Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening.

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140.

BACKGROUND: SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), suggesting a role in inflammation. RESULTS: We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa. CONCLUSIONS: This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses.

Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with substantial T cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the polycomb-repressive complex 2 (PRC2) core components embryonic ectoderm development (EED) or suppressor of zeste 12 homolog (SUZ12), a prevalent genetic event in malignant peripheral nerve sheath tumors (MPNSTs) and sporadically in other cancers, drove a context-dependent immune-desert TME. PRC2 inactivation reprogramed the chromatin landscape that led to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., IFN-γ signaling) to PRC2-regulated developmental and cellular differentiation transcriptional programs. Further, PRC2 inactivation led to diminished tumor immune infiltrates through reduced chemokine production and impaired antigen presentation and T cell priming, resulting in primary resistance to ICB. Intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) enhanced tumor immune infiltrates and sensitized PRC2-loss tumors to ICB. Our results identify molecular mechanisms of PRC2 inactivation-mediated, context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.

PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry.

Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor-mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)-dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy. SIGNIFICANCE: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context-specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007.

Antibiotics in Dentoalveolar Surgery, a Closer Look at Infection, Alveolar Osteitis and Adverse Drug Reaction.

PURPOSE: To execute an evidence-based review answering the following questions: "What antibiotic type and mode of delivery are most effective at reducing inflammatory complications in third molar and dental implant surgery? What are the types and rates of antibiotic-related adverse reactions in the context of third molar surgery, infective endocarditis, medication-related osteonecrosis of the jaw (MRONJ) and osteoradionecrosis (ORN)?" MATERIAL AND METHODS: We performed a comprehensive literature review of peer-reviewed studies using MEDLINE/PubMed, Cochrane, Scopus/Elsevier, Google Scholar, and Wiley online library databases. RESULTS: Twenty-five studies were reviewed for third molar surgery. Although there is some evidence that systemic antibiotics reduce inflammatory complications (infection and alveolar osteitis), routine use is not recommended for third molar surgery. For at-risk cases, a single preoperative dose of amoxicillin is preferred. Clindamycin, amoxicillin-clavulanic acid and erythromycin have a high adverse risk profile. Eight studies were reviewed for dental implant surgery. Antibiotics with dental implant placement showed little reduction in post surgery infection and minimal improvement in long-term success. A comprehensive search found limited data on antibiotic-related adverse effects in the context of infective endocarditis, MRONJ and ORN. CONCLUSIONS: A set of clinical recommendations are presented to better guide evidence-based and standardized antibiotic usage on the basis of the literature discussed in this review. This review highlights the need for further research focusing on antibiotic type and timing of delivery with adverse drug reaction as a primary outcome measure when assessing treatment outcomes and complications in dentoalveolar surgery. This will better elucidate the risks vs benefits of antibiotic in dentoalveolar surgery.

Catheter-directed Thrombolysis for Neonatal IVC and Bilateral Renal Vein Thrombosis: A Case Report.

Renal vein thrombosis is the most common non-catheter-associated venous thromboembolism event in neonates, accounting for up to 20% of cases. Although mortality rates are lower than a variety of other forms of pediatric thrombosis, renal vein thrombi are associated with significant short-term and long-term sequelae. This report presents the case of a full-term neonate presenting with bilateral renal vein thrombosis with inferior vena cava involvement treated with catheter-directed thrombolysis. This case report intends to highlight the value of a multidisciplinary approach to pediatric venous thromboembolism and to outline relevant procedural details and current laboratory and imaging monitoring of catheter-directed thrombolysis.

Yttrium-90 Radioembolization in the Office-Based Lab.

