A Cu-Based Metal-Organic Framework Cu-Cip with Cuproptosis for Cancer Therapy and Inhibition of Cancer Cell Migration.

Microflora within cancer cells plays a pivotal role in promoting metastasis of cancer. However, contemporary anticancer research often overlooks the potential benefits of combining anticancer and antibacterial agents. Consequently, a metal-organic framework Cu-Cip with cuproptosis and antibacterial properties was synthesized for cancer therapy. To enhance the anticancer effect of the material, Mn2+ was loaded into Cu-Cip, yielding Mn@Cu-Cip. The fabricated material was characterized using single-crystal X-ray diffraction, PXRD, and FT-IR. By interacting with overexpressed H2O2 to produce ROS and accumulating Cu ions in cancer cells, MOFs exhibited excellent anticancer performance. Moreover, the material displayed the function of damaging Staphylococcus aureus and Escherichia coli, revealing the admirable antibacterial properties of the material. In addition, the antibacterial ability could inhibit tumor cell migration. The Cu-based MOF revealed promising applications in the field of tumor treatment.

Construction of Core-Shell MOF CSMnP with Enzyme-Like Activity for Chemotherapy and Chemodynamic Therapy.

Materials with enzyme-like activity have received a lot of attention in the field of tumor catalytic therapy. Here, biocompatible core-shell MOF CSMnP with two valence states of Mn ion, which could process chemodynamic therapy (CDT), was designed and synthesized. Besides, it could also promote a series of catalytic processes in the tumor microenvironment (TME). CSMnP catalyzed endogenous hydrogen peroxide (H2O2) to oxygen (O2) via catalase-like activity and then combined with the outer layer Mn(II)-PBC to convert O2 into superoxide radicals (•O2-), exhibiting oxidase-like activity. Besides, intracellular glutathione (GSH) could be effectively consumed through the glutathione oxidase-like activity of Mn3+. The occurrence of the cascade reactions effectively amplified the enzymatic production to enhance CDT. Furthermore, the therapeutic effect of CSMnP was improved through the loading of cationic drug DOX. The loading capacity was 11.10 wt %, which was 2.2 times that of Mn(III)-PBC (4.95 wt %), and the release of DOX showed a characteristic response. Therefore, the core-shell MOF with enzyme-like activity had a potential application for tumor combination therapy.

Silencing of TRAF5 enhances necroptosis in hepatocellular carcinoma by inhibiting LTBR-mediated NF-κB signaling.

Background: Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis and high mortality. This study aimed to explore the oncogenic mechanisms of TRAF5 in HCC and provide a novel therapeutic strategy for HCC. Methods: Human HCC cell lines (HepG2, HuH7, SMMC-LM3, and Hep3B), normal adult liver epithelial cells (THLE-2), and human embryonic kidney cells (HEK293T) were utilized. Cell transfection was performed for functional investigation. qRT-PCR and western blotting were used to detect mRNA expression of TRAF5, LTBR, and NF-κB and protein expression of TRAF5, p-RIP1(S166)/RIP1, p-MLKL(S345)/MLKL, LTBR, and p-NF-κB/NF-κB. Cell viability, proliferation, migration, and invasion were evaluated using CCK-8, colony formation, wound healing, and Transwell assays. Cell survival, necrosis, and apoptosis were assessed using flow cytometry and Hoechst 33342/PI double staining. Co-immunoprecipitation and immunofluorescence were performed to determine the interaction between TRAF5 and LTBR. A xenograft model was established to validate the role of TRAF5 in HCC. Results: TRAF5 knockdown inhibited HCC cell viability, colony formation, migration, invasion, and survival but enhanced necroptosis. Additionally, TRAF5 is correlated with LTBR and TRAF5 silencing down-regulated LTBR in HCC cells. LTBR knockdown inhibited HCC cell viability, while LTBR overexpression eliminated the effects of TRAF5 deficiency on inhibiting HCC cell proliferation, migration, invasion, and survival. LTBR overexpression abolished the promotive function of TRAF5 knockdown on cell necroptosis. LTBR overexpression undid the suppressive effect of TRAF5 knockdown on NF-κB signaling in HCC cells. Moreover, TRAF5 knockdown suppressed xenograft tumor growth, inhibited cell proliferation, and promoted tumor cell apoptosis. Conclusions: TRAF5 deficiency facilitates necroptosis in HCC by suppressing LTBR-mediated NF-κB signaling.

