Chondroitin Sulfate-Modified Hydroxyapatite for Caspase-1 Activated Induced Pyroptosis through Ca Overload/ER Stress/STING/IRF3 Pathway in Colorectal Cancer.

Immune checkpoint inhibitors, are the fourth most common therapeutic tool after surgery, chemotherapy, and radiotherapy for colorectal cancer (CRC). However, only a small proportion (≈5%) of CRC patients, those with "hot" (immuno-activated) tumors, benefit from the therapy. Pyroptosis, an innovative form of programmed cell death, is a potentially effective means to mediate a "cold" to "hot" transformation of the tumor microenvironment (TME). Calcium-releasing hydroxyapatite (HAP) nanoparticles (NPs) trigger calcium overload and pyroptosis in tumor cells. However, current limitations of these nanomedicines, such as poor tumor-targeting capabilities and insufficient calcium (Ca) ion release, limit their application. In this study, chondroitin sulfate (CS) is used to target tumors via binding to CD44 receptors and kaempferol (KAE) is used as a Ca homeostasis disruptor to construct CS-HAP@KAE NPs that function as pyroptosis inducers in CRC cells. CS-HAP@KAE NPs bind to the tumor cell membrane, HAP released Ca in response to the acidic environment of the TME, and kaempferol (KAE) enhances the influx of extracellular Ca, resulting in intracellular Ca overload and pyroptosis. This is associated with excessive endoplasmic reticulum stress triggered activation of the stimulator of interferon genes/interferon regulatory factor 3 pathway, ultimately transforming the TME from "cold" to "hot".

Identification of PANoptosis-related genes as prognostic indicators of thyroid cancer.

Background: Thyroid cancer (THCA) has become a common malignancy in recent years, with the mortality rate steadily increasing. PANoptosis is a unique kind of programmed cell death (PCD), including pyroptosis, necroptosis, and apoptosis, and is involved in the proliferation and prognosis of numerous cancers. This paper demonstrated the connection between PANoptosis-related genes and THCA based on the analyses of Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, which have not been evaluated yet. Methods: We identified PANoptosis-related differentially expressed genes (PRDEGs) by multi-analyzing the TCGA-THCA and GEO datasets. To identify the significant PRDEGs, a prognostic model was constructed using least absolute shrinkage and selection operator regression (LASSO). The predictive values of the significant PRDEGs for THCA outcomes were determined using Cox regression analysis and nomograms. Gene enrichment analyses were performed. Finally, immunohistochemistry was carried out using the human protein atlas. Results: A LASSO regression model based on nine PRDEGs was constructed, and the prognostic value of key PRDEGs was explored via risk score. Univariate and multivariate Cox regression were implemented to identify further three significant PRDEGs closely related to distant metastasis, lymph node metastasis, and tumor stage. Then, a nomogram was constructed, which presented high predictive accuracy for 5 years survival of THCA patients. Gene enrichment analyses in THCA were strongly associated with PCD pathways. CASP6 presented significantly differential expression during clinical T stage, N stage, and PFI events (P < 0.05 for all) and demonstrated the highest degree of diagnostic efficacy in PRDEGs (HR: 2.060, 95 % CI: 1.170-3.628, P < 0.05). Immunohistochemistry showed CASP6 was more abundant in THCA tumor tissue. Conclusion: A potential prognostic role for PRDEGs in THCA was identified, providing a new direction for treatment. CASP6 may be a potential therapeutic target and a novel prognostic biomarker for THCA.

