Vitamin D Improves Klebsiella-Induced Severe Pneumonia in Rats by Regulating Intestinal Microbiota.

Background: In the context of progressively uncontrolled drug resistance of bacteria, the difficulty of treating Klebsiella (KP)-induced pneumonia increases. Searching for drugs other than antibiotics has become an urgent task. Vitamin D (VD), meanwhile, is shown to be capable of treating pneumonia. Therefore, we aimed to explore the effects and mechanisms of VD on KP-infected rats. Methods: Male Sprague Dawley rats were divided into the Control, VD, KP and KP+VD groups. A rat pneumonia model was induced using an intratracheal drop of 2.4×108 CFU/mL KP. VD treatment was performed by gavage using 5 µg/kg. Subsequently, the survival of the rats was recorded, and the lungs, bronchoalveolar lavage fluid, and feces of the rats were collected 4 days after KP infection. Next, the water content of lung tissues was measured by the wet-to-dry weight ratio. Histopathological changes of lung tissues were observed by Hematoxylin and Eosin staining and the levels of inflammatory factors (TNF-α, IL-1ß, MCP1) were detected using ELISA. The feces of rats in each group were also subjected to 16S rDNA gene analysis of intestinal microbiota. Results: Compared with the KP group, the KP+VD group showed a significant increase in survival, a significant decrease in water content and bacterial counts in the lungs, a significant improvement in lung injury, and a significant decline in the levels of TNF-α, IL-1ß, and MCP1. According to the 16S rDNA sequencing, VD altered the structure of the intestinal bacterial community in the KP-infected rats and made the species richness similar to that of healthy rats. Additionally, the abundance of Anaeroglobus was significantly increased in the KP+VD group. Conclusion: VD modulates intestinal microbiota to increase the resistance of rats to pneumonia caused by Klebsiella infection.

Consolidative chemotherapy after definitive concurrent chemoradiotherapy for esophageal squamous cell carcinoma patients: a population based cohort study.

BACKGROUND: The role of consolidative chemotherapy (CCT) for locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients treated with definitive concurrent chemoradiotherapy (dCCRT) is unclear. We aimed to compare the overall survival (OS) of those treated with vs without CCT via a population based approach. METHODS: Eligible LA-ESCC patients diagnosed between 2011 and 2017 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders between groups. The hazard ratio (HR) of death and incidence of esophageal cancer mortality (IECM) were compared between those with vs without CCT. We also evaluated the OS in supplementary analyses via alternative approaches. RESULTS: Our primary analysis consisted of 368 patients in whom covariates were well balanced after PS weighting. The HR of death when CCT was compared to without was 0.67 (95% confidence interval 0.52-0.86, P = 0.002). The HR of IECM was 0.66 (P = 0.04). The HR of OS remained similarly in favor of CCT in supplementary analyses. CONCLUSIONS: We found that CCT was associated with significantly improved OS for LA-ESCC patients treated with dCCRT. Randomized controlled trials were needed to confirm this finding.

Effectiveness evaluation of adjuvant concurrent chemoradiotherapy for patients with positron emission tomography-staged esophageal squamous cell carcinoma after complete resection: A population-based cohort study.

BACKGROUND: The role of adjuvant concurrent chemoradiotherapy (ACCRT) is unclear for patients with esophageal squamous cell carcinoma (ESCC) who receive esophagectomy with clean margins. We compared the survival of the ACCRT versus observation groups for these patients staged with positron emission tomography (PET) via a population-based approach. METHODS: Eligible patients with locally advanced ESCC diagnosed between 2011 and 2017 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders between groups. The hazard ratios (HR) of death and incidence of esophageal cancer mortality (IECM) were compared between the ACCRT and observation groups. We also evaluated overall survival (OS) in subgroups of either with or without lymph node metastases. RESULTS: Our primary analysis consisted of 105 patients in whom the covariates were well balanced after PS weighting. The HR for death when ACCRT was compared with observation was 0.58 (95% confidence interval 0.28-1.21, p = 0.15). The results were also not significantly different for IECM or in the subgroup analyses. CONCLUSION: We found that for patients with PET-staged ESCC who received esophagectomy with clean margins, the survival was not statistically different between ACCRT and observation. Further studies (randomized or larger sample size) are needed to clarify this issue.

Press tack needle stimulation for blunt chest trauma: a randomized double-blind control trial.

