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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a high incidence worldwide and a high associated mortality. Well-recognized risk factors that cause a predisposition to the development of HCC include chronic infection with the hepatitis B or C virus, alcohol-related and non-alcohol-related fatty liver disease, and cirrhosis. In these chronically diseased livers, benign regenerative nodules can increase in size and develop cellular atypia that progress into dysplastic nodules and ultimately HCC. This sequence of hepatocarcinogenesis is coupled with changes in nodule vascularity, including progressive decreased density of portal triads and induced neoangiogenesis, resulting in increased hepatic arterial recruitment. Changes in vascularity result in an array of patterns of nodule enhancement and washout, which can be sensitively depicted with dynamic real-time contrast-enhanced US. Regenerative nodules are isoenhancing relative to the liver with all phases, while HCC classically shows avid arterial phase hyperenhancement with late mild washout. In between, there is great variation as nodules evolve through progressive grades of dysplasia toward HCC. Observed patterns of enhancement and washout can be used to diagnose or stratify the risk of malignancy in liver nodules by using the diagnostic algorithm described by the American College of Radiology Liver Imaging Reporting and Data System (LI-RADS). This facilitates the detection and close monitoring of potential early-stage disease. LI-RADS categorizes nodules according to a probabilistic likelihood for HCC with criteria for LR-5 nodules that are highly specific for the diagnosis of HCC, allowing treatment without exposing the patient to invasive biopsy.

Aims Our objective was to compare the efficacy of pre-treatment with different classes of anti-arrhythmic drugs (AADs) in patients with atrial fibrillation (AF) undergoing electrical cardioversion. Methods and results We performed a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing different AADs in patients with AF undergoing electrical cardioversion. We grouped AADs into five network nodes: no treatment or rate control, Class Ia, Class Ic, Class III, and amiodarone. Outcomes were (i) acute restoration and (ii) maintenance of sinus rhythm. We searched MEDLINE and EMBASE from inception until June 2020. We used Python 3.8.3 and R 3.6.2 for data analysis. We evaluated the overall certainty of evidence with the GRADE framework. We included 28 RCTs. Compared with no treatment or rate control, Class III AADs [odds ratio (OR): 2.41; 95% credible interval (CrI): 1.37 to 4.62, high certainty] and amiodarone (OR: 2.58; 95% CrI: 1.54 to 4.37, high certainty) improved restoration of sinus rhythm. Amiodarone improved long-term maintenance of sinus rhythm when compared with no treatment or rate control (OR: 5.37; 95% CrI: 4.00–7.39, high certainty), Class Ic (OR: 1.89; 95% CrI: 1.05–3.45, moderate certainty) and Class III AADs (OR: 2.19; 95% CrI: 1.39–3.26, high certainty). Conclusion Before electrical cardioversion of AF, treatment with Class III AADs or amiodarone improves the acute restoration of sinus rhythm. Amiodarone is most likely to improve the maintenance of sinus rhythm after electrical cardioversion, but Class Ic and Class III AADs are also effective.

Supplementary Figure 1. Detection of MSH6 somatic mutations by cDNA and genomic DNA sequencing. A-D, cDNA sequencing (A) revealed a heterozygous T1219I mutation that was also confirmed by sequencing the genomic DNA of cell line 119 (B) and the fresh frozen tumor from patient 119 (C). The T1219I mutation was not present in genomic DNA from a blood sample of patient 119 (D) demonstrating it to be of somatic rather than germline origin.

Oral administration of AZD is compatible with TMZ chemotherapy in vivo.

AZD and TMZ administration do not significantly influence body weights of treated animals.

Purpose: The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor–initiating cell lines (BTIC).Experimental Design:MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O6-benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts.Results: We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-naïve gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status.Conclusions: These data demonstrate that endogenous MSH6 mutations may be present before alkylator therapy and occur in at least two histologic subtypes of adult glial neoplasms, with this report serving as the first to note these mutations in oligodendroglioma. These findings broaden our understanding of the clinical response to temozolomide in gliomas. Clin Cancer Res; 20(18); 4894–903. ©2014 AACR.

