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Patients with hormone receptor (HR)-positive tumors breast cancer usually experience a relatively low pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). Here, we derived a 10-microRNA risk score (10-miRNA RS)-based model with better performance in the prediction of pCR and validated its relation with the disease-free survival (DFS) in 755 HR-positive breast cancer patients (273, 265, and 217 in the training, internal, and external validation sets, respectively). This model, presented as a nomogram, included four parameters: the 10-miRNA RS found in our previous study, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, and volume transfer constant (Ktrans). Favorable calibration and discrimination of 10-miRNA RS-based model with areas under the curve (AUC) of 0.865, 0.811, and 0.804 were shown in the training, internal, and external validation sets, respectively. Patients who have higher nomogram score (>92.2) with NAC treatment would have longer DFS (hazard ratio=0.57; 95%CI: 0.39–0.83; P=0.004). In summary, our data showed the 10-miRNA RS-based model could precisely identify more patients who can attain pCR to NAC, which may help clinicians formulate the personalized initial treatment strategy and consequently achieves better clinical prognosis for patients with HR-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is one of the most prevalent cancers worldwide but its etiology remains unclear. Obesity is recognized as a risk factor for BC, and many obesity-related genes may be involved in its occurrence and development. Research assessing the complex genetic mechanisms of BC should not only consider the effect of a single gene on the disease, but also focus on the interaction between genes. This study sought to construct a gene interaction network to identify potential pathogenic BC genes.Methods: The study included 953 BC patients and 963 control individuals. Chi-square analysis was used to assess the correlation between demographic characteristics and BC. The joint density-based non-parametric differential interaction network analysis and classification (JDINAC) was used to build a BC gene interaction network using single nucleotide polymorphisms (SNP). The odds ratio (OR) and 95% confidence interval (95% CI) of hub gene SNPs were evaluated using a logistic regression model. To assess reliability, the hub genes were quantified by edgeR program using BC RNA-seq data from The Cancer Genome Atlas (TCGA) and identical edges were verified by logistic regression using UK Biobank datasets. Go and KEGG enrichment analysis were used to explore the biological functions of interactive genes.Results: Body mass index (BMI) and menopause are important risk factors for BC. After adjusting for potential confounding factors, the BC gene interaction network was identified using JDINAC. LEP, LEPR, XRCC6, and RETN were identified as hub genes and both hub genes and edges were verified. LEPR genetic polymorphisms (rs1137101 and rs4655555) were also significantly associated with BC. Enrichment analysis showed that the identified genes were mainly involved in energy regulation and fat-related signaling pathways.Conclusion: We explored the interaction network of genes derived from SNP data in BC progression. Gene interaction networks provide new insight into the underlying mechanisms of BC. [ABSTRACT FROM AUTHOR]

Purpose: For estrogen receptor (ER)-positive breast cancer, neoadjuvant endocrine therapy (NET) has been shown to be as effective as neoadjuvant chemotherapy (NACT). We evaluated the prognostic significance of Preoperative Endocrine Prognostic Index (PEPI). Methods: We conducted a prospective, multi-center, non-randomized, controlled trial that enrolled postmenopausal early-stage strongly ER-positive (≥ 50%) and HER2-negative breast cancer patients. All patients were given 4-month NET before surgery. The primary objective was to investigate the 5-year recurrence-free survival (RFS) in patients who had PEPI 0–1 or pathological complete response (pCR) without chemotherapy. Patients who had PEPI 0–1 or pCR were recommended to receive adjuvant endocrine therapy only and patients had PEPI ≥ 2 may receive adjuvant chemotherapy at the discretion of the treating physician. Results: A total of 410 patients were included and 352 patients constituted the per-protocol population. Overall, 9 patients (2.5%) had pCR (ypT0/is ypN0), 128 patients (36.4%) had PEPI = 0, and 56 patients (15.9%) had PEPI = 1. After a median follow-up of 60 months (4–104 months), patients who had PEPI 0–1 or pCR showed an improved 5-year RFS [99.5% (95% CI 98.5–99.9%) for PEPI 0–1 or pCR group vs. 93.7% (95% CI 89.6–97.8%) for PEPI ≥ 2 group, P = 0.028]. No survival difference was detected between patients received adjuvant chemotherapy vs. no chemotherapy among PEPI ≥ 2 cases. Conclusion: PEPI 0–1 or pCR may be used to define a group of ER-positive and HER2-negative postmenopausal early breast cancer patients with low relapse risk for whom adjuvant chemotherapy can be safely withheld. Studies on the identification and alternative treatment options for endocrine-resistant tumors are warranted. Clinical trial registration: NCT01613560. [ABSTRACT FROM AUTHOR]

