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Wound healing in response to acute injury is mediated by the coordinated and transient activation of parenchymal, stromal, and immune cells that resolves to homeostasis. Environmental, genetic, and epigenetic factors associated with inflammation and aging can lead to persistent activation of the microenvironment and fibrosis. Here, we identify opposing roles of interleukin-4 (IL-4) cytokine signaling in interstitial macrophages and type II alveolar epithelial cells (ATIIs). We show that IL4Ra signaling in macrophages promotes regeneration of the alveolar epithelium after bleomycin-induced lung injury. Using organoids and mouse models, we show that IL-4 directly acts on a subset of ATIIs to induce the expression of the transcription factor SOX9 and reprograms them toward a progenitor-like state with both airway and alveolar lineage potential. In the contexts of aging and bleomycin-induced lung injury, this leads to aberrant epithelial cell differentiation and bronchiolization, consistent with cellular and histological changes observed in interstitial lung disease. [Display omitted] • IL4Ra signaling in Cx3cr1+ macrophages promotes regeneration of the lung epithelium • IL-4-induced Sox9 reprograms ATIIs into a fetal-like state with airway potential • Aging primes ATIIs with hyperresponsiveness to IL-4 cytokines • Loss of IL4Ra in ATIIs reduces its airway lineage potential and bleomycin-induced fibrosis Cai et al. have shown that type 2 cytokines directly impact adult epithelial stem cells by inducing Sox9 and lineage plasticity during aging. This link between aging, inflammation, and regenerative outcomes offers a potential strategy for the treatment of maladaptive epithelial remodeling in age-related and chronic inflammatory conditions. [ABSTRACT FROM AUTHOR]

Background Although the role of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) in pulmonary sarcoidosis has previously been investigated, the determining factors in diagnosing sarcoidosis by EBUS-TBNA without rapid on-site evaluation (ROSE) are unclear. Methods Patients with clinically and radiographically suspected sarcoidosis underwent EBUS-TBNA without ROSE in a prospective study. Presence of non-caseating epithelioid cell granulomas was pathologic evidence of sarcoidosis. Results The EBUS-TBNA was performed in 120 patients, 111 of whom had confirmed sarcoidosis. For the patients with sarcoidosis (62 stage I, 49 stage II) EBUS-TBNA provided sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 93.69%, 100%, 100%, 56.25%, and 94.17%, respectively, in the diagnosis of sarcoidosis. Diagnostic yield of EBUS-TBNA for sarcoidosis was associated with disease stage, but not associated with serum angiotensin converting enzyme level, number of lymph node stations sampled per patient, or total number of passes performed per patient. At EBUS-TBNA, 284 mediastinal and hilar lymph nodes were aspirated in 111 patients. Multivariate logistic regression revealed that short-axis diameter and more than 1 needle pass per lymph node were independent risk factors associated with positive pathology. No major procedure-related complications were observed. Conclusions Endobronchial ultrasound-guided transbronchial needle aspiration is a safe procedure with high sensitivity for diagnosing sarcoidosis, having a higher diagnostic yield in stage I than stage II. To obtain a higher diagnostic yield of EBUS-TBNA in pulmonary sarcoidosis without ROSE, operators should select the largest mediastinal or hilar lymph node accessible and puncture with 3 to 5 passes. [ABSTRACT FROM AUTHOR]

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure that has enabled mediastinal and hilar lymph node assessment with a high sensitivity, but its role in the diagnosis of intrathoracic tuberculosis (TB) has not been established. Methods: We prospectively studied 59 patients suspected of having TB with thoracic lymph node lesions or intrapulmonary lesions accessible by EBUS-TBNA at a clinical center for thoracic medicine from January 2010 to December 2011. Bronchoscopic findings, EBUS-TBNA procedures, pathologic findings, and microbiologic results were recorded. Results: Of 59 eligible patients, 41 patients had TB, 5 had lung cancer, 7 had inflammation, and 6 had sarcoidosis. Sensitivity was 85%, specificity was 100%, positive and negative predictive values were 100% and 75%, respectively, and accuracy was 90% by EBUS-TBNA for TB. Pathologic findings were consistent with TB in 80% of patients (33 of 41), and in 27% (11 of 41) the smear was positive. A total of 37 patients with TB had cultures, of whom 17 (46%) were positive. There were 80 mediastinal and hilar lymph nodes and 5 intrapulmonary lesions that were biopsied in the 41 patients with TB. Multivariate logistic regression revealed that short-axis diameter was an independent risk factor associated with positive pathology, smear, and culture (p < 0.05). Additionally, pathology showing necrosis was an independent risk factor associated with a positive culture. Conclusions: Endobronchial ultrasound-guided transbronchial needle aspiration has a high diagnostic yield in the investigation of suspected intrathoracic TB by means of aspiration of intrathoracic lymph nodes and tracheobronchial wall-adjacent lung lesions. [Copyright &y& Elsevier]

