Presumed periventricular venous infarction on magnetic resonance imaging and its association with increased white matter edema in CADASIL.

OBJECTIVES: Venous pathology could contribute to the development of parenchymal lesions in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aim to identify presumed periventricular venous infarction (PPVI) in CADASIL and analyze the associations between PPVI, white matter edema, and microstructural integrity within white matter hyperintensities (WMHs) regions. METHODS: We included forty-nine patients with CADASIL from a prospectively enrolled cohort. PPVI was identified according to previously established MRI criteria. White matter edema was evaluated using the free water (FW) index derived from diffusion tensor imaging (DTI), and microstructural integrity was evaluated using FW-corrected DTI parameters. We compared the mean FW values and regional volumes with different levels of FW (ranging from 0.3 to 0.8) in WMHs regions between the PPVI and non-PPVI groups. We used intracranial volume to normalize each volume. We also analyzed the association between FW and microstructural integrity in fiber tracts connected with PPVI. RESULTS: We found 16 PPVIs in 10 of 49 CADASIL patients (20.4%). The PPVI group had larger WMHs volume (0.068 versus 0.046, p = 0.036) and higher FW in WMHs (0.55 versus 0.52, p = 0.032) than the non-PPVI group. Larger areas with high FW content were also found in the PPVI group (threshold: 0.7, 0.47 versus 0.37, p = 0.015; threshold: 0.8, 0.33 versus 0.25, p = 0.003). Furthermore, higher FW correlated with decreased microstructural integrity (p = 0.009) in fiber tracts connected with PPVI. CONCLUSIONS: PPVI was associated with increased FW content and white matter degeneration in CADASIL patients. CLINICAL RELEVANCE STATEMENT: PPVI is an important factor related with WMHs, and therefore, preventing the occurrence of PPVI would be beneficial for patients with CADASIL. KEY POINTS: •Presumed periventricular venous infarction is important and occurs in about 20% of patients with CADASIL. •Presumed periventricular venous infarction was associated with increased free water content in the regions of white matter hyperintensities. •Free water correlated with microstructural degenerations in white matter tracts connected with the presumed periventricular venous infarction.

Intralesional Bacillus Calmette-Guérin injections and hypo-fractionated radiation synergistically induce systemic antitumor immune responses.

Radiotherapy, an important treatment for multiple malignancies, produces systemic anti-tumor effects in combination with immunotherapies, especially immune checkpoint inhibitors (ICBs). However, for some patients who do not respond to ICB treatment or show ICB-induced autoimmune symptoms, new alternatives need to be explored. Innovative immunomodulatory strategies, including the administration of immunostimulants, could be used to improve the immunogenicity induced by radiotherapy. In this study, we explored the synergistic effect of Bacillus Calmette-Guérin (BCG) combined with hypo-fractionated radiotherapy (H-RT) in inducing anti-tumor immune responses. We observed the systemic and abscopal effects of this combination in mice with 4 T1 breast cancer. H-RT combined with BCG could remodel the immune microenvironment and alleviate leukocyte-like responses by increasing the infiltration of CD8 + T cells, promoting the maturation of dendritic cells (DCs), decreasing the infiltration of immunosuppressive cells, and downregulating the expression of immunosuppressive cytokines. Therefore, this combination could enhance the systemic anti-tumor response, leading to the regression of untreated synchronous tumors and a decrease in the systemic metastatic burden. These results highlight the potential of BCG in assisting antitumor therapy and the therapeutic potential of this combination treatment.

Prognostic value of PD-L1 and Siglec-15 expression in patients with nasopharyngeal carcinoma.

Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) might be involved in the activation of important pathways related to tumor immune escape, along with programmed death-ligand 1 (PD-L1). Here, we aimed to investigate the correlation between the expression of Siglec-15 and PD-L1 in nasopharyngeal carcinoma (NPC) patients. We determined the expression of PD-L1 via immunohistochemical staining and that of Siglec-15 via immunofluorescence staining in 182 NPC tissue samples. A significant correlation was identified between the PD-L1 and Siglec-15 expression (P = 0.000). Moreover, Kaplan-Meier survival curves showed that PD-L1 expression was associated with improved overall survival (OS) (P = 0.025) and Siglec-15 expression was associated with improved distant failure-free survival (D-FFS) (P = 0.048). Moreover, multivariate Cox analysis showed that PD-L1 and Siglec-15 were independent predictors of OS (P = 0.020) and D-FFS (P = 0.047), respectively. The results of the log-rank test and Cox regression analyses showed that patients exhibiting no PD-L1/Siglec-15 expression had significant advantages regarding OS, compared to other groups (P = 0.037). PD-L1 and Siglec-15 may represent novel biomarkers for predicting the prognosis of NPC patients. Siglec-15 may be considered as a potential target for the development of therapeutics for NPC treatment in the future.

Patient-Derived Organoids Can Guide Personalized-Therapies for Patients with Advanced Breast Cancer.

Most breast cancers at an advanced stage exhibit an aggressive nature, and there is a lack of effective anticancer options. Herein, the development of patient-derived organoids (PDOs) is described as a real-time platform to explore the feasibility of tailored treatment for refractory breast cancers. PDOs are successfully generated from breast cancer tissues, including heavily treated specimens. The microtubule-targeting drug-sensitive response signatures of PDOs predict improved distant relapse-free survival for invasive breast cancers treated with adjuvant chemotherapy. It is further demonstrated that PDO pharmaco-phenotyping reflects the previous treatment responses of the corresponding patients. Finally, as clinical case studies, all patients who receive at least one drug predicate to be sensitive by PDOs achieve good responses. Altogether, the PDO model is developed as an effective platform for evaluating patient-specific drug sensitivity in vitro, which can guide personal treatment decisions for breast cancer patients at terminal stage.

FBXL19-AS1 aggravates the progression of hepatocellular cancer by downregulating KLF2.

PURPOSE: To uncover the role of FBXL19-AS1 in aggravating the progression of hepatocellular cancer (HCC) by downregulating kruppel-likefactor2 (KLF2). METHODS: FBXL19-AS1 level in HCC tissues and adjacent normal tissues were firstly determined. Its level in HCC with different tumor sizes (≤ 5 cm or > 5 cm) and different tumor stages (stage I-II or III-IV) was examined as well. Subcellular distribution of FBXL19-AS1 was detected. The regulatory effect of FBXL19-AS1 on viability, apoptosis and cell cycle progression of HCC cells was assessed. RNA immunoprecipitation (RIP) assay was conducted to explore the interaction between FBXL19-AS1 with EZH2 and SUZ12. Moreover, chromatin immunoprecipitation (ChIP) assay was carried out to identify the recruitment ability of FBXL19-AS1 on EZH2 and H3K27me3. Finally, the potential role of KLF2 in FBXL19-AS1-mediated HCC proliferation was investigated. RESULTS: FBXL19-AS1 was highly expressed in HCC tissues, especially in those larger than 5 cm in tumor size and worse tumor stage. FBXL19-AS1 was mainly distributed in nucleus and interacted with EZH2 and SUZ12. Knockdown of FBXL19-AS1 suppressed proliferation, cell cycle progression and induced apoptosis of HCC cells. Moreover, silence of FBXL19-AS1 attenuated the recruitment ability of EZH2 on KLF2. Knockdown of KLF2 reversed the regulatory effect of FBXL19-AS1 on proliferative ability of HCC cells. CONCLUSIONS: Long non-coding RNA (lncRNA) FBXL19-AS1 is upregulated in HCC. It accelerates proliferative ability, cell cycle progression and suppresses apoptosis of tumor cells through interacting with KLF2, thus aggravating the progression of HCC.

Increased extracellular fluid is associated with white matter fiber degeneration in CADASIL: in vivo evidence from diffusion magnetic resonance imaging.