A multifunctional black phosphorus nanosheet-based immunomagnetic bio-interface for heterogeneous circulating tumor cell capture and simultaneous self-identification in gastric cancer patients.

A single epithelial cell adhesion molecule (EpCAM) for circulating tumor cell (CTCs) isolation has been proved to be low in efficiency as it fails to recognize EpCAM-negative CTCs. Meanwhile, the current immunocytochemical (ICC) identification strategy for the captured cells is tedious and time-consuming. To address these issues, we designed a dual-labeled fluorescent immunomagnetic nanoprobe (BP-Fe3O4-AuNR/Apt), by loading magnetic Fe3O4 nanoparticles and gold nanorods (AuNRs) onto black phosphorus (BP) nanosheets and then linking them with Cy3-labeled EpCAM and Texas red-labeled tyrosine protein kinase 7 (PTK7) aptamers, which created a high-performance bio-interface for efficient, heterogeneous CTC capture and rapid self-identification with high accuracy. As few as 5 CTCs could be captured from 1.0 mL PBS, mixed cell solution and lysed blood. What's more, the presence of BP and AuNRs on this capturing interface also allowed us to preliminarily investigate the potential photothermal therapeutic effect of the probe toward CTC elimination. The applicability of the probe was further demonstrated in gastric cancer patients. By detecting the number of CTCs in the blood of gastric cancer patients, the correlations between the CTC number and the disease stage, as well as distant metastasis were systematically explored.

Glucometer Readout for Portable Detection of Heterogeneous Circulating Tumor Cells in Lung Cancer Captured on a Dual Aptamer Functionalized Wrinkled Cellulose Hydrogel Interface.

The rarity of circulating tumor cells (CTCs) poses a great challenge to their clinical application as reliable "liquid biopsy" markers for cancer diagnosis. Meanwhile, the epithelial-mesenchymal transition (EMT) led to a reduced efficiency in capturing cells with lost or downregulated epithelial cell adhesion molecule (EpCAM) expressions. In this study, we proposed an integrated, highly efficient strategy for heterogeneous CTC capture and portable detection from the blood of non-small-cell lung cancer (NSCLC) patients. First, the cellulose wrinkled hydrogel with excellent biocompatibility and high specific area was employed as the biointerface to capture heterogeneous CTCs with an improved capture efficiency in virtue of dual targeting against epithelial and mesenchymal ones. Meanwhile, the strategy of glucometer readout was introduced for the quantification of captured CTCs on the same hydrogel interface by a detection probe, Au-G-MSN-Apt, which was fabricated via entrapping glucose into the amino group functionalized mesoporous silica nanoparticle (MSN) framework sealed by l-cysteine modified gold nanoparticles (AuNPs) and then linked with dual aptamers of EpCAM and Vimentin. The number of captured CTCs on the hydrogel could be reflected according to the portable glucose meter (PGM) readings. Moreover, it was found that the captured cells maintained a higher viability on the hydrogel and could be in situ recultured without releasing from the substrate. Finally, this integrated strategy was successfully applied to inspect the correlations between the number of heterogeneous CTCs in the blood of NSCLC patients with disease stage and whether there was distant metastasis.

Prevalence of sarcopenia was higher in women than in men: a cross-sectional study from a rural area in eastern China.

