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Papillary adenoma of the lung, a rare and benign tumor, is easily confused with other primary benign or malignant lung tumors and especially with lung adenocarcinoma that has a papillary growth pattern. Enhanced understanding and an accurate diagnosis of papillary adenomas of the lung are crucial for clinical treatment and prognostic assessment. A 61-year-old man who presented with an opportunistic finding in relation to a left lower lobe lung nodule during an examination was admitted to The First Hospital of China Medical University (Shenyang, China) for further treatment. Computed tomography (CT) revealed a well-circumscribed left lower lobe nodule (diameter, ~1 cm), comprising branched papillae with a fibrovascular core and no other structural components. The tumor cells appeared relatively uniform in shape and well arranged with round or oval nuclei. No nucleoli or mitotic figures were observed. Immunohistochemically, the papillary structures of the tumor cells were strongly and diffusely positive for cytokeratin (CK), CK7, Napsin-A and thyroid transcription factor 1. The Ki-67 index was ~1%. A pathological diagnosis of primary papillary adenoma of the lung was made based on these findings. A left lower-lobe wedge resection was performed and the patient's postoperative course was uneventful. Surgical resection is the preferred treatment. Papillary adenoma of the lung is very rare, and its clinical manifestations and CT images are non-specific. It is important to avoid misdiagnosing of papillary adenoma of the lung as another type of lung tumor, especially adenocarcinoma. A clear understanding of the morphological and immunohistochemical features of papillary adenomas is important for the diagnosis of this rare lung tumor. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is the most common malignant neoplasm of the thyroid gland; fine needle aspiration cytology is the most basic and reliable diagnostic method before PTC operation. However, it is not clear which cell morphological changes can be used as a reliable standard for the diagnosis of PTC. A retrospective analysis was performed on 337 patients with PTC confirmed by postoperative histology. An additional 197 randomly selected patients with benign thyroid lesions were included in the study and used as a control group. True papillary arrangements, swirl arrangements, and escape arrangements had high specificity, all of which were 100%, but only swirl arrangements had ideal sensitivity (77.61%). The nuclear volume characteristics had a high sensitivity of more than 90%, but the specificities of both nuclear crowding and nuclear overlap were too low, only 16.34% and 23.35%. The sensitivities of five nuclear structural characteristics were more than 90%, but only the specificity of intranuclear cytoplasmic pseudoinclusions (INCIs) reached 100%, nuclear contour irregularity and pale nuclei with powdery chromatin also had ideal interpretation value except for grooves and marginally placed micronucleoli. Although the sensitivity of psammoma bodies (PBs) was low, the specificity was 100%. In terms of preparation methods, the method of liquid-based preparation (LBP) is obviously better than that of conventional smears. The diagnostic efficiency by the combined detection method of parallel tests showed that without reducing the specificity, the sensitivity increased with the increase of the number of morphological characteristics and finally reached 98.81%. The INCIs and swirl arrangements are the most common and important indicators for the diagnosis of PTC, whereas papillary-like arrangements, the crowding and overlap of nuclear, grooves, marginally placed micronucleoli, and multinucleated giant cells are of little significance for the diagnosis of PTC.

Abstract. Rationale:. Polymorphous low-grade adenocarcinoma is a low-risk infiltrative malignant tumor of the salivary glands. However, some of these tumors are more malignant than the low-grade tumors and therefore, according to the most recent recommendation of the World Health Organization, they are renamed as polymorphous adenocarcinomas (PACs). Primary polymorphous low-grade adenocarcinomas/PACs of the lungs are rare. Herein, we report a case of primary PAC of the lung with bronchial cartilage and perineural invasion, and lymph node metastasis. Patient concerns:. A 58-year-old man had developed fever half a month prior, without chills or other accompanying symptoms, and the underlying reasons were unknown. His self-measured temperature was up to 39°C, accompanied by cough and expectoration, yellow and thin sputum, and shortness of breath. The patient's general state was normal, and respiratory sounds originating from the right lung were weak. Enhancement computed tomography revealed that the bronchial lumen of the basal segment of the lower lobe of the right lung was narrow; soft tissue density nodules were seen, with a range of approximately 2.4 cm × 1.3 cm. Diagnosis:. Based on clinical information, morphological features, and immunohistochemistry results, the pathological diagnosis was primary PAC of the lungs. Intervention:. Thoracoscopic resection of the middle and lower lobes of the right lung was performed, further extended dissection of the mediastinal lymph nodes was performed. Outcomes:. The postoperative course was uneventful. Lessons:. Primary PAC of the lung is rare and may cause misdiagnosis. When encountering a lung tumor with diverse tissue structures, uniform cell type and nerve invasion, we should consider the possibility of PAC. Morphological and immunohistochemical features can be useful for diagnosing primary PAC of the lungs.