BACKGROUND: White matter hyperintensities (WMHs) are one of the hallmarks of cerebral small vessel disease (CSVD), but the pathological mechanisms underlying WMHs remain unclear. Recent studies suggest that extracellular fluid (ECF) is increased in brain regions with WMHs. It has been hypothesized that ECF accumulation may have detrimental effects on white matter microstructure. To test this hypothesis, we used cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a unique CSVD model to investigate the relationships between ECF and fiber microstructural changes in WMHs. METHODS: Thirty-eight CADASIL patients underwent 3.0 T MRI with multi-model sequences. Parameters of free water (FW) and apparent fiber density (AFD) obtained from diffusion-weighted imaging (b = 0 and 1000 s/mm2) were respectively used to quantify the ECF and fiber density. WMHs were split into four subregions with four levels of FW using quartiles (FWq1 to FWq4) for each participant. We analyzed the relationships between FW and AFD in each subregion of WMHs. Additionally, we tested whether FW of WMHs were associated with other accompanied CSVD imaging markers including lacunes and microbleeds. RESULTS: We found an inverse correlation between FW and AFD in WMHs. Subregions of WMHs with high-level of FW (FWq3 and FWq4) were accompanied with decreased AFD and with changes in FW-corrected diffusion tensor imaging parameters. Furthermore, FW was also independently associated with lacunes and microbleeds. CONCLUSIONS: Our study demonstrated that increased ECF was associated with WM degeneration and the occurrence of lacunes and microbleeds, providing important new insights into the role of ECF in CADASIL pathology. Improving ECF drainage might become a therapeutic strategy in future.

Glymphatic Dysfunction: A Bridge Between Sleep Disturbance and Mood Disorders.

Mounting evidence demonstrates a close relationship between sleep disturbance and mood disorders, including major depression disorder (MDD) and bipolar disorder (BD). According to the classical two-process model of sleep regulation, circadian rhythms driven by the light-dark cycle, and sleep homeostasis modulated by the sleep-wake cycle are disrupted in mood disorders. However, the exact mechanism of interaction between sleep and mood disorders remains unclear. Recent discovery of the glymphatic system and its dynamic fluctuation with sleep provide a plausible explanation. The diurnal variation of the glymphatic circulation is dependent on the astrocytic activity and polarization of water channel protein aquaporin-4 (AQP4). Both animal and human studies have reported suppressed glymphatic transport, abnormal astrocytes, and depolarized AQP4 in mood disorders. In this study, the "glymphatic dysfunction" hypothesis which suggests that the dysfunctional glymphatic pathway serves as a bridge between sleep disturbance and mood disorders is proposed.

Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics.

Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer type with high morbidity in Southeast Asia, however the pathogenic mechanism of this disease is poorly understood. Using integrative pharmacogenomics, we find that NPC subtypes maintain distinct molecular features, drug responsiveness, and graded radiation sensitivity. The epithelial carcinoma (EC) subtype is characterized by activations of microtubule polymerization and defective mitotic spindle checkpoint related genes, whereas sarcomatoid carcinoma (SC) and mixed sarcomatoid-epithelial carcinoma (MSEC) subtypes exhibit enriched epithelial-mesenchymal transition (EMT) and invasion promoting genes, which are well correlated with their morphological features. Furthermore, patient-derived organoid (PDO)-based drug test identifies potential subtype-specific treatment regimens, in that SC and MSEC subtypes are sensitive to microtubule inhibitors, whereas EC subtype is more responsive to EGFR inhibitors, which is synergistically enhanced by combining with radiotherapy. Through combinational chemoradiotherapy (CRT) screening, effective CRT regimens are also suggested for patients showing less sensitivity to radiation. Altogether, our study provides an example of applying integrative pharmacogenomics to establish a personalized precision oncology for NPC subtype-guided therapies.

Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?