OBJECTIVES: Blunt chest trauma is often associated with severe pain, reduced lung function and decreased sleep quality. This study aims to investigate the immediate and long-term effect of acupuncture on these factors using a randomized control double-blind design. METHODS: A total of 72 patients were randomized into 2 groups: treatment group (press tack acupuncture) and control group (press tack placebo). The face rating scale, numerical rating scale (NRS), portable incentive spirometer and Verran Snyder-Halpern sleep scale were measured at baseline, immediately after the intervention, and at the 4th day, with 2-weeks and 3-months follow-ups. RESULTS: There were no significant changes between the groups at the baseline measurements, with the exception of hypertension comorbidity. Immediately after the intervention and on the 4th day follow-up, the patients in the treatment group showed a significantly lower face rating scale when compared to the control (P < 0.05). There were no significant changes in any of the other measurements between the groups (P > 0.05). Subgroup analysis revealed that the NRS for turn over on the 4th day was reduced significantly in the treatment group of patients without lung contusion (P < 0.05). For patients without pleural drainage, cough NRS in the treatment group was significantly reduced in the 2-week follow-up (P < 0.05). CONCLUSIONS: This study showed that press tack acupuncture effects on pain reduction were inconclusive. However, future studies on the effect of acupuncture on blunt chest trauma patients are needed. CLINICAL TRIAL REGISTRATION: clinicaltirl.gov: NCT04318496.

ADAM9 functions as a transcriptional regulator to drive angiogenesis in esophageal squamous cell carcinoma.

Hypoxia and angiogenesis play key roles in the pathogenesis of esophageal squamous cell carcinoma (ESCC), but regulators linking these two pathways to drive tumor progression remain elusive. Here we provide evidence of ADAM9's novel function in ESCC progression. Increasing expression of ADAM9 was correlated with poor clinical outcomes in ESCC patients. Suppression of ADAM9 function diminished ESCC cell migration and in vivo metastasis in ESCC xenograft mouse models. Using cellular fractionation and imaging, we found a fraction of ADAM9 was present in the nucleus and was uniquely associated with gene loci known to be linked to the angiogenesis pathway demonstrated by genome-wide ChIP-seq. Mechanistically, nuclear ADAM9, triggered by hypoxia-induced translocation, functions as a transcriptional repressor by binding to promoters of genes involved in the negative regulation of angiogenesis, and thereby promotes tumor angiogenesis in plasminogen/plasmin pathway. Moreover, ADAM9 suppresses plasminogen activator inhibitor-1 gene transcription by interacting with its transcription factors at the promoter. Our findings uncover a novel regulatory mechanism of ADAM9 as a transcriptional regulator in angiogenesis and highlight ADAM9 as a promising therapeutic target for ESCC treatment.

Acupuncture for blunt chest trauma: A protocol for a double-blind randomized control trial.

INTRODUCTION: Blunt chest trauma (BCT) accounts for up to 65% of polytrauma patients. In patients with 0 to 2 rib fractures, treatment interventions are typically limited to oral analgesics and breathing exercises. Patients suffering from BCT experience symptoms of severe pain, poor sleep, and inability to perform simple daily life activities for an extended period of time thereafter. In this trial, we aim to investigate the efficacy of acupuncture as a functional and reliable treatment option for blunt chest trauma patients. METHODS: The study is designed as a double-blind randomized control trial. We will include 72 patients divided into 2 groups; the acupuncture group (Acu) and placebo group (Con). The acupuncture group will receive true acupuncture using a uniquely designed press tack needle. The control group will receive placebo acupuncture treatment through the use of a similarly designed press tack needle without the needle element. The acupoints selected for both groups are GB 34, GB 36, LI 4, LU 7, ST 36, and TH 5. Both groups will receive 1 treatment only following the initial visit to the medical facility and upon diagnosis of BCT. Patient outcome measurements include: Numerical Rating Scale, Face Rating Scale, respiratory function flowmeter, Verran Snyder-Halpern sleep scale, and the total amount of allopathic medication used. Follow-up time will be scheduled at 4 days, 2 weeks, and lastly 3 months. EXPECTED OUTCOME: The results of this study can potentially provide a simple and cost-effective analgesic solution to blunt chest trauma patients. This novel study design can serve as supporting evidence for future double-blind studies within the field of acupuncture. OTHER INFORMATION: The study will be conducted in the thoracic surgical department and acupuncture department in China Medical University Hospital, Taichung, Taiwan. The study will be conducted on blunt chest trauma patients and is anticipated to have minimum risk of adverse events. Enrollment of the patients and data collection will start from March 2020. Study completion time is expected in March 2022. PROTOCOL REGISTRATION: (CMUH109-REC1-002), (NCT04318496).

