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Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood. Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity. Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema1wheeze1rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity. Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.

Background: The anomalous origin of the left common carotid artery from the pulmonary artery is extremely scarce. At present, there are few relevant research and medical treatment data. This case is intended to provide relevant information and share treatment experiences. Case information: A 6-year-old child was diagnosed with patent ductus arteriosus and underwent surgery five years ago with occasional dizziness. After examination, it was found that the abnormality of her left common carotid artery originated from the pulmonary artery, and the patient underwent arterial ligation with the monitoring of cerebral oxygen consumption by near-infrared spectroscopy after careful preoperative evaluation. At present, it has been two years after the operation, and the patient is in good condition and has received regular follow-up. Conclusion: For patients with an abnormal left common carotid artery from the pulmonary artery, after careful preoperative evaluation such as cerebral angiography, under the monitoring of cerebral oxygen consumption by near-infrared spectroscopy, ligation of the proximal end of the artery of abnormal origin is safe and feasible.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by complex pathogenesis, of which oxidative stress has long been regarded as a major mechanism. Previously, the protective effects of estradiol on SH-SY5Y cells against Aβ42-induced injuries were demonstrated. In this study, the protection of SH-SY5Y cells by estradiol from H2O2-caused oxidative stress injury and Alzheimer's mice was further confirmed. H2O2 downregulated, whereas estradiol upregulated miR-223 expression. miR-223 overexpression promoted cell viability, inhibited cell apoptosis, reduced ROS levels, enhanced Superoxide Dismutase (SOD) activity, and decreased malondialdehyde (MDA) content. However, miR-223 inhibition exerted opposite effects. miR-223 directly targeted forkhead box O3 (FOXO3) and inhibited FOXO3 expression. H2O2 increased, whereas estradiol decreased thioredoxin interacting protein (TXNIP) levels; FOXO3 positively regulated TXNIP protein levels. In SH-SY5Y cells, FOXO3 overexpression increased, whereas FOXO3 knockdown reduced the cell apoptosis and ROS levels. FOXO3 bound to TXNIP promoter region and activated TXNIP transcription, whereas the activation could be partially inhibited by estradiol. Collectively, the FOXO3/TXNIP axis is downstream of miR-223. miR-223 enhances the neuroprotection of estradiol against oxidative stress injury through the FOXO3/TXNIP axis.

Background Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. Methods Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. Results Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31–1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0–1 vs. 2–3 HR 0.09 [95% CI, 0.02–0.33]; p p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01–0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08–1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. Conclusion Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

This study comprehensively analyzed air pollution in Chengdu (CD), a megacity in southwest China, evaluated the Variation Characteristics of air quality during 2015-2018, and conducted Random Forest classification of air pollution data of 2017. The classification results showed three pollution periods: severe (December, January and February), ozone (May‒August), and slight (March and November). These features were combined with potential source contribution function (PSCF), concentration weighted trajectory (CWT) and backward trajectory model (HYSPLIT) for simulating spatio-temporal trajectory of air polluted during each pollution periods. The results show that PM

Summary Background: Application of distant skin flaps in facial defect reconstruction has limitations such as leaving a patch like appearance and being restricted by the length of the vascular pedicles. Leveraging the abundance of blood supply from superficial muscular aponeurotic system (SMAS), a local skin flap pedicled by SMAS can be used to avoid the aforementioned problems. Herein, we report the clinical application as well as the anatomical study of SMAS-pedicled skin flaps. Methods: This study enrolled patients who underwent facial defect reconstruction surgery between 2013 and 2018 using SMAS-pedicled skin flaps. The flaps were designed according to the size and location of the defect. A follow-up was performed to evaluate the treatment outcomes and incidence of adverse events. In addition, six cadaveric heads were used to perform an anatomical study on the distribution and blood supply of SMAS. Results: Twenty-three cases underwent the defect reconstruction surgery in the frontal regions (three cases), temporal region (four cases), periocular region (four cases), nasal region (seven cases), and other regions (five cases). All the flaps survived well. During the follow-up period up to 12 months, the flaps showed a satisfactory appearance, blood supply, and elasticity. The distribution and blood supply of SMAS at different anatomical regions have been successfully observed. Abundant vascular networks could be found in the SMAS layer. Conclusion: Based on the broad distribution of SMAS and the abundant blood supply, an SMAS-pedicled skin flap could be flexibly designed and versatilely used to reconstruct post-traumatic or post-excisional facial defects.

Selectively attenuating the protection offered by heat shock protein 90 (HSP90), which is indispensable for the stabilization of the essential regulators of cell survival and works as a cell guardian under oxidative stress conditions, is a potential approach to improve the efficiency of cancer therapy. Here, we designed a biodegradable nanoplatform (APCN/BP-FA) based on a Zr(iv)-based porphyrinic porous coordination network (PCN) and black phosphorus (BP) sheets for efficient photodynamic therapy (PDT) by enhancing the accumulation of the nanoplatforms in the tumor area and attenuating the protection of cancer cells. Owing to the favorable degradability of BP, the nanosystem exhibited accelerated the release of the HSP90 inhibitor tanespimycin (17-AAG) and an apparent promotion in the reactive oxygen species (ROS) yield of PCN as well as expedited the degradation of the PCN-laden BP nanoplatforms. Both in vitro and in vivo results revealed that the elevated amounts of ROS and reduced cytoprotection in tumor cells were caused by the nanoplatforms. This strategy may provide a promising method for attenuating cytoprotection to aid efficient photodynamic therapy.

Comparison of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy or with bevacizumab in real-world non-small cell lung cancer (NSCLC) patients was lacking. 310 patients of advanced NSCLC with common EGFR mutation receiving first-generation EGFR-TKI monotherapy or with bevacizumab were included and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutation were analysed. Patients receiving EGFR-TKI and bevacizumab were significantly younger, had better performance status and with high incidence of brain metastasis (55.8%). In the propensity-score matched cohort, PFS (13.5 vs. 13.7 months; log-rank p = 0.700) was similar between the two groups. The OS (61.3 vs. 34.2 months; log-rank p = 0.010) and risk reduction of death (HR 0.42 [95% CI 0.20–0.85]; p = 0.017) were significantly improved in EGFR-TKI plus bevacizumab group. Analysis of treatment by brain metastasis status demonstrated EGFR-TKI plus bevacizumab in patients with brain metastasis was associated with significant OS benefit compared to other groups (log-rank p = 0.030) and these patients had lower early-CNS and early-systemic progressions. The secondary T790M did not significantly differ between EGFR-TKI plus bevacizumab and EGFR-TKI monotherapy groups (66.7% vs. 75.0%, p = 0.460). Forty-one (31.1%) and 31 (23.5%) patients received subsequent osimertinib and chemotherapy, respectively. The post-progression OS of osimertinib and chemotherapy were 22.1 and 44.9 months in EGFR-TKI plus bevacizumab group and were 10.0 and 14.1 months in EGFR-TKI monotherpay group, respectively. First-generation EGFR-TKI with bevacizumab improved treatment efficacy in real-world patients of NSCLC with EGFR mutation. Patients with brain metastasis received additional OS benefit from this treatment.