Emerging evidence demonstrates the critical role of the immune response in the mechanisms relating to mood disorders, such as major depression (MDD) and bipolar disorder (BD). This has cast a spotlight on a specialized branch committed to the research of dynamics of the fine interaction between emotion (or affection) and immune response, which has been termed as "affective immunology." Inflammatory cytokines and gut microbiota are actively involved in affective immunology. Furthermore, abnormalities of the astrocytes and microglia have been observed in mood disorders from both postmortem and molecular imaging studies; however, the underlying mechanisms remain elusive. Notably, the crosstalk between astrocyte and microglia acts as a mutual and pivotal intermediary factor modulating the immune response posed by inflammatory cytokines and gut microbiota. In this study, we propose the "altered astrocyte-microglia crosstalk (AAMC)" hypothesis which suggests that the astrocyte-microglia crosstalk regulates emotional alteration through mediating immune response, and thus, contributing to the development of mood disorders.

HeLa Cell-Derived Paclitaxel-Loaded Microparticles Efficiently Inhibit the Growth of Cervical Carcinoma.

AIM: Tumor cell-derived microparticles (MP) can function as a targeted delivery carrier for anti-tumor drugs. Here, we aimed to generate paclitaxel-loaded microparticles (MP-PTX) from HeLa cells and examined its therapeutic potential on human cervical carcinoma. METHODS: MP-PTX was generated from HeLa cells by ultraviolet radiation and subsequent centrifugation. The particle size, drug loading rate, and stability of MP-PTX were examined in vitro. Flow cytometry and the MTT assay were performed to test the inhibitory effect of MP-PTX using different cell lines. Immunodeficient mice bearing HeLa cervical carcinoma were treated with 0.9% normal saline, MP, paclitaxel (PTX) (2.5 mg/kg), or MP-PTX (PTX content identical to PTX group) every day for 6 consecutive days. Tumor volume and animal survival were observed. Micro 18F-FDG PET/CT was performed to monitor the therapeutic efficacy. The proliferation activity of cells and microvessel density in tumor tissues were determined by immunohistochemical staining using Ki-67 and CD31, respectively. RESULTS: Dynamic laser scattering measurements showed that the particle size of MP-PTX was 285.58 ± 2.95 nm and the polydispersity index was 0.104 ± 0.106. And the particle size of MP-PTX was not change at 4°C for at least one week. More than 1% of PTX in the medium could be successfully encapsulated into HeLa cell-derived MP. When compared with PTX, MP-PTX treatment significantly increased apoptosis of tumor cells and reduced their proliferation. In addition, MP-PTX showed lower toxicity to normal human umbilical vein endothelial cells (HUVEC) than PTX. In vivo studies further demonstrated that MP-PTX treatment significantly inhibited the growth of cervical carcinoma, prolonged the survival of tumor-bearing mice, and reduced the toxicity of PTX. Immunohistochemical staining revealed that MP-PTX treatment led to decreased Ki-67 positive tumor cells and decreased microvessel density in tumor tissues. CONCLUSION: Our results demonstrated that HeLa-derived MP-PTX significantly enhanced the anti-cancer effects of PTX with reduced toxicity, which may provide a novel strategy for the treatment of cervical carcinoma.

Management of Chemotherapy for Stage II Nasopharyngeal Carcinoma in the Intensity-Modulated Radiotherapy Era: A Review.

