bluuebunny/crossref_metadata_2025 huggingface dataset:
Depatuxizumab Mafodotin (ABT-414)-induced Glioblastoma Cell Death Requires EGFR Overexpression, but not EGFRY1068 Phosphorylation
Authors: von Achenbach Caroline , Silginer Manuela , Blot Vincent , Weiss William A. , Weller Michael
Published: May 2020

Glioblastomas commonly (40%) exhibit epidermal growth factor receptor (EGFR) amplification; half of these tumors carry the EGFRvIII deletion variant characterized by an in-frame deletion of exons 2–7, resulting in constitutive EGFR activation. Although EGFR tyrosine kinase inhibitors had only modest effects in glioblastoma, novel therapeutic agents targeting amplified EGFR or EGFRvIII continue to be developed.

Depatuxizumab mafodotin (ABT-414) is an EGFR-targeting antibody–drug conjugate consisting of the mAb 806 and a toxic payload, monomethyl auristatin F. Because glioma cell lines and patient-derived glioma-initiating cell models expressed too little EGFR in vitro to be ABT-414–sensitive, we generated glioma sublines overexpressing EGFR or EGFRvIII to explore determinants of ABT-414–induced cell death.

Overexpression of EGFRvIII induces sensitization to ABT-414 more readily than overexpression of EGFR in vitro and in vivo. Exposure to ABT-414 in vivo eliminated EGFRvIII-expressing tumor cells, and recurrent tumors were devoid of EGFRvIII expression. There is no bystander killing of cells devoid of EGFR expression. Surprisingly, either exposure to EGF or to EGFR tyrosin kinase inhibitors reduce EGFR protein levels and are thus not strategies to promote ABT-414–induced cell killing. Furthermore, glioma cells overexpressing kinase-dead EGFR or EGFRvIII retain binding of mAb 806 and sensitivity to ABT-414, allowing to dissociate EGFR phosphorylation from the emergence of the “active” EGFR conformation required for ABT-414 binding.

The combination of EGFR-targeting antibody–drug conjugates with EGFR tyrosine kinase inhibitors carries a high risk of failure. Promoting EGFR expression rather than phosphorylation should result in glioblastoma cell sensitization to ABT-414.
Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma
Authors: Reddy Gireesh B. , Kerr David L. , Spasojevic Ivan , Tovmasyan Artak , Hsu David S. , Brigman Brian E. , Somarelli Jason A. , Needham David , Eward William C.
Published: May 2020

Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied in vitro for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; ex vivo pulmonary metastatic assay model; and in vivo pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation in vivo with t1/2 approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells in vitro at 0.2–2 μmol/L IC50; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the ex vivo lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.
EWS-FLI1–regulated Serine Synthesis and Exogenous Serine are Necessary for Ewing Sarcoma Cellular Proliferation and Tumor Growth
Authors: Issaq Sameer H. , Mendoza Arnulfo , Kidner Ria , Rosales Tracy I. , Duveau Damien Y. , Heske Christine M. , Rohde Jason M. , Boxer Matthew B. , Thomas Craig J. , DeBerardinis Ralph J. , Helman Lee J.
Published: May 2020

Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma, translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Recent insights have revealed that the oncogenic transcription factor EWS-FLI1 can impact Ewing sarcoma cellular metabolism, regulating expression of 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in de novo serine synthesis. Here, we have examined the importance of serine metabolism in Ewing sarcoma tumorigenesis and evaluated the therapeutic potential of targeting serine metabolism in preclinical models of Ewing sarcoma. We show that PHGDH knockdown resulted in decreased Ewing sarcoma cell proliferation, especially under serine limitation, and significantly inhibited xenograft tumorigenesis in preclinical orthotopic models of Ewing sarcoma. In addition, the PHGDH inhibitor NCT-503 caused a dose-dependent decrease in cellular proliferation. Moreover, we report a novel drug combination in which nicotinamide phosphoribosyltransferase (NAMPT) inhibition, which blocks production of the PHGDH substrate NAD+, synergized with NCT-503 to abolish Ewing sarcoma cell proliferation and tumor growth. Furthermore, we show that serine deprivation inhibited Ewing sarcoma cell proliferation and tumorigenesis, indicating that Ewing sarcoma cells depend on exogenous serine in addition to de novo serine synthesis. Our findings suggest that serine metabolism is critical for Ewing sarcoma tumorigenesis, and that targeting metabolic dependencies should be further investigated as a potential therapeutic strategy for Ewing sarcoma. In addition, the combination strategy presented herein may have broader clinical applications in other PHGDH-overexpressing cancers as well.
DCLK1-Isoform2 Alternative Splice Variant Promotes Pancreatic Tumor Immunosuppressive M2-Macrophage Polarization
Authors: Chandrakesan Parthasarathy , Panneerselvam Janani , May Randal , Weygant Nathaniel , Qu Dongfeng , Berry William R. , Pitts Kamille , Stanger Ben Z. , Rao Chinthalapally V. , Bronze Michael S. , Houchen Courtney W.
Published: May 2020

Tumor-associated M2-macrophages are one of the most abundant immunosuppressive cell types in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the molecular mechanisms responsible for the generation of M2-macrophages are unclear. Here, we demonstrated that overexpression of DCLK1-isoform2 in AsPC1 and MIA PaCa2 cells resulted in the polarization of M1-macrophages toward an M2 phenotype via secreted chemokines/cytokines. These M2-macrophages enhanced parental PDAC cell migration, invasion, and self-renewal, and this was associated with increased expression of Snail and Slug. We observed distinct expression of Dclk-isoform2, marked infiltration of M2-macrophages, and a marginal increase of CD8+ T cells in 20-week-old KPCY mice pancreas compared with 5 weeks old. Utilizing an autochthonous mouse model of pancreatic adenocarcinoma, we observed distinct immunoreactive Dclk1 and arginase1 in tissues where CD8+ T-cell infiltration was low and observed a paucity of DCLK1 and arginase1 staining where CD8+ T-cell infiltration was high. Finally, we found that DCLK1-isoform2 tumor-educated M2-macrophages inhibit CD8+ T-cell proliferation and granzyme-B activation. Inhibition of DCLK1 in an organoid coculture system enhanced CD8+ T-cell activation and associated organoid death. We conclude that DCLK1-isoform2 is a novel initiator of alternate macrophage activation that contributes to the immunosuppression observed in the PDAC TME. These data suggest that tumor DCLK1-isoform2 may be an attractive target for PDAC therapy, either alone or in conjunction with immunotherapeutic strategies.
Gefitinib Inhibits Invasion and Metastasis of Osteosarcoma via Inhibition of Macrophage Receptor Interacting Serine-Threonine Kinase 2
Authors: Maloney Caroline , Kallis Michelle P. , Edelman Morris , Tzanavaris Christopher , Lesser Martin , Soffer Samuel Z. , Symons Marc , Steinberg Bettie M.
Published: May 2020

Most patients with osteosarcoma have subclinical pulmonary micrometastases at diagnosis. Mounting evidence suggests that macrophages facilitate metastasis. As the EGFR has been implicated in carcinoma–macrophage cross-talk, in this study, we asked whether gefitinib, an EGFR inhibitor, reduces osteosarcoma invasion and metastatic outgrowth using the K7M2-Balb/c syngeneic murine model. Macrophages enhanced osteosarcoma invasion in vitro, which was suppressed by gefitinib. Oral gefitinib inhibited tumor extravasation in the lung and reduced the size of metastatic foci, resulting in reduced metastatic burden. Gefitinib also altered pulmonary macrophage phenotype, increasing MHCII and decreasing CD206 expression compared with controls. Surprisingly, these effects are mediated through inhibition of macrophage receptor interacting protein kinase 2 (RIPK2), rather than EGFR. Supporting this, lapatinib, a highly specific EGFR inhibitor that does not inhibit RIPK2, had no effect on macrophage-promoted invasion, and RIPK2−/− macrophages failed to promote invasion. The selective RIPK2 inhibitor WEHI-345 blocked tumor cell invasion in vitro and reduced metastatic burden in vivo. In conclusion, our results indicate that gefitinib blocks macrophage-promoted invasion and metastatic extravasation by reprogramming macrophages through inhibition of RIPK2.
Targeting the PI3K/AKT Pathway Overcomes Enzalutamide Resistance by Inhibiting Induction of the Glucocorticoid Receptor
Authors: Adelaiye-Ogala Remi , Gryder Berkley E. , Nguyen Yen Thi Minh , Alilin Aian Neil , Grayson Adlai R. , Bajwa Wardah , Jansson Keith H. , Beshiri Michael L. , Agarwal Supreet , Rodriguez-Nieves Jose Antonio , Capaldo Brian , Kelly Kathleen , VanderWeele David J.
Published: May 2020