Prognostic effect of incongruous lymph node status in early-stage non-small cell lung cancer.

INTRODUCTION: Tumor recurrence is an important issue for patients with stage I non-small cell lung cancer (NSCLC) and adjuvant therapy is considered of no benefit to a tumor less than 4 cm. The purpose of this study was to evaluate the impact of positron emission tomography/computed tomography (PET/CT) on tumor recurrence in patients with a completely resected pN0 NSCLC less than 4 cm. METHODS: Between January 2011 and December 2016, 211 consecutive patients with diagnoses of stage I NSCLC less than 4 cm after complete resection were included. The maximum of standard uptake value (SUVmax) of primary tumor and the presence of positive lymph nodes on PET/CT scans were documented. Disease-free survival was evaluated by the Kaplan-Meier method and recurrence risk factors were identified by univariable and multivariable analyses. RESULTS: Patients with positive lymph nodes on PET/CT had a lower 5-year disease-free survival (37.6% vs 72.7%, p < 0.001). Multivariable analysis demonstrated that the tumor SUVmax >2.93, the presence of positive lymph nodes on PET/CT, and poor differentiation were significant factors for tumor recurrence. Patients with the tumor SUVmax >2.93 and positive lymph nodes on PET/CT simultaneously had 5.33-fold increase in the risk of recurrence (p < 0.001). CONCLUSION: The presence of positive lymph nodes on PET/CT scans can be a good indicator in predicting patients with high risk of developing recurrence in pN0 NSCLC less than 4 cm. This result helps identify patients likely to benefit from adjuvant therapy.

Resveratrol-mediated ADAM9 degradation decreases cancer progression and provides synergistic effects in combination with chemotherapy.

Metastasis is a crucial hallmark of cancer progression and remains the primary cause of patient deaths. Metastasis-associated proteases contribute to cancer progression by disrupting the extracellular matrix interaction to facilitate the spreading of cancer cells to other organs. ADAM9, a type of metalloprotease, has been reported to promote tumor biology and is associated with clinicopathological features such as poor outcome, therapy resistance, and metastasis formation. Targeting ADAM9 might serve as a putative therapeutic application; however, this option is currently unavailable. Resveratrol, a polyphenol from plants, has been shown to be promising for cancer treatment due to its wide variety of biological effects with few side effects. In this study, we demonstrated that resveratrol inhibits cancer cell migration and viability in lung and esophageal cancer cells through the regulation of ADAM9. Mechanistically, resveratrol inhibits ADAM9 protein expression in cancer cells through the ubiquitin-proteasome pathway. Moreover, resveratrol provides synergistic anticancer effects when combined with clinical chemotherapeutics. Our data suggests that resveratrol may inhibit human lung cancer and ESCC progression by inhibiting ADAM9 expression, thus providing a potential mechanism for the anticancer action of resveratrol.

A rare case of synchronous multiple primary lung cancer with different responses to gefitinib.

Differentiating multiple primary lung cancer (MPLC) from lung metastasis is important, and the pathology and gene mutations may be different between the tumors. A lung biopsy to differentiate lesions should be considered, especially when the response of different tumors to treatment is distinct.

Targeting positive feedback between BASP1 and EGFR as a therapeutic strategy for lung cancer progression.

Rationale: Brain metastasis in patients with lung cancer is life-threatening. However, the molecular mechanism for this catastrophic disease remains elusive, and few druggable targets are available. Therefore, this study aimed to identify and characterize proteins that could be used as therapeutic targets. Methods: Proteomic analyses were conducted to identify differentially expressed membrane proteins between brain metastatic lung cancer cells and primary lung cancer cells. A neuronal growth-associated protein, brain acid soluble protein 1 (BASP1), was chosen for further investigation. The clinical relevance of BASP1 in lung adenocarcinoma was first assessed. Tyrosine kinase activity assays and in vitro and in vivo functional assays were conducted to explore the oncogenic mechanisms of BASP1. Results: The protein levels of BASP1 were positively associated with tumor progression and poor prognosis in patients with lung adenocarcinoma. Membrane-bound BASP1 increased EGFR signaling and stabilized EGFR proteins by facilitating their escape from the ubiquitin-proteasome pathway. Reciprocally, activation of EGFR recruited more BASP1 to the plasma membrane, generating a positive feedback loop between BASP1 and EGFR. Moreover, the synergistic therapeutic effects of EGFR tyrosine kinase inhibitor and arsenic trioxide led to a reduction in the level of BASP1 protein observed in lung cancer cells with acquired resistance to EGFR inhibitors. Conclusions: The reciprocal interaction between BASP1 and EGFR facilitates EGFR signaling in brain metastatic lung cancer. Targeting the newly identified BASP1-EGFR interaction could open new venues for lung cancer treatment.