Nasopharyngeal carcinoma is an endemic disease with a high prevalence in Southeast Asia, Mediterranean countries, and Northern Africa. With substantial advances in screening and diagnosis, increasingly more early-stage (stage I~II) patients are being diagnosed. The undebated treatment modality for stage I patients is radiotherapy alone. However, controversies exist for patients with stage II disease, mostly revolving around the management of chemotherapy. However, the use of intensity-modulated radiotherapy for the treatment of nasopharyngeal carcinoma has increased recently, which has drastically improved survival outcomes. Thus, many oncologists have considered omitting chemotherapy for stage II patients in the intensity-modulated radiotherapy era. Unfortunately, prospective studies comparing concurrent radio-chemotherapy with intensity-modulated radiotherapy alone are limited. Notably, stage II nasopharyngeal carcinoma consists of three subgroups, among which stage T2N1M0 disease is unique and potentially warrants additional treatment including chemotherapy. Additionally, molecular biology techniques are advancing at an incredible speed. Instead of adopting a one-size-fits-all recommendation, exploring potential predictive biomarkers to select patients who are likely to derive benefit from chemotherapy is a better choice. In this review, we summarize the data from studies and reviews regarding chemotherapy for stage II nasopharyngeal carcinoma in the intensity-modulated radiotherapy era and discuss chemotherapy utility. Eventually, we conclude that IMRT alone may be sufficient for stage II nasopharyngeal carcinoma, but this needs to be verified by prospective studies in the near future, the evidence collected thus far suggests that concurrent chemo-radiotherapy without induction or adjuvant chemotherapy is yet to be necessary for patients with stage II disease.

Chronic chemotherapy with paclitaxel nanoparticles induced apoptosis in lung cancer in vitro and in vivo.

AIM: Paclitaxel (PTX) is an effective antitumor drug. Previous research demonstrated that paclitaxel nanoparticles (PTX-NPs) exhibited the greatest antitumor effect at 15 hours after light onset (15 HALO), but the mechanism in chronic chemotherapy is still unknown. In our study, we investigated whether PTX-NPs regulated Period2 (Per2) during chronic chemotherapy to induce apoptosis in vivo and in vitro. METHODS: To improve the antitumor effect and reduce organ damage induced by PTX treatment, PTX-NPs were prepared using a film dispersion method. Then, A549 cells were treated with PTX-NPs at 0, 5, 10, 15, and 20 HALO. An annexin/PI V-FITC apoptosis kit was measured for apoptosis, and PI was analyzed for cell cycle. The relative mechanism was detected by RT-PCR and Western blotting. Tumor volume and weight were measured to evaluate the antitumor effect of the PTX-NPs, and H&E staining was performed to assess organ damage. RESULTS: Cell cycle analysis demonstrated that PTX-NPs blocked cell cycle in G2 phase and that the ratio of cell death was significantly increased in A549 cells, while the ratios of cells in G2 phase and of apoptotic cells were highest at 15 HALO. Evaluation of in vivo antitumor activity revealed that PTX-NPs inhibited tumor growth and decreased tumor weight at 15 HALO. RT-PCR and Western blotting demonstrated that PTX-NPs upregulated Per2 mRNA and protein expression, and the highest Per2 expression was observed at 15 HALO in vivo and in vitro. Meanwhile, Bax mRNA and protein expression was upregulated, while Bcl-2 mRNA and protein expression was downregulated after PTX-NPs treatment in vivo. Moreover, H&E staining revealed that PTX-NPs reduced liver damage at 15 HALO. CONCLUSION: PTX-NPs exhibited the most effective antitumor activity and reduced liver damage at 15 HALO through upregulation of Per2 expression to induce apoptosis in vivo and in vitro.

Abnormal corpus callosum induced by diabetes impairs sensorimotor connectivity in patients after acute stroke.