Background: There were limited studies specifically evaluating whether the difference of the prevalence of sarcopenia exists in men and women in older adults from rural areas in China. The aim of this study was to compare the prevalence of sarcopenia between men and women in a rural area in eastern China and to explore the underlying causes. Methods: This study included 1,105 participants aged 60-89 years. Muscle mass was measured by bio-electrical impedance analysis. Hand grip strength was measured by Jamar Hydraulic Hand Dynamometer. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia-2019 Consensus. Data were analyzed using log-binomial and linear regression. Results: The prevalence of sarcopenia was 21.7% in women and 12.9% in men among the study cohort. After adjusting for age, education level, number of diseases, income level, smoking, drinking, and eating habits, proportion of people with sarcopenia was 1.49-fold greater in women than in men (PR = 1.49, 95% CI [1.01-2.26], P = 0.055). Conclusions: The prevalence of sarcopenia in elderly women in this rural area of eastern China is higher than in men, suggesting that women in rural areas in China seem to be more vulnerable for sarcopenia, thus early screening and prevention need to be provided for them to address such gender disparity in health.

The direct and indirect effects of length of hospital stay on the costs of inpatients with stroke in Ningxia, China, between 2015 and 2020: A retrospective study using quantile regression and structural equation models.

Importance: Length of hospital stay (LOHS) is the main cost-determining factor of hospitalization for stroke patients. However, previous analyses involving LOHS did not consider confounding or indirect factors, or the effects of other factors on LOHS and inpatient costs. Objective: To investigate the direct and indirect effects of LOHS on the hospitalization costs of inpatients with ischemic and hemorrhagic stroke. Design setting and participants: This was a population-based, retrospective, and observational study that analyzed data acquired from the Nationwide Inpatient Sample between 2015 and 2020 relating to ischemic and hemorrhagic stroke in Ningxia, China. Main outcomes and measures: Hospitalizations were identified by the International Classification of Diseases 10th Revision (ICD-10). Inpatient costs were described by the median M (P25, P75). We used a quantile regression model to estimate the linear relationships between a group of independent variables X and the quantile of the explained variable hospitalization cost (Y). A structural equation model (SEM) was then used to investigate the direct and indirect effects of LOHS on inpatient costs. Results: The study included 129,444 patients with ischemic stroke and 15,525 patients with hemorrhagic stroke. The median LOHS was 10 (8-13) days for ischemic stroke and 15 (10-22) days for hemorrhagic stroke. The median M (P25, P75) of inpatient costs was $1020 (742-1545) for ischemic stroke and 2813 (1576-6191) for hemorrhagic stroke. The total effect of LOHS on inpatient costs was 0.795 in patients with ischemic stroke. The effect of yearof discharge (X4) and CCI (X8) on inpatient costs was dominated by an indirect effect through the LOHS. The indirect effect was -0.071 (84.52% of the total effect value) and 0.034 (69.39% of the total effect value), respectively. The total effect of LOHS on inpatient costs in patients with hemorrhagic stroke was 0.754. The influence of CCI on inpatient costs was dominated by an indirect effect through LOHS; the indirect effect value was -0.028 (77.78% of the total effect value). The payment type, surgery, method of discharge, and hospital level also exerted an impact on inpatient costs by direct and indirect effects through the LOHS. Conclusions and relevance: Length of hospital stay (LOHS) was identified as the main factor influencing hospitalization costs. However, other social factors were shown to indirectly influence hospitalization costs through the LOHS. Taking effective measures to further reduce hospitalization costs remains an effective way to control hospitalization costs for stroke patients.

Erythrocyte Membrane-Coated Invisible Acoustic-Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

[Mechanism of Huangqi Guizhi Wuwu Decoction in treatment of rheumatoid arthritis based on UPLC-LTQ-Orbitrap-MS, network pharmacology, and cell experiment].

