Human Umbilical Cord Mesenchymal Stem Cells Improve Lung Function in Chronic Obstructive Pulmonary Disease Rat Model Through Regulating Lung Microbiota.

BACKGROUND: The use of human umbilical cord mesenchymal stem cells (UC-MSCs) has shown promise in improving the pathophysiological characteristics of rats with chronic obstructive pulmonary disease (COPD). However, more research is needed to understand the exact mechanism behind their therapeutic effects and their impact on lung microbiota. METHODS: To investigate this, rats were randomly assigned to one of 3 groups: Control, COPD + vehicle, and COPD + UC-MSCs group. Lung function changes after UC-MSCs therapy were evaluated weekly for 6 weeks. Additionally, lactate dehydrogenase (LDH), TNF (tumor necrosis factor)-α, IL (interleukin)-6, and IL-1ß level in bronchoalveolar lavage fluid (BALF) were analyzed. Arterial blood gas and weight were recorded. Hematoxylin and eosin (HE) staining was used to examine lung pathology, while changes in the lung microbiota were evaluated through 16S rRNA sequencing. RESULTS: The administration of UC-MSCs in rats led to a progressive amelioration of COPD, as demonstrated by enhanced lung function and reduced inflammatory response. UC-MSCs treatment significantly altered the structure and diversity of the lung microbiota, effectively preventing microbiota dysbiosis. This was achieved by increasing the abundance of Bacteroidetes and reducing the levels of Proteobacteria. Additionally, treatment with UC-MSCs reduced the activation of pathways associated with COPD, including microbial metabolism, ABC transporters, and Quorum sensing. The group of UC-MSCs showed increased metabolic pathways, such as amino acid biosynthesis, purine metabolism, starch and sucrose metabolism, and biosynthesis of secondary metabolites, compared to the COPD group. CONCLUSIONS: The use of UC-MSCs was found to reduce inflammation and improve lung function in rats with COPD. The mechanism may be related to the lung microbiota, as UC-MSCs improved the communities of lung microbiota and regulated dysregulated metabolic pathways.

The target region focused imaging method for scanning ion conductance microscopy.

Scanning ion conductance microscopy (SICM) has developed rapidly and has wide applications in biomedicine, single-cell science and other fields. SICM scanning speed is limited by the conventional raster-type scanning method, which spends most of time on imaging the substrate and does not focus enough on the target area. In order to solve this problem, a target region focused (TRF) method is proposed, which can effectively avoid the scanning of unnecessary substrate areas and enables SICM to image the target area only to achieve high-speed and effective local scanning. TRF method and conventional hopping mode scanning method are compared in the experiments using breast cancer cells and rat basophilic leukemia cells as experimental materials. It was demonstrated that our method can reduce the scanning time for a single sample image significantly without losing scanning information or compromising the quality of imaging. The TRF method developed in this paper can provide an efficient and fast scanning strategy for improving the imaging performance of SICM systems, which can be applied to the dynamic features of cell samples in the fields of biology and pharmacology analysis.

Dual Enzyme Cascade-Activated Popcorn-Like Nanoparticles Efficiently Remodeled Stellate Cells to Alleviate Pancreatic Desmoplasia.

In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors.

Enhancement of Microglia Functions by Developed Nano-Immuno-Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment.

Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and D PPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist (D PAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors.

Occlusion of two semicircular canals does not disrupt normal hearing in adult mice.

Vertigo is a debilitating disease affecting 15-20% of adults worldwide. Vestibular peripheral vertigo is the most common cause of vertigo, often due to Meniere's disease and benign paroxysmal positional vertigo. Although some vertigo symptoms can be controlled by conservative treatment and/or vestibular rehabilitation therapy, these treatments do not work for some patients. Semicircular canal occlusion surgery has proven to be very effective for these patients with intractable vertigo. However, its application is limited due to concern that the procedure will disrupt normal hearing. In this study, we investigated if occlusion of two semicircular canals would jeopardize auditory function by comparing auditory function and hair cell morphology between the surgical and contralateral ears before and after the surgery in a mouse model. By measuring the auditory brainstem response and distortion product otoacoustic emission 4 weeks post-surgery, we show that auditory function does not significantly change between the surgical and contralateral ears. In addition, confocal imaging has shown no hair cell loss in the cochlear and vestibular sensory epithelia, and scanning electron microscopy also indicates normal stereocilia morphology in the surgical ear. More importantly, the endocochlear potential measured from the surgical ear is not significantly different than that seen in the contralateral ear. Our study suggests that occlusion of two semicircular canals does not disrupt normal hearing in the mouse model, providing a basis to extend the procedure to patients, even those with normal hearing, benefitting more patients with intractable vertigo attacks.