OBJECTIVES: To test the hypothesis that abnormal corpus callosum (CC) induced by diabetes may impair inter-hemispheric sensorimotor functional connectivity (FC) that is associated with poor clinical outcome after stroke. METHODS: Forty-five patients with acute ischaemic stroke in the middle cerebral artery territory and 14 normal controls participated in the study. CC was divided into five subregions on three-dimensional T1-weighted image. The microstructural integrity of each subregion of CC was analysed by DTI and the inter-hemispheric FCs in primary motor cortex (M1-M1 FC) and primary sensory cortex (S1-S1 FC) were examined by resting-state functional magnetic resonance imaging. RESULTS: Diabetic patients (n = 26) had significantly lower fractional anisotropy (FA) in the isthmus of CC (CCisthmus) when compared with non-diabetic patients (n = 19) and normal controls (p < 0.0001). In addition, diabetic patients had the lowest M1-M1 FC (p = 0.015) and S1-S1 FC (p = 0.001). In diabetic patients, reduced FA of CCisthmus correlated with decreased M1-M1 FC (r = 0.549, p = 0.004) and S1-S1 FC (r = 0.507, p = 0.008). Decreased M1-M1 FC was independently associated with poor outcome after stroke in patients with diabetes (odds ratio = 0.448, p = 0.017). CONCLUSIONS: CC degeneration induced by diabetes impairs sensorimotor connectivity and dysfunction of motor connectivity can contribute to poor recovery after stroke in patients with diabetes. KEY POINTS: • Abnormal isthmus of corpus callosum in stroke patients with diabetes. • Abnormal isthmus of corpus callosum correlated with decreased inter-hemispheric sensorimotor connectivity. • Decreased motor connectivity correlated with poor stroke outcome in diabetic patients.

Naproxen Nanoparticle-Loaded Thermosensitive Chitosan Hydrogel for Prevention of Postoperative Adhesions.

Postoperative adhesions are the most common complications of peri-abdominal surgery; they not only affect the patient's quality of life but also increase the risk of a subsequent surgery. The use of implantable dressings to physically block surgical wounds is the primary solution to prevent postoperative adhesions. In this study, we prepared naproxen nanoparticles that were loaded with chitosan hydrogel (CS/Nap hydrogel) to prevent postoperative adhesions. Our data confirmed that the prepared CS/Nap hydrogel was thermosensitive and suitable for injection. The efficacy of anti-adhesion in a rat model revealed that the hydrogel effectively separated from the wounds of the abdominal wall and cecum. On day 7 postsurgery, the wounds were completely covered by a new epithelial layer, whereas wounds in the negative control group were glued together. Additionally, the in vivo toxicity study showed that the CS/Nap hydrogel had fewer toxic and side effects on major tissues and organs, including the liver, spleen, heart, lung, and kidney. We showed that a drug delivery system based on CS/Nap hydrogel has the potential not only to prevent postoperative abdominal adhesions and relieve pain but also to contribute to the administration of the hydrophobic drug naproxen.

Alterations in the hippocampal-thalamic pathway underlying secondarily generalized tonic-clonic seizures in mesial temporal lobe epilepsy: A diffusion tensor imaging study.

OBJECTIVE: The epileptogenic network underlying secondarily generalized tonic-clonic seizures (sGTCS) in mesial temporal lobe epilepsy (mTLE) is not well understood. Here, we investigated alterations in the probabilistic hippocampal-thalamic pathway (pHTP) underlying sGTCS using diffusion tensor imaging and resting-state functional magnetic resonance imaging in a cohort of TLE patients with hippocampal sclerosis (HS). METHODS: We consecutively recruited 51 unilateral TLE-HS patients (26 with and 25 without sGTCS) and 22 healthy controls. Probabilistic tractography was used to track the pHTP. Raw fractional anisotropy (FA) and mean diffusivity (MD) of the pHTP were corrected by the FA/MD of the hemispheric white matter on the same side. The volume of the thalamic subregion connected to the hippocampus (TSCH) was investigated. Fractional amplitude of low-frequency fluctuations of the hippocampus, the TSCH, and the thalamic subregion unconnected to the hippocampus in resting-state functional magnetic resonance imaging were also calculated. RESULTS: After correction, the sGTCS group showed lower FA than the non-sGTCS group (P = 0.03), and lower FA as well as higher MD than controls in the ipsilateral pHTP. The non-sGTCS group only showed higher corrected MD in the ipsilateral pHTP relative to controls. Corrected FA or MD in the contralateral pHTP did not differ among groups. The TSCH was located in the mesial aspect of the thalamus, and it was atrophied in the sGTCS group compared to the non-sGTCS group and controls. The sGTCS group had lower fractional amplitude of low-frequency fluctuations in the ipsilateral hippocampus and TSCH compared to controls. SIGNIFICANCE: In TLE-HS, sGTCS was associated with impaired integrity of the pHTP as well as structural and functional abnormalities in the medial thalamus. The medial thalamus is important in seizure generalization in mTLE.