The Impact of Pretreatment PET/CT Nodal Status on Esophageal Squamous Cell Carcinoma After Neoadjuvant Chemoradiation.

BACKGROUND: For advanced esophageal cancer, the clinical significance of pretreatment nodal status (cN) as determined by different examinations remains unclear. PATIENTS AND METHODS: Patients with esophageal squamous cell carcinoma who underwent neoadjuvant chemoradiation and surgery were analyzed in this study. Pretreatment cN status assessed by CT, EUS, and PET/CT and clinicopathological features were used to evaluate tumor recurrence and long-term survival. RESULTS: Two hundred and twenty-two patients were identified in this study. Pretreatment PET/CT cN0 [odds ratio (OR) cN0 versus cN+, 5.316, p < 0.001] and pretreatment CT cN0 (OR 1.957, p = 0.032) both independently predicted ypN0. Pretreatment PET/CT cN0 was also associated with a lower recurrence rate and longer survival across the entire study group. Among patients with ypN0, pretreatment PET/CT cN+ indicated poor disease-free survival [hazard ratio (HR) 2.777, p = 0.001] and overall survival (HR 2.211, p = 0.034) compared with pretreatment PET/CT cN0, which predicted a favorable prognosis. CONCLUSIONS: Data from the current study suggest that pretreatment lymph node status as assessed by PET/CT is strongly correlated with survival outcomes after neoadjuvant chemoradiation and surgery in patients with esophageal squamous cell carcinoma. ypN0 patients can achieve better survival outcomes when pretreatment cN0 is assessed by PET/CT.

Airway inflammation and remodeling of cigarette smoking exposure ovalbumin-induced asthma is alleviated by CpG oligodeoxynucleotides via affecting dendritic cell-mediated Th17 polarization.

Cigarette smoking (CS) is common in asthma, aggravating inflammatory reactions. However, the current treatment strategies for asthma are still not effective enough, and novel therapeutic approaches are required for CS-induced asthmatic disorders. We here investigated the ability of CpG oligodeoxynucleotides (CpG-ODNs) to inhibit airway inflammation and remodeling in ovalbumin (OVA)-associated asthma in mice exposed to chronic CS, revealing potential mechanistic insights. Lung tissue specimens were histologically analyzed. Th1/Th2/Th17 associated cytokines in serum, bronchoalveolar lavage fluid (BALF), and lung specimens were quantitated by ELISA, qRT-PCR and immunoblot. Parameters of bone marrow-derived dendritic cells (BMDCs) functions were evaluated as well. The results showed that BALB/c mice after CS and OVA treatments developed an asthmatic phenotype with airway inflammation involving both eosinophils and neutrophils, goblet cell metaplasia, airway remodeling, and elevated OVA-specific serum IgE, serum IL-17A, and BALF Th17/Th2 associated cytokines. CpG-ODNs and budesonide were found to synergistically inhibit inflammatory cell recruitment in the lung, airway remodeling, IgE synthesis, and Th17/Th2 associated cytokines. Mechanistically, CpG-ODNs and budesonide acted synergistically on BMDCs via downregulation of TSLP receptor (TSLPR) and IL-23 production, and subsequently contributed to dampen Th17/Th2 polarization in CS-associated asthma. In conclusion, combined administration of CpG-ODNs and budesonide, in a synergistic manner, inhibits airway inflammation, and tissue remodeling mediated by BMDCs by regulating IL-23 secretion and blocking TSLP signaling, which subsequently contribute to alleviate Th17/Th2 imbalance in CS-associated asthma.

Effectiveness of image-guided radiotherapy for locally advanced esophageal squamous cell carcinoma patients treated with definitive concurrent chemoradiotherapy.

