Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors, progesterone receptors and lacks HER2 overexpression. This absence of critical molecular targets poses ...significant challenges for conventional therapies. Immunotherapy, remarkably immune checkpoint blockade, offers promise for TNBC treatment, but its efficacy remains limited. Epigenetic dysregulation, including altered DNA methylation, histone modifications, and imbalances in regulators such as BET proteins, plays a crucial role in TNBC development and resistance to treatment. Hypermethylation of tumor suppressor gene promoters and the imbalance of histone methyltransferases such as EZH2 and histone deacetylases (HDACs) profoundly influence tumor cell proliferation, survival, and metastasis. In addition, epigenetic alterations critically shape the tumor microenvironment (TME), including immune cell composition, cytokine signaling, and immune checkpoint expression, ultimately contributing to immune evasion. Targeting these epigenetic mechanisms with specific inhibitors such as EZH2 and HDAC inhibitors in combination with immunotherapy represents a compelling strategy to remodel the TME, potentially overcoming immune evasion and enhancing therapeutic outcomes in TNBC. This review aims to comprehensively elucidate the current understanding of epigenetic modulation in TNBC, its influence on the TME, and the potential of combining epigenetic therapies with immunotherapy to overcome the challenges posed by this aggressive breast cancer subtype.
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Abstract
Metasurfaces have provided a promising approach to enhance the nonlinearity at subwavelength scale, but usually suffer from a narrow bandwidth as imposed by sharp resonant features. Here, we ...counterintuitively report a broadband, enhanced second-harmonic generation, in nanopatterned hyperbolic metamaterials. The nanopatterning allows the direct access of the mode with large momentum, rendering the rainbow light trapping, i.e. slow light in a broad frequency, and thus enhancing the local field intensity for boosted nonlinear light-matter interactions. For a proof-of-concept demonstration, we fabricated a nanostructured Au/ZnO multilayer, and enhanced second harmonic generation can be observed within the visible wavelength range (400-650 nm). The enhancement factor is over 50 within the wavelength range of 470-650 nm, and a maximum conversion efficiency of 1.13×10
−6
is obtained with a pump power of only 8.80 mW. Our results herein offer an effective and robust approach towards the broadband metasurface-based nonlinear devices for various important technologies.
A novel H7N9 influenza A virus first detected in March 2013 has since caused more than 130 human infections in China, resulting in 40 deaths. Preliminary analyses suggest that the virus is a ...reassortant of H7, N9 and H9N2 avian influenza viruses, and carries some amino acids associated with mammalian receptor binding, raising concerns of a new pandemic. However, neither the source populations of the H7N9 outbreak lineage nor the conditions for its genesis are fully known. Using a combination of active surveillance, screening of virus archives, and evolutionary analyses, here we show that H7 viruses probably transferred from domestic duck to chicken populations in China on at least two independent occasions. We show that the H7 viruses subsequently reassorted with enzootic H9N2 viruses to generate the H7N9 outbreak lineage, and a related previously unrecognized H7N7 lineage. The H7N9 outbreak lineage has spread over a large geographic region and is prevalent in chickens at live poultry markets, which are thought to be the immediate source of human infections. Whether the H7N9 outbreak lineage has, or will, become enzootic in China and neighbouring regions requires further investigation. The discovery here of a related H7N7 influenza virus in chickens that has the ability to infect mammals experimentally, suggests that H7 viruses may pose threats beyond the current outbreak. The continuing prevalence of H7 viruses in poultry could lead to the generation of highly pathogenic variants and further sporadic human infections, with a continued risk of the virus acquiring human-to-human transmissibility.
Input uncertainty and deficiencies in the key elements of hydrologic models are fundamental challenges to improving model performance. Evapotranspiration (ET) models are sensitive to energy imbalance ...and energy interaction between the canopy and surface, and these errors can bias model simulation. This paper presents a Bayesian framework that accounts for energy imbalance and energy interaction uncertainty in calibration of the Shuttleworth‐Wallace (SW) model and discusses whether these efforts can improve the SW model performance. Specifically, the DiffeRential Evolution Adaptive Metropolis (DREAM) algorithm is used to analyze the energy imbalance error and energy interaction correction during SW model calibration, and Bayesian model evidence (BME) is used to scrutinize multiple hypotheses about alternative representations of energy. The results indicate that explicit treatment of the energy imbalance and conceptual corrections of the energy interaction significantly reduce the uncertainty of model parameters and provide energy corrections that are more appropriate and largely improve the SW model performance. Moreover, the optimal model selected by BME is mostly consistent with that evaluated using traditional statistical criteria (TSC) during a validation period. This result shows that the improved SW model also provides the best predictions, and thus consistent model selection should also be asymptotically efficient. The findings may allow improvement of ET model performance, and hence the accuracy of hydrologic and climatic simulations, toward fully understanding the key process underlying hydrologic and climatic variability and change over land.