EGCG-NPs inhibition HO-1-mediated reprogram iron metabolism against ferroptosis after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH), a devastating disease with a high mortality rate and poor outcomes, tightly associated with the dysregulation of iron metabolism and ferroptosis. (-)-Epigallocatechin-3-gallate (EGCG) is one of major bioactive compounds of tea catechin because of its well-known iron-chelating and antioxidative activities. However, the findings of iron-induced cell injuries after SAH remain controversial and the underlying therapeutic mechanisms of EGCG in ferroptosis is limited. Here, the ability of EGCG to inhibit iron-induced cell death following the alleviation of neurological function deficits was investigated by using in vivo SAH models. As expected, EGCG inhibited oxyhemoglobin (OxyHb)-induced the over-expression of HO-1, which mainly distributed in astrocytes and microglial cells. Subsequently, EGCG blocked ferrous iron accumulation through HO-1-mediated iron metabolic reprogramming. Therefore, oxidative stress and mitochondrial dysfunction was rescued by EGCG, which resulted in the downregulation of ferroptosis and ferritinophagy rather than apoptosis after SAH. As a result, EGCG exerted the superior therapeutic effects in the maintenance of iron homeostasis in glial cells, such as astrocytes and microglial cells, as well as in the improvement of functional outcomes after SAH. These findings highlighted that glial cells were not only the iron-rich cells in the brain but also susceptible to ferroptosis and ferritinophagy after SAH. The detrimental role of HO-1-mediated ferroptosis in glial cells can be regarded as an effective therapeutic target of EGCG in the prevention and treatment of SAH.

Has_circ_0071803 promotes colorectal cancer progression by regulating miR-330-5p/MAPK signaling pathway.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. A lack of effective targeted therapies against CRC makes the treatment challenging. Here, we report a circular RNA (circRNA), has_circ_0071803, functioning as an oncogene in CRC. Circ_0071803 was upregulated in CRC tissues and cell lines, and its expression levels were inversely correlated with the prognosis and survival rate of patients with CRC. Circ_0071803 knockdown suppressed cell proliferation, migration, and invasion in CRC. Moreover, we found that circ_0071803 sponged miR-330-5p, thereby upregulating mitogen-activated protein kinase 1 (MAPK1) in CRC cells. The suppression of cell activities by circ_0071803 knockdown were rescued by miR-330-5p inhibition or MAPK1 overexpression. Collectively, our findings elucidate that circ_0071803 promotes CRC progression by regulating the miR-330-5p/MAPK1 pathway, providing potential therapeutic targets for designing effective targeted treatments.

Bio-engineered nano-vesicles for IR820 delivery: a therapy platform for cancer by surgery and photothermal therapy.

Long-term unsolved health problems from pre-/intra-/postoperative complications and thermal ablation complications pose threats to liver-cancer patients. To reduce the threats, we propose a multimodal-imaging guided surgical navigation system and photothermal therapy strategy to improve specific labeling, real-time monitoring and effective treatment of hepatocellular carcinoma. Using a bioengineering approach, G-Nvs@IR820, a kind of human-cell-membrane nano-vesicle, was generated with growth arrest-specific 6 (Gas6) expressed on the membrane and with near-infrared absorbing dye (IR820) loaded into it, which is proven to be an effective nanoparticle-drug-delivery system for Axl-overexpressing hepatocellular carcinoma. G-Nvs@IR820 shows excellent features in vitro and in vivo. As Gas6 binds to Axl specifically, G-Nvs@IR820 has good targeting ability to the tumor site and also has a good ability to guide the further accurate obliteration of carcinoma from adjacent normal tissue in surgery with its highly resolved fluorescence/photoacoustic/surgical-navigation signals. Moreover, the G-Nvs@IR820 represented a new perspective for photothermal therapy. Briefly, Nvs@IR820 was synthesized at a gram scale with high affinity, specificity, and safety. It has promising potential in clinical application for IGS and PTT in Axl-overexpressing hepatoma carcinoma.

Evaluation of the synergistic effects of epigallocatechin-3-gallate-loaded PEGylated-PLGA nanoparticles with nimodipine against neuronal injury after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke with high mortality and morbidity. Although serious side effects might occur, nimodipine, a second-generation 1,4-dihydropyridine calcium channel blocker, is clinically used to improve neurological outcomes after SAH. Recently, (-)-epigallocatechin-3-gallate (EGCG) has been reported to inhibit Ca2+ overloading-induced mitochondrial dysfunction, oxidative stress, and neuronal cell death after SAH; however, low bioavailability, instability, and cytotoxicity at a high dose limited the clinical application of EGCG. To overcome these limitations, PEGylated-PLGA EGCG nanoparticles (EGCG-NPs) were constructed to enhance the bioavailability by using the double-emulsion method. Antioxidative activity, cytotoxicity, behavioral, and immunohistochemistry studies were carried out to determine the neuroprotective effectiveness after cotreatment with EGCG-NPs (75 mg/kg/d preconditioning for 7 days before SAH) and nimodipine (10 mg/kg/d after 30 min of SAH) by using in vivo SAH models. The optimized EGCG-NPs with a Box-Behnken design showed a small particle size of 167 nm, a zeta potential value of -22.6 mV, an encapsulation efficiency of 86%, and a sustained-release profile up to 8 days in vitro. Furthermore, EGCG-NPs (75 mg/kg/d) had superior antioxidative activity to free EGCG (100 mg/kg/d). EGCG-NPs combined with nimodipine exhibited significant synergistic effects against neuronal cell death by suppressing oxidative stress, Ca2+ overloading, mitochondrial dysfunction, and autophagy after SAH. These results suggest that cotreatment with EGCG-NPs and nimodipine may serve as a promising novel strategy for the treatment of SAH.