Olaparib nanoparticles potentiated radiosensitization effects on lung cancer.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) is a key enzyme in the repair process of DNA strand breaks (DSBs). Olaparib (Ola) is a PARP inhibitor that is involved in arresting PARP release from radiotherapy (RT)-induced damaged DNA to potentiate the effect of RT. Although the underlying mechanisms for the radiosensitization effects of Ola are well understood in vitro, the radiosensitization effects in vivo are still unclear. Moreover, poor water solubility and severe toxicity are two major impediments for the clinical success of Ola. MATERIALS AND METHODS: Here, we developed olaparib nanoparticles (Ola-NPs) and investigated their radiosensitization mechanisms and toxicity using human non-small-cell lung cancer xenograft models in mice. RESULTS: The prepared Ola-NPs showed a mean size of 31.96±1.54 nm and a lower polydispersity index of about 0.126±0.014. In addition, the sensitization enhancement ratio of Ola-NPs (3.81) was much higher than that of free Ola (1.66). The combination of Ola-NPs and RT (Ola-NPs + RT) significantly inhibited tumor growth and prolonged survival in mice. The mechanism of enhanced antitumor efficacy might be related to the inhibition of DSB repair and the promotion of cell apoptosis in vivo. No additional toxicity caused by Ola-NPs was observed. CONCLUSION: This study demonstrated the principle of using Ola-NPs as a potent radiosensitizer to improve the therapeutic effect of RT relative to free Ola (P<0.05 in all cases).

Prognostic value of TIGAR and LC3B protein expression in nasopharyngeal carcinoma.

PURPOSE: Autophagy, the process responsible for degrading cytoplasmic organelles to sustain cellular metabolism, has been associated with cancer initiation and progression. As TP53-induced glycolysis and apoptosis regulator (TIGAR) is among the important genes that can regulate autophagy, we aimed to investigate the correlation between the expression levels of TIGAR and the autophagy-related protein microtubule-associated protein 1 light chain 3 (LC3B), as well as their association with clinical outcomes, in nasopharyngeal carcinoma (NPC) patients. METHODS: We detected the expressions of TIGAR and LC3B in 182 NPC tissue samples via immunohistochemical staining. RESULTS: A significant correlation between TIGAR and LC3B expressions was identified (P=0.045). Moreover, survival analysis showed that TIGAR- or LC3B+ expression was associated with improved overall survival, local regional failure-free survival, distant failure-free survival, and failure-free survival rates, compared with TIGAR+ or LC3B- expression, respectively. Meanwhile, when combining TIGAR with LC3B expression in terms of prognostic value, patients with TIGAR+/LC3B- expression were significantly disadvantaged with regard to overall survival, local regional failure-free survival, distant failure-free survival, and failure-free survival compared with other groups based on the log-rank test and Cox regression analyses (all P<0.05). CONCLUSION: TIGAR and LC3B may be novel biomarkers for predicting the prognosis of NPC patients and could be utilized as potential targets for future therapeutics aimed at treating NPC patients.

In vitro and in vivo apatinib inhibits vasculogenic mimicry in melanoma MUM-2B cells.