Background The E6 and E7 proteins in human papillomavirus 16 (HPV 16) are the main oncogenes in the occurrence of lung cancer. In recent studies, we found that E6 and E7 downregulated the expression of LKB1 in lung cancer cells. However, it is still unclear how E6 and E7 regulate LKB1 in lung cancer cells. Methods Double directional genetic manipulation and nuclear plasma separation technology were performed to explore the molecular mechanism of E6 and E7 inhibiting the antitumor activity of LKB1 in well‐established lung cancer cell lines. Results E6 but not E7 significantly downregulated the expression of tumor suppressor KIF7 at protein level, and the inhibition of KIF7 further reduced the expression of LKB1 both in the nuclei and in the cytoplasm, whereas reduced the expression of p‐LKB1 in the cytoplasm only. This suggested that HPV 16 E6 but not E7 downregulates the antitumor activity of LKB1 by downregulating the expression of p‐LKB1 in the cytoplasm only. Conclusions Here, we demonstrated for the first time that E6 but not E7 inhibits the antitumor activity of LKB1 in lung cancer cells by downregulating the expression of KIF7. Our findings provide new evidence to support the important role of KIF7 in the pathogenesis of lung cancer and suggests new therapeutic targets.

Objective To quantitatively describe the stress of the ligamentum flavum (LF) using the finite element method and to compare the stress at different parts of the healthy LF. Methods Based on the high resolution computed tomography imaging data of a healthy 22‐year‐old man, three‐dimensional nonlinear L4–5 lumbar finite element model (FEM) representing intact condition was developed. The LF, as the object of the present research, was incorporated into the spinal model in the form of solid three‐dimensional structure. The model’s validity is verified by comparing its biomechanical indices, such as range of motion and axial compression pressure displacement, with published results under specific loading conditions. To authenticate the accuracy of the solid LF, the lamina attachments, the central cross‐section, and other anatomy indicators were compared with figures in the published literature. After the average and maximum von Mises stress on the surface of LF under various working conditions were measured using ANSYS and AutoCAD software, the surface stress difference in the LF between the ventral and dorsal sides as well as the lateral and lamina parts were determined. Results The FEM predicted a similar tendency for biomechanical indices as shown in previous studies. The lamina attachments, the central cross‐section, and the height as well as the width of the LF in the healthy FEM were in accordance with published results. In the healthy model, the average and maximum von Mises stress in the shallow layer of the LF were, respectively, 1.40, 2.28, 1.76, 1.48, 1.38 and 1.79, 2.41, 1.46, 1.42, 1.71 times that in the deep layer under a compressive preload of 500 N incorporated with flexion, extension, and lateral and rotational moments (10 Nm). The most conspicuous difference in surface stress was observed with the flexion motion, with a nearly 241% difference in the maximum stress and a 228% difference in the average stress compared to those in other states. As far as the whole dorsal side of the LF was concerned, the maximum surface stress was almost all concentrated in the dorsal neighboring facet joint portion. In addition, the maximum and average stress were, respectively, 77%, 72%, 15%, 11%, 71% and 153%, 39%, 54%, 200%, 212% higher in the lateral part than in the lamina part. Conclusion Based on the predisposition of LF hypertrophy in the human spine and the stress distribution of this study, the positive correlation between LF hypertrophy and its stress was confirmed.

Background: The role of macrophages (Mφs) in tendon injury healing is controversy. The aims of this study were to determine whether there is a shift in Mφs polarisation after an acute and chronic tendon injury ​and to assess whether the Mφs polarisation between the partial and complete rupture is different. Methods: This systematic review of the scientific literature was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane guidelines. PubMed database and Excerpta Medica Database (EMBASE) were used for specific search criteria. Only studies measuring Mφs using specific cell markers in Achilles tendon tissue and rotator cuff tendon tissue were included, respectively. Results: Five Achilles tendon injury studies and four rotator cuff injury studies were included. Expression of the pan Mϕs marker Cluster of Differentiation (CD) 68 was significantly upregulated in acute Achilles tendon ruptures compared to intact tendons, while no significant changes were found in Mφs polarisation markers CD80 (M1 Mφs) and CD206 (M2 Mφs). High levels of CD86 (M1 Mφs) and CD206 were observed in acute partial rupture. Expression of CD68 and CD206 were significantly upregulated in chronic rotator cuff tendinopathy and downregulated as structural failure increases. A low level of CD206 was observed in complete tendon rupture regardless of acute or chronic injury. Discussion and conclusion: In spite of the limited number of articles included, findings from this study suggested that the process of inflammation plays an important role in acute Achilles tendon injuries, indicated by the increased expression of CD68+ Mφs. Low levels of CD206+ Mφs were constantly observed in complete Achilles tendon rupture, while high levels of CD80+ Mφs and CD206+ Mφs were observed in partial Achilles tendon rupture, which suggested the potential correlation between M2 Mφs and tendon structure. For chronic rotator cuff injury, CD68+ Mφs and CD206+ Mφs were higher in tendinopathic tissues in comparison to the intact control tissues. Both CD68+ Mφs and CD206+ Mφs has an inverse relation to the structural failure in the torn rotator cuff tendon. After tendon rupture, the time point of biopsy specimen collection is an important factor, which could occur in the acute phase or chronic phase. Collectively, the understanding of the roles in Mφs after tendon injury is inadequate, and more research efforts should be devoted to this direction. The translational potential of this article: This article provided a potential implication on how pan Mφs or M2 Mφs might be associated with ruptured or torn tendon structure. Managing Mφs numbers and phenotypes may lead to possible novel therapeutic approaches to the management of early tendinopathy, early acute tendon rupture, hence, promote healing after restoration surgery. Keywords: Achilles, Macrophages, Rotator cuff, Tendon