Evaluation of (-)-epigallocatechin-3-gallate (EGCG)-induced cytotoxicity on astrocytes: A potential mechanism of calcium overloading-induced mitochondrial dysfunction.

(-)-epigallocatechin-3-gallate (EGCG), the main component of green tea, has long been explored in the treatment and/or prevention of central nervous system (CNS) disorders. However, EGCG has been recently shown to exhibit acute and subacute toxicity. Although a lot of work has been done, the mechanisms of EGCG-induced mitochondrial dysfunction has not been delineated in primary astrocyte. Here, the mitotoxic effect of EGCG on primary astrocytes was investigated by measuring Ca2+ overloading-induced mitochondrial dysfunction. As expected, EGCG dose-dependently inhibited astrocytes growth depending on Ca2+ overloading, especially at 50 µM EGCG group. It is interesting to note that Ca2+ influx from the extracellular space was responsible for an increase in the cytosolic Ca2+ level ([Ca2+]i) by opening voltage-gated calcium channels (VGCCs) and, consequently, mitochondrial Ca2+ ([Ca2+]m) overloaded via the mitochondrial Ca2+ uniporter (MCU). As a result, mitochondrial dysfunction was induced, including the opening of the mitochondrial permeability transition pore (mPTP), mitochondrial membrane depolarization, an increasing in reactive oxygen species (ROS), and cytochrosome c (cyt c) releasing. Therefore, more apoptotic cells were observed in 50 µM EGCG group than that of in 1 µM EGCG group. These findings suggested that a high dose of EGCG was toxic to astrocytes partly by targeting mitochondria via calcium pathway, which would extend our understanding of the toxicity of EGCG and the underlying mechanisms.

CDCA7L promotes glioma proliferation by targeting CCND1 and predicts an unfavorable prognosis.

Cell division cycle associated 7 like (CDCA7L) belongs to the JPO protein family, recently identified as a target gene of c­Myc and is frequently dysregulated in multiple cancers. However, to the best of our knowledge, no studies to date have been carried out to investigate the functions of CDCA7L in glioma. Thus, in this study, the expression level of CDCA7L and its association with the prognosis in glioma were detected through the TCGA database. The mRNA expression levels of CDCA7L in glioblastoma (GBM) tissues and normal brain tissues were detected by RT­qPCR and western blot analysis. To explore the role of CDCA7L in glioma, CDCA7L siRNA was constructed and transfected into U87 glioma cells. The expression levels of CDCA7L and cyclin D1 (CCND1) in glioma U87 cells following transfection with CDCA7L siRNA were measured by RT­qPCR and western blot analysis. CCK­8, colony formation, EdU and Transwell assays were used to measure the effects of CDCA7L on U87 cell proliferation, and flow cytometry was used to monitor the changes in the cell cycle following transfection with CDCA7L siRNA. Xenograft tumors were examined in vivo for the carcinogenic effects, as well as the mechanisms and prognostic value of CDCA7L in glioma tissues. The results revealed that CDCA7L was highly expressed in human GBM tissues, and a high expression of CDCA7L was associated with a poor prognosis of glioma patients through the TCGA database. We demonstrated that CDCA7L was highly expressed in human GBM tissues and 3 glioma cell lines. The downregulation CDCA7L expression significantly inhibited the proliferation and colony formation ability of U87 cells by blocking cell cycle progression in the G0/G1 phase. In addition, we found that the mRNA and protein levels of CCND1 were markedly decreased following transfection with CDCA7L siRNA compared with NC siRNA in vitro. The downregulation CDCA7L expression reduced the number of invading cells. Consistent with the results of the in vitro assays, the xenograft assay, immunohistochemistry (IHC) assay and western blot analysis demonstrated that, in response to CDCA7L inhibition, tumor growth was inhibited, Ki­67 and CCND1 expression levels were decreased in vivo. On the whole, the results of the current study indicate that CDCA7L is highly expressed in human glioma tissues and that a high CDCA7L expression predicts a poor prognosis of glioma patients. CDCA7L promotes glioma U87 cell growth through CCND1.

