bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in PIK3CA-Mutant Lung Squamous Cell Carcinoma
Authors: Shi Ruoshi , Li Ming , Raghavan Vibha , Tam Shirley , Cabanero Michael , Pham Nhu-An , Shepherd Frances A. , Moghal Nadeem , Tsao Ming-Sound
Published: August 2018

Purpose:

Lung squamous cell carcinoma (LUSC) is a major subtype of non–small cell lung cancer characterized by multiple genetic alterations, particularly PI3K pathway alterations which have been identified in over 50% of LUSC cases. Despite being an attractive target, single-agent PI3K inhibitors have demonstrated modest response in LUSC. Thus, novel combination therapies targeting LUSC are needed.

Experimental Design:

PI3K inhibitors alone and in combination with CDK4/6 inhibitors were evaluated in previously established LUSC patient-derived xenografts (PDX) using an in vivo screening method. Screening results were validated with in vivo expansion to 5 to 8 mice per arm. Pharmacodynamics studies were performed to confirm targeted inhibition of compounds.

Results:

Consistent with results from The Cancer Genome Atlas analysis of LUSC, genomic profiling of our large cohort of LUSC PDX models identified PI3K pathway alterations in over 50% of the models. In vivo screening using PI3K inhibitors in 12 of these models identified PIK3CA mutation as a predictive biomarker of response (<20% tumor growth compared with baseline/vehicle). Combined inhibition of PI3K and CDK4/6 in models with PIK3CA mutation resulted in greater antitumor effects compared with either monotherapy alone. In addition, the combination of the two drugs achieved targeted inhibition of the PI3K and cell-cycle pathways.

Conclusions:

PIK3CA mutations predict response to PI3K inhibitors in LUSC. Combined PI3K and CDK4/6 inhibition enhances response to either single agents alone. Our findings provide a rationale for clinical testing of combined PI3K and CDK4/6 inhibitors in PIK3CA-mutant LUSC.
Identification of Tissue-Specific DNA Methylation Signatures for Thyroid Nodule Diagnostics
Authors: Yim John H. , Choi Audrey H. , Li Arthur X. , Qin Hanjun , Chang Sue , Tong Sun-Wing T. , Chu Peiguo , Kim Byung-Wook , Schmolze Daniel , Lew Ryan , Ibrahim Yasmine , Poroyko Valeriy A. , Salvatierra Sylvana , Baker Alysha , Wang Jinhui , Wu Xiwei , Pfeifer Gerd P. , Fong Yuman , Hahn Maria A.
Published: August 2018

Purpose:

Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer.

Experimental Design: For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules.

Results:

By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81–100], sensitivity of 100% (95% CI, 87–100), positive predictive value of 97% (95% CI, 83–100), and negative predictive value of 100% (95% CI, 86–100).

Conclusions:

These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules.

See related commentary by Mitmaker et al., p. 457
Rates ofERBB2Alterations across Melanoma Subtypes and a Complete Response to Trastuzumab Emtansine in anERBB2-Amplified Acral Melanoma
Authors: Gottesdiener Lee S. , O'Connor Shannon , Busam Klaus J. , Won Helen , Solit David B. , Hyman David M. , Shoushtari Alexander N.
Published: August 2018

Purpose:

Patients with BRAF V600 wild-type melanoma whose tumors progress on checkpoint inhibition currently have limited therapeutic options, and additional rational treatment targets are needed. ERBB2 alterations may be amenable to targeted inhibition, but the rate of ERBB2 alterations across melanoma subtypes is not well described.

Patients and Methods:

All patients with nonuveal melanoma (cutaneous, acral, mucosal, and unknown primary) whose tumors underwent multigene sequencing with MSK-IMPACT at Memorial Sloan Kettering Cancer Center (New York, NY) from 2014 to 2018 were reviewed for known or likely oncogenic somatic alterations in ERBB2 and the other known canonical driver genes BRAF, NRAS, KIT, NF1, GNAQ, and GNA11.

Results:

A patient with acral melanoma resistant to checkpoint inhibition was found to have ERBB2 amplification and achieved a durable complete response to trastuzumab emtansine. Tumor sequencing results from 732 melanoma cases were analyzed for ERBB2 and canonical driver gene alterations. ERBB2 amplifications were detected in acral (3%) and mucosal (3%) melanomas. ERBB2 mutations were found in cutaneous (1%), acral (2%), and mucosal (2%) subtypes and frequently cooccurred with NF1 alterations. Among the 140 patients whose tumors lacked canonical driver alterations, ERBB2 amplifications were detected in acral (7%) and mucosal (6%) melanomas.

Conclusions:

ERBB2 amplification is present in a minority of acral lentiginous and mucosal melanomas. Activating mutations in ERBB2 were identified in nonuveal melanoma subtypes and are frequently comutated with canonical drivers. HER2 could represent a therapeutically relevant target across melanoma subtypes.
Ultrahigh Dose-rate Radiotherapy: Next Steps for FLASH-RT
Authors: Harrington Kevin J.
Published: August 2018

A new way of delivering radiotherapy at very high dose rates is described and compared with conventional radiotherapy. The ultrahigh dose-rate therapy reduces damage to normal pig skin and exerts potent activity against spontaneous nasal tumors in cat patients. The implications for clinical development of this approach are discussed.