Background and objective: E6 and E7 proteins in human papillomavirus (HPV) 16 are major oncogenes in several types of tumors, including lung cancer. Previous studies have demonstrated that both E6 and E7 oncoproteins can upregulate GLUT1 protein and mRNA expression levels in lung cancer cells. Thus, the present study aimed to investigate the main differences in the molecular mechanisms of GLUT1 expression regulated by E6 and E7. Methods: The double directional genetic manipulation and immunofluorescence were performed to explore the molecular mechanism of E6 or E7 upregulating the expression of GLUT1 in H1299 and A549 cell lines. Results: The overexpression of E6 in well-established lung cancer cell lines upregulated thioredoxin (Trx) protein expression. Notably, plasmid transfection or small interfering RNA transfection with E7 had no regulatory effect on Trx expression. As an important disulfide reductase of the intracellular antioxidant system, Trx plays important role in maintaining oxidative stress balance and protecting cells from oxidative damage. The overexpression of Trx increased the activation of NF-κB by upregulating p65 expression and promoting p65 nuclear translocation, and further upregulated GLUT1 protein and mRNA expression levels. The results of the present study demonstrated that E6, but not E7, upregulated GLUT1 expression in lung cancer cells by activating NF-κB due to the participation of Trx. Conclusion: These results suggest that Trx plays an important role in the pathogenesis of HPV-associated lung cancer, and propose a novel therapeutic target for HPV-associated lung cancer.

K. galanga is an aromatic medicinal herb. It is locally to India and distributed in China, Myanmar, Indonesia, Malaysia, and Thailand. K. galanga is a Traditional Chinese Herb Medicine (TCHM), which has been applied to treat cold, dry cough, toothaches, rheumatism, hypertension and so on. In addition, it has been used widely as spices since its highly aromas. The aim of this review is to compile and update the current progresses of ethnomedicinal uses, phytochemistry, pharmacology and toxicology of K. galanga. All the data on K. galanga were based on different classical literary works, multiple electronic databases including SciFinder, Web of Science, PubMed, etc. The results showed that ninety-seven compounds have been identified from rhizome of K. galanga, including terpenoids, phenolics, cyclic dipeptides, flavonoids, diarylheptanoids, fatty acids and esters. Modern pharmacology studies revealed that extracts or secondary metabolites of the herb possessed anti-inflammatory, anti-oxidant, anti-tumorous, anti-bacterial, and anti-angiogenesis effects, which were closely related to its abundant ethnomedicinal uses. In conclusion, although previous research works have provided various information of K. galanga, more in-depth studies are still necessary to systemically evaluate phytochemistry, pharmacological activities, toxicity and quality control of this herb.

Triptriolide (T11) is a natural diterpene diepoxide that derived from Chinese traditional herb medicine (TCHM) Tripterygium wilfordii Hook.F (TWHF). From a structural point of view, T11 is very similar to triptolide (T9), one of the most effectively compounds in TWHF that have already been systematically investigated in the past decades. However, the basic functions and medicinal properties of T11 have not yet been well investigated mainly due to its low abundance in its plant organ. The present study aimed to investigate the protective effects of T11 on puromycin aminonucleoside (PAN) induced apoptotic mouse podocytes and the underlying mechanism. The results showed that T11 had no significant toxicity in podocytes in high dosage, and showed prominent protective effects on PAN induced podocytes injury. Further studies indicated that T11 might exert its protective effects by inhibiting of apoptosis and restoring of survival in PAN induced podocytes.