Background Glioblastoma multiforme (GBM) is the most common aggressive malignant brain tumor. However, the molecular mechanism of glioblastoma formation is still poorly understood. To identify candidate genes that may be connected to glioma growth and development, weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between gene sets and clinical characteristics. We also explored the function of the key candidate gene. Methods Two GBM datasets were selected from GEO Datasets. The R language was used to identify differentially expressed genes. WGCNA was performed to construct a gene co-expression network in the GEO glioblastoma samples. A custom Venn diagram website was used to find the intersecting genes. The GEPIA website was applied for survival analysis to determine the significant gene, FUBP3. OS, DSS, and PFI analyses, based on the UCSC Cancer Genomics Browser, were performed to verify the significance of FUBP3. Immunohistochemistry was performed to evaluate the expression of FUBP3 in glioblastoma and adjacent normal tissue. KEGG and GO enrichment analyses were used to reveal possible functions of FUBP3. Microenvironment analysis was used to explore the relationship between FUBP3 and immune infiltration. Immunohistochemistry was performed to verify the results of the microenvironment analysis. Results GSE70231 and GSE108474 were selected from GEO Datasets, then 715 and 694 differentially expressed genes (DEGs) from GSE70231 and GSE108474, respectively, were identified. We then performed weighted gene co-expression network analysis (WGCNA) and identified the most downregulated gene modules of GSE70231 and GSE108474, and 659 and 3915 module genes from GSE70231 and GSE108474, respectively, were selected. Five intersection genes (FUBP3, DAD1, CLIC1, ABR, and DNM1) were calculated by Venn diagram. FUBP3 was then identified as the only significant gene by survival analysis using the GEPIA website. OS, DSS, and PFI analyses verified the significance of FUBP3. Immunohistochemical analysis revealed FUBP3 expression in GBM and adjacent normal tissue. KEGG and GO analyses uncovered the possible function of FUBP3 in GBM. Tumor microenvironment analysis showed that FUBP3 may be connected to immune infiltration, and immunohistochemistry identified a positive correlation between immune cells (CD4 + T cells, CD8 + T cells, and macrophages) and FUBP3. Conclusion FUBP3 is associated with immune surveillance in GBM, indicating that it has a great impact on GBM development and progression. Therefore, interventions involving FUBP3 and its regulatory pathway may be a new approach for GBM treatment.

Background. As a transitional state between normal aging and Alzheimer’s disease (AD), mild cognitive impairment (MCI) is characterized by a worse cognitive decline than that of natural aging. The association between AD and gut microbiota has been reported in a number of studies; however, microbial research regarding MCI remains limited. Methods. This study examined 48 participants, of whom 22 were MCI cases and 26 were normal control cases. Fecal samples were collected for 16S ribosomal RNA (rRNA) quantitative arrays and bioinformatics analysis. Results. A principal coordinates analysis (PCoA) and nonmetric multidimensional scaling (NMDS) both demonstrated that the microbial composition of participants with MCI deviated from that of healthy control participants. Multiple bacterial species were significantly increased (e.g., Staphylococcus intermedius) or decreased (e.g., Bacteroides salyersiae) in samples from the MCI group. Conclusion. The composition of gut microbiota differed between normal control and MCI cases. This is the first study to identify a signature series of species in the gut microbiota of individuals with MCI. The results provide a new direction for the future development of an early diagnosis and probiotic regimen.

Gastric cancer (GC) is the third leading cause of cancer‑related mortality and the fifth most common type of cancer worldwide. GC stem cells (GCSCs) have been reported to be responsible for the malignant behavior of GC. However, the key molecular mechanism controlling GCSC function remains unclear. The present study aimed to investigate the function of retinoic acid‑related orphan receptor β (RORβ) in GC. The expression levels of RORβ in GC cells and clinical GC tissues were analyzed using western blotting, reverse transcription‑quantitative PCR (RT‑qPCR) and immunohistochemistry. The association between RORβ expression levels and GCSC markers was analyzed using Gene Set Enrichment Analysis, and GeneChip was performed to identify differentially expressed genes between control and RORβ‑overexpressing GC cells. CCK‑8 and flow cytometric assays were used to evaluate the effect of RORβ on cell viability and apoptosis, respectively. The effect of RORβ on the self‑renewal capacity of GCSCs was measured using a sphere formation assay, the expression levels of induced pluripotent stem (iPS) factors and epithelial‑mesenchymal transition (EMT)‑related factors were measured by RT‑qPCR and western blotting, and the tumorigenic capacity was measured by an in vivo mouse model. Finally, the impact of RORβ on the Wnt signaling pathway was determined using western blotting and a TOP/FOP flash assay. The results revealed that the expression levels of RORβ were downregulated in GC tissues compared with para‑carcinoma tissues, and were inversely associated with the expression levels of GCSC markers. The overexpression of RORβ upregulated the expression levels of the pro‑apoptotic gene, Bcl‑2 like protein 11, which subsequently inhibited the viability and promoted the apoptosis of GC cells. In addition, RORβ decreased the sphere forming ability, and downregulated the expression levels of iPS cell‑ and EMT‑related factors. In vivo, RORβ suppressed the tumorigenic capacity and stemness of GC cells. Mechanistically, RORβ was revealed to decrease the activity of the Wnt/β‑catenin signaling pathway in GCSCs. In conclusion, the findings of the present study identified RORβ as a novel suppressor of GCSCs and highlighted the prospect of RORβ as a novel candidate target for stem cell‑based GC therapy.

Fever is a extremely common symptom in infants and young children. Due to the lowresistance of infants and young, long-term fever may cause damage to the child's body. Clinically,some children with long-term fever was eventually diagnosed with Kawasaki disease (KD). KD, anautoimmune disease, is a systemic vasculitis mainly affecting children younger than 5 years old. Dueto the delayed therapy and diagnosis, coronary artery abnormalities (CAAs) develop in children with KD, and leads to a high risk of acquired heart disease. Later, patients may have myocardial infarctionor even die a sudden death. Unfortunately, at present, the pathogenesis of KD remains unknownand KD lacks of specific and sensitive biomarkers, thus bringing difficulties to diagnosis and therapy.Therefore it is a highly focused topic to research on the mechanism of KD. Some scholars believethat KD is caused by the cross reaction of external infection and organ tissue composition, herebytriggering disorder of the immune system and producing a variety of cytokines. On the basis ofconsidering the cytokines such as vascular endothelial cells, inflammatory factors, adhesion factorsand chemokines, endothelial cell growth factors, put forward a kind of dynamic model of pathogenesisof KD by the theory of ordinary differential equation. It is found that the dynamic model can showcomplex dynamic behavior, such as the forward and backward bifurcation of the equilibria. This articlereveals the possible complexity of KD infection, and provides a theoretical references for the researchof pathogenic mechanism and clinical treatment of KD.