See related article by Vozenin et al., p. 35
MERTK Mediates Intrinsic and Adaptive Resistance to AXL-targeting Agents
Authors: McDaniel Nellie K. , Cummings Christopher T. , Iida Mari , Hülse Justus , Pearson Hannah E. , Vasileiadi Eleana , Parker Rebecca E. , Orbuch Rachel A. , Ondracek Olivia J. , Welke Noah B. , Kang Grace H. , Davies Kurtis D. , Wang Xiaodong , Frye Stephen V. , Earp H. Shelton , Harari Paul M. , Kimple Randall J. , DeRyckere Deborah , Graham Douglas K. , Wheeler Deric L.
Published: August 2018

The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases (RTK) play an important role in promoting growth, survival, and metastatic spread of several tumor types. AXL and MERTK are overexpressed in head and neck squamous cell carcinoma (HNSCC), triple-negative breast cancer (TNBC), and non–small cell lung cancer (NSCLC), malignancies that are highly metastatic and lethal. AXL is the most well-characterized TAM receptor and mediates resistance to both conventional and targeted cancer therapies. AXL is highly expressed in aggressive tumor types, and patients with cancer are currently being enrolled in clinical trials testing AXL inhibitors. In this study, we analyzed the effects of AXL inhibition using a small-molecule AXL inhibitor, a monoclonal antibody (mAb), and siRNA in HNSCC, TNBC, and NSCLC preclinical models. Anti-AXL–targeting strategies had limited efficacy across these different models that, our data suggest, could be attributed to upregulation of MERTK. MERTK expression was increased in cell lines and patient-derived xenografts treated with AXL inhibitors and inhibition of MERTK sensitized HNSCC, TNBC, and NSCLC preclinical models to AXL inhibition. Dual targeting of AXL and MERTK led to a more potent blockade of downstream signaling, synergistic inhibition of tumor cell expansion in culture, and reduced tumor growth in vivo. Furthermore, ectopic overexpression of MERTK in AXL inhibitor–sensitive models resulted in resistance to AXL-targeting strategies. These observations suggest that therapeutic strategies cotargeting both AXL and MERTK could be highly beneficial in a variety of tumor types where both receptors are expressed, leading to improved survival for patients with lethal malignancies. Mol Cancer Ther; 17(11); 2297–308. ©2018 AACR.
Unraveling the Interaction between Carboxylesterase 1c and the Antibody–Drug Conjugate SYD985: Improved Translational PK/PD by Using Ces1c Knockout Mice
Authors: Ubink Ruud , Dirksen Eef H.C. , Rouwette Myrthe , Bos Ebo S. , Janssen Ingrid , Egging David F. , Loosveld Eline M. , van Achterberg Tanja A. , Berentsen Kim , van der Lee Miranda M.C. , Bichat Francis , Raguin Olivier , van der Vleuten Monique A.J. , Groothuis Patrick G. , Dokter Wim H.A.
Published: August 2018

Carboxylesterase 1c (CES1c) is responsible for linker-drug instability and poor pharmacokinetics (PK) of several antibody–drug conjugates (ADC) in mice, but not in monkeys or humans. Preclinical development of these ADCs could be improved if the PK in mice would more closely resemble that of humans and is not affected by an enzyme that is irrelevant for humans. SYD985, a HER2-targeting ADC based on trastuzumab and linker-drug vc-seco-DUBA, is also sensitive to CES1c. In the present studies, we first focused on the interaction between CES1c and SYD985 by size- exclusion chromatography, Western blotting, and LC/MS-MS analysis, using recombinant CES1c and plasma samples. Intriguingly, CES1c activity not only results in release of the active toxin DUBA but also in formation of a covalent bond between CES1c and the linker of vc-seco-DUBA. Mass spectrometric studies enabled identification of the CES1c cleavage site on the linker-drug and the structure of the CES1c adduct. To assess the in vivo impact, CES1c−/− SCID mice were generated that showed stable PK for SYD985, comparable to that in monkeys and humans. Patient-derived xenograft (PDX) studies in these mice showed enhanced efficacy compared with PDX studies in CES1c+/+ mice and provided a more accurate prediction of clinical efficacy of SYD985, hence delivering better quality data. It seems reasonable to assume that CES1c−/− SCID mice can increase quality in ADC development much broader for all ADCs that carry linker-drugs susceptible to CES1c, without the need of chemically modifying the linker-drug to specifically increase PK in mice. Mol Cancer Ther; 17(11); 2389–98. ©2018 AACR.
Digital PCR-Based T-cell Quantification–Assisted Deconvolution of the Microenvironment Reveals that Activated Macrophages Drive Tumor Inflammation in Uveal Melanoma
Authors: de Lange Mark J. , Nell Rogier J. , Lalai Rajshri N. , Versluis Mieke , Jordanova Ekaterina S. , Luyten Gre P.M. , Jager Martine J. , van der Burg Sjoerd H. , Zoutman Willem H. , van Hall Thorbald , van der Velden Pieter A.
Published: August 2018

Uveal melanoma progression can be predicted by gene expression profiles enabling a clear subdivision between tumors with a good (class I) and a poor (class II) prognosis. Poor prognosis uveal melanoma can be subdivided by expression of immune-related genes; however, it is unclear whether this subclassification is justified; therefore, T cells in uveal melanoma specimens were quantified using a digital PCR approach. Absolute T-cell quantification revealed that T-cell influx is present in all uveal melanomas associated with a poor prognosis. However, this infiltrate is only accompanied by differential immune-related gene expression profiles in uveal melanoma with the highest T-cell infiltrate. Molecular deconvolution of the immune profile revealed that a large proportion of the T-cell–related gene expression signature does not originate from lymphocytes but is derived from other immune cells, especially macrophages. Expression of the lymphocyte-homing chemokine CXCL10 by activated macrophages correlated with T-cell infiltration and thereby explains the correlation of T-cell numbers and macrophages. This was validated by in situ analysis of CXCL10 in uveal melanoma tissue with high T-cell counts. Surprisingly, CXCL10 or any of the other genes in the activated macrophage-cluster was correlated with reduced survival due to uveal melanoma metastasis. This effect was independent of the T-cell infiltrate, which reveals a role for activated macrophages in metastasis formation independent of their role in tumor inflammation.