Abstract Background The transcription factor PR domain containing 16 (PRDM16) is known to play a significant role in the determination and function of brown and beige fat. However, the role of PRDM16 in tumor biology has not been well addressed. Here we investigated the impact of PRDM16 on tumor growth and metastasis in lung cancer. Methods UALCAN database, immunoblotting and immunohistochemistry analysis were used to assess PRDM16 expression in lung cancer patients. Kaplan-Meier plotter database was used to analyze the overall survival of patients with lung cancer stratified by PRDM16 expression. PRDM16 overexpression and knockdown experiments were conducted to assess the effects of PRDM16 on growth and metastasis in vitro and in vivo, and its molecular mechanism was investigated in lung adenocarcinoma cells by chromatin immunoprecipitation-sequencing (ChIP-Seq), real time-quantitative PCR (RT-qPCR), luciferase assay, xenograft models and rescue experiments. Results PRDM16 was downregulated in lung adenocarcinomas, and its expression level correlated with key pathological characteristics and prognoses of lung adenocarcinoma patients. Overexpressing PRDM16 inhibited the epithelial-to-mesenchymal transition (EMT) of cancer cells both in vivo and in vitro by repressing the transcription of Mucin-4 (MUC4), one of the regulators of EMT in lung adenocarcinomas. Furthermore, deleting the PR domain from PRDM16 increased the transcriptional repression of MUC4 by exhibiting significant differences in histone modifications on its promoter. Conclusions Our findings demonstrate a critical interplay between transcriptional and epigenetic modifications during lung adenocarcinoma progression involving EMT of cancer cells and suggest that PRDM16 is a metastasis suppressor and potential therapeutic target for lung adenocarcinomas.

Abstract Background Disabled-2 (Dab2) is known as a tumor suppressor as well as a Wnt pathway inhibitor. We previously reported that Dab2 was down-regulated due to gene promoter hypermethylation in lung cancer. Here, we aim to study if X-ray irradiation can induce de-methylation of the Dab2 gene and subsequently up-regulate its expression, and also to attempt to suppress the malignant biological behavior of and enhance the radiosensitivity in lung cancer cells with hypermethylation of the Dab2 gene. Methods Immunostaining was performed to investigate the relationship between Dab2 expression and lung cancer clinicopathological characteristics. Bisulfite sequencing PCR (BSP) was used to evaluate the methylation status of lung cancer cells with or without X-ray treatment. Real-time PCR and western Blot were performed to investigate the expression of Dab2, Wnt pathway factors, DNMTs and methyl CpG binding protein 2 (MeCP2). Colony Formation, matrigel invasion and xenograft experiment were performed to evaluate the malignant biological behavior of lung cancer cells with irradiation. Results The result of immunostaining of Dab2 in lung cancer tissues showed that decreased Dab2 expression was positively correlated with poor differentiation, lymph node metastasis, advanced TNM stage and poor prognosis. X-ray treatment significantly up-regulated Dab2 expression and inhibited Wnt factors in LK2 cells (with hypermethylation of the Dab2 gene promoter, P

Background and Objective: Small cell lung cancer (SCLC) is characterized by rapid growth, strong invasion, and early metastasis. However, the cause of its occurrence remains unclear. High-risk HPV infection is closely related to the occurrence of non-small cell lung cancer and cervical small cell neuroendocrine carcinoma. Methods: The expression levels of E6 mRNA and E7 mRNA in HPV16 were detected by qRT-PCR in the bronchial brushing and transbronchial needle aspiration (TBNA) of 310 patients with lung cancer and with benign lung diseases. To make the design of this experiment scientific and reasonable, the expression levels in lung squamous cell carcinoma were taken as positive controls, while those in benign cells were taken as negative controls. Results: The expression levels of E6 mRNA and E7 mRNA in SCLC group were significantly higher than those in benign cell group and slight higher than those in squamous cell carcinoma group. The expression levels of E6 mRNA and E7 mRNA in the central type of SCLC were significantly higher than those in the peripheral type of SCLC. Conclusions: We speculate that the occurrence of some small cell carcinoma is the same as that of some squamous cell carcinoma, which is closely related to HPV16 infection. The overexpression of E6 mRNA and E7 mRNA is in some benign lesion cells, which may be related to HPV transient infection.