lncRNA small nucleolar RNA host gene 20 predicts poor prognosis in glioma and promotes cell proliferation by silencing P21.

BACKGROUND: In multiple cancers, long non-coding RNA small nucleolar RNA host gene 20 (lncRNA SNHG20) is generally dysregulated. In the present study, both the biological role and clinicopathological value of lncRNA SNHG20 in glioma are explored. METHODS: Real-time PCR was employed to determine lncRNA SNHG20 expression in glioma patients. The prognostic role of expression of lncRNA SNHG20 was evaluated in a retrospective cohort study. In addition, the association between lncRNA SNHG20 expression and the clinicopathological features of glioma patients, such as tumor recurrence, survival status, follow-up time, WHO grade, resection extent, tumor location, Karnofsky performance scale score, cystic change, tumor size, gender and age, was discussed. By constructing and transfecting siRNAs that targeted lncRNA SNHG20 into the glioma U87 cells, the effects of lncRNA SNHG20 on the proliferation and cell cycle of U87 cells were assessed through cell counting kit-8, colony formation and cell cycle assays, respectively. In addition, Western blot and real-time PCR measured the expression levels of P21 and CCNA1 in U87 cells after being transfected with SNHG20 siRNA. RESULTS: Our results suggested the high expression of lncRNA SNHG20 in human glioma tissues compared with normal brain tissues, which was related to recurrence-free survival and poor overall survival in glioma patients. According to the existing retrospective cohort study, high lncRNA SNHG20 expression was associated with tumor size, extent of resection, WHO grade, follow-up time, survival status and recurrence. Besides, knocking down the expression of lncRNA SNHG20 could inhibit the proliferation and colony formation abilities of glioma U87 cells through cell cycle arrest. Consequently, the expression of CCNA1 was inhibited, and the expression of P21 was up-regulated in U87 cells. CONCLUSION: A high lncRNA SNHG20 expression level predicts the poor prognosis for glioma patients. Moreover, lncRNA SNHG20 can promote glioma proliferation through silencing P21 and thus lncRNA SNHG20 is an independent potential prognostic biomarker for glioma patients.

Molecular evolution of influenza B virus during 2011-2017 in Chaoyang, Beijing, suggesting the free influenza vaccine policy.

Two influenza B virus lineages, B/Victoria and B/Yamagata, are co-circulating in human population. While the two lineages are serologically distinct and TIV only contain one lineage. It is important to investigate the epidemiological and evolutionary dynamics of two influenza B virus lineages in Beijing after the free influenza vaccine policy from 2007. Here, we collected the nasopharyngeal swabs of 12657 outpatients of influenza-like illness and subtyped by real-time RT-PCR during 2011-2017. The HA and NA genes of influenza B were fully sequenced. The prevalence is the highest in the 6-17 years old group among people infected with influenza B. Yamagata-lineage virus evolved to two inter-clade from 2011-2014 to 2014-2017. The amino acids substitutions of HA1 region were R279K in strains of 2011-2014 and L173Q, M252V in strains of 2014-2017. Substitutions L58P, I146V were observed in HA1 region of Victoria-lineage virus in 2011-2012 and I117V, N129D were showed in 2015-2017. Phylogenetic analysis of NA showed Yamagata-Victoria inter-lineage reassortant occurred in 2013-2014. Influenza B mainly infect the school-aged children in Beijing and the free influenza vaccine inoculation does not seem to block school-age children from infection with influenza B. The antigen characteristics of circulating influenza B were different to the recommended vaccine strains. We concluded that the Victoria-lineage vaccine strain should been changed and the free influenza vaccine should be revalued.