In this study, ultra-high performance liquid chromatography-linear ion trap/electrostatic field orbit trap combined-type mass spectrometry(UPLC-LTQ-Orbitrap-MS) was used to analyze the main active components of Huangqi Guizhi Wuwu Decoction(HQGZ). A total of 50 active components were identified from HQGZ and 108 potential targets of the components related to the treatment of rheumatoid arthritis were retrieved based on network pharmacology, including 87 key targets, followed by Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment of the targets. The result indicated that HQGZ may exert therapeutic effects mainly through the sphingolipid signaling pathway, tumor necrosis factor(TNF) signaling pathway, as well as the positive regulation of ribonucleic acid(RNA) polymerase Ⅱ promoter transcription, inflammatory response and other biological processes. At the same time, cell experiment was performed to verify the key proteins in the TNF signaling pathway. The results demonstrated that HQGZ significantly reduced the expression of caspase-3(CASP3), TNF, relaxed(RELA) protein, and IkappaB kinase beta(IKBKB) in fibroblast-like synoviocytes induced by TNF-α. The results of UPLC-LTQ-Orbitrap-MS, network pharmacology and cell experiment showed that the active components in HQGZ may inhibit inflammatory response and regulate immune function and cell apoptosis by modulating key proteins in TNF signaling pathway to treat rheumatoid arthritis.

Divinylsulfonamides enable the construction of homogeneous antibody-drug conjugates.

Methods that site-specifically attach payloads to an antibody with controlled DAR (Drug-Antibody Ratio) are highly desirable for the generation of homogeneous antibody-drug conjugates (ADCs). We describe the use of N-phenyl-divinylsulfonamide scaffold as a linker platform to site-specifically construct homogeneous DAR four ADCs through a disulfide re-bridging approach. Several monomethyl auristatin E (MMAE)-linkers were synthesized and the drug-linkers that contain electron-donating groups on the phenyl of the linker showed high stability. Her2-targeted MMAE-linker-herceptin and EGFR targeted MMAE-linker-cetuximab conjugates were prepared. The conjugates demonstrated high efficacy and selectivity for killing target-positive cancer cells in vitro. The EGFR-targeted conjugates also showed significant antitumor activities in vivo.

Influence of acupuncture on the expression of VIP, SP, NKA and NKB, cAMP/cGMP and HE content and treatment of bronchial asthma in rats.

This research was set up to explore the neural mechanisms of acupuncture in the treatment of bronchial asthma in rats by detecting the content of substance P(SP), vasoactive intestinal peptide (VIP), neurokinin A(NKA), neurokinin B (NKB), cyclic adenosine monophosphate/cyclic guanosine monophosphate ratio (cAMP/cGMP) and hematoxylin-eosin (HE) staining for the pathological changes of lung tissue, in order to Institute Certain Experimental and Theoretical Foundation for Traditional Chinese Medicine (TCM) Prevention and Treatment of Bronchial Asthma. For this purpose, fifty healthy adult Wistar male rats, weighing 200-250 g, were randomly divided into 5 groups: normal control group A, asthma control group B, asthma acupuncture group C, adrenalectomy (ADX)-asthma  group D, adrenalectomy (ADX)-asthma acupuncture group E. Group A was raised with other groups at the same period; Group B was induced asthma by ovalbumin; Group C was induced asthma as Group B and then acupunctured five acupoints (bilateral Feishu, bilateral Fengmen, and Dazhui); Group D was induced asthma after adrenalectomy; group E was treated with acupuncture on the basis of group D. HE staining was performed in the lung tissue of rats from each group, and histopathologic changes were observed. SP, VIP, NKA, NKB in each rat lung tissue were measured by immunohistochemistry. cAMP/cGMP was measured with ELISA to speculate the neural mechanisms of acupuncture in the treatment of bronchial asthma. The results were as: decrease of cAMP/cGMP and VIP and increase of SP, NKA, NKB in the lung tissue are the neural mechanisms of an asthma attack. The increase of cAMP/cGMP and decrease of NKA, NKB, SP and VIP in the lung tissue of group C indicated the improvement of bronchial asthma symptoms. It is possible that the decrease of NKA and NKB, increase of cAMP/cGMP and a slight change of SP and VIP in group E were related to the reduction of glucocorticoid after ADX which influenced the effect of acupuncture. The neural regulation mechanisms of acupuncture in the treatment of bronchial asthma were related to bronchiectasis caused by stimulation of adrenergic nerve and inhibition of the vagus nerve function by acupuncture, and related to the release of inflammatory mediators.