Molecular and genetic analysis of BTICs identifies subgroups with endogenous mutations in EGFR and PTEN.

Rapamycin partially inhibits growth of most BTICs irrespective of EGFR or PTEN mutational status.

Pharmacological inhibition of EGFR and PI3K/mTORC1/2 signaling in BTICs.

Purpose: The EGFR and PI3K/mTORC1/2 pathways are frequently altered in glioblastoma (GBM), but pharmacologic targeting of EGFR and PI3K signaling has failed to demonstrate efficacy in clinical trials. Lack of relevant models has rendered it difficult to assess whether targeting these pathways might be effective in molecularly defined subgroups of GBMs. Here, human brain tumor–initiating cell (BTIC) lines with different combinations of endogenous EGFR wild-type, EGFRvIII, and PTEN mutations were used to investigate response to the EGFR inhibitor gefitinib, mTORC1 inhibitor rapamycin, and dual mTORC1/2 inhibitor AZD8055 alone and in combination with temozolomide (TMZ)Experimental Design:In vitro growth inhibition and cell death induced by gefitinib, rapamycin, AZD8055, and TMZ or combinations in human BTICs were assessed by alamarBlue, neurosphere, and Western blotting assays. The in vivo efficacy of AZD8055 was assessed in subcutaneous and intracranial BTIC xenografts. Kaplan–Meier survival studies were performed with AZD8055 and in combination with TMZ.Results: We confirm that gefitinib and rapamycin have modest effects in most BTIC lines, but AZD8055 was highly effective at inhibiting Akt/mTORC2 activity and dramatically reduced the viability of BTICs regardless of their EGFR and PTEN mutational status. Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts and mTORC1/2 signaling in orthotopic BTIC xenografts. AZD8055 was synergistic with the alkylating agent TMZ and significantly prolonged animal survival.Conclusion: These data suggest that dual inhibition of mTORC1/2 may be of benefit in GBM, including the subset of TMZ-resistant GBMs. Clin Cancer Res; 20(22); 5756–67. ©2014 AACR.

Gefitinib inhibits growth of EGFRvIII and PTENwt BTICs.

Supplementary Figure Legends from Dual mTORC1/2 Blockade Inhibits Glioblastoma Brain Tumor Initiating Cells In Vitro and In Vivo and Synergizes with Temozolomide to Increase Orthotopic Xenograft Survival

Implantable loop recorders (ILRs) provide practitioners with high-quality electrocardiographic data over an extended monitoring period. These data can guide the diagnosis and management of patients with atrial fibrillation (AF).This review summarizes the available evidence and consensus statements supporting the use of ILRs in the detection of AF, as well as monitoring of patients with known AF. Future directions for research are also discussed.ILRs are the gold standard for detecting AF, providing superior diagnostic yield compared to other modes of ambulatory electrocardiography monitoring. Both experimental evidence and consensus statements support the use of ILRs in clinical settings where the diagnosis of AF may significantly change management, or where a high degree of sensitivity is needed. ILRs may also be used to monitor patients following AF ablation. More evidence is needed to better inform how ILR-detected AF should change management.