Evaluation of the neuroprotective effect of EGCG: a potential mechanism of mitochondrial dysfunction and mitochondrial dynamics after subarachnoid hemorrhage.

(-)-Epigallocatechin-3-gallate (EGCG), the main bioactive component of tea catechins, exhibits broad-spectrum health efficacy against mitochondrial damage after subarachnoid hemorrhage (SAH). The mechanisms, however, are largely unknown. Here, the ability of EGCG to rescue mitochondrial dysfunction and mitochondrial dynamics following the inhibition of cell death was investigated by using in vitro and in vivo SAH models. EGCG blocked the cytosolic channel ([Ca2+])i influx via voltage-gated calcium channels (VGCCs), which induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization and reactive oxygen species (ROS) release. As expected, EGCG ameliorated oxyhemoglobin (OxyHb)-induced impairment of mitochondrial dynamics by regulating the expression of Drp1, Fis1, OPA1, Mfn1, and Mfn2. As a result, EGCG restored the increases in fragmented mitochondria and the mtDNA copy number in the OxyHb group to almost the normal level after SAH. In addition, the normal autophagic flux induced by EGCG at both the initiation and formation stages regulated Atg5 and Beclin-1 after SAH for the timely elimination of damaged mitochondria. In the end, EGCG increased the neurological score by decreasing cell death through the cyt c-mediated intrinsic apoptotic pathway. The results revealed the mechanisms behind the neuroprotective effects of EGCG via inhibition of the overloaded [Ca2+]i-induced mitochondrial dysfunction and the imbalanced mitochondrial fusion and fission cycle. Therefore, the simultaneous inhibition and timely elimination of damaged mitochondria could determine the therapeutic effect of EGCG.

p38 Inhibitor Protects Mitochondrial Dysfunction by Induction of DJ-1 Mitochondrial Translocation After Subarachnoid Hemorrhage.

p38 mitogen-activated protein kinase (MAPK) is a major player in mitochondrial dysfunction after subarachnoid hemorrhage (SAH). Moreover, DJ-1, which responds to oxidative stress and translocates to mitochondria, maintains mitochondrial homeostasis. Although a few studies have demonstrated that DJ-1 indirectly regulates p38 activation, the relationship between DJ-1 and p38 in mitochondrial dysfunction after SAH has not been delineated. Using an in vitro SAH model, alterations in p38, p-p38, DJ-1, and autophagic-related protein expression were detected. As expected, p38 inhibitor significantly blocked excessive expression of p38 and p-p38 after SAH, whereas total DJ-1 expression and mitochondrial DJ-1 were up-regulated. Further analysis showed that p38 inhibitor significantly blocked oxyhemoglobin (OxyHb) induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization and reactive oxygen species (ROS) release. In addition, p38 inhibitor restored OxyHb-induced abnormal autophagic flux at the initiation and formation stage by regulating Atg5, beclin-1, the ratio of LC3-II/LC3-I, and p62 expression. This study suggested that overexpression of p38 induced the accumulation of mitochondrial dysfunction partly due to abnormal activation of autophagy, which largely relied on DJ-1 mitochondrial translocation.

MiR-129-5p inhibits glioma cell progression in vitro and in vivo by targeting TGIF2.

This study purposed to explore the correlation between miR-129-5p and TGIF2 and their impacts on glioma cell progression. Differentially expressed miRNA was screened through microarray analysis. MiR-129-5p expression levels in glioma tissues and cells were measured by qRT-PCR. CCK-8 assay, flow cytometer, transwell assay and wound-healing assay were employed to detect cell proliferation, apoptosis and cycle, invasiveness and migration, respectively. Dual-luciferase reporting assay was performed to confirm the targeted relationship between miR-129-5p and TGIF2. The effects of TGIF2 expression on cell biological functions were also investigated using the indicated methods. Tumour xenograft was applied to explore the impact of miR-129-5p on tumorigenesis in vivo. MiR-129-5p expression was down-regulated in both glioma tissues and glioma cells, while TGIF2 expression was aberrantly higher than normal level. Dual-luciferase reporter assay validated the targeting relation between miR-129-5p and TGIF2. Overexpression of miR-129-5p or down-regulation of TGIF2 inhibited the proliferation, invasion and migration capacity of glioma cells U87 and U251, and meanwhile blocked the cell cycle as well as induced cell apoptosis. MiR-129-5p overexpression repressed the tumour development in vivo. MiR-129-5p and TGIF2 had opposite biological functions in glioma cells. MiR-129-5p could inhibit glioma cell progression by targeting TGIF2, shining light for the development of target treatment for glioma.