The effect of total glucoside of paeony on gut microbiota in NOD mice with Sjögren's syndrome based on high-throughput sequencing of 16SrRNA gene.

PURPOSE: To investigate the effect of total glucoside of paeony (TGP) on gut microbiota in NOD mice with Sjögren's syndrome (SS), using high-throughput sequencing of 16SrRNA gene. METHODS: Twenty-four NOD mice were randomly assigned to 4 groups (n = 6 per group): sham group receiving deionized water (0.4 ml), hydroxychloroquin group receiving hydroxychloroquin (0.4 ml), TGP group receiving TGP (0.4 ml), and TGP + hydroxychloroquin group receiving 0.4 ml TGP and 0.4 ml hydroxychloroquin. Balb/c mice (n = 6) receiving 0.4 ml deionized water were used as a control group. After intragastric injection of drugs for 8 weeks, feces were collected for high-throughput sequencing of 16SrRNA gene. RESULTS: The sequencing of 16SrRNA gene resulted in 3686 OTUs, and 10 phyla and 69 genera were identified. Compared with the control group, the indices of Chao, Ace and Shannon in the other 4 groups were significantly lower (P < 0.05), and the Simpson index were significantly higher in the TGP, hydroxychloroquine, and sham groups (P < 0.05). Compared with the sham group, the indices of Chao, Ace and Shannon were significantly higher (P < 0.05), whereas the Simpson index was significantly lower (P < 0.05) in the TGP and TGP + hydroxychloroquine groups. At phylum level, Bacteroidetes was least abundant (36.1%), and Firmicutes was most abundant (56.28%) in the TGP + hydroxychloroquine group. Compared with the other 4 groups, Bacteroidetes was significantly less abundant (P < 0.05) and Firmicutes was significantly more abundant (P < 0.05) in the TGP + hydroxychloroquine group. Verrucomicrobia was most abundant (12.26%) in the hydroxychloroquine, and was significantly more abundant compared with the other 3 groups (P < 0.05). At genus level, compared with the control group, the abundance of Lactobacillus and Incertae of Phylum Firmicutes and Desulfovibrio of Phylum Proteobacteria was significantly increased, and the abundance of Bacteroides and Alloprevotella of Phylum Bacteroidetes and Pseudoflavonifractor of Phylum Firmicutes was significantly decreased in the TGP + hydroxychloroquine group (P < 0.05). Compared with the hydroxychloroquine group, the abundance of Akkermansia of Phylum Verrucomicrobia was significantly decreased in the TGP and TGP + hydroxychloroquine groups (P < 0.05). The abundance of Alistipes of Phylum Bacteroidetes and Desulfovibrio of Phylum Proteobacteria was significantly increased in the TGP + hydroxychloroquine group (P < 0.05). CONCLUSIONS: TGP increases the growth of many key beneficial bacteria, inhibits the growth of dominant pathogenic bacteria, and increases the diversity and abundance of gut microorganisms, especially when combined with hydroxychloroquine. Our findings suggest that TGP may be effective to treat SS by improving the microecological structure of the gut.

Qualitative and quantitative imaging features of pulmonary subsolid nodules: differentiating invasive adenocarcinoma from minimally invasive adenocarcinoma and preinvasive lesions.