The effect of apatinib on the formation of vasculogenic mimicry (VM) was studied in a malignant melanoma cell line. MUM-2B cells cultured in three-dimensional Matrigel were treated with varying concentrations (0, 0.01, 0.05, 0.1, 0.5 µmol/L) of apatinib to test its effect on VM in vitro, followed by MTT proliferation and transwell invasion assays to determine the effect of apatinib on cell proliferation and invasion of MUM-2B cells. In vivo, we used a melanoma cancer model to test the effect of short-term apatinib (100, 200, 300 mg/kg) treatment on VM. Western blotting, immunohistochemistry staining, and CD31-PAS dual staining were performed to assess the expression of VEGFR-2, ERK-1/2, PI3K, and MMP-2, and formation of VM. The results showed apatinib-treated groups formed a lesser number of VM in 3D matrigel, while the cell viability in MTT proliferation assay and the number of migration cells in transwell invasion assay were significantly lower in apatinib-treated groups. In addition, short-term apatinib treatment inhibited angiogenesis, VM formation, and tumor growth in models of melanoma cancer. Mice in apatinib-treated groups showed a markedly reduced expression of VEGFR-2, ERK-1/2, PI3K, and MMP-2. In summary, apatinib could inhibit the expression of VEGFR-2, and downregulate the ERK1/2/PI3K/MMP-2 signaling cascade, which may be one of the underlying mechanisms by which apatinib inhibits angiogenesis and the development of VM in models of melanoma cancer, and restrains the formation of VM by MUM-2B cells. Apatinib shows inhibitory effects on cell proliferation and invasion of MUM-2B cells, which is a close relationship with the VM.

The diagnostic role of DNA methylation in sporadic endometrial cancer: a systematic review and meta-analysis.

BACKGROUND: Although increasing numbers of methylated genes have been identified as biomarkers for endometrial cancer, the results have been inconsistent. We therefore carried out a systematic review and meta-analysis to evaluate the diagnostic accuracy of methylated genes as markers for sporadic endometrial cancer. RESULTS: A total of 22 studies including 1930 participants (sporadic endometrial cancer patients and normal individuals) met our eligibility criteria. The pooled sensitivity and specificity were 0.93 (95% confidence interval: 0.91-0.94) and 0.48 (95% confidence interval: 0.46-0.50), respectively. The area under the summary receiver operating characteristic curve was 0.8834. The presence of DNA methylation was significantly associated with lymph node metastasis of endometrial cancer (pooled odds ratio: 0.28, 95% confidence interval: 0.15-0.52, p < 0.001). MATERIALS AND METHODS: We searched the relevant literature systematically using the PubMed and Web of Science databases up to April 2017. Diagnostic accuracy variables were pooled and analyzed using Meta-DiSc software. Sensitivity analysis and publication bias were evaluated using Review Manager. CONCLUSIONS: This meta-analysis suggests that the detection of DNA methylation is associated with lymph node metastasis, with high sensitivity but relatively low specificity for the diagnosis of sporadic endometrial cancer.

Glycyrrhetinic Acid-Modified Norcantharidin Nanoparticles for Active Targeted Therapy of Hepatocellular Carcinoma.

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been confirmed to have a good anti-tumor effect against hepatocellular carcinoma (HCC). However, its use is limited by its poor water solubility and low tumortargeting efficacy. In the present study, an active-targeted drug delivery nanoplatform was designed to deliver NCTD using a glycyrrhetinic acid (GA)-decorated copolymer (mPEG-PCL-PEI-GA, MPG). The NCTD-loaded polymeric nanoparticles (MPG/NCTD) formed by self-assembly in water exhibited a mean hydrodynamic diameter of roughly 89 nm. In vitro studies revealed that GA-conjugated nanoparticles (AT NPs) had superior cytotoxicity and higher targeting efficacy on HepG2 cells compared to non-conjugated nanoparticles (Non-AT NPs, NAT NPs). Determination of cell apoptosis and cell cycle phase showed that AT NPs resulted in increased cell apoptosis and a distinct increase in the G2 phase (65.30 ± 3.52%, P < 0.01) and S phase (46.39 ± 1.39%, P < 0.01). Evaluation of in vivo anti-tumor activity showed that the AT NPs significantly inhibited tumor growth and prolonged survival of tumor-bearing mice. The expression of Ki-67 and CD31 revealed that AT NPs inhibited cell proliferation and resulted in a decreased microvessel density (MVD). The results indicated that NCTD-loaded GA-modified nanoparticles may have great potential in HCC-targeted therapy.