Alzheimer's disease (AD) is a neurodegenerative disease. Thioredoxin and thioredoxin-interacting protein (TXNIP) complexes help sustain cell oxidation/reduction balance. In the present study, we verified the neuroprotective role of estradiol against amyloid-beta 42 in SH-SY5Y cells through inhibiting TXNIP expression, promoting cell viability and DNA synthesis ability, inhibiting cell apoptosis, and affecting caspase and Bax/Bcl-2 apoptotic signaling. miR-106b-5p could bind to TXNIP 3'-untranslated region to inhibit the expression level of TXNIP. Within SH-SY5Y cells, miR-106b-5p inhibition repressed cell viability and DNA synthesis ability and promoted cell apoptosis through caspase and Bax/Bcl-2 apoptotic signaling, while miR-106b-5p overexpression or TXNIP knockdown exerted the opposite effects on SH-SY5Y cells; TXNIP knockdown remarkably attenuated the roles of miR-106b-5p inhibition. In conclusion, estradiol treatment on SH-SY5Y cells downregulates TXNIP expression and upregulates miR-106b-5p expression. miR-106b-5p exerts a neuroprotective effect on SH-SY5Y cells by promoting cell proliferation and inhibiting cell apoptosis through targeting TXNIP.

Intervertebral disc degeneration (IDD) is the most common cause of low-back pain. Accumulating evidence indicates that the expression profiling of noncoding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs), are different between intervertebral disc tissues obtained from healthy individuals and patients with IDD. However, the roles of ncRNAs in IDD are still unclear until now. In this review, we summarize the studies concerning ncRNA interactions and regulatory functions in IDD. Apoptosis, aberrant proliferation, extracellular matrix degradation, and inflammatory abnormality are tetrad fundamental pathologic phenotypes in IDD. We demonstrated that ncRNAs are playing vital roles in apoptosis, proliferation, ECM degeneration, and inflammation process of IDD. The ncRNAs participate in underlying mechanisms of IDD in different ways. MiRNAs downregulate target genes’ expression by directly binding to the 3′-untranslated region of mRNAs. CircRNAs and lncRNAs act as sponges or competing endogenous RNAs by competitively binding to miRNAs and regulating the expression of mRNAs. The lncRNAs, circRNAs, miRNAs, and mRNAs widely crosstalk and form complex regulatory networks in the degenerative processes. The current review presents novel insights into the pathogenesis of IDD and potentially sheds light on the therapeutics in the future.

Women with macromastia experienced constitutional and psychosocial symptoms which could be improved by vertical scar or Inverted-T scar reduction mammaplasty. The authors conducted the first systematic review and meta-analysis in an attempt to declare the differences of the vertical scar versus the Inverted-T scar reduction technique by comparing the postoperative complications and aesthetic effects. PubMed, EMBASE, Web of Science, Scopus and Cochrane Central Register of Controlled Trials databases for clinical studies were searched through June 30, 2019. Cumulative analysis was conducted using the Review Manager Version 5.3 software. The summary odds ratio (OR) was estimated using random effect models at 95% confidence intervals (CIs), statistical heterogeneity was tested using the Chi-square test and risk of bias was assessed using the Cochrane Handbook 5.1.0 and the Newcastle-Ottawa scale (NOS). Two randomized controlled trials (RCT) and nine observational comparative studies were included. The vertical scar method was significantly lower than the Inverted-T scar method in overall incidence of complications (OR: 2.06; 95%CI, 1.15 to 3.70; P: 0.002) and wound dehiscence (OR: 4.62; 95%CI, 2.33 to 9.16; P

Lactate, the main contributor to the acidic tumor microenvironment, not only promotes the proliferation of tumor cells, but also closely relates to tumor invasion and metastasis. Here, a tumor targeting nanoplatform, designated as Me&Flu@MSN@MnO2-FA, was fabricated for effective tumor suppression and anti-metastasis by interfering with lactate metabolism of tumor cells. Metformin (Me) and fluvastatin sodium (Flu) were incorporated into MnO2-coated mesoporous silicon nanoparticles (MSNs), the synergism between Me and Flu can modulate the pyruvate metabolic pathway to produce more lactate, and concurrently inhibit lactate efflux to induce intracellular acidosis to kill tumor cells. As a result of the restricted lactate efflux, the extracellular lactate concentration is reduced, and the ability of the tumor cells to migrate is also weakened. This ingenious strategy based on Me&Flu@MSN@MnO2-FA showed an obvious inhibitory effect on tumor growth and resistance to metastasis.

BACKGROUND Conjoined twinning is a rare congenital malformation, and the resultant huge body wall defects after separation of conjoined twins represent a real challenge to surgeons. METHODS From 2004 to 2009, authors performed body wall reconstruction for 2 pairs of thoraco-omphalopagus twins and 1 pair of ischiopagus tetrapus twins. Before separation, the techniques of tissue expansion and tractive training were adopted to acquire sufficient skin for final coverage. After separation, the defects of thoracic cage and abdominal myofascial system were repaired with synthetic materials. The closure of the wounds was performed with artificial skin temporarily or by the use of local flaps in 1 stage. RESULTS The first pair of thoraco-omphalopagus twins died of circulatory and respiratory failure after emergency surgery, and the other 2 pairs of conjoined twins survived. The second pair of thoraco-omphalopagus twins had wound dehiscence and partial flap necrosis after surgery. The expanded polytetrafluoroethylene mesh in 1 sister of the ischiopagus twins was removed because of local infection 4 years after surgery. CONCLUSIONS Compressive anatomical understandings and advanced skills in plastic surgery are required for body wall reconstruction in the separation of conjoined twins. In addition, the multidisciplinary team approach has an important role for obtaining satisfactory final surgical outcome.

Summary Background Repairing body wall defects is a critical step in the treatment of some congenital deformities, and this procedure may need the help from plastic surgeons. Although there are many articles about congenital deformities, body wall defects of these malformations are rarely studied as independent targets. Methods In this article, the authors present an LDT classification for congenital body wall defects according to the position of the defects, the tissue layers involved, and the surgical urgency, each of which is represented by letters L, D, and T, respectively. That is, the defects in different areas ( L ), full-thickness ( D 1 ), or partial ( D 0A , D 0B ) defects, defects needing instant repair ( T 2 ), semi-elective repair ( T 1 ), or elective repair ( T 0 ). Based on this classification system, the authors have performed body wall reconstruction on two pairs of thoraco-omphalopagus twins, one pair of ischiopagus tetrapus twins, and an infant and an adult, both of whom were diagnosed with pentalogy of Cantrell associated with ectopia cordis. Results Except for one pair of thoraco-omphalopagus twins who died after emergency separation, all the other patients survived. Another pair of thoraco-omphalopagus twins suffered from wound dehiscence and partial flap necrosis, respectively, after surgery. An expanded polytetrafluoroethylene mesh in one sister of the ischiopagus twins was removed because of infection. Conclusions LDT classification not only can help doctors categorise different congenital body wall defects rapidly and easily, but can also guide the reconstruction of these defects. It may have clinical value to plastic surgeons to some extent.