BACKGROUND: Image-guided radiotherapy (IGRT) is an advanced radiotherapy technique to improve the accuracy of treatment delivery. However, a recent randomized controlled trial (RCT) for prostate cancer patients treated with radiotherapy either via IGRT or routine care (no daily IGRT) reported a statistically significant worse overall survival for those treated with IGRT. This raised the concern regarding the effectiveness of IGRT for definitive concurrent chemoradiotherapy (dCCRT) for locally advanced esophageal squamous cell carcinoma (LA-ESqCC). METHODS: Eligible LA-ESqCC patients diagnosed between 2011 and 2015 were identified via the Taiwan Cancer Registry. We estimated propensity scores to construct a 1:1 propensity-score-matched groups and balance observable potential confounders. The hazard ratio (HR) of death as well as other outcomes was compared between IGRT and non-IGRT matched groups during the entire follow-up period. The impact of additional covariables was considered in the sensitivity analysis. RESULTS: Our study population included 590 patients in the primary analysis. The HR for death when IGRT was compared with non-IGRT was 0.92 (95% confidence interval 0.77-1.10, P = 0.35). There were also no significant differences for other outcomes or sensitivity analyses. CONCLUSIONS: In this updated nonrandomized study using real world data, we found that the overall survival of LA-ESqCC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT, although the hazard ratio was less than unity, ie, in favor of IGRT. The results should be interpreted with caution given the nonrandomized design and RCTs are needed to clarify our findings. KEY POINTS: Significant findings of the study: The OS of LA-ESqCC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT, although the hazard ratio was less than unity, ie, in favor of IGRT. WHAT THIS STUDY ADDS: In this updated nonrandomized study using real world data with additional potential confounders, our study provided a reasonable tentative evidence of lack of RCT as suggested in the literature.

CpG-ODNs and Budesonide Act Synergistically to Improve Allergic Responses in Combined Allergic Rhinitis and Asthma Syndrome Induced by Chronic Exposure to Ovalbumin by Modulating the TSLP-DC-OX40L Axis.

The experimental model of combined allergic rhinitis and asthma syndrome (CARAS) has shown that CpG oligodeoxynucleotides (CpG-ODNs) are potential inhibitors of type 2 helper cell-driven inflammatory responses. Currently available CpG-ODNs modestly inhibit allergic responses in CARAS, while a combination strategy for upper airway treatment by co-administration of CpG-ODNs and glucocorticoids may show good efficacy. This study aimed to assess the therapeutic effects of CpG-ODNs combined with budesonide (BUD) on upper and lower-airway inflammation and remodeling in mice with CARAS induced by chronic exposure to ovalbumin (OVA), exploring the possible underlying molecular mechanisms. A BALB/c mouse model of chronic CARAS was established by systemic sensitization and repeated challenge with OVA. Treatment with CpG-ODNs or BUD by intranasal administration was started 1 h after OVA challenge. Then, nasal mucosa and lung tissues were fixed and stained for pathologic analysis. The resulting immunologic variables and TSLP-DC-OX40L axis parameters were evaluated. Both CpG-ODNs and BUD intranasal administration are effective on reducing Th2-type airway inflammation and tissue remodeling. Co-administration of CpG-ODNs and BUD was more effective than each monotherapy in attenuating upper and lower-airway inflammation as well as airway remodeling in chronic CARAS. Notably, combination of CpG-ODNs with BUD modulated the TSLP-DC-OX40L axis, as demonstrated by decreased TSLP production in the nose and lung, alongside decreased TSLPR and OX40L in DC. Intranasal co-administration of CpG-ODNs and BUD synergistically alleviates airway inflammation and tissue remodeling in experimental chronic CARAS, through shared cellular pathways, as a potent antagonist of the TSLP-DC-OX40L axis.

ADAM9 promotes lung cancer progression through vascular remodeling by VEGFA, ANGPT2, and PLAT.

Lung cancer has a very high prevalence of brain metastasis, which results in a poor clinical outcome. Up-regulation of a disintegrin and metalloproteinase 9 (ADAM9) in lung cancer cells is correlated with metastasis to the brain. However, the molecular mechanism underlying this correlation remains to be elucidated. Since angiogenesis is an essential step for brain metastasis, microarray experiments were used to explore ADAM9-regulated genes that function in vascular remodeling. The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo. Furthermore, simultaneous high expression of ADAM9 and VEGFA or of ADAM9 and ANGPT2 was correlated with poor prognosis in a clinical dataset. These findings suggest that ADAM9 promotes tumorigenesis through vascular remodeling, particularly by increasing the function of VEGFA, ANGPT2, and PLAT.

ADAM9 enhances CDCP1 by inhibiting miR-1 through EGFR signaling activation in lung cancer metastasis.