FAM83A (family with sequence similarity 83, member A) has been found to be highly expressed in cancers. The purpose of this study was to clarify the role and mechanism of FAM83A in lung cancers. The expression of FAM83A in lung cancer cells was enhanced by gene transfection or knocked down by small interfering RNA interference. The key proteins of the Wnt signaling pathway, the Hippo signaling pathway, and epithelial–mesenchymal transition (EMT) were examined using Western blot. The proliferation and invasion of lung cancer cells were examined using cell proliferation, colony formation, and invasion assays. The expression of FAM83A in lung cancer tissues was significantly increased and was correlated with advanced tumor–node–metastasis (TNM) stage and poor prognosis. Overexpression of FAM83A enhanced the proliferation, colony formation, and invasion of lung cancer cells. Meanwhile, FAM83A overexpression increased the expression of active β-catenin and Wnt target genes and the activity of EMT. Furthermore, in FAM83A-overexpressed cells, the activity of Hippo pathway was downregulated, whereas the expression of yes-associated protein (YAP) and its downstream targets cyclin E and CTGF were upregulated. The inhibitor of the Wnt signaling pathway, XAV-939, reversed the promoting effect of FAM83A on YAP, cyclin E, and CTGF. On knocking down the expression of FAM83A, we obtained the opposite results. However, the inhibitor of GSK3β, CHIR-99021, restored the expression of YAP, cyclin E, and CTGF after FAM83A was knocked down. FAM83A is highly expressed in lung cancers and correlated with advanced TNM stage and poor prognosis. FAM83A promotes the proliferation and invasion of lung cancer cells by regulating the Wnt and Hippo signaling pathways and EMT process.

MicroRNAs are known to be important in a variety of cancer types. The specific expression and roles of miR-338-3p in the context of gastric cancer, however, remains largely unknown. In this study, we found that miR-338-3p was expressed significantly lower in established/primary human gastric cancer cells than that in human gastric epithelial cells; miR-338-3p is also decreased in human gastric cancer tissues and was positively associated with the worse prognosis of patients with gastric cancer. Enforced expression of miR-338-3p could inhibit cell growth, survival, and proliferation, while inducing cell apoptosis. In addition, miR-338-3p negatively regulated SOX5 expression through directly binding to the 3′-untranslated region of SOX5, and an inverse correlation was found between miR-338-3p and SOX5 messenger RNA expression in gastric cancer tissues. Furthermore, miR-338-3p-induced inactivation of Wnt/β-catenin signaling was greatly abrogated by SOX5 upregulation. Finally, we found that hypoxic conditions were linked with reduced miR-338-3p expression in the context of gastric cancer. In conclusion, miR-338-3p acts as a tumor suppressor in gastric cancer, possibly by directly targeting SOX5 and blocking Wnt/β-catenin signaling. These findings might provide novel therapeutic targets for gastric cancer.

As one of the most common genetic conditions, Duchenne muscular dystrophy (DMD) is a fatal disease caused by a recessive mutation resulting in muscle weakness in both voluntary and involuntary muscles and, eventually, in death because of cardiovascular failure. Currently, there is no pharmacologically curative treatment of DMD, but there is evidence supporting that mesenchymal stem cells (MSCs) are a novel solution for treating DMD. This systematic review focused on elucidating the therapeutic efficacy of MSCs on the DMD in vivo model. A key issue of previous studies was the material-choice, naïve MSCs or modified MSCs; modified MSCs are activated by culture methods or genetic modification. In summary, MSCs seem to improve pulmonary and cardiac functions and thereby improve survival regardless of them being naïve or modified. The improved function of distal skeletal muscles was observed only with primed MSCs treatment but not naïve MSCs. While MSCs can provide significant benefits to DMD mouse models, there is little to no data on the results in human patients. Due to the limited number of human studies, the differences in study design, and the insufficient understanding of mechanisms of action, more rigorous comparative trials are needed to elucidate which types of MSCs and modifications have optimal therapeutic potential.

Abstract We evaluated Sofosbuvir (SOF), the anti-hepatitis C virus prodrug of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine-5′-monophosphate, for potential inhibitory activity against DENV replication. Both cell-based and biochemical assays, based on use of purified DENV full-length NS5 enzyme, were studied. Cytopathic effect protection and virus yield reduction assays confirmed that SOF possessed anti-DENV activity in cell culture with a 50% effective concentration (EC50) of 4.9 µM and 1.4 µM respectively. Real-time RT-PCR verified that SOF inhibits generation of viral RNA with an EC50 of 9.9 µM. Purified DENV NS5 incorporated the active triphosphate form (SOF-TP) into nascent RNA, causing chain-termination. Relative to the natural UTP, the incorporation efficiency of SOF-TP was low (discrimination value = 327.5). In a primer extension assay, SOF-TP was active against DENV NS5 wild-type polymerase activity with an IC50 of 14.7 ± 2.5 µM. The S600T substitution in the B Motif of DENV polymerase conferred 4.3-fold resistance to SOF-TP; this was due to decreased incorporation efficiency rather than enhanced excision of the incorporated SOF nucleotide. SOF has antiviral activity against DENV replication. The high discrimination value in favor of UTP in enzyme assays may not necessarily preclude antiviral activity in cells. SOF may be worthy of evaluation against severe DENV infections in humans.