PURPOSE: To evaluate the feasibility and benefits of performing yttrium-90 radioembolization in an office-based lab (OBL) compared to a hospital setting. MATERIALS AND METHODS: A radioembolization program was established in March 2019 in an OBL that is managed by the radiology department of a tertiary care center. Mapping and treatment angiograms performed in the OBL from March 2019 through January 2020 were compared to mapping and treatment angiograms performed in the hospital during the same time period. RESULTS: One hundred seventy-six mapping and treatment angiograms were evaluated. There was no difference in the proportion of mapping versus treatment angiograms performed at each site, the proportion of lobar versus selective dose vial administrations, or the mean number of dose vials administered per treatment procedure. Procedure start delays were longer in the hospital than in the OBL (28.6 minutes vs 0.8 minutes; P < .0001), particularly for procedures that were not scheduled as the first case of the day (hospital later case delay, 38.8 minutes vs OBL later case delay, 0.5 minutes; P < .0001). Procedures performed in the hospital took longer on average than procedures performed in the OBL (2 hours, 1.8 minutes vs 1 hour, 44.4 minutes; P = .0004), particularly for procedures that were not scheduled as the first case of the day (hospital later case duration, 2 hours, 7.4 minutes vs OBL later case duration, 1 hour, 43 minutes; P = .0006). CONCLUSIONS: Establishing a radioembolization program within an OBL is feasible and might provide more efficient procedure scheduling than the hospital setting.

Comparative Analysis of Safety and Efficacy of Transarterial Chemoembolization for the Treatment of Hepatocellular Carcinoma in Patients with and without Pre-Existing Transjugular Intrahepatic Portosystemic Shunts.

PURPOSE: To compare the safety and efficacy of transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients with and without transjugular intrahepatic portosystemic shunts (TIPS). MATERIALS AND METHODS: This single-institution study included a retrospective review of 50 patients who underwent transarterial chemoembolization for HCC between January 2010 and April 2017. Twenty-five patients had preexisting TIPS, and 25 patients were selected to control for age, sex, and target tumor size. Baseline median Model for End-Stage Liver Disease (MELD; 13 TIPS, 9 control; P < .001) and albumin-bilirubin (ALBI; 3 TIPS, 2 control; P < .001) differed between groups. Safety was assessed on the basis of Common Terminology Criteria for Adverse Events (CTCAE) and change in MELD and ALBI grade assessed between 3 and 6 months. Efficacy was assessed by tumor response and time to progression (TTP). RESULTS: There was 1 severe adverse event (CTCAE grade >2) in the TIPS group. There was no difference in the change in MELD or ALBI grade. Although there was no difference in tumor response (P = .19), more patients achieved a complete response in the control group (19/25, 76%) than in the TIPS group (13/25, 52%). There was no difference in TTP (P = .82). At 1 year, 2 patients in the control group and 3 patients in the TIPS group received a liver transplant. Seven patients died in the TIPS group. CONCLUSIONS: Transarterial chemoembolization is as safe and effective in patients with TIPS as in patients without TIPS, despite worse baseline liver function. Severe adverse events are rare and may be transient.

Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors.

PURPOSE: BET bromodomain inhibitors have emerged as a promising therapy for numerous cancer types in preclinical studies, including neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumor (MPNST). However, potential mechanisms underlying resistance to these inhibitors in different cancers are not completely understood. In this study, we explore new strategy to overcome BET inhibitor resistance in MPNST.Experimental Design: Through modeling tumor evolution by studying genetic changes underlying the development of MPNST, a lethal sarcoma with no effective medical treatment, we identified a targetable addiction to BET bromodomain family member BRD4 in MPNST. This served as a controlled model system to delineate mechanisms of sensitivity and resistance to BET bromodomain inhibitors in this disease. RESULTS: Here, we show that a malignant progression-associated increase in BRD4 protein levels corresponds to partial sensitivity to BET inhibition in MPNST. Strikingly, genetic depletion of BRD4 protein levels synergistically sensitized MPNST cells to diverse BET inhibitors in culture and in vivo. CONCLUSIONS: Collectively, MPNST sensitivity to combination genetic and pharmacologic inhibition of BRD4 revealed the presence of a unique addiction to BRD4 in MPNST. Our discovery that a synthetic lethality exists between BET inhibition and reduced BRD4 protein levels nominates MPNST for the investigation of emerging therapeutic interventions such as proteolysis-targeting chimeras (PROTACs) that simultaneously target bromodomain activity and BET protein abundance.

Radiation exposure and coronary artery calcium scans in the society for heart attack prevention and eradication cohort.