BACKGROUND: To explore the role of qualitative and quantitative imaging features of pulmonary subsolid nodules (SSNs) in differentiating invasive adenocarcinoma (IAC) from minimally invasive adenocarcinoma (MIA) and preinvasive lesions. METHODS: We reviewed the clinical records of our institute from October 2010 to December 2015 and included 316 resected SSNs from 287 patients: 260 pure ground-glass nodules, 47 part-solid nodules with solid components ≤5 mm, and 9 ground-glass nodules (GGNs) with cystic airspaces. According to the pathologic review results, 307 SSNs in addition to nine GGNs with cystic airspaces were divided into two groups: A, including atypical adenomatous hyperplasia (AAH) (n=15), adenocarcinoma in situ (AIS) (n=56), and MIA (n=41); B, including 195 IACs. Univariate and binary logistic regression analyses were conducted to identify independent risk factors for IAC. RESULTS: Univariate analysis showed significant differences between groups regarding patient age, mean diameter, mean and relative computed tomography (CT) values, volume, mass (all P<0.001), and morphological features including lobulated sign (P<0.001), spiculated sign (P=0.028), vacuole sign/air bronchogram (P<0.001), and pleural retraction (P=0.017). Binary logistic regression and receiver operating characteristic analysis indicated the SSN mass as the only independent risk factor of IAC (odds ratio, 1.007; P<0.001), with an optimal cutoff value of 283.2 mg [area under curve (AUC): 0.859; sensitivity: 68.7%; specificity: 92.9%]. Among lepidic, acinar, and papillary adenocarcinomas, we found significant differences for the vacuole sign/air bronchogram (P=0.032) and mean and relative CT values (P<0.001). All nine GGNs with cystic airspaces were IACs. CONCLUSIONS: The SSN mass with an optimal cutoff value of 283.2 mg may be reliable for differentiating IAC from MIA and preinvasive lesions.

CT diagnosis of pleural and stromal invasion in malignant subpleural pure ground-glass nodules: an exploratory study.

OBJECTIVES: To assess the risk of visceral pleural invasion (VPI) and improve the diagnosis of invasive adenocarcinoma (IA) in pure ground-glass nodules (pGGNs) in contact with pleura, through a comprehensive analysis of the thin-section CT features of subpleural malignant pGGNs. METHODS: CT findings and clinical information of 115 consecutive patients in our hospital between January 2012 and December 2015 who met the following criteria were retrospectively studied: (a) thin-section CT within 1 month before surgery proved pGGN in contact with pleura, and (b) the pGGN was confirmed as malignancy by surgery. Univariate analysis and a multivariate logistic regression analysis were conducted to identify the independent risk factors of IA and VPI. RESULTS: No pleural invasion was observed microscopically in any of the pGGNs. Univariate analysis indicated that tumour shape (p = 0.004), relative density (p = 0.038) and the existence of pleural retraction (p < 0.001) were significantly different between the invasive group and pre- or minimally invasive group. Multivariate logistic regression analysis revealed that pleural retraction (OR, 5.663; p < 0.001), lobulated tumour shape (OR, 4.812; p = 0.016) and tumour relative density greater than 1.60 (OR, 4.449; p = 0.001) were independent risk factors of IA. CONCLUSIONS: Pulmonary adenocarcinoma manifesting as pGGN generally does not invade the pleura. A comprehensive consideration of tumour shape, relative density and tumour-pleural relationship can independently predict IA. KEY POINTS: • This study showed that pGGN-like adenocarcinoma generally does not invade the pleura. • This study suggested that persistent pGGN with pleural retraction, lobulated shape and high relative density (> 1.60) may very likely be invasive adenocarcinoma. • Using "relative density" can reduce confounding of contrast agent and respiratory status in analysis of CT images.

The impact of chemotherapy on persistent ground-glass nodules in patients with lung adenocarcinoma.