Background: Atrial fibrillation (AF) is frequently reported as a complication of noncardiac surgery. It is unknown whether new-onset perioperative AF is associated with an increased risk of stroke and death beyond the perioperative period. We performed a systematic review and meta-analysis to assess the long-term risks of stroke and mortality associated with new-onset perioperative AF after noncardiac surgery. Methods: MEDLINE and EMBASE were searched from inception to March 2020 for studies reporting on the association between perioperative AF and the risk of stroke and death occurring beyond 30 days after noncardiac surgery. Reference screening, study selection, data extraction, and quality assessment were performed in duplicate. Data were pooled using inverse variance-weighted random-effects models and presented as risk ratios (RRs). Results: From 7344 citations, we included 31 studies (3,529,493 patients). The weighted mean incidence of perioperative AF was 0.7%. During a mean follow-up of 28.1 ± 9.4 months, perioperative AF was associated with an increased risk of stroke (1.5 vs 0.9 strokes per 100 patient-years; RR: 2.9, 95% confidence interval [CI]: 2.1-3.9, I2 = 78%). Perioperative AF was also associated with a significantly higher risk of all-cause mortality (21.0 vs 7.6 deaths per 100 patient-years; RR: 1.8, 95% CI: 1.5-2.2, I2 = 94%). The pooled adjusted hazard ratios for stroke and all-cause mortality were 1.9 (95% CI: 1.6-2.2, I2 = 31%) and 1.5 (95% CI: 1.3-1.7, I2 = 20%), respectively. Conclusions: Patients who had perioperative AF after noncardiac surgery had a higher long-term risk of stroke and mortality compared with patients who did not. Whether this risk is modifiable with oral anticoagulation therapy should be investigated. Résumé: Contexte: La fibrillation atriale (FA) est une arythmie fréquemment attribuée à une complication d’une chirurgie non cardiaque. On ne sait toutefois pas si l’apparition d’une FA périopératoire est associée à un risque accru d’accident vasculaire cérébral et de décès au-delà de la période périopératoire. Nous avons donc procédé à un examen et à une méta-analyse systématiques dans le but d’évaluer les risques à long terme d’accident vasculaire cérébral et de décès associés à l’apparition d’une FA périopératoire à la suite d’une chirurgie non cardiaque. Méthodologie: Des recherches ont été effectuées dans MEDLINE et EMBASE depuis leur création jusqu’à mars 2020 pour y relever les études signalant l’association entre la FA périopératoire et le risque d’accident vasculaire cérébral et de décès survenant au-delà de 30 jours à la suite d’une chirurgie non cardiaque. Le tri des références, la sélection des études, l’extraction des données et l’évaluation de la qualité ont été effectués en double. Les données ont été regroupées à l’aide de modèles à effets aléatoires pondérés par l’inverse de la variance et présentées sous forme de rapports de risques relatifs (RR). Résultats: Parmi 7 344 références, nous avons inclus 31 études (3 529 493 patients). L’incidence moyenne pondérée de FA périopératoire était de 0,7 %. Dans le cadre d’un suivi moyen de 28,1 ± 9,4 mois, la FA périopératoire était associée à un risque accru d’accident vasculaire cérébral (1,5 vs 0,9 accident vasculaire cérébral par 100 années-patients; RR de 2,9; intervalle de confiance [IC] à 95 %; de 2,1 à 3,9; I2 = 78 %). La FA périopératoire était également associée à un risque considérablement plus élevé de décès toutes causes confondues (21,0 vs 7,6 décès par 100 années-patients; RR de 1,8; IC à 95 %; de 1,5 à 2,2; I2 = 94 %). Les rapports de risques instantanés ajustés regroupés d’accident vasculaire cérébral et de décès toutes causes confondues étaient de 1,9 (IC à 95 %; de 1,6 à 2,2; I2 = 31 %) et de 1,5 (IC à 95 %; de 1,3 à 1,7; I2 = 20 %), respectivement. Conclusions: Les patients qui souffraient de FA périopératoire à la suite d’une chirurgie non cardiaque présentaient un risque accru à long terme d’accident vasculaire cérébral et de décès par rapport aux patients qui n’en souffraient pas. Il serait approprié d’examiner la possibilité de modifier ce risque par une anticoagulothérapie orale.

Pulmonary atresia with intact ventricular septum (PA/IVS) is a rare lesion with wide anatomic variability. A rare variant exists, marked by right-sided dilatation, an Ebsteinoid tricuspid valve, and severe tricuspid regurgitation. Neonatal cone valvuloplasty allows for a biventricular circulation and avoids complications of prosthetic valves; however, this technique inevitably requires reintervention to exchange the right ventricle-to-pulmonary artery conduit as the patient grows. We present a successful complete repair cone tricuspid valvuloplasty in a 9-day-old (2.8 kg) neonate with trisomy 21, pulmonary atresia with intact ventricular septum, and an Ebsteinoid tricuspid valve.