Implications:

The current report uses an innovative digital PCR method to study the immune environment and demonstrates that absolute T-cell quantification and expression profiles can dissect disparate immune components.
Pediatric Dilemma: Endovascular versus Surgical Intervention for Spinal Vascular Malformations
Authors: Nikova Alexandrina , Ganchev Dimitar , Birbilis Theodossios
Published: August 2018

Objective: Spinal arteriovenous malformations (AVM) manifest in the pediatric population very differently from the ones in adulthood. Despite that fact, the treatment strategy is quite the same, which provokes a question – whether some of the therapies have an advantage and if so, in which age group. Methods: For this reason, the authors searched the world literature between 1989 and 2018 for spinal AVM in children and further categorized the studies into two age groups: < 12 and ≥12. Results: The total number of included studies in this meta-analysis is 35. Seventeen of them are on the subject of AVM and 15 on the subject of arteriovenous fistula. Three studies encompass both types of lesions. Conclusion: After processing the data, we observed that there is no relationship between age group and the utilized management, except for the endovascular AVF in children less than 12 years of age. Because of this, it should be strongly considered in further management planning.
Psoriasis Vulgaris Exacerbation during Treatment with a PD-1 Checkpoint Inhibitor: Case Report and Literature Review
Authors: De Bock Marlies , Hulstaert Eva , Kruse Vibeke , Brochez Lieve
Published: August 2018

Objective: The incidence of immune-related adverse events is growing as the use of checkpoint inhibitors is exponentially increasing. Cutaneous adverse events are among the most frequent immune-related adverse events. The purpose of this case report and literature review is to highlight psoriasis as a potential adverse event with need for early recognition. Case Report and Literature Review: We describe the case of a 65-year-old woman with psoriasis exacerbation while treated with nivolumab (anti-PD-1) for a stage IV melanoma. She had a history of scalp psoriasis but she presented with psoriatic lesions on both lower and upper limbs. Our patient was treated with topical steroids. So far, 34 other cases with an exacerbation of psoriasis during treatment with anti-PDL-1 or PD-1 therapy have been reported in the literature. A broad range of therapies are described, without any available guidelines for this particular condition. Conclusion: Psoriasis exacerbation is an established side effect of PD-1/PDL-1 checkpoint inhibitors with 35 reported cases. Early recognition and management are challenging as there are no clear guidelines available. A close collaboration between oncologist and dermatologist is mandatory to manage this immune-related adverse event.
Ado-Trastuzumab Emtansine-Induced Pulmonary Toxicity: A Single-Institution Retrospective Review
Authors: Egloff Heidi , Kidwell Kelley M. , Schott Anne
Published: August 2018

Purpose: T-DM1 is an antibody drug conjugate with proven efficacy in metastatic breast cancer for progressive disease refractory to trastuzumab. Drug-induced pneumonitis is a rare serious potential adverse effect. The purpose of this review was to estimate the incidence of pulmonary toxicity at our institution. Methods: A retrospective analysis of electronic medical record data inclusive of all women and men aged 18 years and older treated with T-DM1 at out institution was undertaken. The records were reviewed for clinical symptoms and/or radiographic evidence concerning for pneumonitis. We identified variables of interest with regard to potential risk factors for toxicity. Results: A total of 50 patients were included, 6 (12%) of whom had radiographic and/or clinical symptoms concerning for T-DM1-induced pneumonitis. All 6 patients had metastatic or unresectable breast cancer. Of the 6 patients, 5 (83%) had suspected pulmonary metastases, 1 (17%) had a history of underlying lung disease, and 5 (83%) had a history of prior taxane therapy. Pulmonary metastases (p = 0.38), the median number of treatment cycles (p = 0.29), prior taxane therapy (p = 0.99), underlying lung disease (p = 0.99), and hormone receptor positivity (p = 0.66) did not have any statistical significance for an association with pneumonitis. Conclusion: Pneumonitis is a recognized toxic effect of T-DM1. While our sample size was small, the number of events was higher than described in the literature, which may be an artifact of referral bias. Future studies with a larger sample population may detect potential risk factors for toxicity.
Unilateral Multifocal Intraocular Lens Implantation in a Patient with Adie’s Pupil
Authors: LoBue Stephen A. , Mano Fukutaro , Schaefer Erin , LoBue Thomas D.
Published: August 2018

Purpose: To report a case of a patient with unilateral Adie’s pupil who underwent bilateral cataract extraction with multifocal and monofocal posterior chamber intraocular lens (IOL) implantation. Methods: A 74-year-old woman presented to our institution complaining of worsening near vision. Gross examination revealed a 6-mm fixed pupil on the right eye (OD) and a 5-mm pupil reacting to 3 mm with light on the left eye (OS). Slit lamp examination revealed a tonic pupil with an exaggerated pupillary constriction to dilute pilocarpine OD. Dilated exam revealed 2–3+ nuclear and cortical lens changes bilaterally. The patient’s active lifestyle, personality, and biometry measurements made her a good candidate for multifocal IOL (MfIOL) implantation OS. Femtosecond laser-assisted cataract extraction with a ReSTOR +3 ADD (SN60D1) implantation was performed OS. Monofocal lens implantation (SN60WF) was performed OD 6 months later. Results: One year postoperatively, our patient had an uncorrected visual acuity (VAsc) of 20/15 for distance and J10 for near OD. Her VAsc was 20/25 +1 for distance and J1 for near OS. Visual acuity when using both eyes was 20/15 for distance and J1 for near. Conclusion: Optimizing success for MfIOL implantation is a multifactorial process. Large pupils preoperatively are of particular concern, as this may lead to increased dysphotopsia with pupil-dependent MfIOLs. Thus, patients with unilateral mydriasis, such as Aide’s pupil, may have a beneficial outcome combining multifocal-monofocal implantation after bilateral cataract extraction, especially if they are not a candidate for monovision but desire spectacle independence.
Atezolizumab-Induced Stevens-Johnson Syndrome in a Patient with Non-Small Cell Lung Carcinoma
Authors: Chirasuthat Phatcharawat , Chayavichitsilp Pamela
Published: August 2018