Objective: Endoscopic treatment of superficial esophageal carcinoma has been increasingly conducted around the world. Because no lymph nodes are removed in such a procedure, the risk of lymph node metastases (LNMs) should be clearly understood. The aim of the present study was to accurately clarify the pattern of lymphatic spread in patients with superficial esophageal squamous cell carcinoma and analyze the factors potentially related to LNMs. Methods: The pattern of lymphatic spread was studied in 189 patients who had undergone radical lymphadenectomy from 2006 to 2011. The risk factors associated with LNMs were determined by multivariate logistic regression analysis. According to the depth of tumor invasion, mucosal tumors were classified as M1, M2, and M3 and submucosal tumors as SM1, SM2, and SM3. Results: A total of 4252 lymph nodes were resected (average, 23 ± 9; range, 12-68). LNMs occurred in 49 patients (25.9%). The frequency of LNMs was 4.3% in those with mucosal and 33.1% in those with submucosal cancer. LNMs were found in 0%, 0%, 11.8%, 24.0%, 20.5%, and 43.8% of the M1, M2, M3, SM1, SM2, and SM3 cancer, respectively. For submucosal cancer, SM3 cancer (P = .006) and lymphovascular invasion (P = .001) were significant independent risk factors for LNMs. Paratracheal nodes were the most frequently involved. “Skip” metastases occurred in 20 of 49 patients (40.8%). Conclusions: Endoscopic treatment can be attempted when the tumor is limited to the lamina propria mucosa. However, 2-field radical lymphadenectomy with careful upper mediastinal lymph node resection should be conducted for submucosal squamous cell carcinoma. [Copyright &y& Elsevier]

Purpose: Standard treatment for advanced non-small cell lung cancer (NSCLC) consists of platinum based combination chemotherapy but efficacy is limited and treatment can be toxic. This trial evaluated a weekly regimen of docetaxel and gemcitabine for advanced NSCLC. The primary endpoint was objective response rate. Other endpoints were 1-year survival, median survival, median duration of response, median disease-free progression, safety, and quality of life.Patients and methods: Fifty patients with advanced NSCLC were treated. Patients received docetaxel (1 per week, 36 mg/m2) weeks 1–6 and gemcitabine (1 per week, 900 mg/m2) weeks 1, 2, 4, and 5. Each 8-week cycle was repeated for a total of three cycles. Patients completed quality of life surveys (FACT-L) before each cycle.Results: The median age was 68.5 years; 74% were >60 years old. In the intent-to-treat (ITT) analysis of response, 10 patients had a partial response (20%) and five patients had stable disease (10%). The 1-year survival was 32%; median survival for all patients was 6.9 months (range, <1–26.2) and the median progression-free survival was 5.1 months (range, <1–25.5). Toxicities (> grade 3) included neutropenia, thrombocytopenia, GI disorders (nausea, vomiting, dehydration, diarrhea, stomach pain), and asthenia; 10 patients experienced hematological toxicities that were > grade 3. Quality of life decreased during the study.Conclusions: This study demonstrated that the nonplatinum doublet (docetaxel + gemcitabine) given on a weekly schedule for advanced NSCLC had efficacy similar to that reported with other regimens and was well tolerated. Therefore, this non-platinum based regimen appears promising and warrants further evaluation. [Copyright &y& Elsevier]