Differential expression of microRNAs contributed to the health efficacy of EGCG in in vitro subarachnoid hemorrhage model.

(-)-Epigallocatechin-3-gallate (EGCG) exhibits a broader spectrum health efficacy in subarachnoid hemorrhage (SAH) therapy; the mechanisms, however, are largely unknown. Given that miRNAs play important roles in regulation of thousands of gene expressions, the effect of EGCG on the expression of miRNAs was investigated to explore the multi-targeting actions of EGCG by using an in vitro SAH model. MTT and western blot assays were used to assess the health effects of EGCG in SAH progression; the results showed that oxyhemoglobin (OxyHb)-induced cell proliferation and excessive autophagic activation were significantly inhibited by 50 µM EGCG, but not by 1 µM EGCG. By high throughput sequencing analysis, the miRNA profiles of normal, SAH and EGCG (1 and 50 µM) groups were compared and a total of 953 miRNAs were identified. Of 192 differentially expressed miRNAs, 43 miRNAs were significantly differentially expressed in SAH (p < 0.01). However, EGCG significantly increased the number of differential expressions of miRNAs, which showed 144 and 138 miRNAs (112 and 115 upregulated, 32 and 23 downregulated, p < 0.01) in 1 µM and 50 µM EGCG groups, respectively. Among all the differentially expressed miRNAs, 13 miRNAs were shared by the three groups. 5 miRNAs (miR-218-5p, miR-218b, miR-143-3p, miR-101a-3p, miR-30a-3p) were detected in both SAH and EGCG 1 µM groups, and 104 miRNAs were shared by the EGCG 1 µM and EGCG 50 µM groups. Only 1 miRNA (miR-532-5p) was discovered in both SAH and EGCG 50 µM groups. Moreover, 24, 22 and 20 specific differentially expressed miRNAs were discovered in SAH, 1 µM and 50 µM EGCG groups, respectively. The predicted target genes of differentially expressed miRNAs showed that the most impacted MAPK signaling pathway, particularly the upregulated p38 expression in the SAH group, was restored to the normal level in both EGCG groups, but the calcium signaling pathway was enriched only in the EGCG 50 µM group. These results revealed that differential expression of miRNAs is fundamental to understand the multiple targets actions of EGCG in SAH therapy, and simultaneously targeting more robust signaling pathways could determine the therapeutic effects of EGCG.

Reduction in Autophagy by (-)-Epigallocatechin-3-Gallate (EGCG): a Potential Mechanism of Prevention of Mitochondrial Dysfunction After Subarachnoid Hemorrhage.

Mitochondrial dysfunction and subsequent autophagy, which are common features in central nervous system (CNS) disorders, were found to contribute to neuronal cell injury after subarachnoid hemorrhage (SAH). (-)-Epigallocatechin-3-gallate (EGCG), the main biological active of tea catechin, is well known for its beneficial effects in the treatment of CNS diseases. Here, the ability of EGCG to rescue cellular injury and mitochondrial function following the improvement of autophagic flux after SAH was investigated. As expected, EGCG-protected mitochondrial function depended on the inhibition of cytosolic Ca2+ concentration ([Ca2+]i) influx via voltage-gated calcium channels (VGCCs) and, consequently, mitochondrial Ca2+ concentration ([Ca2+]m) overload via mitochondrial Ca2+ uniporter (MCU). The attenuated [Ca2+]i and [Ca2+]m levels observed in the EGCG-treated group likely lessened oxyhemoglobin (OxyHb)-induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization, mitochondrial membrane permeability transition pore (mPTP) opening, reactive oxygen species (ROS), and cytochrosome c (cyt c) releasing. Subsequently, EGCG can restore the disrupted autophagy flux after SAH both at the initiation and formation stages by regulating Atg5, LC3B, and Becn-1 (Beclin-1) mRNA expressions. Thus, precondition EGCG resulted in autophagosomes and more autolysosomes compared with SAH group. As a result, EGCG pre-treatment increased the neurological score and decreased cell death. This study suggested that the mitochondrial dysfunction and abnormal autophagy flux synergistically contribute to SAH pathogenesis. Thus, EGCG can be regarded as a new pharmacological agent that targets both mitochondria and altered autophagy in SAH therapy.