Cholinergic Neuron Targeting Nanosystem Delivering Hybrid Peptide for Combinatorial Mitochondrial Therapy in Alzheimer's Disease.

Mitochondrial dysfunction in neurons has recently become a promising therapeutic target for Alzheimer's disease (AD). Regulation of dysfunctional mitochondria through multiple pathways rather than antioxidation monotherapy indicates synergistic therapeutic effects. Therefore, we developed a multifunctional hybrid peptide HNSS composed of antioxidant peptide SS31 and neuroprotective peptide S14G-Humanin. However, suitable peptide delivery systems with excellent loading capacity and effective at-site delivery are still absent. Herein, the nanoparticles made of citraconylation-modified poly(ethylene glycol)-poly(trimethylene carbonate) polymer (PEG-PTMC(Cit)) exhibited desirable loading of HNSS peptide through electrostatic interactions. Meanwhile, based on fibroblast growth factor receptor 1(FGFR1) overexpression in both the blood-brain barrier and cholinergic neuron, an FGFR1 ligand-FGL peptide was modified on the nanosystem (FGL-NP(Cit)/HNSS) to achieve 4.8-fold enhanced accumulation in brain with preferred distribution into cholinergic neurons in the diseased region. The acid-sensitive property of the nanosystem facilitated lysosomal escape and intracellular drug release by charge switching, resulting in HNSS enrichment in mitochondria through directing of the SS31 part. FGL-NP(Cit)/HNSS effectively rescued mitochondria dysfunction via the PGC-1α and STAT3 pathways, inhibited Aß deposition and tau hyperphosphorylation, and ameliorated memory defects and cholinergic neuronal damage in 3xTg-AD mice. The work provides a potential platform for targeted cationic peptide delivery, harboring utility for peptide therapy in other neurodegenerative diseases.

DDX5: an expectable treater for viral infection- a literature review.

Background and Objective: DEAD-box protein (DDX)5 plays important roles in multiple aspects of cellular processes that require modulating RNA structure. Alongside the canonical role of DDX5 in RNA metabolism, many reports have shown that DDX5 influences viral infection by directly interacting with viral proteins. However, the functional role of DDX5 in virus-associated cancers, as well as the identity of DDX5 in virus infection-associated signaling pathways, has remained largely unexplained. Here, we further explore the precise functions of DDX5 and its potential targets for antiviral treatment. Methods: We searched the PubMed and PMC databases to identify studies on role of DDXs, especially DDX5, during various viral infection published up to May 2022. Key Content and Findings: DDX5 functions as both a viral infection helper and inhibitor, which depends on virus type. DDXs proteins have been identified to play roles on multiple aspects covering RNA metabolism and function. Conclusions: DDX5 influences viral pathogenesis by participating in viral replication and multiple viral infection-related signaling pathways, it also plays a double-edge sword role under different viral infection conditions. Deep investigation into the mechanism of DDX5 modulating immune response in host cells revealed that it holds highly potential usage for future antiviral therapy. We reviewed current studies to provide a comprehensive update of the role of DDX5 in viral infection.

[Clinical analysis and surgical treatment of congenital external auditory canal stenosis complicated with external auditory canal cholesteatoma].