Epicanthoplasty combined with double-eyelid blepharoplasty is one of the most popular cosmetic procedures in Asians. However, the postoperative medial canthal scar is a concerned issue. Here the authors adopted some modifications of Z-epicanthoplasty to minimize the canthal scar. Modifications of Z-epicanthoplasty were mainly in three aspects. First, supratarsal creases were created before epicanthoplasty to prevent the impact of tension variation on epicanthal incisions, caused by elevating and tightening of the upper eyelid skin. Second, one triangle flap was determined according to the transposition of another one in Z-plasty, and hence, it can be guaranteed that the incisions were closed free of tension with more accuracy and less injury to surrounding tissues. Third, linear scar contracture was avoided by adopting discontinuous incisions, and the resulting skin bulge was eliminated by making an additional stitch to anchor the pretarsal skin on the tarsal plate. The follow-up interval was 1 month to 2 years, with a median of 6.5 months. From January 2012 to December 2015, 237 female and 4 male patients received the surgery. Except five (2.07%) patients, who were not satisfied with the color of incision scars in medial canthal area, none complained about scars 6 months after surgery. The appearance of the supratarsal crease was natural, and the medial canthal scar was inconspicuous in close observation at 2 years. The modifications of Z-epicanthoplasty are safe and effective. It is potentially helpful to minimize postoperative medial canthal scars. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

To provide information about necrotizing fasciitis (NF), how to recognize it, and evidence-based treatment.This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.After completing this continuing education activity, you should be able to: ABSTRACT: Necrotizing fasciitis is a threatening, rapidly progressive, infectious disease of the soft tissue. In this article, based on 3 cases, the authors aim to summarize the clinical experience of patients with necrotizing fasciitis and the current concepts of the treatment and management of this disease.

To observe the clinical effect of "Yinqi Guiyuan" needling in the treatment of primary insomnia.A total of 79 primary insomnia outpatients were randomly divided into treatment group (After treatment, the total score of PSQI, ISI and the score of each item were all significantly reduced in the two groups relevant to their own pre-treatment ("Yinqi Guiyuan" needling and Estazolam are comparable in treatment primary insomnia, and the former is superior to the latter in avoiding hypnotic drug use and in improving daytime function.

Alzheimer's disease (AD), a massive challenge to global health, is featured with the extracellular plaques made up of amyloid-β 42 (Aβ42) and the intracellular neurofibrillary pathology composed of the microtubule-associated protein tau. Women seem to have a higher vulnerability to AD. In the present study, we identified Thioredoxin-interacting protein (TXNIP) as a specifically highly-expressed gene in the hippocampus in female AD patients by bioinformatics analysis. Consistently, in the hippocampus in female AD mice, apoptosis and TXNIP expression were enhanced while TRX expression was suppressed. In Aβ42-stimulated SH-SY5Y cells, the administration of estradiol significantly rescued Aβ42-suppressed cell viability and protein level of TRX while inhibited Aβ42-induced increases in ROS production, cell apoptosis, ΔΨm, and the protein levels of PERK, IREα, and TXNIP, further confirming the potential role of estrogen in AD progression and the involvement of TXNIP/TRX axis. Furthermore, the protective effects of estradiol against Aβ42-induced in vitro neurotoxicity on SH-SY5Y cells could be significantly reversed by AMPK inhibitor, Compound C, indicating that estradiol could improve Aβ42-induced AD via TXNIP/TRX and AMPK signaling. In summary, we demonstrated the cellular function of estradiol on Aβ42-induced in vitro neurotoxicity on SH-SY5Y cells and a novel mechanism of TXNIP/TRX axis involved in estradiol function via AMPK signaling.

Epilepsy is a chronic neurological disease. Astrogliosis is an important pathological change in epileptic lesions. Studies have reported that ibuprofen can affect autophagy and/or inhibit cell proliferation in many diseases. This study investigated the effect and significance of ibuprofen on autophagy of astrocytes during pentylenetetrazol (PTZ) induced epilepsy. 60 male Sprague–Dawley (SD) rats were randomly divided into five groups: control group (received normal saline), PTZ group, 3-methyladenine (3-MA) + PTZ group, ibuprofen + PTZ group and 3-MA + ibuprofen + PTZ group. Dose of each agent was 35 mg/kg (PTZ), 10 mg/kg (3-MA) and 30 mg/kg (ibuprofen) and all drugs were administered intraperitoneally 15 times on alternate days (29 days). Human astrocytes were cultured in vitro. Behavioral performance (i.e., latency, grade and duration of seizures) and EEG of rats were observed and recorded. Proliferation of astrocytes was detected by CCK-8 method. Immunofluorescence and Western blot test were used to detect the expression of LC3 and GFAP. Mean number, grade and duration of seizures were markedly reduced in ibuprofen + PTZ group and 3-MA + ibuprofen + PTZ group (P

Facial aging is a complex process influencing every layer of the facial structure. Most accepted surgical techniques for facial rejuvenation involve certain manipulation of the superficial musculoaponeurotic system (SMAS). Out of these SMAS-based techniques, SMAS plication or suspension provides excellent outcomes with shorter convalescence and fewer potential complications. Herein, we would like to present our own technique combining SMAS plication, periauricular purse-string, and malar fat pad elevation technique for mid and lower facelift.Through a classical periauricular and temporal incision, a periauricular permanent purse-string suture was woven into the SMAS to suspend sagging soft tissue of the mid and lower face after superficial undermining, then plication of inner and outer SMAS of the purse-string loop was performed to further secure suspension, and at last the malar fat pad was elevated for midface rejuvenation. The shape of the loop varies with patients' age; for younger patients, the loop is more vertical, and for older patients, the loop is more horizontal. Patient-reported outcomes were described using the FACE-Q questionnaire.From January 2010 to June 2015, a total of 138 patients were treated with this technique by a same surgeon. Follow-up duration ranged from 1 to 6 years. Preoperative and postoperative photographs were recorded and analyzed. The complications rates were low, and satisfaction rates were high. Patients felt that they appeared 7.3 years younger than their actual age on average and were most satisfied with the appearance of their lower face and jawline.Periauricular purse-string reinforced with SMAS plication and malar fat pad elevation technique produces esthetically pleasing outcomes, besides being simple, safe, and personalized.

Background To report a case of femtosecond laser-assisted removal of an intracorneal chestnut. Case presentation A chestnut was obliquely protruding to the stroma of cornea and it was localized at the paracentral region on the left eye of a 32-year-old man. The best-corrected visual acuity (BCVA, in decimal values) was 0.6 in the injured eye. The white ulcers with feathery edges or satellite infiltrates were not observed in the lesion, and the anterior chamber was deep and quiet. Anterior segment optical coherence tomography (AS-OCT) demonstrated that the original entry path of the foreign body had been sealed, spanning a thickness of approximate 152 μm. In view of location of the intraocular chestnut at the paracentral region, femtosecond laser was applied according to the procedures of IntraLase Enabled Keratoplasty (IEK) to create an anterior lamellar flap rapidly and precisely. The lamellar flap was easily separated with a flap lifter, and the chestnut was removed entirely using a pair of forceps. In 3 days after surgery, the patient complained of mild pain and blurred vision. These symptoms were relieved after treatment with the eyedrops. At three-month follow-up, the corneal wound was healed well, and the BCVA was greatly improved to 1.2 in the left eye. A dot-like haze was observed corresponding to the scar at the site of foreign body removal. No surgical induction of corneal astigmatism was found in the corneal topography. Conclusions Without induction of a visually significant scar and corneal astigmatism, the IEK procedure of femtosecond laser is of particular interest as it provides a unique method for removal of intracorneal foreign bodies impinging on the visual axis.