Coronary artery calcium (CAC) scoring is used in asymptomatic patients to improve their clinically predicted risk for future cardiovascular events. Current CT protocols seek to reduce radiation exposure without diminishing image quality. Reported radiation exposure remains widely variable (0.8-5 mSv) depending on the type of protocol. In this study, we report the radiation exposure of CAC scoring from the Society for Heart Attack Prevention and Eradication (SHAPE) early detection program cohort sites, which spanned multiple centers using 64-MDCT (multi-detector computed tomography) scanners. We reviewed radiation exposure in milliSieverts (mSv) for 82,214 participants from the SHAPE early detection program cohort who underwent CAC scoring. This occurred over a 2.5-year period (2012-2014) divided among 33 sites in 7 countries with four different types 64-MDCT scanners. The effective radiation dose was reported as mSv. Mean radiation dosing amongst all 82,214 participants was 1.03 mSv, a median dose of 0.94 mSv. The mean radiation dose ranged from 0.76 to 1.31 mSv across the 33 sites involved with the SHAPE program cohort. Subgroup analysis by age, gender or body mass index (BMI) less than 30 kg/m2 showed no variability. Radiation dose in patients with BMI > 30 kg/m2 were significantly greater than other subgroups (µ = 1.96 mSv, p < 0.001). The use of 64-MDCT scanners and protocols provide the effective radiation dose for CAC scoring, which is approximately 1 mSv. This is consistently lower than previously reported for CAC scanning, regardless of scanner type, age or gender. In contrast, a greater BMI influenced mean radiation doses.

Internal mammary artery-to-pulmonary vasculature fistula: Systematic review of case reports.

The formation of a fistula between the internal mammary artery and the pulmonary vasculature (IMA-to-PV) is a rare anomaly. The etiology can be congenital; however, most recent cases have been associated with coronary artery bypass grafting, trauma, inflammatory conditions, chronic infections, or neoplasia. The knowledge base on the formation of these fistulas is derived primarily from case reports. To our knowledge, no systematic reviews or guidelines are available that provide information on how to manage these cases, and the treatment of an IMA-to-PV fistula is controversial. To our knowledge, this report is the first to review 80 cases of IMA-to-PV fistulas reported in the literature. We describe the etiologies, clinical presentation, and management of these fistulas.

Extrahepatic metastasis risk of hepatocellular carcinoma based on α-fetoprotein and tumor staging parameters at cross-sectional imaging.

BACKGROUND: Extrahepatic metastases have important implications in the clinical management of hepatocellular carcinoma (HCC). The purpose of this study was to validate tumor staging parameters and serum AFP as risk factors of HCC metastasis. PATIENTS AND METHODS: In this retrospective case-control study, patients with a new diagnosis of HCC (N=236), median age 57 years (range 28-89 years), and male-to-female ratio of 183/53 were divided into a "no-met" group (N=101) without extrahepatic metastasis or a "met" group with extrahepatic metastases (N=135). Metastasis risk factors based on tumor staging parameters (size, number, infiltration, and vascular invasion) and serum AFP level were calculated as odds ratio (OR). Sensitivities of the risk factors as metastasis screening tests were also calculated. RESULTS: AFP >400 µg/mL, index tumor size >5 cm, and vascular invasion individually had strong association with metastasis, with OR (95% confidence interval) of 11.5 (5.9-22.1), 17.7 (9.0-34.8), and 18.9 (8.2-43.9), respectively, but with moderate sensitivities as metastasis screening tests, with 71.9% (65.7-77.3), 75.6% (69.6-80.7), and 58.5% (52.1-64.7), respectively. Composite multiparametric criteria, eg, a logical union of 1) tumor size outside of Milan criteria, 2) AFP threshold >35 µg/mL, and 3) vascular invasion, had excellent OR up to 55.6 (13.0-237.1) with screening sensitivity 98.5% (95.8-99.6). CONCLUSION: Serum AFP, tumor size, and vascular invasion are strongly associated with extrahepatic metastasis of HCC, especially when combined into a multiparametric metastasis prediction criterion.

The role of nerve microenvironment for neurofibroma development.