The sediment-water interface in the coastal ocean is a highly dynamic zone controlling biogeochemical fluxes of greenhouse gases, nutrients, and metals. Processes in the sediment mixed layer (SML) control the transfer and reactivity of both particulate and dissolved matter in coastal interfaces. Here we map the global distribution of the coastal SML based on excess 210Pb (210Pbex) profiles and then use a neural network model to upscale these observations. We show that highly dynamic regions such as large estuaries have thicker SMLs than most oceanic sediments. Organic carbon preservation and SMLs are inversely related as mixing stimulates oxidation in sediments which enhances organic matter decomposition. Sites with SML thickness >60 cm usually have lower organic carbon accumulation rates (<50 g C m−2 yr−1) and total organic carbon/specific surface area ratios (<0.4 mg m−2). Our global scale observations reveal that reworking can accelerate organic matter degradation and reduce carbon storage in coastal sediments. The authors map the global distribution of the mixed layer in coastal ocean sediments, based on a neural network model. These observations reveal that mixing can accelerate organic matter degradation and reduce carbon storage in the coastal ocean. [ABSTRACT FROM AUTHOR]

Background: Horizontal gene transfer (HGT) plays a critical role in the spread of antibiotic resistance and the evolutionary shaping of bacterial communities. Conjugation is the most well characterized pathway for the spread of antibiotic resistance, compared to transformation and transduction. While antibiotics have been found to induce HGT, it remains unknown whether non-antibiotic pharmaceuticals can facilitate conjugation at a microbial community-wide level. Results: In this study, we demonstrate that several commonly consumed non-antibiotic pharmaceuticals (including carbamazepine, ibuprofen, naproxen and propranolol), at environmentally relevant concentrations (0.5 mg/L), can promote the conjugative transfer of IncP1-α plasmid-borne antibiotic resistance across entire microbial communities. The over-generation of reactive oxygen species in response to these non-antibiotic pharmaceuticals may contribute to the enhanced conjugation ratios. Cell sorting and 16S rRNA gene amplicon sequencing analyses indicated that non-antibiotic pharmaceuticals modulate transconjugant microbial communities at both phylum and genus levels. Moreover, microbial uptake ability of the IncP1-α plasmid was also upregulated under non-antibiotic pharmaceutical exposure. Several opportunistic pathogens, such as Acinetobacter and Legionella, were more likely to acquire the plasmid conferring multidrug resistance. Conclusions: Considering the high possibility of co-occurrence of pathogenic bacteria, conjugative IncP1-α plasmids and non-antibiotic pharmaceuticals in various environments (e.g., activated sludge systems), our findings illustrate the potential risk associated with increased dissemination of antibiotic resistance promoted by non-antibiotic pharmaceuticals in complex environmental settings. A5CekS1hSG7sRJ8ebfxUwd Video abstract [ABSTRACT FROM AUTHOR]

Radium isotopes are powerful proxies in oceanography and hydrology. Radium mass balance models, including assessments of submarine groundwater discharge (SGD), often overlook particle scavenging (PS) as a pathway for dissolved radium removal from the world ocean. Here, we build a global ocean 226Ra mass balance model and reevaluate the potential importance of PS. We find that PS is the major 226Ra sink for the upper ocean, removing about 96% of the total input from various sources. Aside from vertical exchange with the lower ocean, SGD is the largest 226Ra source into the upper ocean. The biological pump transfers particles to the deep ocean, resulting in a major but often overlooked impact on the global 226Ra marine budget. Our findings suggest that radium mass balance models should consider PS in systems with high siliceous algae production and export fluxes and long water residence times to prevent underestimation of large‐scale SGD fluxes. Plain Language Summary: Radium is a very powerful tracer for many oceanographic processes. A common assumption in radium investigations is that incorporation into particles plays a negligible role in mass balances. Contrary to this assumption, we found that particle scavenging related to the so‐called "biological pump" is the largest sink for 226Ra in the global ocean, and that submarine groundwater discharge is the largest terrestrial input. Particle scavenging can be even more important in highly productive coastal systems with long water residence times and high particle burial efficiencies. Particle scavenging, which has been overlooked in many mass balance calculations, may be important for 226Ra and 228Ra budgets from local to global scales. Key Points: Particle scavenging is the major 226Ra sink for the upper ocean, removing about 96% of the total input from various sourcesSubmarine groundwater discharge (SGD) is the largest terrestrial 226Ra source into the upper ocean, followed by river input and sediment diffusionParticle scavenging can be important in coastal oceans with high primary production and particle burial efficiencies [ABSTRACT FROM AUTHOR]

Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy [...]