To investigate the relationship between the expression of microtubule-associated protein LC3 and the numbers of CD68 + microglia, CD4 + T lymphocytes and CD8 + T lymphocytes, as well as the clinical significance of those factors in gliomas.The study group consisted of 127 patients with gliomas who were operated to our hospital, we examined the expression of LC3 by Immunohistochemistry and Western blot, and we assessed the numbers of CD68 + microglia, CD4 + T lymphocytes and CD8 + T lymphocytes by Immunohistochemistry, we analyze the relationship between all the factors and explore the significance.Immunohistochemistry and Western blotting showed that the expression of LC3 in normal brain tissue, low-grade gliomas, and high-grade gliomas are elevated to varying degrees (P 0.01); Immunohistochemical detection showed that the numbers of CD68 + microglia, CD4 + T lymphocytes and CD8 + T lymphocytes in gliomas was higher than that in normal brain tissues (P 0.01), and the high-grade gliomas were higher than those in low-grade gliomas (P 0.01); The results of Spearman correlation showed that the expression of LC3 was positively correlated with the numbers of CD68 + microglia, CD4 + T lymphocytes, and CD8 + T lymphocytes (P 0.05); Furthermore, survival analysis showed that LC3, CD68 + microglia, CD8 + T lymphocytes and tumor grade were independent prognostic factors of glioma.LC3 may be one of the factors that affect the tumor cellular immunity response in gliomas. The simultaneous detection of LC3, CD68 + microglia and CD8 + T lymphocytes can be used to assess the prognosis of glioma.

BackgroundThe immune cells in the local environments surrounding non-small cell lung cancer (NSCLC) implicate the balance of pro- and antitumor immunity; however, their transcriptomic profiles remain poorly understood.MethodsA transcriptomic microarray study of bronchoalveolar lavage (BAL) cells harvested from tumor-bearing lung segments was performed in a discovery group. The findings were validated (1) in published microarray datasets, (2) in an independent group by RT-qPCR, and (3) in non-diseased and tumor adjacent non-neoplastic lung tissue by immunohistochemistry and in BAL cell lysates by immunoblotting.ResultThe differential expression of 129 genes was identified in the discovery group. These genes revealed functional enrichment in Fc gamma receptor-dependent phagocytosis and circulating immunoglobulin complex among others. Microarray datasets analysis (n = 607) showed that gene expression of BAL cells of tumor-bearing lung segment was also the unique transcriptomic profile of tumor adjacent non-neoplastic lung of early stage NSCLC and a significantly gradient increase of immunoglobulin genes’ expression for non-diseased lungs, tumor adjacent non-neoplastic lungs, and tumors was identified (ANOVA, p

The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and “slip” into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment. Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625–40. ©2018 AACR.

Despite abundant data supporting c-Src as a metastasis-promoting oncogene, activating mutations of c-Src are rare. This suggests that trans-interacting proteins may have a critical role in regulating c-Src activation. Here, we first report the discovery of Src homology 3 (SH3) domain-binding glutamic acid-rich-like protein (SH3BGRL), a novel c-Src activator in mice. Ectopic expression of murine SH3BGRL (mSH3BGRL) strongly promoted both tumor cell invasion and lung metastasis. Molecularly, mSH3BGRL specifically bound the inactive form of c-Src phosphorylated at Tyr527, promoting Tyr416 phosphorylation of c-Src and subsequent FAK-mediated activation of ERK and AKT signaling pathways. Targeting endogenous c-Src alone was sufficient to abolish mSH3BGRL-induced cancer metastasis in vivo. Unexpectedly, human SH3BGRL (hSH3BGRL) in turn suppressed tumorigenesis and metastasis in nature. We attempted site-specific reversion of hSH3BGRL amino-acid sequence to mSH3BGRL and found V108A substitution sufficient to restore SH3BGRL function as a c-Src activator and metastasis promoter. Notably, the somatic mutation R76C of hSH3BGRL can similarly act as hSH3BGRL-V108A and mSH3BGRL in tumorigenesis and metastasis. Our results uncover an evolutionarily controversial role of SH3BGRL in driving tumor metastasis through c-Src activation, and suggests that hSH3BGRL mutation status could be relevant to cancer diagnosis and therapy.

We aimed to compare contrast-enhanced ultrasound (CEUS) with contrast-enhanced computed tomography (CECT) for evaluating the treatment response to transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). Treatment responses of 130 patients who underwent TACE were evaluated by CEUS and CECT. We initially compared the abilities of CEUS and CECT to detect residual tumour, which were confirmed by histology or angiography. Then, we compared the tumour response to TACE assessed by CEUS and CECT, according to Modified Response Evaluation Criteria in Solid Tumours (mRECIST). The sensitivity and accuracy of detecting residual tumour by CEUS vs. CECT were 95.9 % vs. 76.2 % (p

The tumor suppressor protein ELL-associated factor 2 (Eaf2) serves an important role in lens development and maturation; however, its role in oxidative stress‑induced cataract formation remains unclear. In the present study, an in vitro apoptosis model was constructed by treating HLE‑B3 cells with 50 µM hydrogen peroxide (H2O2), and was confirmed by flow cytometry. Subsequently, overexpression of Eaf2 was induced in H2O2‑induced HLE‑B3 cells by ligating Eaf2 cDNA to a pcDNA3.0 plasmid and the role of Wnt3a in the function of Eaf2 was also assessed by inhibiting the expression of the gene in Eaf2‑overexpression cells. The expression levels of glycogen synthase kinase 3β, β‑catenin, Eaf2, caspase 3, Wnt3a, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein were examined using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Immunocytochemistry was used to locate Eaf2 and Wnt3 protein expression in the H2O2‑induced HLE‑B3 cells. The results indicated that Eaf2 was able to effectively suppress H2O2‑induced apoptosis of HLE cells via inhibition of caspase 3 production and activation of Wnt3a signaling. In addition, knockdown of Wnt3a in Eaf2‑overexpression cells evidently counteracted the effect of Eaf2 in antagonizing H2O2‑induced apoptosis. Taken together, these findings suggested that Eaf2 may suppress oxidative stress‑induced apoptosis of HLE‑B3 cells exerted through the activation of Wnt3a signaling.

The pathological mechanism of Alzheimer's disease (AD) needs to be elucidated. The Bcl-2 associated athanogene 5 (Bag5) is an important member in the Bag family. However, the role of Bag5 in AD has not yet been elucidated. In this study, we found that expression of Bag5 is elevated in the brains of AD transgenic Tg2576 mice at both mRNA levels and proteins. In vitro experiments indicated that Aβ1-42 treatment led to the upregulation of Bag5 in a dose-dependent manner. In addition, our results indicated that inhibition of Bag5 using small RNA interferences exacerbated Aβ1-42-induced neurotoxicity. On one hand, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay demonstrated that inhibition of Bag5 exacerbated Aβ1-42-related cell death. On the other hand, silence of endogenous Bag5 promotes the generation of reactive oxygen species (ROS) and malondialdehyde (MDA) induced by Aβ1-42. Finally and importantly, it was shown that knockdown of Bag5 exacerbated Aβ1-42-induced apoptosis and caspase-3 cleavage. These data suggest that induction of Bag5 might have a neuroprotective effect in AD.