The PI3K–AKT pathway has pleiotropic effects and its inhibition has long been of interest in the management of prostate cancer, where a compensatory increase in PI3K signaling has been reported following androgen receptor (AR) blockade. Prostate cancer cells can also bypass AR blockade through induction of other hormone receptors, in particular the glucocorticoid receptor (GR). Here we demonstrate that AKT inhibition significantly decreases cell proliferation through both cytostatic and cytotoxic effects. The cytotoxic effect is enhanced by AR inhibition and is most pronounced in models that induce compensatory GR expression. AKT inhibition increases canonical AR activity and remodels the chromatin landscape, decreasing enhancer interaction at the GR gene (NR3C1) locus. Importantly, it blocks induction of GR expression and activity following AR blockade. This is confirmed in multiple in vivo models, where AKT inhibition of established xenografts leads to increased canonical AR activity, decreased GR expression, and marked antitumor activity. Overall, our results demonstrate that inhibition of the PI3K/AKT pathway can block GR activity and overcome GR-mediated resistance to AR-targeted therapy. Ipatasertib is currently in clinical development, and GR induction may be a biomarker to identify responsive patients or a responsive disease state.
CHK1/2 Inhibitor Prexasertib Suppresses NOTCH Signaling and Enhances Cytotoxicity of Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma
Authors: Zeng Ling , Nikolaev Anatoly , Xing Chuan , Della Manna Deborah L. , Yang Eddy S.
Published: May 2020

Platinum-based chemoradiotherapy is a mainstay of organ-preserving therapy for patients with head and neck squamous cell carcinoma cancer (HNSCC). However, the disease eventually becomes resistant to treatment necessitating new therapies. Checkpoint kinase 1 and 2 (CHK1/2) are serine/threonine kinases that activate cell-cycle checkpoints and serve a critical role in the DNA-damage response (DDR). As resistance to cisplatin and radiation may involve a heightened DDR, we hypothesized that prexasertib, an inhibitor of CHK1/2, may enhance the cytotoxicity induced by cisplatin and irradiation in HNSCC. In this study, we found that combining prexasertib with cisplatin and radiation significantly decreased the in vitro survival fraction in HNSCC cell lines both with and without radiotherapy. Reduced survival was accompanied by inhibition of DNA repair checkpoint activation, which resulted in persistent DNA damage and increased apoptosis. In addition, NanoString analysis with the PanCancer Pathways Panel revealed that prexasertib downregulated NOTCH signaling target genes (NOTCH1, NOTCH2, and NOTCH3) and their associated ligands (JAG1, JAG2, SKP2, MAML2, and DLL1). Prexasertib also reduced NOTCH1, NOTCH3 and HES1 protein expression. Importantly, a significant tumor growth delay was observed in vivo in both human papillomavirus (HPV)-positive UM-SCC47 and HPV-negative UM-SCC1 cell line xenografts treated with prexasertib, cisplatin, and radiotherapy without increased toxicity as measured by mouse body weight. Taken together, prexasertib reduced NOTCH signaling and enhanced the in vitro and in vivo response of HNSCCs to cisplatin and radiation, suggesting combination therapy may increase clinical benefit. A clinical trial has recently completed accrual (NCT02555644).
Early Assessment of Molecular Progression and Response by Whole-genome Circulating Tumor DNA in Advanced Solid Tumors
Authors: Davis Andrew A. , Iams Wade T. , Chan David , Oh Michael S. , Lentz Robert W. , Peterman Neil , Robertson Alex , Shah Abhik , Srivas Rohith , Wilson Timothy J. , Lambert Nicole J. , George Peter S. , Wong Becky , Wood Haleigh W. , Close Jason C. , Tezcan Ayse , Nesmith Ken , Tezcan Haluk , Chae Young Kwang
Published: May 2020