Deregulation of RAS signaling in Neurofibromatosis type 1 (NF1) results in the development of multiple neurofibromas, complex tumor of the peripheral nerves with no effective medical treatment. There is increasing evidences that neurofibroma initiates through loss of NF1 function in the Schwann cell lineage, followed by a cascade of interactions with other cell types in the surrounding tumor microenvironment. In NF1 patients, neurofibromas always develop along peripheral nerves and do not migrate to distant organs, including the central nervous system. In this study, we sought to identify the contributions of these peripheral nerves in neurofibroma formation. Using in vivo and in vitro three-dimensional (3D) culturing system, we show that peripheral nerves are absolutely required for neurofibroma tumorigenesis and report a novel 3D skin raft culture system for neurofibroma formation in vitro to decipher tumor pathogenesis. This interaction between neoplastic Schwann cells and their surrounding neural microenvironment has important implications for understanding early cellular events that dictate tumorigenesis. It also provides fertile ground for the elucidation of intrinsic and extrinsic factors within the nerve microenvironment that likely play essential roles in neurofibroma development and, therefore, viable therapeutic targets in neurofibroma therapy.

Light-induced plasticity in leaf hydraulics, venation, anatomy, and gas exchange in ecologically diverse Hawaiian lobeliads.

Leaf hydraulic conductance (Kleaf ) quantifies the capacity of a leaf to transport liquid water and is a major constraint on light-saturated stomatal conductance (gs ) and photosynthetic rate (Amax ). Few studies have tested the plasticity of Kleaf and anatomy across growth light environments. These provided conflicting results. The Hawaiian lobeliads are an excellent system to examine plasticity, given the striking diversity in the light regimes they occupy, and their correspondingly wide range of Amax , allowing maximal carbon gain for success in given environments. We measured Kleaf , Amax , gs and leaf anatomical and structural traits, focusing on six species of lobeliads grown in a common garden under two irradiances (300/800 µmol photons m(-2)  s(-1) ). We tested hypotheses for light-induced plasticity in each trait based on expectations from optimality. Kleaf , Amax , and gs differed strongly among species. Sun/shade plasticity was observed in Kleaf , Amax, and numerous traits relating to lamina and xylem anatomy, venation, and composition, but gs was not plastic with growth irradiance. Species native to higher irradiance showed greater hydraulic plasticity. Our results demonstrate that a wide set of leaf hydraulic, stomatal, photosynthetic, anatomical, and structural traits tend to shift together during plasticity and adaptation to diverse light regimes, optimizing performance from low to high irradiance.

Diffusion-weighted imaging of the liver in patients with chronic liver disease: comparison of monopolar and bipolar diffusion gradients for image quality and lesion detection.

OBJECTIVE: The objective of our study was to compare diffusion-weighted imaging (DWI) sequences using a bipolar versus a monopolar single-shot echo-planar imaging (EPI) gradient design for image quality and for lesion detection and characterization in patients with liver disease. MATERIALS AND METHODS: In this retrospective study, 77 patients with chronic liver disease who underwent MRI including bipolar and monopolar DWI at 1.5 T were assessed. Two independent observers reviewed the DWI studies for image quality and the detection and characterization of liver lesions. The reference standard for diagnosis was established by consensus review of two different observers using imaging characteristics on conventional MRI sequences, lesion stability over time, pathologic correlation, or a combination of these findings. The estimated signal-to-noise ratio (SNR) of liver parenchyma and apparent diffusion coefficients (ADCs) of the liver and lesions were calculated for both sequences. ROC analysis was conducted to evaluate the performance of ADC for the diagnosis of hepatocellular carcinoma (HCC). RESULTS: Eighty-five lesions, 50 HCCs and 35 benign lesions, were detected with the reference standard in 38 patients. There was equivalent image quality for the bipolar and monopolar sequences (p = 0.24-0.42). The HCC detection rate for observers 1 and 2 was slightly better with bipolar DWI (50.0% and 52.0%, respectively) compared with monopolar DWI (44.0% and 46.0%); however, this difference did not reach statistical significance. The estimated SNR was higher with the monopolar sequence than with the bipolar sequence (p ≤ 0.001). The AUC for the ROC curve was 0.691 for bipolar DWI and 0.649 for monopolar DWI when ADC was used for the characterization of HCC, which is not a statistically significant difference (p = 0.59). CONCLUSION: The higher estimated SNR yielded by the monopolar DWI sequence did not translate into better HCC detection compared with the bipolar DWI sequence. ADC has a limited role for HCC characterization in patients with liver disease.

Cells of origin in the embryonic nerve roots for NF1-associated plexiform neurofibroma.