Atezolizumab is a humanized anti-PD-L1 immune checkpoint antibody that is currently used in many kinds of advanced carcinoma including metastatic non-small cell lung cancer. The cutaneous side effect profile reported only 20% of the patients which had only mild maculopapular rash that required no treatment. There is no case report of anti-PD-L1 antibody-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) eruptions. To the best of our knowledge, there is no case report of atezolizumab-induced SJS or SJS/TEN induced by anti-PD-L1 immune checkpoint antibodies. We believe that our report will be useful to dermatologists who are consultants in the inpatient settings, as atezolizumab is an anti-neoplastic agent that has a potential to be used in multiple malignancies.
Protective Effects of Hydrogen Sulfide Against Cigarette Smoke Exposure-Induced Placental Oxidative Damage by Alleviating Redox Imbalance via Nrf2 Pathway in Rats
Authors: Zhao Fusheng , Lei Fang , Yan Xiang , Zhang Senfeng , Wang Wen , Zheng Yu
Published: August 2018

Background/Aims: Cigarette smoke exposure (CSE) during pregnancy is a well-recognized health hazard that causes placental damage. Hydrogen sulfide (H2S) has been reported to protect multiple organs from injury. However, the protective effects of H2S have not been tested in the placenta. This study aimed to explore the potential of H2S in protecting placenta against oxidative injury induced by CSE during pregnancy and the possible underlying mechanisms. Methods: Pregnant SD rats were randomly divided into 4 groups: NaCl, NaHS (a donor of H2S), CSE and CSE+NaHS. Placental oxidative damage was detected by 8-hydroxy-2-deoxyguanosine (8-OHdG) stain and malondialdehyde (MDA) assay. Placental redox status was assessed by measuring reactive oxygen species (ROS), total antioxidant capacity (T-AOC) and glutathione (GSH) levels, as well as copper/zinc SOD (SOD1), manganese SOD (SOD2), catalase (CAT) and glutathione peroxidase (GPx) activities and expressions. Meanwhile, nuclear factor erythroid 2-related factor 2 (Nrf2) was analyzed by immunohistochemistry, real-time PCR and Western blot. Results: We found that NaHS markedly reduced the elevated levels of 8-OHdG and MDA induced by CSE. Further, NaHS treatment effectively mitigated CSE-induced placental redox imbalance by inhibiting ROS production, restoring T-AOC level, increasing GSH/GSSG ratio, and augmenting SOD1 SOD2, CAT and GPx activities and expressions. More notably, NaHS administration also reversed the aberrant decrease of Nrf2 due to CSE in rat placentas. Conclusion: Our data demonstrate that H2S can protect against CSE-induced placental oxidative damage probably by alleviating redox imbalance via Nrf2 pathway.
Triplet Chemotherapy (FOLFOXIRI) Plus Bevacizumab Versus Doublet Chemotherapy (FOLFOX/FOLFIRI) Plus Bevacizumab in Conversion Therapy for Metastatic Colorectal Cancer: a Meta-Analysis
Authors: Shui Lin , Wu Yu-Shen , Lin Huapeng , Shui Pixian , Sun Qin , Chen Xiaopin
Published: August 2018

Background/Aims: Conversion therapy can convert unresectable metastatic colorectal cancer (mCRC) into resectable. However, the optimal conversion regimen was not yet defined. This meta-analysis aimed to compare the efficacy and safety of the triplet chemotherapy (FOLFOXIRI) plus bevacizumab (Bev) with doublet chemotherapy (FOLFOX/FOLFIRI) plus Bev in conversion therapy. Methods: Randomized controlled trials (RCTs) from databases, including Pubmed, EMBASE, Cochrane clinical trials, clinicaltrial.gov and some conferences, were searched from the inception to November 2017. The R0 resection, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the incidence of adverse events were pooled with the use of hazard ratio (HR) or risk ratio (RR). Results: Four RCTs with 1013 patients were included. FOLFOXIRI plus Bev regimen significantly improved the overall R0 resection rate (RR 1.41, 95% confidence interval (CI) 1.07-1.85, I2=37%), liver R0 resection rate (RR 2.28, 95% CI 1.34-3.89, I2=0%), ORR (RR 1.20, 95% CI 1.09-1.32, I2=0%), PFS (HR 0.72, 95% CI 0.62-0.84, I2=36%) and OS (HR 0.80, 95% CI 0.66-0.97, I2=0%). There was no significant difference in any Grade≥3 adverse event (RR 1.08, 95% CI 0.99-1.17, I2=0%) between two regimens. FOLFOXIRI-Bev was associated with a higher risk of neutropenia (RR 1.77, 95% CI 1.13-2.79, I2=68%) and diarrhea (RR 1.65, 95% CI 1.17-2.32, I2=0%). Conclusions: Triplet chemotherapy plus Bev significantly improved the R0 resection rates, ORR, PFS and OS in comparison with doublet chemotherapy plus Bev in conversion therapy for mCRC patients, with a higher risk of neutropenia and diarrhea.
Endoplasmic Reticulum Stress Affects Lipid Metabolism in Atherosclerosis Via CHOP Activation and Over-Expression of miR-33
Authors: Sun Yan , Zhang Dai , Liu Xiaoli , Li Xuesong , Liu Fang , Yu Yi , Jia Shuo , Zhou Yujie , Zhao Yingxin
Published: August 2018