Triptolide(T9) is a predominant bioactive component extracted from Chinese herb Tripterygium wilfordii Hook F. (TwHF), and has multiple pharmacological activities, such as immunosuppressive and anti-inflammatory activities, et al. However, severe adverse effects and toxicity, particularly nephrotoxicity, limit its clinical application. It has been demonstrated that the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway could alleviate T9-induced nephrocyte damage. The aim of this study was to investigate the potential protective role of triptriolide (T11) against T9-induced nephrocyte apoptosis in vitro and in vivo. Renal injury models were established in human kidney 2 (HK2) cells and BALB/c mice using T9, and the protective effects of T11 were probed in vitro and in vivo, respectively. T9 induced nephrocyte damage in HK2 cells and BALB/c mice by induction of reactive oxygen species (ROS), lactate dehydrogenase (LDH), malondialdehyde (MDA) and glutathione (GSH) and reduction of superoxide dismutase (SOD), which resulted in the apoptosis of nephrocyte and injury of renal function. While, pretreatment of T11 effectively reversed these changes, resulting in the obvious decrease of oxidative stress and renal function parameters, ameliorated nephrocyte apoptosis, improved cell morphology, and higher increase of Nrf2, NAD(P)H: quinine oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1) protein levels in vitro and in vivo. Altogether, T11 protected against T9-induced nephrocyte apoptosis possibly via suppressing oxidative stress.

We determined the effects of enhanced recovery after surgery (ERAS) in patients undergoing radical surgery for gastric carcinoma. Sixty patients undergoing radical gastrectomy for gastric carcinoma in Lishui Hospital between March and October 2016 were randomized to receive either ERAS (30 patients) or conventional care (30 patients, controls). Clinical, economic, and laboratory indices were analyzed. ERAS patients showed faster recovery and shorter postoperative hospital stays than the controls (P

Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RARα) and stabilizes RARα protein in the presence of all-trans retinoic acid which is known to induce RARα degradation, leading to enhanced transcription of RARα-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopalmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARα. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.

Nrf2 (Nuclear Factor Erythroid 2 Related Factor 2) transcription factor not only regulates oxidative stress response, but also represses inflammation by regulating cytokines production and cross-talking with NF-κB signaling pathways. Nrf2 plays an essential role in liver injury induced by oxidative stress and inflammation. Triptriolide (T11) is a minor component of Tripterygium wilfordii Hook F. (TwHF), which can be obtained by hydrolysis reaction of triptolide (T9). The major purpose of this study is to clarify the regulating effects of T11 on oxidative stress and inflammation in vivo and in vitro. LPS-stimulated RAW 264.7 cells were used to verify the regulating effects of T11 on oxidative stress (ROS and Nrf2 signaling pathway) and inflammatory cytokines production (TNF-α, IL-6 and IL-1β). The antioxidant responsive element (ARE) luciferase assay was employed to evaluate Nrf2 activation effect of T11 in HEK-293T cells. Lipopolysaccharides (LPS) induced acute liver injury (ALI) in BALB/c mice were used to study the protective effects (ALT, AST, MDA, SOD, histopathology and neutrophils/macrophages filtration) and the underlying protection mechanisms of ALI amelioration (Nrf2 and NF-κB signaling pathway) of T11. Firstly, the results showed that T11 can not only effectively decrease the productions of inflammatory cytokines (TNF-α, IL-6 and IL-1β), ROS and NO in LPS-stimulated RAW 264.7 cells, but also further significantly increase the activity of Nrf2 in HEK-293T cells. Secondly, the results suggested that T11 could dramatically decrease the oxidative stress responses (SOD and MDA) and inflammation (histopathology, neutrophils/macrophages filtration, TNF-α, IL-6 and IL-1β production) in LPS-induced ALI in BALB/c mice. Finally, the results implied that T11 could dramatically increase Nrf2 protein expression and decrease p-TAK1, p-IκBα and NF-κB protein expression both in vivo and in vitro. In conclusion, our findings indicated that T11 could alleviate LPS induced oxidative stress and inflammation by regulating Nrf2 and NF-κB signaling pathways in vitro and in vivo, which offers a novel insights for the application of TwHF in clinical.