Neurofibromatosis type 1 is a tumor-predisposing genetic disorder. Plexiform neurofibromas are common NF1 tumors carrying a risk of malignant transformation, which is typically fatal. Little is known about mechanisms mediating initiation and identity of specific cell type that gives rise to neurofibromas. Using cell-lineage tracing, we identify a population of GAP43(+) PLP(+) precursors in embryonic nerve roots as the cells of origin for these tumors and report a non-germline neurofibroma model for preclinical drug screening to identify effective therapies. The identity of the tumor cell of origin and facility for isolation and expansion provides fertile ground for continued analysis to define factors critical for neurofibromagenesis. It also provides unique approaches to develop therapies to prevent neurofibroma formation in NF1 patients.

BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in neurofibromatosis type 1 (NF1) patients. There is no effective treatment for MPNSTs and they are typically fatal. To gain insights into MPNST pathogenesis, we utilized an MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, in MPNSTs we found upregulation of a chromatin regulator, Brd4, and show that BRD4 inhibition profoundly suppresses both growth and tumorigenesis. Our findings reveal roles for BET bromodomains in MPNST development and report a mechanism by which bromodomain inhibition induces apoptosis through induction of proapoptotic Bim, which may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate epigenetic mechanisms underlying the balance of anti- and proapoptotic molecules and that bromodomain inhibition can shift this balance in favor of cancer cell apoptosis.

Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors.

Neurofibromatosis type I (NF1) is an autosomal disorder that affects neural crest-derived tissues, leading to a wide spectrum of clinical presentations. Patients commonly present with plexiform neurofibromas, benign but debilitating growths that can transform into malignant peripheral nerve sheath tumors (MPNST), a main cause of mortality. Currently, surgery is the primary course of treatment for MPNST, but with the limitation that these tumors are highly invasive. Radiotherapy is another treatment option, but is undesirable because it can induce additional mutations. Patients with MPNST may also receive doxorubicin as therapy, but this DNA-intercalating agent has relatively low tumor specificity and limited efficacy. In this study, we exploited a robust genetically engineered mouse model of MPNST that recapitulates human NF1-associated MPNST to identify a novel small chemical compound that inhibits tumor cell growth. Compound 21 (Cpd21) inhibits growth of all available in vitro models of MPNST and human MPNST cell lines, while remaining nontoxic to normally dividing Schwann cells or mouse embryonic fibroblasts. We show that this compound delays the cell cycle and leads to cellular apoptosis. Moreover, Cpd21 can reduce MPNST burden in a mouse allograft model, underscoring the compound's potential as a novel chemotherapeutic agent.

On the thermodynamics and kinetics of hydrophobic interactions at interfaces.

We have studied how primitive hydrophobic interactions between two or more small nonpolar solutes are affected by the presence of surfaces. We show that the desolvation barriers present in the potential of mean force between the solutes in bulk water are significantly reduced near an extended hydrophobic surface. Correspondingly, the kinetics of hydrophobic contact formation and breakage are faster near a hydrophobic surface than near a hydrophilic surface or in the bulk. We propose that the reduction in the desolvation barrier is a consequence of the fact that water near extended hydrophobic surfaces is akin to that at a liquid-vapor interface and is easily displaced. We support this proposal with three independent observations. First, when small hydrophobic solutes are brought near a hydrophobic surface, they induce local dewetting, thereby facilitating the reduction of desolvation barriers. Second, our results and those of Patel et al. (Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 17678-17683) show that, whereas the association of small solutes in bulk water is driven by entropy, that near hydrophobic surfaces is driven by enthalpy, suggesting that the physics of interface deformation is important. Third, moving water away from its vapor-liquid coexistence, by applying hydrostatic pressure, leads to recovery of bulklike signatures (e.g., the presence of a desolvation barrier and an entropic driving force) in the association of solutes. These observations for simple solutes also translate to end-to-end contact formation in a model peptide with hydrophobic end groups, for which lowering of the desolvation barrier and acceleration of contact formation are observed near a hydrophobic surface. Our results suggest that extended hydrophobic surfaces, such as air-water or hydrocarbon-water surfaces, could serve as excellent platforms for catalyzing hydrophobically driven assembly.

CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and ß-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.