A total synthesis of the diarylheptanoid (±)-centrolobine is described. The 2,6-cis-tetrahydropyran core of the natural product was constructed using a gold-catalyzed intramolecular cyclization of a secondary alcohol onto an allyl aryl ether. A B-alkyl Suzuki cross-coupling of the vinyl tetrahydropyran fragment with an aryl iodide completed the assembly of the centrolobine skeleton.

Vendor-managed inventory (VMI) has become a widely used tool for supply chain performance improvement. However, not all VMI implementations are successful. Therefore, the aims of this research are to contribute to a better understanding of the critical issues surrounding VMI implementation, and to support corporate practice with a methodology for evaluating the VMI readiness of firms. Fifteen features that determine the suitability of VMI are identified. These can be broadly categorised as product-, company-, and supplier-related features. The framework developed in this research is validated through its application in 10 case study firms. The framework can be used by other firms to support the decision of whether or not to adopt VMI by providing valuable insight into how firms score on suitability for VMI adoptions along several dimensions.

Somatic mutations in the catalytic domain of isocitrate dehydrogenase (IDH) 1/2 and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG) appear to be among the earliest events in gliomagenesis and may contribute to malignant transformation. The lack of cell lines with endogenous mutations has been one of the major challenges in studying IDH1/2-mutant glioma and developing novel therapeutics for these tumors. Here, we describe the isolation of a glioma brain tumor stem cell line (BT142) with an endogenous R132H mutation in IDH1, aggressive tumor-initiating capacity, and 2-HG production. The neurosphere culture method was used to establish a brain tumor stem cell line from an IDH1-mutant anaplastic oligoastrocytoma sample, and an orthotopic xenograft system was developed to allow its rapid expansion. Production of 2-HG by glioma cells with endogenous IDH1 mutations was confirmed by mass spectrometry. BT142 retained an endogenous R132H IDH1 mutation in culture and possessed aggressive tumor-initiating capacity, allowing it to be readily propagated in orthotopic xenografts of nonobese diabetic/severe combined immune deficiency (NOD SCID) mice. Endogenous 2-HG production by BT142 was detectable in both cell culture medium and xenograft animal serum. BT142 is the first brain tumor cell line with an endogenous IDH1 mutation and detectable 2-HG production both in vitro and in vivo, which thus provides a unique model for studying the biology of IDH1-mutant glioma and in vivo validation of compounds targeting IDH1-mutant cells.

While up to 45% of women quit smoking during pregnancy, nearly 80% return to smoking within a year after delivery. Interventions to prevent relapse have had limited success. The study objective was to understand what influences return to smoking after pregnancy among women who quit smoking during pregnancy, with a focus on the role of social networks. We conducted in-depth, semi-structured interviews during the postpartum hospital stay with women who quit smoking while pregnant. Over 300 pages of transcripts were analyzed using qualitative methods to identify common themes. Respondents [n = 24] were predominately white (63%), had at least some college education (54%) and a mean age of 26 years (range = 18-36). When reflecting on the experience of being a smoker who quit smoking during pregnancy, all participants emphasized the importance of their relationships with other smokers and the changes in these relationships that ensued once they quit smoking. Three common themes were: (1) being enmeshed in social networks with prominent smoking norms (2) being tempted to smoke by members of their social networks, and (3) changing relationships with the smokers in their social networks as a result of their non-smoking status. We found that women who quit smoking during pregnancy found themselves confronted by a change in their social network since most of those in their social network were smokers. For this reason, smoking cessation interventions may be most successful if they help women consider restructuring or reframing their social network.