BACKGROUNDS: To evaluate the response of persistent ground glass nodules (GGNs) in patients with lung adenocarcinoma treated with platinum-based chemotherapy on computed tomography (CT). METHODS: We retrospectively studied patients with GGNs that met the following criteria: (I) GGNs found in patients with lung adenocarcinoma, which persist for more than 3 months; (II) patients treated with platinum-based (cisplatin or carboplatin) chemotherapy for at least 2 cycles; (III) ground glass proportion ¡Ý50%. For each patient, if more than two CTs satisfied the inclusion criteria, then the baseline and last CTs were used for analysis, defined as CT1 and CT2. A total of 91 persistent pulmonary GGNs in 51 patients fulfilled the inclusion criteria. We defined growth as a nodule ¡Ý2 mm increase in diameter or showing up a solid portion. GGN response to therapy was assessed and compared with the baseline CT. Differences in CT findings were analyzed using a paired t-test and Pearson ¦Ö2 test. RESULTS: Between 2010 and 2015, 25 of the 51 (49%) were male and 26 of the 51 (51%) were female. The average age at time of detection of a GGN was 63.8 (range, 36-84) years. Mean follow-up duration was 24.1¡À17.9 months. During the follow-up periods, on a per-nodule basis, 94.5% of GGNs (n=86) remained unchanged in size. Only 5.5% GGNs (n=5) in 5 patients increased in size. The nodules CT feature in each lung adenocarcinoma clinical stage show no difference. No significant difference was found in the size, attenuation, volume, and mass of GGN between baseline and post-treatment measurements, regardless of the type of chemotherapy (P>0.05). CONCLUSIONS: The clinical course of GGNs in patients with lung adenocarcinoma is predominantly indolent, and platinum-based chemotherapy may have no effect on the growth of persistent GGNs.

Gastric cancer-derived heat shock protein-gp96 peptide complex enhances dendritic cell activation.

AIM: To investigate the role of heat shock protein (HSP)-glycoprotein (gp)96 in dendritic cells (DCs) and lymphocytes induction in gastric cancer (GC). METHODS: Human GC cell lines KATOIII, MKN-28 and SGC-7901 were infected with adenovirus gp96 at a multiplicity of infection of 100. gp96-GC antigen peptide complexes were purified. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, lactate dehydrogenase (LDH) release assay and enzyme-linked immunosorbent assay were used to determine allo-reactive T cell stimulation, natural killer (NK) cell activity and expression of cytokines (such as interleukin (IL)-10, IL-12, interferon (IFN)-γ and tumor necrosis factor (TNF)-α), respectively. Effect of cytotoxic T lymphocyte (CTL) on DCs incubated with HSP-gp96 was also evaluated by LDH release. All assays were performed in triplicate and the average values were reported. Comparison between groups was conducted using Student's t test. RESULTS: T cells incubated with HSP-gp96 exhibited a marked increase in proliferation in a dose-dependent manner (P < 0.05). NK cell activity after gp96-GC peptide complex treatment was significantly higher than that after antigen peptide treatment (P < 0.05). The activity of CTLs incubated with DCs from three GC cells lines was obviously higher than that stimulated by GC antigen at ratios of 50: 1, 25: 1, 10: 1, and 5: 1 (P < 0.05). Furthermore, the secretion of TNF-α, IL-10, IL-12 (P70) and IFN-γ markedly increased after incubation with HSP-gp96 (P < 0.05). CONCLUSION: HSP-gp96 promotes T cell response, enhances DC antigen presentation and induces cytokine secretion, as well. HSP-gp96 has potential as immunotherapy for elimination of residual GC cells.

Estrogen Receptor-ß Modulation of the ERα-p53 Loop Regulating Gene Expression, Proliferation, and Apoptosis in Breast Cancer.