Objective:To investigate the clinical features, diagnosis, and treatment experience of congenital stenosis of an external auditory canal with external auditory canal cholesteatoma. Methods:The clinical data of 152 patients（153 ears） with congenital external auditory canal stenosis complicated with external auditory canal cholesteatoma treated in the Department of Otorhinolaryngology Head and Neck Surgery of Beijing Tongren Hospital affiliated to Capital Medical University from January 2009 to December 2019 were analyzed retrospectively, including the age of onset, clinical manifestations, signs, audiology, high-resolution computed tomography（HRCT） of the temporal bone, mode of operation and so on. According to the preoperative imaging findings, intraoperative findings,and pathological results, 152 patients with congenital external auditory canal stenosis with external auditory canal cholesteatoma were treated with canaloplasty and tympanoplasty while clearing the cholesteatoma. Results:All patients were followed up for 2-2.5 years, there was no recurrence of cholesteatoma, and the reconstructed external auditory canal was spacious. The hearing levels of 108 ears who underwent hearing reconstruction were significantly improved, and the average hearing threshold was reduced by 20-35 dB. Conclusion:The stenosis of the external auditory meatus is easy to be complicated with cholesteatoma of the external auditory canal,and the occurrence of cholesteatoma of the external auditory canal is directly related to the diameter of the external auditory canal meatus.But the time of occurrence of the cholesteatoma is not directly related to the diameter of the external auditory canal. Severe congenital stenosis of the external auditory canal with auricle deformity is easy to be missed and misdiagnosed due to retroauricular redness, swelling, and ulceration. For this kind of patient, cholesteatoma should be treated first, and then plastic surgery such as auricle reconstruction should be performed. Retroauricular incisions should be avoided to create conditions for auricle reconstruction in the future.

SIRT3-mediated mitochondrial autophagy in refeeding syndrome-related myocardial injury in sepsis rats.

Background: Myocardial injury induced by refeeding syndrome (RFS) is one of the important causes of deterioration in critically ill patients. Sirtuin-3 (SIRT3) has been shown to regulate mitochondrial autophagy in myocardial ischemia/reperfusion injury; however, the role of mitochondrial autophagy on RFS-related myocardial injury in patients in critical condition has not been reported on. Methods: Thirty Sprague-Dawley (SD) rats were divided into 3 groups (n=10 each group): the control group; the standard calorie refeeding (SCR) group; and the low calorie refeeding (LCR) group. The rats were weighed every third or four days from day 1 to day 14. On day 14, all rats were anesthetized and received an echocardiography test. Blood and bronchoalveolar lavage fluid (BALF) were collected and tested for arterial oxygen pressure (PaO2), phosphorus (P), and calcium (Ca), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin 1 (cTnI), myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), and IL-6. The histopathological change of hearts and lungs were evaluated, and lung injury score was calculated. Mitochondrial autophagy related proteins (including Beclin1, LC3, mitofusin-2, Mfn2, PINK1, Parkin, and SIRT3) were analyzed using a Western blot. To evaluate the effect of SIRT3, 20 rats were divided into 2 groups (n=10 each group): The adeno-associated virus 9 (AAV9-Nc) group; and the AAV9-SIRT3 overexpression (AAV9-SIRT3) group. The protocols for rats were the same as the SCR group since day 22 after injection of AAV9. The protein expressions of PINK1, Parkin, and SIRT3 were compared between the AAV9-Nc group and AAV9-SIRT3 group. Results: SCR caused significant decline in cardiac contractility and increased inflammatory cell infiltration in myocardial tissue. Meanwhile, Beclin1, LC3, PINK1, Parkin, and SIRT3 levels decreased, while Mfn2 showed no significant change. Furthermore, significant positive correlations were also found between SIRT3 and P, PINK1, and Parkin, and significant negative correlations were found between SIRT3 and CK-MB, LDH, and cTnI. Overexpression of SIRT3 activated the PINK1/Parkin mediated mitochondrial autophagy. Conclusions: SIRT3 has an essential role in RFS-related myocardial injury during LPS induced chronic sepsis in rats, probably via regulating mitochondrial autophagy.

Body mass index rebound and pubertal timing in girls with and without a family history of breast cancer: the LEGACY girls study.