Background/Aims: Endoplasmic reticulum (ER) stress is an important event in atherosclerosis. Recent studies have shown that ER stress deregulates cholesterol metabolism via multiple pathways. This study aimed to determine the relationship between ER stress and lipid metabolism and to verify that upregulation of miR-33 is involved in this process. Methods: An atherosclerosis model was established in apolipoprotein E-deficient (ApoE-/-) mice fed a Western diet, and THP-1 derived macrophages were used in this study. Hematoxylin-eosin and Oil Red O staining were used to quantify the atherosclerotic plaques. 1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate labeled oxidized low-density lipoprotein binding assay and a Cholesterol Efflux Fluorometric Assay Kit were used to observe cholesterol uptake and efflux. The mRNA and protein levels of biomarkers associated with ER stress and cholesterol metabolism in atherosclerotic plaques and macrophages were evaluated by real-time PCR and western blotting, respectively. Immunofluorescence was used to observe alterations of ABCA1 localization. Small interfering RNAs were used to knock down CHOP and miR-33 in macrophages to alter CHOP and miR-33 expression. Results: Atherosclerotic lesions and systemic lipid levels were ameliorated after inhibition of ER stress (tauroursodeoxycholic acid) in vivo. In vitro studies confirmed that ER stress regulated the lipid catabolism of macrophages by promoting cholesterol uptake, inhibiting cholesterol efflux, and modulating the expression of related transporters. CHOP contributed to lipid metabolism disorder following ER stress. Furthermore, over-expression of miR-33 was involved in ER stress that induced lipid metabolism disorder in macrophages. These findings support a model of ER stress induction by oxidized low-density lipoprotein that affects macrophage lipid catabolism disorder. Conclusion: Our data shed new light on the relationship between ER stress and lipid metabolism in vivo and in vitro, and confirm that upregulation of miR-33 is involved in this process. The relationship between ER stress and miR-33 represents a novel target for the treatment of atherosclerosis.
Administration of Thyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus of Male Rats Mimics the Metabolic Cold Defense Response
Authors: Zhang Zhi , Machado Frederico , Zhao Li , Heinen Charlotte A. , Foppen Ewout , Ackermans Mariette T. , Zhou Jiangning , Bisschop Peter H. , Boelen Anita , Fliers Eric , Kalsbeek Andries
Published: August 2018

Background: Cold exposure increases thyrotropin-releasing hormone (TRH) expression primarily in the hypothalamic paraventricular nucleus (PVN). The PVN is a well-known hypothalamic hub in the control of energy metabolism. TRH terminals and receptors are found on PVN neurons. We hypothesized that TRH release in the PVN plays an important role in the control of thermogenesis and energy mobilization during cold exposure. Methods: Male Wistar rats were exposed to a cold environment (4°C) or TRH retrodialysis in the PVN for 2 h. We compared the effects of cold exposure and TRH administration in the PVN on plasma glucose, corticosterone, and thyroid hormone concentrations, body temperature, locomotor activity, as well as metabolic gene expression in the liver and brown adipose tissue. Results: Cold exposure increased body temperature, locomotor activity, and plasma corticosterone concentrations, but blood glucose concentrations were similar to that of room temperature control animals. TRH administration in the PVN also promptly increased body temperature, locomotor activity and plasma corticosterone concentrations. However, TRH administration in the PVN markedly increased blood glucose concentrations and endogenous glucose production (EGP) compared to saline controls. Selective hepatic sympathetic or parasympathetic denervation reduced the TRH-induced increase in glucose concentrations and EGP. Gene expression data indicated increased gluconeogenesis in liver and lipolysis in brown adipose tissue, both after cold exposure and TRH administration. Conclusions: We conclude that TRH administration in the rat PVN largely mimics the metabolic and behavioral changes induced by cold exposure indicating a potential link between TRH release in the PVN and cold defense.
The Risk of Second Primary Colorectal Adenocarcinomas Is Not Increased among Patients with Gastroenteropancreatic Neuroendocrine Neoplasms: A Nationwide Population-Based Study
Authors: Stemann Lau Tobias , Dam Gitte , Jepsen Peter , Grønbæk Henning , Krogh Klaus , Gregersen Tine
Published: August 2018

Background: Second primary colorectal adenocarcinomas (SPCA) may occur with a higher frequency in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In a nationwide population-based study, we investigated the risk of SPCA in GEP-NEN patients and compared it to the general population. Methods: Using the nationwide Danish registries, we identified 2,831 GEP-NEN patients (median age 63 years [IQR 50–73 years], 53% women) diagnosed in 1995–2010. We used Cox regression to compare the incidence of SPCA in GEP-NEN patients relative to a gender- and age-matched general population sample of 56,044 persons. Results: We observed 20 SPCAs among the 2,831 GEP-NEN patients with a total time at risk of 14,003 years (incidence = 143 per 100,000 person-years) and 770 colorectal adenocarcinomas in the general population of 56,044 persons with a total time at risk of 466,801 years (incidence = 165 per 100,000 person-years). The hazard ratio (HR) of SPCA from GEP-NEN diagnosis to the end of follow-up was 1.22 (95% CI: 0.78–1.92) in GEP-NEN patients compared to the general population. This nonsignificant association was the result of a strong positive association in the first 6 months after diagnosis of GEP-NEN (HR = 9.43 [95% CI: 4.98–17.86]) followed by a negative association in the remainder of the follow-up period (HR = 0.50 [95% CI: 0.20–1.21]). Conclusion: In this population-based study, there was no increased risk of SPCA among GEP-NEN patients. The clinical workup in newly diagnosed GEP-NEN patients likely explains the positive short-term association followed by a negative association.
Avaliação da aplicação dos métodos indiretos de predição do gradiente de pressão de poros em projetos de poços da Bacia Sergipe-Alagoas
Authors: Silva Mariana Do Nascimento , Santos João Paulo Lobo dos , Oliveira Rafael De Castro , Souza Itson Santos de , Cunha Acto De Lima
Published: August 2018