International audience; Keywords: human T-cell leukemia virus type-1, adult T-cell leukemia, HBZ, histone acetyl transferase activity, p53 ABSTRACT Adult T-cell leukemia (ATL) is an often fatal malignancy caused by infection with the complex retrovirus, human T-cell Leukemia Virus, type 1 (HTLV-1). In ATL patient samples, the tumor suppressor, p53, is infrequently mutated; however, it has been shown to be inactivated by the viral protein, Tax. Here, we show that another HTLV-1 protein, HBZ, represses p53 activity. In HCT116 p53 +/+ cells treated with the DNA-damaging agent, etoposide, HBZ reduced p53-mediated activation of p21/CDKN1A and GADD45A expression, which was associated with a delay in G2 phase-arrest. These effects were attributed to direct inhibition of the histone acetyltransferase (HAT) activity of p300/CBP by HBZ, causing a reduction in p53 acetylation, which has be linked to decreased p53 activity. In addition, HBZ bound to, and inhibited the HAT activity of HBO1. Although HBO1 did not acetylate p53, it acted as a coactivator for p53 at the p21/CDKN1A promoter. Therefore, through interactions with two separate HAT proteins, HBZ impairs the ability of p53 to activate transcription. This mechanism may explain how p53 activity is restricted in ATL cells that do not express Tax due to modifications of the HTLV-1 provirus, which accounts for a majority of patient samples. INTRODUCTION The tumor suppressor, p53, is a central regulator of genome stability in mammalian cells. Following DNA damage, p53 becomes acetylated and phosphorylated at multiple sites, thereby shifting the protein from an unstable, latent form to one that is stable, active and concentrated in the nucleus [1]. This transition allows p53 to bind to promoters of genes involved in cell cycle arrest, such as p21/CDKN1A and GADD45A, and activate their transcription [2–4]. p53 is also able to regulate expression of genes involved in the DNA damage response, apoptosis and in its own regulation [5, 6]. Although certain posttranslational modifications may serve redundant functions, there appears to be separate patterns of acetylation and phosphorylation of p53 that favor either cell cycle arrest and DNA repair or, alternatively, apoptosis [6]. Regardless of these complexities, it is clear that acetylation of p53 is essential in promoting either of the two cellular fates [7]. In general, acetylation has been shown to augment the transcriptional activity and stability of p53. For example, acetylation of lysine residues within the C-terminal domain of the protein have been found

Purpose: The EGFR and PI3K/mTORC1/2 pathways are frequently altered in glioblastoma (GBM), but pharmacologic targeting of EGFR and PI3K signaling has failed to demonstrate efficacy in clinical trials. Lack of relevant models has rendered it difficult to assess whether targeting these pathways might be effective in molecularly defined subgroups of GBMs. Here, human brain tumor–initiating cell (BTIC) lines with different combinations of endogenous EGFR wild-type, EGFRvIII, and PTEN mutations were used to investigate response to the EGFR inhibitor gefitinib, mTORC1 inhibitor rapamycin, and dual mTORC1/2 inhibitor AZD8055 alone and in combination with temozolomide (TMZ) Experimental Design: In vitro growth inhibition and cell death induced by gefitinib, rapamycin, AZD8055, and TMZ or combinations in human BTICs were assessed by alamarBlue, neurosphere, and Western blotting assays. The in vivo efficacy of AZD8055 was assessed in subcutaneous and intracranial BTIC xenografts. Kaplan–Meier survival studies were performed with AZD8055 and in combination with TMZ. Results: We confirm that gefitinib and rapamycin have modest effects in most BTIC lines, but AZD8055 was highly effective at inhibiting Akt/mTORC2 activity and dramatically reduced the viability of BTICs regardless of their EGFR and PTEN mutational status. Systemic administration of AZD8055 effectively inhibited tumor growth in subcutaneous BTIC xenografts and mTORC1/2 signaling in orthotopic BTIC xenografts. AZD8055 was synergistic with the alkylating agent TMZ and significantly prolonged animal survival. Conclusion: These data suggest that dual inhibition of mTORC1/2 may be of benefit in GBM, including the subset of TMZ-resistant GBMs. Clin Cancer Res; 20(22); 5756–67. ©2014 AACR.