BACKGROUND: Heavier body mass index (BMI) is the most established predictor of earlier age at puberty. However, it is unknown whether the timing of the childhood switch to heavier BMI (age at BMI rebound) also matters for puberty. METHODS: In the LEGACY Girls Study (n = 1040), a longitudinal cohort enriched with girls with a family history of breast cancer, we collected paediatric growth chart data from 852 girls and assessed pubertal development every 6 months. Using constrained splines, we interpolated individual growth curves and then predicted BMI at ages 2, 4, 6, 8 and 9 years for 591 girls. We defined age at BMI rebound as the age at the lowest BMI between ages 2 and 8 years and assessed its association with onset of thelarche, pubarche and menarche using Weibull survival models. RESULTS: The median age at BMI rebound was 5.3 years (interquartile range: 3.6-6.7 years). A 1-year increase in age at BMI rebound was associated with delayed thelarche (HR = 0.90; 95% CI = 0.83-0.97) and menarche (HR = 0.86; 95% CI = 0.79-0.94). The magnitude of these associations remained after adjusting for weight between birth and 2 years, was stronger after adjusting for BMI at age 9, and was stronger in a subset of girls with clinically assessed breast development. CONCLUSIONS: Earlier BMI rebound is associated with earlier pubertal timing. Our observation that BMI rebound may be a driver of pubertal timing in girls with and without a family history of breast cancer provides insight into how growth and pubertal timing are associated with breast cancer risk.

Phase-change mesoporous Prussian blue nanoparticles for loading paclitaxel and chemo-photothermal therapy of cancer.

Complete treatment of cancer remains a major challenge today. Herein, a biocompatible drug delivery system named as PCM + PTX@mPBs/PEG was constructed. In this system, Paclitaxel (PTX) was blended with phase-change material (PCM) and loaded in mesoporous Prussian blue nanoparticles (mPBs), and chelated with polyethylene glycol at surface. The blank PCM@mPBs/PEG had uniform particle size distribution, large pore size to load drug, excellent photothermal efficiency and good biocompatibility. After loading PTX, PCM + PTX@mPBs/PEG was demonstrated with a high loading capacity and the drug presented temperature-responsive release characteristics. In addition, PTX can be released under the exposure of an NIR laser. In vitro cell experiments showed that nanoparticles can be exposed to near-infrared irradiation to increase uptake in cells, which enhanced anticancer activity. After tail vein injection of PCM + PTX@mPBs/PEG suspension in tumor-bearing mice, PCM + PTX@mPBs/PEG can accumulate at the tumor site through passive transport. The tumor was effectively suppressed by phototherapy and chemotherapy with few side effects. In summary, compared with photothermal therapy or chemotherapy alone, the prepared PCM + PTX@mPBs/PEG showed synergistic photothermal and chemotherapeutic effects on cancer treatment of mice.

Deletion of Clusterin Protects Cochlear Hair Cells against Hair Cell Aging and Ototoxicity.

Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.

Doxorubicin-Loaded Carbon Dots Lipid-Coated Calcium Phosphate Nanoparticles for Visual Targeted Delivery and Therapy of Tumor.

BACKGROUND: Carbon dots (CDs) have attracted extensive attention in recent years because of their high biocompatibility and unique optical property. But they could not be well applied in the drug delivery system to enable distribution in tumor sites with their low pH sensitivity. They are barriers for drug delivery. CDs as an imaging proper were conjugated with doxorubicin (DOX) lipid-coated calcium phosphate (LCP) nanoparticle, for a pH-sensitive nanocarrier and delivery of the antitumor drugs. MATERIALS AND METHODS: CDs were prepared by one-step hydrothermal treatment of citric acid and ethylenediamine. The nanoparticles were simply prepared by using microemulsion technology to form calcium phosphate (CaP) core and further coated with cationic lipids. RESULTS: The structure was characterized by FTIR, XRD and TEM. In vitro release study revealed that DOX-CDs@LCP was pH dependent. The cytotoxicity assay demonstrated that it exhibited enhanced efficiency compared to the control group (DOX-CDs), but weaker than free DOX. The cellular uptake revealed that these pH-sensitive nanoparticles could be taken up effectively and deliver DOX into the cytoplasm to reach antitumor effect. The fluorescence imaging indicated that DOX-CDs@LCP mostly distributed in the tumor region due to the enhanced permeability and retention effect (EPR) to reduce its systematical toxicity. Importantly, an antitumor activity study demonstrated that the DOX-CDs@LCP nanoparticles had higher antitumor activity than any other groups and lower toxicity. The results showed that LCP could significantly promote the release in tumor microenvironment due to pH-response. The DOX-CDs could enhance load capacity and reduce drug premature releasing; real-time tracking of efficacy as confocal imaging contrast agent. Thus, DOX-CDs@LCP had antitumor capacity and lower systematic toxicity in tumor therapy. CONCLUSION: DOX-CDs@LCP were proven as a promising tumor pH-sensitive and imaging-guided drug delivery system for liver cancer chemotherapy.