No cenário petrolífero atual, a exploração de petróleo em camadas com grandes profundidades é cada vez mais frequente. Com isso, um estudo mais completo das geopressões se faz necessário, visto que essas são as responsáveis pela manutenção da estabilidade do poço. Na previsão de geopressões são utilizados, geralmente, métodos indiretos, que consistem em correlações empíricas que foram calibradas para uma determinada área. Este trabalho teve como principal objetivo fazer uma análise comparativa e técnica das pressões de poros preditas na Bacia Sergipe-Alagoas, utilizando correlações empíricas calibradas para o Golfo do México. No cálculo dos gradientes de pressão de poros foram utilizados dados de dois poços, X e Y, fornecidos pela empresa Z. Os resultados obtidos através dos métodos indiretos foram comparados com os dados de testes de formação realizados nos poços durante a perfuração. Os resultados obtidos mostraram que, para o poço X, os valores preditos foram conclusivos e coerentes, pois os erros relativos médios dos gradientes de pressão de poros oscilaram entre 2,52 e 11,38%, sendo esses valores próximos dos dados medidos nos testes de formação. Já para o poço Y, os resultados preditos foram representativos apenas no intervalo em que o gradiente de poros medido no teste de formação apresentou valor normal.
Mapeamento geoambiental do município de Casa Branca (SP) como subsídio ao planejamento territorial
Authors: Reis Fábio Augusto Gomes Vieira , Amaral Ana Maria Carrascosa do , Giordano Lucilia Do Carmo , Corrêa Claudia Vanessa Dos Santos , Chaves Camila Jardinetti
Published: August 2018

Os estudos geoambientais, embora recentes, ganham cada vez mais espaço como uma importante ferramenta do planejamento ambiental. O planejador primeiro compartimenta o espaço, buscando entender melhor cada parte que compõe o ambiente, e depois o integra para entender suas interações e otimizá-las. A pesquisa teve como principal objetivo elaborar o mapeamento geoambiental do município de Casa Branca, São Paulo, na escala 1:50.000, considerando critérios fisiográficos, geológico-geotécnicos e de uso e ocupação da terra, incluindo a localização das áreas de preservação permanente (APPs). A técnica utilizada para o zoneamento foi a análise multitemática, na qual são elaborados mapas temáticos, que posteriormente são cruzados, diretamente ou em associações específicas, até se chegar a um mapa final de síntese. As etapas metodológicas do zoneamento incluíram: a compartimentação fisiográfica, o mapeamento do uso e cobertura da terra e da localização das APPs, os trabalhos de campo e, por fim, a integração das informações obtidas. Após a execução de todas as etapas, obteve-se uma carta de unidades geoambientais, a partir da qual foram feitas interpretações sobre as  potencialidades e limitações de cada parcela do solo da área de estudo, assim como recomendações, com o intuito de auxiliar no planejamento e nas decisões relacionadas às questões ambientais, além de disponibilizar uma base de dados para futuras pesquisas ambientais na região.
As raízes granulíticas do cinturão Salvador-Esplanada-Boquim, Cráton do São Francisco, Bahia-Sergipe, Brasil
Authors: Barbosa Johildo Salomão Figueirêdo , Marinho Moacyr Moura , Leal Angela Beatriz De Menezes , Oliveira Ernande Melo de , Souza-Oliveira Jailma Santos de , Argollo Roberto Max de , Lana Cristiano , Barbosa Rafael Gordilho , Santos Leila Tatiane Lopes
Published: August 2018

O Cinturão Salvador-Esplanada-Boquim (CSEB) é provavelmente um ramo nordeste do Orógeno Itabuna-Salvador-Curaçá. Neste trabalho, inédito para a região, é apresentada a caracterização petrográfica, petroquímica e geocronológica preliminar das rochas granulíticas da porção central-norte desse cinturão, onde foram separadas quatro unidades granulíticas ácidas e intermediárias, além de bandas de granulitos máficos, granulitos aluminosos e quartzitos. As quatro unidades ácidas e intermediárias são ortogranulitos foliados onde os granulitos máficos encontram-se encaixados sob a forma de lentes. Essas rochas foram atravessadas por diques orosirianos, dacíticos-riolíticos (Diques de Arauá). O estudo litogeoquímico dos granulitos ácidos e intermediários revelou quatro séries cálcio-alcalinas de baixo a alto K, assim denominadas: enderbítica (Ed1), enderbítica (Ed2); charnockítica de composição monzogranítica (MCh) e charnoenderbítica (Ch-Ed). Diagramas multielementares indicam que as quatro unidades possuem anomalias negativas de Nb, Ti e P e baixos teores de high field strenght elements (HFSE), sugerindo haver associação genética ligada a zonas de subducção e arcos vulcânicos. Os granulitos máficos, por sua vez, apontam para uma filiação toleítica com características tipo island-arc tholeiite (IAT). Os dados geocronológicos indicam idades que sugerem a presença de eventos tectônicos ocorridos na área, a saber: formação do protólito do granulito (Ed2) em 2,90 Ga (idade-modelo TDM-Nd); cristalização do granulito (Ed2) em 2582 ± 11 Ma e do MCh em 2473 ± 13 Ma; metamorfismo regional com idades entre 2087 e 2073 Ma; e preenchimento de falhas em forma de diques em torno de 2015 ± 12 Ma. Os dados obtidos, sobretudo aqueles da litogeoquímica, estão permitindo interpretar que essas rochas metamórficas de alto grau se adequam àquelas do tipo arco vulcânico. Essas, ao colidirem no Paleoproterozoico com o Bloco Serrinha, situado a oeste da área estudada, formaram uma cadeia de montanhas, a qual, ao ser erodida, expôs suas raízes granulíticas.
Compartimentação morfoestrutural da Bacia Hidrográfica do Rio Itapemirim, sul do estado do Espírito Santo
Authors: Peixoto-Oliveira Julia , Neves Mirna Aparecida , Calegari Salomão Silva , Guadagnin Felipe
Published: August 2018