Key Points
Energy input uncertainty and energy interactions are constrained in evapotranspiration modeling
The evapotranspiration model is improved by incorporating energy correction terms
Alternative representations of energy are scrutinized using Bayesian model evidence
MicroRNAs (miRNAs) are small noncoding nucleotides that play major roles in the response of host immune cells. Autophagy plays a key role in activating the antimicrobial host defense against ...Mycobacterium tuberculosis (M. tuberculosis). Whether miRNAs specifically influence the activation of macrophage autophagy during M. tuberculosis infection is largely unknown. In the present study, we demonstrate that Mycobacterium bovis Bacillus Calmette-Guérin (BCG) infection of macrophages leads to increased expression of miR-144-3p, which targets autophagy-related gene 4a (ATG4a), to inhibit autophagy activation and antimicrobial responses to BCG. Overexpression of miR-144-3p significantly decreased both mRNA and protein levels of ATG4a, inhibited the formation of autophagosomes in RAW264.7 cells and increased intracellular survival of BCG. However, transfection with miR-144-3p inhibitor led to an increase in ATG4a levels, accelerated the autophagic response in macrophages, and decreased BCG survival in macrophages. The experimental results of this study reveal a novel role of miR-144-3p in inhibiting autophagy activation by targeting ATG4a and enhancing BCG infection, and provide potential targets for developing improved treatment.
INTRODUCTION:
In the United States, it is recommended that pregnancies of unknown location (PUL) are evaluated with serial β-hCG levels until undetectable or location identified. In Britain, a ...declining β-hCG level of greater than 50% is considered low risk for ectopic pregnancy, and serial β-hCG measurements are stopped. We sought to investigate the effectiveness of British criteria in excluding ectopic gestation in the management of PUL in an urban U.S. population.
METHODS:
Retrospective study, collection, and statistical analysis of key data points in all patients seen at Jamaica Hospital Medical Center over a 3-year period between January 1, 2019 and December 31, 2021, with PUL were performed.
RESULTS:
Of 260 patients evaluated for PUL, 52 (20%) were ultimately diagnosed with ectopic pregnancies, 72% (28%) with intrauterine pregnancies, and 136 (52%) with spontaneous or missed abortions. A greater than 50% decrease in β-hCG was identified in 62 (24%) patients and was significantly associated with nonectopic gestation (
P
<.001). Of these patients, only one patient (1.6%) had an ectopic gestation. The β-hCG of the patient with ectopic declined from 649 to 240 in the first 48 hours, and then rose to 546 at 96 hours. A presumptive diagnosis of ectopic was made, for which methotrexate was administered.
CONCLUSION:
Retrospective application of British criteria for PUL successfully predicted greater than 98% of patients with low-risk gestation. Using this criterion would have resulted in 19% fewer visits and 19.9% fewer β-hCG levels drawn. However, one presumptive ectopic was missed. Public health guidelines must balance cost and safety criteria. Larger prospective studies with built-in safety mechanisms and strictly defined outcome criteria are needed to better characterize the safety profile and potential cost savings of the application of the British guidelines for PUL to a U.S. population.
Abstract
Background
B7 homology 4 (B7-H4), a potential target for cancer therapy, has been demonstrated to inhibit T cell cytotoxicity in the early stages of breast cancer. However, B7-H4 ...manipulating breast tumor immune microenvironment (TIME) in the tumor progression remains unknown.
Methods
We engineered T cells with B7-H4-specific chimeric antigen receptors (CARs) and performed a T cell co-culture assay to characterize B7-H4 expression level in breast cancer cells escaping from T cell cytotoxicity. We generated B7-H4 knockout (KO) and overexpression (OE) breast cancer cells to determine the epithelial-to-mesenchymal transition (EMT) and stemness characteristics in vitro and in vivo, including tumor proliferation, migration, metastasis and chemoresistance. The Cancer Genome Atlas breast cancer database was accessed to investigate the correlation between B7-H4 expression levels and EMT characteristics in patients with breast cancer.