Association between metabolic syndrome and prognosis of breast cancer: a meta-analysis of follow-up studies.

BACKGROUND: Metabolic syndrome (MetS) has been suggested to be a risk factor for many cancers, including breast cancer. However, it remains unclear whether MetS predicts poor prognosis in women with breast cancer. A meta-analysis was performed to summarize the association between MetS and clinical outcome in women with breast cancer. METHODS: Cohort studies were identified by search of PubMed and Embase databases. A random-effect model incorporating the potential heterogeneity was applied to pool the results. Subgroup analyses according to the ethnicity and study design were performed. RESULTS: Nine cohort studies with 17,892 women with breast cancer were included. Pooled results showed that MetS was significantly associated with an increased risk of breast cancer recurrence (adjusted risk ratio [RR] = 1.52, 95%, p = 0.02). Subgroup analyses showed that MetS was independently associated with increased recurrence of breast cancer in Caucasians (adjusted RR = 1.75, p = 0.02), but not in Asians (adjusted RR = 1.07, p = 0.81), and MetS was associated with a trend of increased risk of breast cancer recurrence in both the prospective and retrospective studies. Although we failed to show a significant association between MetS and breast cancer related deaths (adjusted RR = 1.24, p = 0.41), MetS was associated with increased risk of all-cause deaths in these patients (adjusted RR = 1.80, p < 0.001). CONCLUSIONS: MetS may predict the risk of cancer recurrence and mortality in women with breast cancer, particularly in Caucasians.

N-Acetyl cysteine effectively alleviates Coxsackievirus B-Induced myocarditis through suppressing viral replication and inflammatory response.

Viral myocarditis caused by Coxsackievirus B (CVB) infection is a severe inflammatory disease of the myocardium, which may develop to cardiomyopathy and heart failure. No effective specific treatment is available. Our previous study demonstrated that suppression of proinflammatory caspase-1 activation effectively inhibited CVB replication. N-acetyl cysteine (NAC) is a widely used antioxidant. In this study, we found that NAC significantly alleviated the myocardial injury caused by CVB type 3 (CVB3) under in vivo condition. Importantly, NAC treatment simultaneously suppressed viral replication and inflammatory response in both myocardium and cell culture. The antiviral and anti-inflammation mechanism of NAC, while independent of its antioxidant property, relies on its inhibition on caspase-1 activation. Moreover, NAC promotes procaspase-1 degradation via ubiquitin proteasome system, which further contributes to caspase-1 down-regulation. NAC also inhibits the activity of viral proteases. Taken together, this study shows that NAC exerts potent anti-CVB and anti-inflammation effect through targeting caspase-1. Given that NAC is a clinically approved medicine, we recommend NAC as a valuable therapeutic agent for viral myocarditis caused by CVB.

Association Between Metabolic Syndrome and Breast Cancer Risk: An Updated Meta-Analysis of Follow-Up Studies.

Background: Association between metabolic syndrome (MetS) and incidence of breast cancer remains to be validated. Moreover, whether menopausal status of the women affects this association is unclear. A meta-analysis was performed to summarize the association between MetS and breast cancer risk. Methods: Follow-up studies were identified by search of PubMed and Embase databases published until May 26, 2019. A random-effect model or fixed-effect model was applied to pool the results according to the heterogeneity. Subgroup analyses according to the menopausal status, ethnic groups, cancer histopathological features, and study design characteristics. Results: Overall, 17 follow-up studies with 602,195 women and 15,945 cases of breast cancer were included. Results of meta-analysis showed that MetS defined by the revised National Cholesterol Education Program's Adults Treatment Panel III criteria was associated with significantly increased risk for breast cancer incidence (adjusted risk ratio [RR] = 1.15, p = 0.003). Subgroup analyses showed that MetS was associated with significantly increased risk of breast cancer in postmenopausal women (adjusted RR = 1.25, p < 0.001), but significantly reduced breast cancer risk in premenopausal women (adjusted RR = 0.82, p < 0.001). Further analyses showed that the association between MetS and increased risk of breast cancer were mainly evidenced from studies including Caucasian and Asian women, reporting invasive breast cancer, and of retrospective design. Conclusions: Menopausal status may affect the association between MetS and breast cancer incidence. Postmenopausal women with Mets are associated with increased risk of breast cancer.