Purpose: The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor–initiating cell lines (BTIC). Experimental Design: MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O6-benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts. Results: We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-naïve gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status. Conclusions: These data demonstrate that endogenous MSH6 mutations may be present before alkylator therapy and occur in at least two histologic subtypes of adult glial neoplasms, with this report serving as the first to note these mutations in oligodendroglioma. These findings broaden our understanding of the clinical response to temozolomide in gliomas. Clin Cancer Res; 20(18); 4894–903. ©2014 AACR.

BACKGROUND: Glioblastoma (GBM) is a devastating disease and the most lethal of adult brain tumours. Despite standard surgery, radiation and chemotherapy, the median survival is 15 months, thought to be due, in part, to recurrence from a small reservoir of brain tumour initiating cells. Our laboratory discovered adult neural stem cells, now found to be present in the brains of all adult mammals, through the development of the clonal neurosphere assay. This assay has contributed to the identification of adult human brain tumour initiating cells (BTICs), which may represent a reservoir that leads to GBM recurrence and death. Building upon the identification of growth factors and cytokines that converge on the cytoplasmic signal transducer and activator of transcription 3 (STAT3) to maintain the adult neural stem cell undifferentiated state, and the fact that STAT3 is abnormally active in GBM and may be one of the causes of tumour growth and therapeutic resistance, targeting the janus kinase (JAK)/STAT3 signalling pathway has become a major research focus for our laboratory. Here, we report the GBM translational potential of R333, a JAK/SYK inhibitor in development for other indications by Rigel Pharmaceuticals. METHODS: We have developed a cellular resource of more than 100 BTIC lines derived from GBM patients. Collaborative studies with academic and industry partners has resulted in the identification of promising therapeutic candidates that target JAK/STAT3 signalling in GBM. These compounds are tested for their ability to attenuate growth of BTICs in cell culture, on target activity in vitro and in vivo, and for their impact on the the survival of immunocompromised mice that have received BTIC xenografts. We employed this approach to examine the therapeutic potential of R333. RESULTS: In a collection of diverse patient-derived BTIC lines, R333 demonstrated potent, on-target JAK/STAT3 inhibition at low micromolar doses that effectively decreased BTIC viability and clonogenic potential, without affecting human fetal astrocytes. Importantly, R333 could be co-administered with temozolomide without reducing therapeutic response. Using phosphoproteomics, we confirmed the primary target of R333 in BTSCs as activated STAT3. In a BTIC orthotopic xenograft model, systemic treatment with R348, the pro-drug form of R333, resulted in BBB penetration and significant increased overall median survival without major side effects. CONCLUSIONS: These data suggest that R333 (R348) is a potent, BBB-permeable JAK/STAT3 inhibitor, worthy of further clinical evaluation for GBM treatment. These findings support our overall hypothesis that targeting the STAT3 signalling pathway may represent an effective therapeutic approach to managing GBM. SECONDARY CATEGORY: Tumor Biology.