O objetivo deste trabalho foi analisar a compartimentação morfoestrutural da Bacia Hidrográfica do Rio Itapemirim, localizada no sul do estado do Espírito Santo, região Sudeste do Brasil. O arranjo da rede de drenagem e a compartimentação do relevo na região são controlados por estruturas geológicas, de forma similar ao que é descrito ao longo do Sistema de Riftes Cenozoicos do Sudeste do Brasil. O arcabouço geológico da Bacia Hidrográfica do Rio Itapemirim pertence à Província Mantiqueira e, em termos geomorfológicos, à porção Norte da Serra da Mantiqueira. Rochas pré-cambrianas do embasamento cristalino compõem a maior parte do substrato geológico da região, enquanto depósitos sedimentares cenozoicos ocorrem subordinadamente. As ferramentas de trabalho envolveram análise da rede de drenagem, de lineamentos, hipsometria e estudo da distribuição das coberturas sedimentares, utilizando técnicas de sensoriamento remoto e descrições de campo. Foram identificados três compartimentos morfoestruturais na Bacia do Rio Itapemirim, denominados aqui de compartimentos Litorâneo, Cachoeiro e Mantiqueira. Cada compartimento reflete diferentes características do terreno, predominando tanto feições erosivas quanto de agradação, em diferentes patamares topográficos delimitados por lineamentos estruturais. A complexidade dos padrões topográficos e da rede de drenagem da área é resultante de regiões com predomínio de processos erosivos ou deposicionais controlados por processos tectônicos atuantes ao longo do Cenozoico.
Variação temporal da descarga sólida em suspensão e identificação de minerais a partir de aperfeiçoamento de método de amostragem automática no Córrego Riacho Fundo, Brasília, Distrito Federal
Authors: Aquino Igor Guedes de , Roig Henrique Llacer , Oliveira Elton Souza , Garnier Jérémie , Guimarães Edi Mendes , Koide Sérgio
Published: August 2018

Este estudo buscou contribuir com informações sedimentométricas sobre o Córrego Riacho Fundo (CRF), afluente do Lago Paranoá, Brasília, Distrito Federal, historicamente o principal transportador de sedimentos da bacia. Utilizamos método acústico com o equipamento River Surveyour M9 da Sontek, para levantamento de vazão, e amostrador automático ISCO 6712, para amostragem de água e sedimentos, com coleta em ponto fixo em relação ao leito do córrego e coleta com adaptação para amostragem a 40 cm de profundidade da superfície d’água. A mineralogia de uma seleção de amostras de sedimentos coletados foi determinada por difratometria de raios X. Além disso, a turbidez das águas foi medida por meio de sonda multiparamétrica flutuando a 40 cm da superfície. Os resultados obtidos permitiram elaborar uma nova curva-chave do CRF, com vazões medidas em cotas nunca registradas. O novo método de coleta implantado possibilitou obter informações em cotas que não haviam sido amostradas antes e permitiu também diminuir a dispersão dos dados entre concentração e cota. Assim, comparando os dois métodos, com o método fixo obteve-se R2 = 0,28, e com o método com flutuabilidade, R2 = 0,45. A adaptação com flutuação também favoreceu uma boa correlação entre turbidez e concentração, apresentando R2 = 0,92. A análise de histerese mostrou que a maioria dos eventos ocorre no sentido anti-horário. A quantidade total de sedimentos suspensos por evento de chuva variou entre 43 e 1.258 t com o método adaptado, e entre 47 e 10.142 t com o método de coleta fixa. A mineralogia dos sedimentos é composta por saponita, vermiculita, ilita, muscovita, caolinita, gibbsita, diásporo, quartzo, rutilo e hematita. O uso do amostrador automático permitiu identificar maior número de minerais quando comparados outros estudos na região.
“Greetings from the Fort” – Ontology and Style in the Writings of Viktor Ivančić
Authors: Brebanović Predrag
Published: August 2018

Drawing on the narratological concepts developed by G. Genette and D. Cohn, the paper argues that the writings of Viktor Ivančić are replete with signals of fictionality. Acknowledged as co-ordinates for mapping his work, they serve to reorganize it – by means of inserted marking-points and internal mirroring – as an intricate (inter)textual system in which journalism is turned into literature. The generically ambiguous text “Umjesto pogovora: pozdrav iz vojne utvrde,” which concludes the 2007 collection of journalistic pieces Animal Croatica: eseji o patriotizmu, is offered as case in point and a most expedient starting point for an analysis of Ivančić’s entire oeuvre.
Two new species of Pentacalia (Compositae, Senecioneae) from northern Andes
Authors: CALVO JOEL , BUIRA ANTONI
Published: August 2018

Recent collections carried out in southern Colombia (Putumayo) and southern Ecuador (Zamora-Chinchipe) lead us to describe two new species of Pentacalia based on morphological evidence. One of them displays lateral, axillary synflorescences and disciform capitula, whereas the other keys out in the group of terminal synflorescences and disciform capitula. Taxonomically useful characters are provided to easily distinguish each species from its closest relatives, as well as detailed pictures of living plants and distribution maps. Adjusted keys for the Colombian and Ecuadorian species are also presented.
Watsonia vicschuettei (Iridaceae, Watsonieae), a replacement name for the illegitimate Watsonia palustris
Authors: POTGIETER CHRISTINA JOHANNA , JOHNSON ISABEL MARION
Published: August 2018