Following publication of the original article

Objective: The present study aims to identify the differently expressed microRNA (miRNA) molecules and target genes of miRNA in the immune tolerance (IT) and immune activation (IA) stages of chronic hepatitis B (CHB). Methods: miRNA expression profiles of peripheral blood mononuclear cells (PBMCs) at the IT and IA stages of CHB were screened using miRNA microarrays and authenticated using a quantitative real-time polymerase chain reaction (RT-PCR). Gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) were used to analyze the significant functions and pathways of possible target genes of miRNAs. Assays of the gain and loss of function of the miRNAs were performed to verify the target genes in THP-1 cell lines. The luciferase reporter test was used on 293T cells as direct targets. Results: Significantly upregulated miR-548 and miR-4804 were observed in the miRNA microarrays and confirmed by RT-PCR in PBMCs at the IT and IA stages of CHB. GO and KEGG analysis revealed that MiR-548 and miR-4804 could be involved in numerous signaling pathways and protein binding activity. IFNγR1 was predicted as a target gene and validated as the direct gene of MiR-548. Significant negative correlation was found between the miR-548ah and mRNA levels of IFN-γR1 in CHB patients. Conclusions: The abnormal expression profiles of miRNA in PBMCs could be closely associated with immune activation of chronic HBV infection. miR-548, by targeting IFN-γR1, may represent a mechanism that can facilitate viral pathogenesis and help determine new therapeutic molecular targets.

p130cas (p130 Crk-associated substrate) is a scaffolding protein and plays an important role in regulating focal adhesion and driving cell migration. Also, the destruction of E-cadherin/β-catenin adhesive complex is one of the changes that characterizes the invasive phenotype of tumors. The aim of this study is to evaluate the role of p130cas, E-cadherin, and β-catenin expression in patients with non-small cell lung cancer (NSCLC). We examined the expression of p130cas, E-cadherin, and β-catenin in 105 lung cancer tissues and paired adjacent normal lung tissues using immunohistochemistry. The overexpression of p130cas was observed in 61.9% (65/105) of lung cancer samples. The overexpression of p130cas was correlated with abnormal expression of E-cadherin and β-catenin (P=0.002 and P=0.006, respectively). Chi-square test showed that the overexpression of p130cas correlated positively with lymph node metastasis and high TNM stage. The Log-Rank test revealed that the mean survival time of patients with p130cas overexpression (36.31 ± 5.66 months) was markedly shorter than those with p130cas normal expression (60.57 ± 6.95 months). Multivariable analysis indicated p130cas overexpression (P

A failure to undergo apoptosis is widely thought to be an important event in cancer formation and progression. Although there have been many studies in vitro that provide evidence for this suggestion, the roles of apoptosis-associated proteins in cancer tissues in vivo are not as yet fully understood. Moreover, multiple marker analyses of apoptosis-associated protein expression in non-small cell lung cancer (NSCLC) tissues are scarce. In the present study, we investigate the expression of a group of apoptosis-associated proteins including bcl-2, caspase-3, fas, fas ligand (fasL) and survivin, and its clinical significance in NSCLC tissues using immunohistochemistry (IHC). Bcl-2 staining in cancer tissue cells was found in cytoplasm and the positive rate was 38.2% (29/76). Caspase-3 staining was mainly seen in cytoplasm of cancer tissue cells (53.9% [41/76]) with a few cases of nuclear staining (6.6% [5/76]). Fas staining was seen in cytomembrane (15.8% [12/76]) and cytoplasm (42.1% [32/76]) of cancer tissue cells. Likewise, fasL also showed staining in cytoplasm (55.3% [42/76]) and cytomembrane (44.7% [34/76]) of cancer tissue cells. Survivin staining was seen in cytoplasm but not nuclear of cancer tissue cells and the positive rate was 48.7% (37/76). Higher cytoplasm expression of bcl-2 was associated with large tumor size (≥ 3cm) in NSCLC (p < 0.05). Decreased cytoplasm expression of fas was associated with poor grade in NSCLC (p < 0.05). A negative correlation was found between bcl-2 and cytoplasm caspase-3 expression in NSCLC (p < 0.001). No separate expression of the apoptosis-associated proteins in NSCLC was linked to overall survival of patients (p > 0.05). Multiple marker analyses revealed caspase-3+/cytomembrane fasL– to be linked to better survival of patients with NSCLC (p < 0.05). These results indicate that apoptosis- -associated proteins may impact a variety of clinicopathological features of NSCLC and may co-operatively influence the prognosis of patients with this malignant tumor. (Folia Histochemica et Cytobiologica 2011, Vol. 49, No. 2, 231–239)