Glioblastoma multiforme (GBM) is a devastating disease that is notoriously resistant to current therapies, leading to dismal patient outcomes and a median survival of just 14.6 months.1 As such, translation of our rapidly expanding knowledge of the molecular biology of GBM together with the growing repertoire of molecular-based chemotherapeutics now available has the potential to dramatically improve patient outcomes. Signal transducer and activator of transcription (STAT)3 signaling has recently come to the forefront of the glioma literature as a common pathway downstream of paracrine leukemia inhibitory factor, interleukin-6, or erythropoietin signaling in GBM.2–4 Recent transcriptional profiling and signaling network analyses have also identified STAT3 and CCAAT (cytidine-cytidine-adenosine-adenosine-thymidine)-enhancer-binding proteins β as 2 key master transcription factors underlying the mesenchymal subtype of GBM.5 Consequently, STAT3 has become a therapeutic target of significant interest in glioma, and a number of small-molecule inhibitors of the STAT3' upstream regulator Janus kinase (JAK)2 are currently in early preclinical investigation in GBM. Inhibition of JAK2 with AG490 or its more potent second-generation analog WP1066 has demonstrated efficacy in reducing survival and proliferation of U87 and U251 glioma cells in vitro and decreasing tumorigenicity of U87 in subcutaneous xenografts.6,7 JAK2/STAT3 blockade has also demonstrated promise as an adjuvant for other therapeutics. Concurrent inhibition of JAK2/STAT3 with cucurbitacin-I (JSI-124) and blockade of epidermal growth factor receptor (EGFR) with Iressa has been recently reported to potently induce apoptosis in GBM cell lines and sensitize them to temozolomide.8 Emerging evidence suggests that high levels of STAT3 activation are also present within brain tumor stem cells (BTSCs), and STAT3 inhibition has been reported to decrease the self-renewal survival and resistance to temozolomide of glioma stemlike cells in vitro.2–4,9,10 Thus, there is strong evidence in the glioma literature for the crucial role of STAT3 in human GBM, and JAK2-targeted therapeutics have yielded promising results against GBM cell lines in vitro. However, the true translational potential of JAK2/STAT3 therapeutics for GBM remained an unanswered question, as these drugs had yet to be thoroughly investigated in a model that accounted for the molecular heterogeneity of human GBM and assessed on-target efficacy in intracranial humanlike GBM tumors in vivo. BTSCs have been postulated to be at the root of the disease initiation, recurrence, and therapeutic resistance that is characteristic of GBM. BTSCs isolated from human GBM tumors capture the molecular heterogeneity and mutation spectrum that are characteristic of the disease.11,12 BTSCs also initiate orthotopic xenograft tumors in nonobese diabetic/severe combined immunodeficient (NOD SCID) mice that emulate the phenotypic and molecular characteristics of their parent human tumors, hence making them the most relevant model currently available for preclinical evaluation of novel GBM therapeutics. Our group has successfully established a large collection of BTSC lines from glioma patients that display the molecular heterogeneity of the disease,13 including rare lines endogenously expressing isocitrate dehydrogenase (IDH1)R132H, differential MGMT promoter methylation status, and mutations in common targets such as PTEN, TP53, and EGFR variant III (unpublished), amongst others.14–16 Here, we use a large panel of patient-derived GBM BTSCs to investigate whether JAK2/STAT3 is (i) a clinically relevant signaling pathway whose activity is crucial in molecularly diverse BTSCs and (ii) amenable to therapeutic targeting in vivo in orthotopic humanlike GBM xenografts. We demonstrate that JAK2/STAT3 signaling is a key driver for proliferation in GBM BTSCs and that on-target inhibition of this pathway results in decreased BTSC survival in vitro and slows disease progression in vivo.

Many women stop smoking during pregnancy. Factors associated with relapse are known, but no intervention prevents the return to smoking among pregnant women. The objective of this study was to determine why women return to smoking after prolonged abstinence during pregnancy by examining mothers' intention to smoke at the time of delivery and the perceptions that shape their intention.We conducted in-depth, semi-structured interviews during their postpartum hospital stay with 24 women who stopped smoking while pregnant. We asked participants whether they intended to resume smoking after pregnancy and why. Transcripts were analyzed using grounded theory-based qualitative methods to identify themes.Participants ranged in age from 18 to 36 years, and 63 percent were white. Three themes emerged from the interviews with the mothers: 1) they did not intend to return to smoking but doubted whether they would be able to maintain abstinence; 2) they believed that it would be possible to protect their newborns from the harms of cigarette smoke; and 3) they felt that they had control over their smoking and did not need help to maintain abstinence after pregnancy.Although most participants did not intend to resume smoking, their intentions may be stymied by their perceptions about second-hand smoke and by their overestimation of their control over smoking. Further study should quantify these barriers and determine their evolution over the first year after pregnancy with the goal of informing more successful, targeted interventions.