To investigate the correlation between drinking behavior combined with polymorphisms of extracellular superoxide dismutase (EC-SOD) and aldehyde dehydrogenase-2 (ALDH2) genes and pancreatic cancer.The genetic polymorphisms of EC-SOD and ALDH2 were analyzed by polymerase chain reaction restriction fragment length polymorphism in the peripheral blood leukocytes obtained from 680 pancreatic cancer cases and 680 non-cancer controls. Subsequently the frequency of genotype was compared between the pancreatic cancer patients and the healthy controls.The relationship of drinking with pancreatic cancer was analyzed.The frequencies of EC-SOD (C/G) and ALDH2 variant genotypes were 37.35% and 68.82% respectively in the pancreatic cancer cases, and were significantly higher than those in the healthy controls (21.03% and 44.56%, all P0.01). People who carried EC-SOD (C/G) (OR=2.24, 95% CI= 1.81-4.03, P0.01) or ALDH2 variant genotypes (OR=2.75, 95% CI=1.92-4.47, P0.01) had a high risk to develop pancreatic cancer. Those who carried EC-SOD (C/G) genotype combined with ALDH2 variant genotype had a high risk for pancreatic cancer (29.56% vs. 6.76%, OR=7.69, 95% CI=3.58-10.51, P0.01). The drinking rate of the pancreatic cancer group (64.12%) was significantly higher than that of the control group (40.15%; OR=2.66, 95% CI=1.30-4.42, P0.01). An interaction between drinking and EC-SOD (C/G)/ALDH2 variant genotypes increased the risk of occurrence of pancreatic cancer (OR=25.00, 95% CI= 11.87-35.64, P0.01).EC-SOD (C/G), ALDH2 variant genotypes and drinking might be the risk factors of pancreatic cancer.

True macromastia is a rare but disabling condition characterized by massive breast growth. The aetiology and pathogenic mechanisms for this disorder remain largely unexplored because of the lack of in vivo or in vitro models. Previous studies suggested that regulation of epithelial cell growth and development by oestrogen was dependent on paracrine growth factors from the stroma. In this study, a co-culture model containing epithelial and stromal cells was used to investigate the interactions of these cells in macromastia. Epithelial cell proliferation and branching morphogenesis were measured to assess the effect of macromastic stromal cells on epithelial cells. We analysed the cytokines secreted by stromal cells and identified molecules that were critical for effects on epithelial cells. Our results indicated a significant increase in cell proliferation and branching morphogenesis of macromastic and non-macromastic epithelial cells when co-cultured with macromastic stromal cells or in conditioned medium from macromastic stromal cells. Hepatocyte growth factor (HGF) is a key factor in epithelial-stromal interactions of macromastia-derived cell cultures. Blockade of HGF with neutralizing antibodies dramatically attenuated epithelial cell proliferation in conditioned medium from macromastic stromal cells. The epithelial-stromal cell co-culture model demonstrated reliability for studying interactions of mammary stromal and epithelial cells in macromastia. In this model, HGF secreted by macromastic stromal cells was found to play an important role in modifying the behaviour of co-cultured epithelial cells. This model allows further studies to investigate basic cellular and molecular mechanisms in tissue from patients with true breast hypertrophy.

FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan-Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. Although molecular diagnostic tools and targeted therapies have been developed over the past few decades, the survival rate is still rather low. Numerous researches suggest that some microRNAs (miRNAs) are key regulators of tumor progression. Among those miRNAs that has attracted much attention for their multiple roles in human cancers, the function of miR-221-3p in EOC has not been elucidated. Herein, we examined the expression of miR-221-3p in EOC patients and cell lines. Our data revealed that higher expression of miR-221-3p was linked to better overall survival in EOC patients. In-vitro experiments indicated that miR-221-3p inhibited EOC cell proliferation and migration. By performing subsequent systematic molecular biological and bioinformatic analyses, we found ADP-ribosylation factor (ARF) 4 is one of the putative target genes, the direct binding relationship was further confirmed by dual-luciferase reporter assay. Finally, a distinct gene expression between miR-221-3p and ARF4 in EOC group and normal group was identified, and the negative correlation between their expression levels in EOC specimens was further confirmed. Taken together, our research uncovered the tumor suppressive role of miR-221-3p in EOC and directly targeted ARF4, suggesting that miR-221-3p might be a novel potential candidate for clinical prognosis and therapeutics of EOC.

5-hydroxytryptamine receptor 1A (5-HT1AR) is closely associated with cognitive functions. Selective serotonin reuptake inhibitors (SSRIs) can protect individuals from brain damage following ischemia/hypoxia. To investigate the function of SSRIs in vascular dementia (VD), we established a rat model of VD, and observed the effect of SSRIs on the expression of 5-HT1AR mRNA and neurotransmitters. Male SD rats (6 months) were randomly assigned into sham, model, and SSRI groups (N = 30). VD was achieved by permanent ligation of the bilateral common carotid artery. Escitalopram, a highly selective 5-HT reabsorption inhibitor, was ip injected into the rats for three consecutive weeks. The Morris water-maze was used to test learning and memory. H&E staining for neuronal injury was conducted on cortical and hippocampal tissues. HPLC was used to determine the levels of dopamine (DA), 5-HT, and norepinephrine (NE). RT-PCR was used to determine expression of 5-HT1AR mRNA. As compared to control rats, model animals demonstrated elongated escape latency, lower platform crossing times, and significant injuries to hippocampal CA1 neurons. This was accompanied by reductions in DA, 5-HT, and NE levels in hippocampal tissues, as well as reduced cortical 5-HT and decreased 5-HT1AR mRNA expression (P < 0.05). Escitalopram treatments reduced escape latency, elevated platform crossing times, improved CA1 neuronal damage, increased DA and 5-HT levels in hippocampal and cortical neurons, as well as elevated expression of 5-HT1AR mRNA (P < 0.05). Therefore, SSRIs may improve cognitive dysfunction of VD rats, possibly by stimulating expression of neurotransmitters and protecting neurons.

Various adjacent flaps have been designed to close infraorbital defect, and each of them is trying to get an aesthetic outcome and meanwhile circumvent eyelid retraction, ectropion, and functional disability. Here, the authors report an adjacent double-lobe flap, which took advantage of nasolabial advancement and infraorbital rotation of the 2 lobes, combinatorially closed a pentagon infraorbital defect by removal of 2 small skin paddles as donor sites, and finally yielded an acceptable aesthetic and functional outcome. This flap may be a new option for closure of polygon infraorbital defects.