A newly discovered South African species of Watsonia Miller (1758: 184), family Iridaceae Jussieu (1789: 57), was described as Watsonia palustris Goldblatt & Manning (2016: 151). During the process of digitizing Watsonia holdings in the Bews Herbarium (NU) we realised that this name is illegitimate according to Art. 53.1 of the ICN (McNeill et al. 2012). Watsonia palustris Goldblatt & J.C.Manning is a later homonym of W. palustris Persoon (1805:43), in itself a superfluous name for Dierama pendulum (Linnaeus f. 1781: 91) Baker (1877: 99). We present a replacement name for this taxon here.
Skull anatomy and phylogenetic assessment of a large specimen of Ecteniniidae (Eucynodontia: Probainognathia) from the Upper Triassic of southern Brazil
Authors: STEFANELLO MICHELI , MÜLLER RODRIGO TEMP , KERBER LEONARDO , MARTÍNEZ RICARDO N. , DIAS-DA-SILVA SÉRGIO
Published: August 2018

Ecteniniidae comprises an endemic radiation of carnivore probainognathian cynodonts from the Late Triassic of South America. Three taxa have been included in this clade: Ecteninion lunensis Martínez et al., 1996 and Diegocanis elegans Martínez et al., 2013 from Argentina, and Trucidocynodon riograndensis Oliveira et al., 2010 from Brazil. Herein, a new specimen (skull and mandible) assigned to T. riograndensis from the Carnian of the Candelária Sequence (Southern Brazil) is described. A phylogenetic analysis recovered the new specimen as the sister taxon of the holotype of T. riograndensis, and both in a trichotomy with E. lunensis and D. elegans, all supporting the monophyly of Ecteniniidae. The new specimen of T. riograndensis is almost 20% larger than its holotype. Therefore, it represents one of the largest specimens of a carnivorous probainognathian from the Late Triassic known to date and contributes to knowledge of size variation in ecteniniids.
Transference and new records in Neoibidionini (Coleoptera, Cerambycidae)
Authors: GALILEO MARIA HELENA M. , NASCIMENTO FRANCISCO E. DE L. , SANTOS-SILVA ANTONIO
Published: August 2018

Compsibidion trinidadense (Gilmour, 1963) is transferred to Glomibidion Napp & Martins, 1985. Thirteen new records for species of Compsibidion Thomson, 1864, and Heterachthes Newman, 1840 are provided. Heterachthes delicatus Martins, 2009, formerly known only from Brazil (Caatinga Biome) is recorded for the first time for French Guiana (tropical moist forests). Additionally, three forgotten records are noted.
Redescription of Castianeira zetes Simon, 1897 (Araneae, Corinnidae, Castianeirinae)
Authors: SANKARAN PRADEEP M. , MALAMEL JOBI J. , JOSEPH MATHEW M. , SEBASTIAN POTHALIL A.
Published: August 2018

The corinnid species Castianeira zetes was described by Simon in 1897. It has been redescribed several times (Gravely 1931; Tikader 1981; Tikader & Biswas 1981; Majumder & Tikader 1991; Biswas & Raychaudhuri 2000; Sen et al. 2015; Dhali et al. 2017), but none of the above works provided comprehensive somatic as well as genitalic descriptions of the species, and it still remains known only by quite poor drawings. The aim of the present paper is to redescribe and illustrate C. zetes in detail based on the type and new materials.
Synopsis of the genus Volxemia Lameere, 1884 (Coleoptera, Cerambycidae)
Authors: MONNÉ MIGUEL A. , MONNÉ MARCELA L.
Published: August 2018

A synopsis of Volxemia is provided. A new species Volxemia solangeae sp. nov. from the state of São Paulo, Brazil is described and illustrated. A key for the known species is provided.
Four new species of Magelona (Annelida: Magelonidae) from Easter Island, Guam and Hawaii
Authors: MAGALHÃES WAGNER F. , BAILEY-BROCK JULIE , WATLING LES
Published: August 2018

Several collections of magelonids from Easter Island, Guam in the Mariana Islands and Hawaii were examined. Five magelonids are fully described and illustrated: Magelona anuheone sp. nov. (Easter Island), M. cf. symmetrica Mortimer & Mackie, 2006 (Guam), M. alexandrae sp. nov. (Hawaii), M. cinthyae sp. nov. (Hawaii) and M. paulolanai sp. nov. (Hawaii and Guam). Magelona anuheone sp. nov. has a distinctly longer than wide prostomium with inflated and well-developed prostomial horns, similar to M. montera from the Indian Ocean. Magelona alexandrae sp. nov. belongs to Magelona species with crenulated upper margin of thoracic postchaetal lamellae and also well-developed prostomial horns. Magelona cinthyae sp. nov. is unique among its congeners in that several collected adult individuals presented two or more eyespots in the prostomium, a feature only previously recorded to pelagic larval stages. Magelona paulolanai sp. nov. belongs to a group of species with rudimentary prostomial horns, simple capillaries on chaetiger 9 and tridentate abdominal hooks. All species are illustrated and compared to their morphologically similar congeners.
A checklist of epibiont suctorian and peritrich ciliates (Ciliophora) on halacarid and hydrachnid mites (Acari: Halacaridae & Hydrachnidia)
Authors: CHATTERJEE TAPAS , DOVGAL IGOR , PEŠIĆ VLADIMIR , ZAWAL ANDRZEJ
Published: August 2018

Based on published records and original data, a list of the epibiont suctorian and peritrich ciliates (Ciliophora) on halacarid and hydrachnid mites is presented. Altogether 13 suctorian and 10 peritrich species from hydrachnid and halacarid mites were listed. From this list, six suctorian and one peritrich species have been reported from halacarid mites, while four suctorian and four peritrich species were found on hydrachnid mites determined up to species level. The remaining specimens were determined upto the generic level. The halacarid and hydrachnid species do not share any suctorian and peritrich species and some of the ciliate species are specific to certain taxonomic groups of the hosts.The host specificity of both suctorian and peritrich ciliates, localization on the host body and environment are discussed. Some ciliate species specific to hydrachnid mites prefer lotic or lentic habitats. In most cases, both suctorian and peritrich ciliates prefer only marine or only fresh water bodies. It was also mentioned that both suctorian and peritrich ciliates have not distinct preferences in localization on their host body.