MicroRNAs (miRNAs), which are endogenous short noncoding RNAs, can regulate genes involved in important biological and pathological functions. Therefore, dysregulation of miRNAs plays a critical role in cancer progression. However, whether the aberrant expression of miRNAs is regulated by oncogenes remains unclear. We previously demonstrated that a disintegrin and metalloprotease domain 9 (ADAM9) promotes lung metastasis by enhancing the expression of a pro-migratory protein, CUB domain containing protein 1 (CDCP1). In this study, we found that this process occurred via miR-1 down-regulation. miR-1 expression was down-regulated in lung tumors, but increased in ADAM9-knockdown lung cancer cells, and was negatively correlated with CDCP1 expression as well as the migration ability of lung cancer cells. Luciferase-based reporter assays showed that miR-1 directly bound to the 3'-untranslated region of CDCP1 and inhibited its translation. Treatment with a miR-1 inhibitor restored CDCP1 protein levels and enhanced tumor cell mobility. Overexpression of miR-1 decreased tumor metastases and increased the survival rate in mice. ADAM9 knockdown reduced EGFR signaling and increased miR-1 expression. These results revealed that ADAM9 down-regulates miR-1 via activating EGFR signaling pathways, which in turn enhances CDCP1 expression to promote lung cancer progression.

Evaluation of the necessity for chest drain placement following thoracoscopic wedge resection.

PURPOSE: To evaluate the outcomes of patients who underwent thoracoscopic wedge resection without chest drain placement. METHODS: The subjects of this retrospective study were 89 patients, who underwent thoracoscopic wedge resection at our hospital between January, 2013 and July, 2015. A total of 45 patients whose underlying condition did not meet the following criteria were assigned to the "chest drain placement group" (group A): peripheral lesions, healthy lung parenchyma, no intraoperative air leaks, hemorrhage or effusion accumulation, and no pleural adhesion. The other 44 patients whose underlying condition met the criteria were assigned to the "no chest drain placement group" (group B). Patient characteristics, specimen data, and postoperative conditions were analyzed and compared between the groups. RESULTS: Group A patients had poorer forced expiratory volume in one second (FEV1) values, less normal spirometric results, significantly higher resected lung volume, a greater maximum tumor-pleura distance, and a larger maximum tumor size. They also had a longer postoperative hospital stay. There was no difference between the two groups in postoperative complications. CONCLUSIONS: Avoiding chest drain placement after a thoracoscopic wedge resection appears to be safe and beneficial for patients who have small peripheral lesions and healthy lung parenchyma.

A Mimicking Esophageal Cancer After Liver Transplant for Hepatocellular Carcinoma: A Rare Posttransplant Metastasis.

Liver transplant is now considered to be a successful treatment modality for early hepatocellular carcinoma. In addition, advances in immunosuppressive therapy have greatly prolonged posttransplant survival of patients with hepatocellular carcinoma. However, both the posttransplant physiologic condition and immunosuppressive therapy affect the patient's natural immunity, resulting in accumulating and more problematic complications. Three years after a male patient with hepatocellular carcinoma underwent living-donor liver transplant, he presented with esophageal metastasis from recurrence of hepatocellular carcinoma. This is an extremely rare complication, perhaps with an ominous prognosis, and, to the best of our knowledge, the first such case to be published in the English literature.

ADAM9 enhances CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis.

Metastasis is the leading cause of death in cancer patients due to the difficulty of controlling this complex process. MicroRNAs (miRNA), endogenous noncoding short RNAs with important biological and pathological functions, may play a regulatory role during cancer metastasis, but this role has yet to be fully defined. We previously demonstrated that ADAM9 enhanced the expression of the pro-migratory protein CDCP1 to promote lung metastasis; however, the regulatory process remains unknown. Here we demonstrate that endogenous miR-218, which is abundant in normal lung tissue but suppressed in lung tumors, is regulated during the process of ADAM9-mediated CDCP1 expression. Suppression of miR-218 was associated with high migration ability in lung cancer cells. Direct interaction between miR-218 and the 3'-UTR of CDCP1 mRNAs was detected in luciferase-based transcription reporter assays. CDCP1 protein levels decreased as expression levels of miR-218 increased, and increased in cells treated with miR-218 antagomirs. Induction of miR-218 inhibited tumor cell mobility, anchorage-free survival, and tumor-initiating cell formation in vitro and delayed tumor metastases in mice. Our findings revealed an integrative tumor suppressor function of miR-218 in lung carcinogenesis and metastasis.