Ke Guo 1,2 , Jing Ping Tang 1,2 , Li Jie 1,2 , Abdul Qader O. Al-Aidaroos 2 , Cheng William Hong 3 , Cheng Peow Bobby Tan 2 , Jung Eun Park 2 , Leyon Varghese 2 , Zhiwei Feng 4 , Jianbiao Zhou 5 , Wee Joo Chng 6 and Qi Zeng 2,7 1 Denotes equal contribution 2 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore 138648, Republic of Singapore 3 Cleveland Clinic Lerner College of Medicine, 9500 Euclid Avenue, Cleveland, OH 44195, USA 4 Nanyang Technological University, School of Biological Sciences, 60 Nanyang Drive, Singapore 637551 5 Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456 6 Department of Haematology-Oncology, National University Cancer Institute, Singapore National University Health System, 5 Lower Kent Ridge Road, S119074 7 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Republic of Singapore Received: February 2, 2012; Accepted: February 21, 2012; Published: February 27, 2012; Keywords: PRL-3 monoclonal antibody, PRL-3 mouse/human chimeric antibody, antibody therapy, intracellular oncoprotein Correspondence: Qi Zeng, // // Abstract Antibodies are considered as ‘magic bullets’ because of their high specificity. It is believed that antibodies are too large to routinely enter the cytosol, thus antibody therapeutic approach has been limited to extracellular or secreted proteins expressed by cancer cells. However, many oncogenic proteins are localized within the cell. To explore the possibility of antibody therapies against intracellular targets, we generated a chimeric antibody targeting the intracellular PRL-3 oncoprotein to assess its antitumor activities in mice. Remarkably, we observed that the PRL-3 chimeric antibody could efficiently and specifically reduce the formation of PRL-3 expressing metastatic tumors. We further found that natural killer (NK) cells were important in mediating the therapeutic effect, which was only observed in a nude mouse model (T-cell deficient), but not in a Severe Combined Immunodeficiency’ ( scid ) mouse model (B- and T-cell deficient), indicating the anticancer effect also depends on host B-cell activity. Our study involving 377 nude and scid mice suggest that antibodies targeting intracellular proteins can be developed to treat cancer.

Summary Overexpression of phosphatase of regenerating liver (PRL)-3 is associated with the progression of diverse human cancers. We show that the overexpression of PRL-3 protein is not directly associated with its transcript levels, indicating the existence of an underlying posttranscriptional regulation. The 5′ untranslanted region (UTR) of PRL-3 mRNA possesses triple GCCCAG motifs capable of suppressing mRNA translation through interaction with PolyC-RNA-binding protein 1 (PCBP1), which retards PRL-3 mRNA transcript incorporation into polyribosomes. Overexpression of PCBP1 inhibits PRL-3 expression and inactivates AKT, whereas knockdown of PCBP1 causes upregulation of PRL-3 protein levels, activation of AKT, and promotion of tumorigenesis. An inverse correlation between protein levels of PRL-3 and PCBP1 in human primary cancers supports the clinical relevance.

Rationale: Hashimoto's encephalopathy (HE) is associated with autoimmune thyroid disease and is complex, diverse, and easily misdiagnosed. However, if HE is diagnosed and treated in a timely manner, an optimal prognosis may be achieved. Patient concerns: We presented a case of a 63-year-old female patient with paroxysmal dizziness, unsteady gait, emotion apathy, progressive cognitive impairment, and unusual magnetic resonance imaging (MRI) findings. Diagnoses: After suffering for almost 8 years, the patient was diagnosed with HE based on clinical manifestation, abnormal electroencephalogram, unusual MRI findings, sensitivity to cortisol treatment, and characteristic high antithyroid peroxidase antibody (TpoAb) titer. Interventions: The patient continued regular glucocorticoids therapy after intravenous methylprednisolone pulse therapy, neurotrophic drugs, traditional Chinese medicine and rehabilitation to relieve hypermyotonia and cognitive impairment. Outcomes: After combined treatment, the patient's symptoms, electroencephalogram (EEG), MRI, and the TpoAb titer gradually improved. However, the patient had to stop glucocorticoids treatment because of severe osteoporosis, fractures and other adverse reactions. Her symptoms fluctuated, and her TpoAb titer increased again. Lessons: HE may cause highly heterogeneous clinical features, particularly MRI findings. Withdrawal of the systematic glucocorticoids treatment can lead to varied outcomes in these patients.

TAZ (WWTR1), identified as a 14-3-3 binding protein with a PDZ binding motif, modulates mesenchymal stem cell differentiation. We now show that TAZ plays a critical role in the migration, invasion, and tumorigenesis of breast cancer cells. TAZ is conspicuously expressed in human breast cancer cell lines in which its expression levels generally correlate with the invasiveness of cancer cells. Overexpression of TAZ in low-expressing MCF10A cells causes morphologic changes characteristic of cell transformation and promotes cell migration and invasion. Conversely, RNA interference–mediated knockdown of TAZ expression in MCF7 and Hs578T cells reduces cell migration and invasion. TAZ knockdown in MCF7 cells also retards anchorage-independent growth in soft agar and tumorigenesis in nude mice. Significantly, TAZ is overexpressed in ∼20% of breast cancer samples. These results indicate that TAZ plays a role in the migration, invasion, and tumorigenesis of breast cancer cells and thus presents a novel target for the detection and treatment of breast cancer. [Cancer Res 2008;68(8):2592–8]

Apoptosis-inducing factor (AIF) exhibits reactive oxygen species (ROS)-generating NADH oxidase activity of unknown significance, which is dispensable for apoptosis. We knocked out the aif gene in two human colon carcinoma cell lines that displayed lower mitochondrial complex I oxidoreductase activity and produced less ROS, but showed increased sensitivity to peroxide- or drug-induced apoptosis. AIF knockout cells failed to form tumors in athymic mice or grow in soft agar. Only AIF with intact NADH oxidase activity restored complex I activity and anchorage-independent growth of aif knockout cells, and induced aif-transfected mouse NIH3T3 cells to form foci. AIF knockdown in different carcinoma cell types resulted in lower superoxide levels, enhanced apoptosis sensitivity and loss of tumorigenicity. Antioxidants sensitized AIF-expressing cells to apoptosis, but had no effect on tumorigenicity. In summary, AIF-mediated resistance to chemical stress involves ROS and probably also mitochondrial complex I. AIF maintains the transformed state of colon cancer cells through its NADH oxidase activity, by mechanisms that involve complex I function. On both counts, AIF represents a novel type of cancer drug target.

We report here that autocrine production of human growth hormone (hGH) results in a phenotypic conversion of mammary carcinoma cells such that they exhibit the morphological and molecular characteristics of a mesenchymal cell, including expression of fibronectin and vimentin. Autocrine production of hGH resulted in reduced plakoglobin expression and relocalization of E-cadherin to the cytoplasm, leading to dissolution of cell-cell contacts and decreased cell height. These phenotypic changes were accompanied by an increase in cell motility, elevated activity of specific matrix metalloproteinases, and an acquired ability to invade a reconstituted basement membrane. Forced expression of plakoglobin significantly decreased mammary carcinoma cell migration and invasion stimulated by autocrine hGH. In vivo , autocrine hGH stimulated local invasion of mammary carcinoma cells concomitant with a prominent stromal reaction in comparison with well delineated and capsulated growth of mammary carcinoma cells lacking autocrine production of hGH. Thus, autocrine production of hGH by mammary carcinoma cells is sufficient for generation of an invasive phenotype. Therapeutic targeting of autocrine hGH may provide a mechanistic approach to prevent metastatic extension of human mammary carcinoma.

