female cohorts (P<0.05). Finally, the in vitro luciferase assay demonstrated that the G allele has a significantly lower transcription activity than the T allele (P = 0.031). Our study provides evidence that the promoter single nucleotide polymorphism (SNP) rs17222919 is a potential genetic protective factor for IS in the Chinese Han population.

Association between VKORC1 gene polymorphisms and ischemic cerebrovascular disease in Chinese Han population.

The vitamin K epoxide reductase subunit 1 gene (VKORC1) plays a key role in vitamin K recycling, and there is a close association between VKORC1 gene single-nucleotide polymorphisms (SNPs) and the required dose of warfarin, an anticoagulant. However, the association between VKORC1 SNPs and ischemic cerebrovascular disease (ICVD) has not been defined. This case-control study involved 370 patients with ICVD and 408 healthy individuals (controls) from Chinese Han population. Two VKORC1 gene SNPs (1639A/G and 1173T/C) were genotyped by PCR-RFLP method. The G allele frequencies of the 1639A/G locus and C allele frequencies of the 1173T/C locus were higher in the ICVD group than in the control group (p = 0.014 and p = 0.008, respectively). Haplotype analysis showed that 1639G-1173C was associated with an increased risk of ICVD (odds ratio (OR) = 1.163, 95 % confidence interval (CI) = 1.137~2.288), while 1639A-1173T was associated with decreased risk of ICVD (OR = 0.620, 95 % CI = 0.437~0.880). Our findings suggested that individuals carrying the 1639G or 1173C allele might be at increased risk for ICVD. Furthermore, the 1639G-1173C haplotype was a risk factor for ICVD, and 1639A-1173T was a protective factor in Chinese Han population.

A novel risk haplotype of ALOX5AP gene is associated with ischemic stroke in Chinese Han population.

Previous studies have implicated that two at-risk haplotypes (HapA and HapB) of gene-encoding 5-lipoxygenase-activating protein (ALOX5AP) were significantly associated with stroke. The aim of this study was to explore the association between haplotypes of ALOX5AP gene and risk for ischemic stroke (IS) in Chinese Han population. A total of 492 patients with IS and 490 matched control subjects were recruited. Six ALOX5AP SNPs (SG13S377, SG13S114, SG13S41, SG13S89, SG13S32 and SG13S35) were genotyped by SNaPshot minisequence technique. A common genetic variant SG13S114/AA in the ALOX5AP gene was associated with IS in this Chinese cohort (OR = 2.514, 95 % CI = 1.667 ~ 3.790). HapA (TGA) and HapB (AAAG) had no significant difference in the patients (36.3 and 18.5 %, respectively) and controls (37.6 and 16.3 %, respectively) (P = 0.631 and P = 0.375, respectively). But, the frequency of Hap (GAAG) was significantly higher in the patients than that in the controls after Bonferroni's adjustment (P = 0.006). To conclude, SG13S114/AA of the ALOX5AP gene was associated with an increased risk for IS. A novel risk haplotype, Hap (GAAG) was a genetic risk factor for IS in this Chinese population.