Sparse quadratic classification rules via linear dimension reduction.

We consider the problem of high-dimensional classification between two groups with unequal covariance matrices. Rather than estimating the full quadratic discriminant rule, we propose to perform simultaneous variable selection and linear dimension reduction on the original data, with the subsequent application of quadratic discriminant analysis on the reduced space. In contrast to quadratic discriminant analysis, the proposed framework doesn't require the estimation of precision matrices; it scales linearly with the number of measurements, making it especially attractive for the use on high-dimensional datasets. We support the methodology with theoretical guarantees on variable selection consistency, and empirical comparisons with competing approaches. We apply the method to gene expression data of breast cancer patients, and confirm the crucial importance of the ESR1 gene in differentiating estrogen receptor status.

Theranostics Applications of Nanoparticles in Cancer Immunotherapy.

With the advancement in the mechanism of immune surveillance and immune evasion in cancer cells, cancer immunotherapy shows promising results for treating cancer with established efficacy and less toxicity. As a result of the off-target effect, the approach for delivering vaccines, adjuvants, or antibodies directly to tumor sites is gaining widespread attention. An effective alternative is to utilize nanoengineered particles, functioning as drug-delivery systems or as antigens themselves. This article reviews the practical implementation of nanotechnology in cancer immunotherapy.

Stress Granule Formation is One of the Early Antiviral Mechanisms for Host Cells Against Coxsackievirus B Infection.

Stress granules (SGs) are intracellular granules formed when cellular translation is blocked and have been reported to be involved in a variety of viral infections. Our previous studies revealed that SGs are involved in the coxsackievirus B (CVB) infection process, but the role of SGs in CVB infection has not been fully explored. In this study, we found that CVB type 3 (CVB3) could induce SG formation in the early phase of infection. Results showed that levels of CVB3 RNA and protein were significantly inhibited during the early stage of CVB3 infection by the elevated formation of SGs, while viral RNA and protein synthesis were significantly promoted when SG formation was blocked. Our findings suggest that SG formation is one of the early antiviral mechanisms for host cells against CVB infection.

RNA-binding protein AUF1 suppresses miR-122 biogenesis by down-regulating Dicer1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the common cancers worldwide, especially in developing countries. Although the chronic infections of hepatitis B and C viruses have been established as the etiological factors of HCC, the mechanism for the tumorigenesis and development of HCC is still unclear. The liver-specific microRNA-122 (miR-122), an established tumor-suppressor miRNA, is often down-regulated in HCC, while the underlying mechanism is not well understood. Here we report that the AU-rich element-binding factor AUF1 suppresses the expression of Dicer1, the type III RNase that is required for microRNA maturation, leading to the inhibited biogenesis of miR-122. Overexpression of AUF1 led to the decreased expression of Dicer1 and miR-122, while the level of the miR-122 precursor (pre-miR-122) was increased. On the other hand, siRNA of AUF1 (siAUF1) increased the levels of Dicer1 mRNA and miR-122, but it reduced the abundance of pre-miR-122. Consistent with the reported data, this study demonstrated that AUF1 and Dicer1 showed opposite expression pattern in both human HCC tissues and cell lines. In addition, AUF1 inhibited the expression of Dicer1 by interacting with the 3' untranslated region (3'UTR) and coding region of DICER1 mRNA. Moreover, the knockdown of AUF1 by siRNA altered the expression of other miRNAs and promoted HCC cell death. In conclusion, AUF1 down-regulates the expression miR-122 by interacting with the 3'UTR and coding region of DICER1 mRNA and suppressing Dicer1 expression. The AUF1/Dicer1/miR-122 pathway might play a critical role in the development of HCC.