Results
Our result found that B7-H4 expression level was significantly reduced in a subset of breast cancer cells that escaped from the cytotoxicity of B7-H4 CAR-T cells. Compared with wild type cells, B7-H4 KO cells prompt EMT and stemness characteristics, including migration, invasion and metastasis, and OE cells vice versa. The increase in H3K27me3 in KO cells confirmed the epigenetic reprogramming of cancer stem cells. The IC50 of doxorubicin or oxaliplatin significantly increased in KO cells, which was in agreement with a decrease in OE cells. Moreover, a trend of downregulated B7-H4 from stage I to stage II breast cancer patients indicates that the low-expressing B7-H4 breast cancer cells escaping from TIME have spread to nearby breast lymph nodes in the cancer progression.
Conclusions
Our study illuminates the novel role of renouncing B7-H4 in breast cancer cells through immune escape, which contributes to EMT processes and provides new insights for breast cancer treatments.
BACKGROUNDThe risk of low back pain (LBP) increases steeply during adolescence, and adolescents with LBP are more likely to have low back pain in their adult years. This study aimed to investigate ...the dose-response relationship between daily screen time and the risk of low back pain among children and adolescents.METHODSPubMed, the Cochrane Library, Embase, and Web of Science were searched to collect relevant studies on daily screen time and the risk of low back pain from the establishment of the database up to December 2022. Two investigators independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. Stata16.0 was used to perform a dose-response meta-analysis and the methodological quality evaluation of the included studies.RESULTSThe results of the meta-analysis showed that there is a positive correlation between daily computer time (OR = 1.32, 1.05-1.60), daily mobile phone time (OR = 1.32, 1.00-1.64), daily TV watching (OR = 1.07, 1.04-1.09) and the risk of low back pain, separately. The dose-response meta-analysis showed that there is a linear relationship between daily computer use and low back pain. The risk of low back pain increased by 8.2% for each 1-hour of daily computer use.CONCLUSIONSScreen time is related to the risk of low back pain, and there is a linear relationship between daily computer use and the risk of low back pain. A number of strategic measures should be taken to prevent adolescents from developing severe low back pain.
Highlights
An ultra-stable all-weather service piezoelectric nanogenerator (PENG) with a wide operating temperature range (-80~80 ℃) and a wide operating relative humidity range (0~100%) is ...proposed.
The PENG based on N doped 4H-SiC exhibits long-term service stability up to 50 days.
The short circuit current density of PENG based on N doped 4H-SiC is enhanced significantly.
Ultra-stable piezoelectric nanogenerator (PENG) driven by environmental actuation sources with all-weather service capability is highly desirable. Here, the PENG based on N doped 4H-SiC nanohole arrays (NHAs) is proposed to harvest ambient energy under low/high temperature and relative humidity (RH) conditions. Finite element method simulation of N doped 4H-SiC NHAs in compression mode is developed to evaluate the relationship between nanohole diameter and piezoelectric performance. The density of short circuit current of the assembled PENG reaches 313 nA cm
−2
, which is 1.57 times the output of PENG based on N doped 4H-SiC nanowire arrays. The enhancement can be attributed to the existence of nanohole sidewalls in NHAs. All-weather service capability of the PENG is verified after being treated at -80/80 ℃ and 0%/100% RH for 50 days. The PENG is promising to be widely used in practice worldwide to harvest biomechanical energy and mechanical energy.
We engineered small molecule responsive allosteric ribozymes based on the genomic hepatitis delta virus (HDV) ribozyme by replacing the P4-L4 stem-loop with an RNA aptamer through a connector stem. ...When embedded in the 3′ untranslated region of a reporter gene mRNA, these RNA devices enabled regulation of cis-gene expression by theophylline and guanine by up to 29.5-fold in mammalian cell culture. Furthermore, a NOR logic gate device was constructed by placing two engineered ribozymes in tandem, demonstrating the modularity of the RNA devices. The significant improvement in the regulatory dynamic range (ON/OFF ratio) of the RNA devices based on the HDV ribozyme should provide new opportunities for practical applications.
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