Enhancers are essential drivers of cell states, yet the relationship between accessibility, regulatory activity, and in vivo lineage commitment during embryogenesis remains poorly understood. Here, we measure chromatin accessibility in isolated neural and mesodermal lineages across a time course of Drosophila embryogenesis. Promoters, including tissue-specific genes, are often constitutively open, even in contexts where the gene is not expressed. In contrast, the majority of distal elements have dynamic, tissue-specific accessibility. Enhancer priming appears rarely within a lineage, perhaps reflecting the speed of Drosophila embryogenesis. However, many tissue-specific enhancers are accessible in other lineages early on and become progressively closed as embryogenesis proceeds. We demonstrate the usefulness of this tissue- and time-resolved resource to definitively identify single-cell clusters, to uncover predictive motifs, and to identify many regulators of tissue development. For one such predicted neural regulator, l(3)neo38 , we generate a loss-of-function mutant and uncover an essential role for neuromuscular junction and brain development. • Tissue- and time-resolved chromatin accessibility during Drosophila embryogenesis • Promoters and enhancers are often accessible early in tissues where not expressed • Enhancer priming, as indicated by accessibility, is relatively rare in Drosophila • l(3)neo38 is an essential regulator of neuromuscular junction and brain development Reddington et al. generate tissue-specific maps of chromatin accessibility across a time course of Drosophila embryogenesis. They dissect the relationship between enhancer/promoter accessibility and activity and demonstrate the power of this resource to annotate single-cell data and identify regulatory elements, predictive sequence features, and many regulators in each lineage's development. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in patients with advanced non-small cell lung cancer (NSCLC), its acquired resistance has become a major clinical problem. Recent studies revealed that miR-21 was involved into the resistance of cytotoxic agents. The aim of this study was to investigate its role in the acquired resistance of NSCLC to EGFR-TKI. Methods: EGFR-TKI-sensitive human lung adenocarcinoma cell line PC9 and the acquired resistant cell line, PC9R, were used. Lentiviral vectors were used to infect PC9 or PC9R to regulate the miR-21 expression. The expression of targeted proteins PTEN and PDCD4 was controlled by RNA interference. MicroRNA array, RT-PCR and TaqMan MicroRNA Assays were used to detect miR-21 expression. The MTT and Annexin V assays were used to determine proliferation and apoptosis. Western Blot and immunohistochemistry were used to analyze target protein expression (PTEN, PDCD4, Akt, p-Akt). We also constructed PC9R xenograft tumor model to observe the relationship between miR-21 and EGFR-TKI resistance in vivo and validated it in the clinical serum specimens of NSCLC patients treated with EGFR-TKI. Result: MiR-21 was overexpressed in the EGFR-TKI resistant cell line PC9R relative to PC9. The level of miR-21 was reversely correlated with the expression of PTEN and PDCD4 and positive correlated with PI3K/Akt pathway. Inhibiting miR-21 with lentivirus vector induces apoptosis in PC9R cell line and inhibiting miR-21with ASO suppressed tumor growth in nude mice treated with EGFR-TKI. Furthermore, serum miR-21 expression in NSCLC patients treated with EGFR-TKI was significantly higher at the time of acquiring resistance than at baseline (p <0.01). Conclusion: miR-21 is involved in acquired resistance of EGFR-TKI in NSCLC, which is mediated by down-regulating PTEN and PDCD4 and activating PI3K/Akt pathway. [Copyright &y& Elsevier]

Extensive-stage small cell lung cancer (ES-SCLC) remains a therapeutic challenge to the medical oncologists. We evaluated the triplet combination of paclitaxel (175 mg/m2 over 1 h), ifosfamide (2.5 gm/m2 over 1 h) and carboplatin (AUC=6 over 0.5 h) (PIC) all given on day 1 of a 21 day schedule. Thirty-five patients were entered with a median age of 59 years (range 40–79). The ECOG PS was 0–1 in 86%. A median of 6 cycles were delivered (range 1–6). The principal toxicity was neutropenia with 66% of patients experiencing grade 4 neutropenia. Only 9% of patients experienced febrile neutropenia. One treatment-related death (3%) due to neutropenic sepsis occurred. Non-hematologic toxicity was minimal. The overall response rate was 71% (15% complete response, 56% partial responses). Quality of life appeared to be stable across time. The median survival time was 9.5 months (95% confidence interval (CI), 6.7–13.2 months) with a 1- and 2-year survival rates of 43% (95% CI, 26–59%) and 16% (95% CI, 2–30%). PIC has activity in ES-SCLC and is associated with a response rate and survival profile similar to other combinations in this disease setting. This regimen has a tolerable toxicity profile and a favorable and convenient administration schedule. [Copyright &y& Elsevier]