Estrogen receptor α (ERα) is a crucial transcriptional regulator in breast cancer, but estrogens mediate their effects through two estrogen receptors, ERα and ERß, subtypes that have contrasting regulatory actions on gene expression and the survival and growth of breast cancer cells. Here, we examine the impact of ERß on the ERα-p53 loop in breast cancer. We found that ERß attenuates ERα-induced cell proliferation, increases apoptosis, and reverses transcriptional activation and repression by ERα. Further, ERß physically interacts with p53, reduces ERα-p53 binding, and antagonizes ERα-p53-mediated transcriptional regulation. ERα directs SUV39H1/H2 and histone H3 lys9 trimethylation (H3K9me3) heterochromatin assembly at estrogen-repressed genes to silence p53-activated transcription. The copresence of ERß in ERα-positive cells abrogates the H3K9me3 repressive heterochromatin conformation by downregulating SUV39H1 and SUV39H2, thereby releasing the ERα-induced transcriptional block. Furthermore, the presence of ERß stimulates accumulation of histone H3 lys4 trimethylation (H3K4me3) and RNA polymerase II (RNA Pol II) on ERα-repressed genes, inducing H3K4me3-associated epigenetic activation of the transcription of these repressed genes that can promote p53-based tumor suppression. ERß also reduced corepressor N-CoR and SMRT recruitment by ERα that could attenuate the crosstalk between ERα and p53. Overall, our data reveal a novel mechanism for ERß's anti-proliferative and pro-apoptotic effects in breast cancer cells involving p53 and epigenetic changes in histone methylation that underlie gene regulation of these cellular activities.

Loss of large tumor suppressor 1 promotes growth and metastasis of gastric cancer cells through upregulation of the YAP signaling.

Accumulating evidence shows that large tumor suppressor 1 (LATS1) as a novel resident governor of cellular homeostasis is implicated in multiple tumorigenic properties including cell growth, apoptosis and metastasis. However, the contribution of LATS1 to gastric carcinoma (GC) remains unclear. The correlation of LATS1 expression with clinicopathologic characteristics, GC prognosis and recurrence was analyzed by immunohistochemistry, Univariate and Kaplan-Meier analysis. Functional experiments were performed to investigate biological behaviors of GC cells and underlying molecular mechanisms. Tumor growth and metastasis was assessed in vivo using orthotopic implantation GC models in severe combined immune deficiency (SCID) mice. Consequently, decreased LATS1 expression was significantly associated with the lymph node metastasis, poor prognosis and recurrence. Ectopic expression of LATS1 decreased GC cell proliferation and invasion in vitro and inhibited tumor growth and liver metastasis in vivo, but depletion of LATS1 expression restored the invasive phenotype. Further observation indicated that YAP pathway was required for LATS1-induced inhibition of cell growth and invasion, and LATS1 restrained nuclear transfer of YAP, downregulated YAP, PCNA, CTGF, MMP-2, MMP-9, Bcl-2 and CyclinD1 expression and upregulated p-YAP and Bax expression. Our findings suggest that LATS1 is a potential candidate tumor suppressor and inhibits the growth and metastasis of GC cells via downregulation of the YAP signaling.

Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site.

Enterovirus 71 (EV71) causes life-threatening diseases with neurological manifestations in young children. However, the treatment of EV71 infections remains an unmet medical need. Idarubicin (IDR) is an anthracycline compound that is used therapeutically for certain types of tumour. In this study, we identified IDR as an EV71 inhibitor, which displayed antiviral potency in the submicromolar range and substantially protected cells from the cytopathic effects and cell death caused by EV71 infections. The antiviral effects extended to several other enterovirus (EV) species, and these effects were independent of cytotoxicity or topoisomerase inhibition. Structure-activity relationship studies indicated the importance of the anthracycline scaffold for anti-EV potency. IDR effectively blocked the synthesis of viral protein and RNA, but not the viral proteolysis processes. Moreover, anthracyclines were demonstrated to suppress EV internal ribosomal entry site (IRES)-mediated translation; conversely, the cellular p53 IRES activity was not sensitive to IDR action. Inhibition of IRES-mediated translation by IDR correlated with the affinity of binding between IDR and the particular IRES. Moreover, IDR impaired binding between the EV71 IRES RNA and hnRNP A1, a known host IRES trans-acting factor. In sum, we have identified a USA FDA-approved anticancer drug with the new indication as a selective EV IRES binder and inhibitor. The finding may also provide leads for the development of novel antiviral therapies directed at the EV IRES RNA.