Background: Selective proteinuria is frequently observed in glomerular diseases characterized by podocyte injury. Although, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has potential therapeutic effects on chronic kidney diseases through decreasing podocyte loss, the mechanism underlying the beneficial effects of 1,25(OH)2D3 on podocytes remains still unknown. The present study tested the hypothesis that 1,25(OH)2D3 directly reduced podocyte apoptosis and loss.Methods: Sprague-Dawley (SD) rats were randomly assigned into three groups: Adriamycin (ADR) group (n=15), ADR+1,25-(OH)2D3 group (n=16), and control group (n=16). Rats in ADR+1,25-(OH)2D3 group were treated with 1,25(OH)2D3 for 8 weeks. The number of podocytes and foot process width (FPW) were detected by transmission electron microscopy. The number of apoptotic podocytes per glomerulus and that of apoptotic nuclei and caspase-3 activity in cultured podocytes were determined by TUNEL staining. The average number of podocytes per glomerulus was quantified by immunohistochemistry. Expressions of p-Smad2/3, p-Smad1/5/8, Fas, Fas-Associated protein with Death Domain (FADD), Bax, and Bcl-2 proteins were examined by Western blot assay.Results: Compared with control group, proteinuria, FPW, apoptotic podocytes, caspase-3 activity, the protein expressions of p-Smad2/3, Fas, FADD, and Bax were significantly increased, podocyte density, p-Smad1/5/8 and Bcl-2 expression were decreased in ADR group. 1,25(OH)2D3 significantly reduced proteinuria, FPW, caspase-3 activity, expressions of p-Smad2/3, Fas, FADD, and Bax and apoptosis of podocytes, but increased serum albumin, number of viable podocytes , p-Smad1/5/8 and Bcl-2 expression in ADR treated rats.Conclusion: ADR-induced podocyte apoptosis was associated with the imbalance of p-Smad2/3, p-Smad1/5/8 the activity of caspase-3 and aberrant expressions of, Fas, FADD, Bax and Bcl-2. The beneficial effects of 1,25(OH)2D3 on podocytes may be attributable to inhibit podocyte apoptosis and the amelioration of podocytopenia.

The interaction of connexin 43 and E-cadherin may play an important role in carcinogenesis and malignant behaviour of tumours. In this study, we examined the relationship between connexin 43 and E-cadherin in human non-small cell lung cancers (NSCLC). Expression levels of connexin 43 and E-cadherin were examined in 107 NSCLC specimens by immunohistochemistry. The connexin 43 gene was transfected into lung cancer LH7 cells. The protein localizations and levels of connexin 43 and E-cadherin were detected using immunofluorescence staining and western blot. Cell cycle and proliferation of lung cancer cells were examined using flow cytometry and MTT. We found that reduced expression of both connexin 43 and E-cadherin significantly correlated to poor differentiation, advanced TNM stage, and lymph note metastasis of NSCLCs. Connexin 43 and E-cadherin expression significantly correlated with each other. Over-expression of connexin 43 significantly induced E-cadherin expression. Moreover, connexin 43-transfected LH7 cells showed significantly decreased cell proliferation. The percentage of cells in G1 phase increased, while the number of cells in S and G2 phases significantly decreased. We concluded that concurrent reduction of connexin 43 and E-cadherin may contribute to the development of lung cancer. Connexin 43 may induce E-cadherin expression and inhibit cell proliferation and progression of lung cancer.

Flaviviruses including Zika, Dengue and Hepatitis C virus cause debilitating diseases in humans, and the former are emerging as global health concerns with no antiviral treatments. We investigated Sophora Flavecens, used in Chinese medicine, as a source for antiviral compounds. We isolated Sophoraflavenone G and found that it inhibited Hepatitis C replication, but not Sendai or Vesicular Stomatitis Virus. Pre- and post-infection treatments demonstrated anti-flaviviral activity against Dengue and Zika virus, via viral RNA polymerase inhibition. These data suggest that Sophoraflavenone G represents a promising candidate regarding anti-Flaviviridae research.

BACKGROUND: We have reported that p120-catenin could regulate β-catenin transcription in lung cancer cells, but the specific mechanism is unclear. METHODS AND RESULTS: In this study, bisulfite sequencing PCR showed that the β-catenin promoter region in SPC-A-1 and LTEP-a-2 lung cancer cell lines has Kaiso binding sites sequences and CpG islands which may combine with Kaiso. The demethylating reagent 5-Aza-2'-deoxycytidine significantly upregulated β-catenin mRNA expression in lung cancer cell lines, whereas expression was significantly reduced following transfection with Kaiso. However, the upregulation of β-catenin mRNA expression after treatment with 5-Aza-2'-deoxycytidine was not reduced by subsequent transfection with Kaiso cDNA. Chromatin immunoprecipitation showed that, in lung cancer cell lines, methylated CpG-dinucleotides sequences combined with Kaiso and the Kaiso binding sites sequence did not. The capacity of Kaiso to combine with p120-catenin isoforms was confirmed by immunoprecipitation. CONCLUSIONS: Based on these results, we concluded that Kaiso participates in the regulation by p120ctn of β-catenin mRNA expression in the lung cancer cell lines.