Smaller tumor size is associated with poor survival in T4b colon cancer.

AIM: To hypothesize that in patients with colon cancer showing heavy intestinal wall invasion without distant metastasis (T4bN0-2M0), small tumor size would correlate with more aggressive tumor behaviors and therefore poorer cancer-specific survival (CSS). METHODS: We analyzed T4bN0-2M0 colon cancer patients in the Surveillance, Epidemiology and End Results (SEER) database. A preliminary analysis of T4bN0-2M0 colon cancer patients at the Fudan University Shanghai Cancer Center is also presented. RESULTS: A total of 1734 T4bN0-2M0 colon cancer patients from the SEER database were included. Kaplan-Meier analysis revealed decreasing CSS with decreasing tumor size (P < 0.001). Subgroup analysis showed a significant association between poorer CSS with smaller tumor size in T4bN0 patients (P = 0.024), and a trend of association in T4bN1 (P = 0.182) and T4bN2 patients (P = 0.191). Multivariate analysis identified tumor size as an independent prognostic factor for CSS in T4bN0-2M0 patients (P = 0.024). Preliminary analysis of Fudan University Shanghai Cancer Center samples suggested the 5-year CSS was 50.0%, 72.9% and 77.1% in patients with tumors ≤ 4.0 cm, 4.0-7.0 cm and ≥ 7.0 cm. CONCLUSION: Smaller tumor size is associated with poorer CSS in the T4bN0-2M0 subset of colon cancer, particularly in the T4bN0M0 subgroup.

Smaller tumor size is associated with poor survival in stage II colon cancer: An analysis of 7,719 patients in the SEER database.

BACKGROUND: We hypothesized that in patients with colon cancer showing heavy intestinal wall invasion without lymph node metastasis (stage II), small tumor size would correlate with more aggressive tumor behaviors and thus poorer cancer-specific survival (CSS). METHODS: We analyzed Caucasian patients with stage II colon cancer based on data from the US Surveillance, Epidemiology, and End Results (SEER) database. Survival was analyzed using the Kaplan-Meier method, and the log-rank test was used to identify differences. Risk factors were analyzed using the Cox proportional hazard model. RESULTS: A total of 7719 stage II colon cancer patients from the SEER database were included in the analysis. The cutoff value (5.0 cm) was determined using the X-tile program. The Kaplan-Meier analysis showed that tumors <5.0 cm had a poorer CSS compared to tumors ≥5.0 cm (p = 0.006). Multivariate analysis indicated that tumor size is an independent prognostic factor for stage II patients, and compared to tumors <5.0 cm, tumors ≥5.0 cm were more likely to result in a better CSS (HR 0.775, 95% CI 0.691-0.870, p < 0.001). Tumor size was also analyzed as a continuous variable in the multivariate analysis, and the CSS decreased with decreasing tumor size (HR 0.958, 95% CI 0.936-0.981, p < 0.001). Subgroup analyses suggested that tumor size is also an independent prognostic factor for stage IIA (p = 0.002) and IIC (p < 0.001) patients. CONCLUSIONS: Smaller tumor size is associated with poor CSS in the stage II colon cancer and particularly in the stage IIA and IIC subgroups.

Predictive value of pretreatment lymphocyte count in stage II colorectal cancer and in high-risk patients treated with adjuvant chemotherapy.