Sprouty (Spry) proteins were found to be endogenous inhibitors of the Ras/mitogen-activated protein kinase pathway that play an important role in the remodeling of branching tissues. We investigated Spry expression levels in various cancers and found that Spry1 and Spry2 were down-regulated consistently in breast cancers. Such prevalent patterns of down-regulation may herald the later application of these isoforms as tumor markers that are breast cancer specific and more profound than currently characterized markers. Spry1 and 2 were expressed specifically in the luminal epithelial cells of breast ducts, with higher expression during stages of tissue remodeling when the epithelial ducts are forming and branching. These findings suggest that Sprys might be involved as a modeling counterbalance and surveillance against inappropriate epithelial expansion. The abrogation of endogenous Spry activity in MCF-7 cells by the overexpression of a previously characterized dominant-negative mutant of Spry, hSpry2Y55F resulted in enhanced cell proliferation in vitro. The hSpry2Y55F stably expressing cells also formed larger and greater number of colonies in the soft-agar assay. An in vivo nude mice assay showed a dramatic increase in the tumorigenic potential of hSpry2Y55F stable cells. The consistent down-regulation of Spry1 and 2 in breast cancer and the experimental evidence using a dominant-negative hSpry2Y55F indicate that Spry proteins may actively maintain tissue integrity that runs amok when their expression is decreased below normal threshold levels. This alludes to a previously unrecognized role for Sprys in cancer development.

The thermogenic activity of brown adipose tissue (BAT), important for adaptive thermogenesis and energy expenditure, is mediated by the mitochondrial uncoupling protein1 (Ucp1) that uncouples ATP generation and dissipates the energy as heat. We show here that Cidea, a protein of unknown function sharing sequence similarity with the N-terminal region of DNA fragmentation factors Dffb and Dffa, is expressed at high levels in BAT. Cidea-null mice had higher metabolic rate, lipolysis in BAT and core body temperature when subjected to cold treatment. Notably, Cidea-null mice are lean and resistant to diet-induced obesity and diabetes. Furthermore, we provide evidence that the role of Cidea in regulating thermogenesis, lipolysis and obesity may be mediated in part through its direct suppression of Ucp1 activity. Our data thus indicate a role for Cidea in regulating energy balance and adiposity.

Metastasis-associated phosphatase of regenerating liver-3 (PRL-3) has pleiotropic effects in driving cancer progression, yet the signaling mechanisms of PRL-3 are still not fully understood. Here, we provide evidence for PRL-3–induced hyperactivation of EGFR and its downstream signaling cascades in multiple human cancer cell lines. Mechanistically, PRL-3–induced activation of EGFR was attributed primarily to transcriptional downregulation of protein tyrosine phosphatase 1B (PTP1B), an inhibitory phosphatase for EGFR. Functionally, PRL-3–induced hyperactivation of EGFR correlated with increased cell growth, promigratory characteristics, and tumorigenicity. Moreover, PRL-3 induced cellular addiction to EGFR signaling, as evidenced by the pronounced reversion of these oncogenic attributes upon EGFR-specific inhibition. Of clinical significance, we verified elevated PRL-3 expression as a predictive marker for favorable therapeutic response in a heterogeneous colorectal cancer (CRC) patient cohort treated with the clinically approved anti-EGFR antibody cetuximab. The identification of PRL-3–driven EGFR hyperactivation and consequential addiction to EGFR signaling opens new avenues for inhibiting PRL-3–driven cancer progression. We propose that elevated PRL-3 expression is an important clinical predictive biomarker for favorable anti-EGFR cancer therapy.

To study feasibility and security of single-incision laparoscopic cholecystectomy (SILC).Clinical trials comparing SILC with conventional laparoscopic cholecystectomy (LC) for benign gallbladder disease published from 2010 to 2012 were retrieved. A meta-analysis was conducted to evaluate operative time, blood loss, conversion rate, post-operative pain, wound satisfaction score, post-operative hospital stay and post-operative complications between SILC group and LC group. A fixed effect model or random effect model was established to collect the data.Eleven random clinical trials on 859 patients qualified for the meta-analysis, 449 patients being allocated to SILC and 410 patients to LC. There was no significant difference between SILC group and LC group for blood loss, conversion rate, post-operative pain, post-operative hospital stay and post-operative complications. However, operative time was significantly longer in SILC group than LC group (IV = 16.66, 95%CI: 9.60 - 23.72, Z = 4.62, P = 0.00). Furthermore, wound satisfaction score was significantly higher in SILC group than in LC group (IV = 0.95, 95%CI: 0.56 - 1.34, Z = 4.76, P = 0.00).SILC may be superior to LC in terms of cosmetic outcome, but not in operative time. Currently, SILC is a safe procedure for proper patients in experienced surgeons.

To explore clinical short and long-term effect of combining dalitong granule (DG) and electroacupuncture group (EA) in the treatment of functional dyspepsia.Totally 640 patients with confirmed functional dyspepsia were randomly divided into 4 groups using a randomized digital table: the DG group, the EA group, the combined group and the control group, 160 cases in each group. The DG group was treated with 6 g DG 3 times daily; the EA group was treated with puncture of points Zusanli (ST36), Zhongwan (CV12), Neiguan (PC6), Taichong (LR3) and Gongsun (SP4) twice daily; the combined group with above-mentioned DG and EA; and the control group with 5 mg mosapride 3 times, 20 mg pantoprazole and 25 mg amitriptylines twice daily. The treatment course was 4 weeks for all groups. The symptom score, quality of life score by Short Form 36 Health Survey Questionnaires (SF-36), plasma motilin by radioimmunoassay, electrogastrographic frequencies by electrogastrogram (EGG) and gastric emptying by B-sonography were examined, and adverse reactions were observed before, at the end of treatment and 60 weeks post-treatment.In the DG group 1 case dropped out for not taking medicine strictly and 1 case was lost to follow-up, while 1 case in the EA group and 2 cases in the combined therapy group were lost to follow-up. Compared with pre-treatment, quality of life score, plasma motilin, electrogastrographic frequencies and gastric emptying were all increased significantly, while symptom score was decreased significantly at the end of treatment in each group (P0.01); in the combined group quality of life score, plasma motilin, electrogastrographic frequencies and gastric emptying were all significantly higher than those in the other groups, while symptom score was significantly lower than in the other groups (P0.05). Compared with at the end of treatment, these indices changed insignificantly in the combined group and the EA group 60 weeks post-treatment (P0.05), but the 4 increased indices were all decreased significantly, and symptom score was increased significantly in the DG and the control groups (P0.05). The short and long-term total effective rates in the combined group were all significantly higher than those in the other treatment groups (P0.05 or P0.01). No serious adverse reaction occurred in the four groups.Combined treatment of DG and EA could increase both plasma motilin and electrogastrographic frequencies, promote gastric emptying, alleviate the symptom of dyspepsia so as to increase quality of life, with better safety and long-term effect.