UNLABELLED: Pretreatment lymphocyte count (LC) has been associated with prognosis and chemotherapy response in several cancers. The predictive value of LC for stage II colorectal cancer (CRC) and for high-risk patients treated with adjuvant chemotherapy (AC) has not been determined. A retrospective review of prospectively collected data from 1332 consecutive stage II CRC patients who underwent curative tumor resection was conducted. A pretreatment LC value <1.3 Giga/L(28.1%, 373/1332) was defined as low LC. A total of 738 patients (55.4%) were considered high-risk, 459 (62.2%) of whom received AC. Patients with low LCs had significantly worse 5-year OS (74.6% vs. 90.2%, p < 0.001) and DFS (61.3% vs. 84.6%, p < 0.001). High-risk patients with low LCs had the poorest DFS (p < 0.001). Multivariate analysis indicated that low LC value or combined with high-risk status were both independent prognostic factors(p <0.001). High-risk, AC-treated patients with high LCs had significantly longer DFS than untreated patients (HR, 0.594; 95% CI, 0.364-0.970; p = 0.035). There was no difference or trend for DFS or OS in patients with low LCs, regardless of the use of AC (DFS, p = 0.692; OS, p = 0.522). Low LC was also independently associated with poorer DFS in high-risk, AC-treated patients (HR, 1.885; 95% CI, 1.112-3.196; p = 0.019). CONCLUSIONS: Pretreatment LC is an independent prognostic factor for survival in stage II CRC. Furthermore, pretreatment LC reliably predicts chemotherapeutic efficacy in high-risk patients with stage II CRC.

Manganese Oxide-Coated Carbon Nanotubes As Dual-Modality Lymph Mapping Agents for Photothermal Therapy of Tumor Metastasis.

Lymph node (LN) status is a major indicator of stage and survival of lung cancer patients. LN dissection is a primary option for lung cancer LN metastasis; however, this strategy elicits adverse effects and great trauma. Therefore, developing a minimally invasive technique to cure LN metastasis of lung cancer is desired. In this study, multiwalled carbon nanotubes (MWNTs) coated with manganese oxide (MnO) and polyethylene glycol (PEG) (namely MWNTs-MnO-PEG) was employed as a lymphatic theranostic agent to diagnose and treat metastatic LNs. After single local injection and lymph drainage were performed, regional LNs were clearly mapped by T1-weighted magnetic resonance (MR) of MnO and dark dye imaging of MWNTs. Meanwhile, metastatic LNs could be simultaneously ablated by near-infrared (NIR) irradiation under the guidance of dual-modality mapping. The excellent result was obtained in mice bearing LNs metastasis models, showing that MWNTs-MnO-PEG as a multifunctional theranostic agent was competent for dual-modality mapping guided photothermal therapy of metastatic LNs.

Laparoscopic Low Anterior Resection and Eversion Technique Combined With a Nondog Ear Anastomosis for Mid- and Distal Rectal Neoplasms: A Preliminary and Feasibility Study.

The transanal eversion and prolapsing technique is a well-established procedure, and can ensure an adequate distal margin for patients with low rectal neoplasms. Potential leakage risks, however, are associated with bilateral dog ear formation, which results from traditional double-stapling anastomosis. The authors determined the feasibility of combining these techniques with a commercial stapling set to achieve a nondog ear (end-to-end) anastomosis for patients with mid- and distal rectal neoplasms. Patients with early-stage (c/ycT1-2N0), mid- to distal rectal neoplasms and good anal sphincter function were included in this study. Laparoscopic low anterior resection was performed with a standard total mesorectal excision technique downward to the pelvic floor as low as possible. The bowel was resected proximal to the lesion with an endoscopic linear stapler. An anvil was inserted extracorporeally into the proximal colon via an extended working pore. The distal rectum coupled with the lesion was prolapsed and everted out of the anus. The neoplasm was resected with a sufficient margin above the dentate line under direct sight. A transrectal anastomosis without dog ears was performed intracorporeally to reconstitute the continuity of the bowel. Eleven cases, 6 male and 5 female patients, were included in this study. The mean operative time was 191 (129-292) minutes. The mean blood loss was 110 (30-300) mL. The median distal margin distance from the lower edge of the lesion to the dentate line was 1.5 (0.5-2.5) cm. All the resection margins were negative. Most patients experienced uneventful postoperative recoveries. No patient had anastomotic leak. Most patients had an acceptable stool frequency after loop ileostomy closure. Our preliminary data demonstrated the safety and feasibility of achieving a sound anastomosis without risking potential anastomotic leakage because of dog ear formation.