Treatment response assessment for patients with advanced solid tumors is complex and existing methods require greater precision. Current guidelines rely on imaging, which has known limitations, including the time required to show a deterministic change in target lesions. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to assess response or resistance to treatment early in the treatment course. Ninety-six patients with advanced cancer were prospectively enrolled (91 analyzed and 5 excluded), and blood was collected before and after initiation of a new, systemic treatment. Plasma cell–free DNA libraries were prepared for either WG or WG bisulfite sequencing. Longitudinal changes in the fraction of ctDNA were quantified to retrospectively identify molecular progression (MP) or major molecular response (MMR). Study endpoints were concordance with first follow-up imaging (FFUI) and stratification of progression-free survival (PFS) and overall survival (OS). Patients with MP (n = 13) had significantly shorter PFS (median 62 days vs. 310 days) and OS (255 days vs. not reached). Sensitivity for MP to identify clinical progression was 54% and specificity was 100%. MP calls were from samples taken a median of 28 days into treatment and 39 days before FFUI. Patients with MMR (n = 27) had significantly longer PFS and OS compared with those with neither call (n = 51). These results demonstrated that ctDNA changes early after treatment initiation inform response to treatment and correlate with long-term clinical outcomes. Once validated, molecular response assessment can enable early treatment change minimizing side effects and costs associated with additional cycles of ineffective treatment.
Preclinical Activity of PI3K Inhibitor Copanlisib in Gastrointestinal Stromal Tumor
Authors: García-Valverde Alfonso , Rosell Jordi , Serna Garazi , Valverde Claudia , Carles Joan , Nuciforo Paolo , Fletcher Jonathan A. , Arribas Joaquín , Politz Oliver , Serrano César
Published: May 2020

KIT or PDGFRA gain-of-function mutations are the primary drivers of gastrointestinal stromal tumor (GIST) growth and progression throughout the disease course. The PI3K/mTOR pathway is critically involved in the transduction of KIT/PDGFRA oncogenic signaling regardless of the type of primary and secondary mutations, and therefore emerges as a relevant targetable node in GIST biology. We evaluated in GIST preclinical models the antitumor activity of copanlisib, a novel pan-class-I PI3K inhibitor with predominant activity against p110α and p110δ isoforms, as single-agent and in combination with first-line KIT inhibitor imatinib. In vitro studies undertaken in one imatinib-sensitive (GIST-T1) and two imatinib-resistant (GIST-T1/670 and GIST430/654) GIST cell models showed that single-agent copanlisib effectively suppressed PI3K pathway activation leading to decreased cell viability and proliferation in both imatinib-sensitive and -resistant cells irrespective of the type of primary or secondary KIT mutations. Simultaneous PI3K and KIT inhibition with copanlisib and imatinib resulted in enhanced impairment of cell viability in both imatinib-sensitive and -resistant GIST cell models, although apoptosis was mostly triggered in GIST-T1. Single-agent copanlisib inhibited GIST growth in vivo, and conjoined inhibition of PI3K and KIT was the most active therapeutic intervention in imatinib-sensitive GIST-T1 xenografts. IHC stain for cleaved-caspase 3 and phospho-S6 support a predominant antiproliferative effect of copanlisib in GIST. In conclusion, copanlisib has single-agent antitumor activity in GIST regardless KIT mutational status or sensitivity to imatinib. Effective KIT inhibition is necessary to achieve synergistic or additive effects with the combination of imatinib and any given PI3K/mTOR pathway inhibition.
Combined Targeting of the BRD4–NUT–p300 Axis in NUT Midline Carcinoma by Dual Selective Bromodomain Inhibitor, NEO2734
Authors: Morrison-Smith Chevaun D. , Knox Tatiana M. , Filic Ivona , Soroko Kara M. , Eschle Benjamin K. , Wilkens Margaret K. , Gokhale Prafulla C. , Giles Francis , Griffin Andrew , Brown Bill , Shapiro Geoffrey I. , Zucconi Beth E. , Cole Philip A. , Lemieux Madeleine E. , French Christopher A.
Published: May 2020

NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET-selective bromodomain inhibitors have demonstrated on-target activity in patients with NMC, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces cooperative depletion of MYC and synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain–selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells in vitro; findings that correspond with potentiated transcriptional effects from combined BET and p300 bromodomain inhibition. In three disseminated NMC xenograft models, NEO2734 provided greater growth inhibition, with tumor regression and significant survival benefit seen in two of three models, compared with a lead clinical BET inhibitor or “standard” chemotherapy. Our findings provide a strong rationale for clinical study of NEO2734 in patients with NMC. Moreover, the synergistic inhibition of NMC growth by CBP/p300 and BET bromodomain inhibition lays the groundwork for greater mechanistic understanding of the interplay between p300 and BRD4-NUT that drives this cancer.
Remission of Food Addiction Does Not Induce Cross-Addiction after Sleeve Gastrectomy and Gastric Bypass: A Prospective Cohort Study
Authors: Chiappetta Sonja , Stier Christine , Hadid Mohamed Ajan , Malo Nina , Theodoridou Sophia , Weiner Rudolf , Weiner Sylvia
Published: May 2020

Background: The hypothesis of “cross-addiction” has never been validated, and numerous aspects speak against it. Objectives: To compare the differences between sleeve gastrectomy (SG) and gastric bypass (GB) procedures concerning cross-addiction. Setting: Center for maximum care in Germany. Methods: We performed a prospective analysis of patients undergoing SG or GB as the first surgical treatment for severe obesity. All patients completed validated questionnaires to evaluate food intake (Yale Food Addiction Scale, YFAS), alcohol intake (Alcohol Use Disorders Identification Test), nicotine use (Fagerstrom Test for Nicotine Dependence), exercise (Exercise Addiction Inventory), drug addiction (20-item Drug Abuse Screening Test), and Internet use disorder (Internet Addiction Test) before the operation (T0) and 6 (T6) and 24 (T24) months postoperatively (ClinicalTrials.gov identifier: NCT02757716). Results: One hundred thirteen patients underwent SG (n = 68) or GB (n = 45). At the follow-up, 61% completed the questionnaires at T6 and 44% at T24. In the YFAS, the percentage of patients diagnosed with food addiction decreased from 69 to 10%, and the mean symptom count decreased from 3.52 ± 1.95 to 1.26 ± 0.99 at T24 (p < 0.0001); these values did not differ between the surgical groups (p = 0.784). No significant evidence of cross-addiction was observed for use of alcohol, nicotine, drugs, the Internet, or exercise in either surgical group. The percentage of patients with moderate nicotine dependence increased in the SG group (+8.9%) at T24, but this was not significant. Conclusion: In this single-center cohort study, surgery for obesity caused significant addiction remission regarding food but without inducing cross-addiction after 2 years. Importantly, no significant differences were seen between the SG and GB procedures.
Potential of Lenvatinib for an Expanded Indication from the REFLECT Trial in Patients with Advanced Hepatocellular Carcinoma
Authors: Maruta Susumu , Ogasawara Sadahisa , Ooka Yoshihiko , Obu Masamichi , Inoue Masanori , Itokawa Norio , Haga Yuki , Seki Atsuyoshi , Okabe Shinichiro , Azemoto Ryosaku , Itobayashi Ei , Atsukawa Masanori , Sugiura Nobuyuki , Mizumoto Hideaki , Koroki Keisuke , Kanayama Kengo , Kanzaki Hiroaki , Kobayashi Kazufumi , Kiyono Soichiro , Nakamura Masato , Kanogawa Naoya , Saito Tomoko , Kondo Takayuki , Suzuki Eiichiro , Nakamoto Shingo , Tawada Akinobu , Chiba Tetsuhiro , Arai Makoto , Kanda Tatsuo , Maruyama Hitoshi , Kato Naoya
Published: May 2020

Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial. Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan. Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7–6.9 for first line, 4.8 months; 95% CI 3.8–5.9 for second or later line, p = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin – bilirubin scores. Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.
A Comparison of Apgar Scores and Changes in the Neonates of Gestational Diabetes Mellitus Patients Treated with Metformin versus Glyburide: A Systematic Review
Authors: Saha Sumanta , Saha Sujata
Published: May 2020

Aims: This study aims to compare the Apgar scores (at different time points after birth) and their changes between the newborns of gestational diabetes mellitus (GDM) patients treated with metformin and glyburide, respectively. Methods: Electronic databases were searched for randomized controlled trials that compared these outcomes between the above-depicted intervention groups. The data about the study design, the population characteristics, the interventions compared, and the outcomes of interest were extracted from the eligible trials. Then, these trials were critically appraised by the Cochrane tool. After that, the effect of the tested interventions on the respective outcomes of interest was reported narratively. Results: The literature search produced 4 single-center trials sourcing data from about 538 participants in the USA, Brazil, and Israel. The risk of detection and performance bias was unclear in the respective trials. The trials primarily reported about the Apgar scores at 1 and 5 min after birth. These scores were not different between glyburide- and metformin-treated GDM patients in any trial. No trial reported the Apgar score at 10 min after birth or the changes in Apgar score between 1, 5, or 10 min after birth. Conclusion: In all trials, the Apgar scores at 1 and 5 min after birth did not vary between the newborns of GDM mothers treated with metformin and glyburide, respectively.
Atypical Clinical Presentation of Hidradenitis Suppurativa in a Patient with Severe Mannose-Binding Lectin Deficiency
Authors: Bhargava Shashank , Becker Nils , Kroumpouzos George
Published: May 2020

Mannose-binding lectin (MBL) deficiency is associated with recurrent infections, autoimmune and inflammatory skin disease, and vascular complications. MBL deficiency is not a recognized comorbidity in hidradenitis suppurativa (HS); the latter is associated with the group of autoinflammatory disorders. A 32-year-old woman presented with a history of recurrent painful, deep-seated abscesses and pustular lesions since the age of 13 years. Lesions were noted predominantly in HS distribution, i.e., submammary, inguinal, and perianal areas were affected. However, unusual locations (jawlines, neck) were also affected. The patient fulfilled the clinical criteria for HS but the presentation was atypical because lesions were noted in unusual locations, most lesions were in Hurley stage 1 (sparsity of sinus tracts and scarring), and most cultures from abscesses and pustular lesions were negative. The excruciating pain caused by constantly developing abscesses had a profound impact on the patient’s quality of life. Laboratory workup showed an exceptionally low serum MBL level. Treatment was challenging with only a temporary, mild response to oral antibiotic therapy and no response to immunosuppressive and hormonal therapies. This atypical HS presentation may reflect an enhancement of proinflammatory mechanisms. Health care providers should be aware of this clinicopathologic presentation so that the establishment of HS diagnosis is not delayed and the patient receives appropriate counseling.
Cytogenetic and Molecular Characterization of Three Mimetic Species of the Genus Alagoasa Bechyné 1955 (Coleoptera: Alticinae) from the Neotropical Region
Authors: Azambuja Matheus , Rosolen Lucas A.M. , Artoni Roberto F. , Santos Mateus H. , Almeida Mara C.
Published: May 2020

Coleoptera is a mega-diverse order, but only about 1% of its species have been analyzed cytogenetically. In this order, the subfamily Alticinae presents many identification problems, mainly due to the occurrence of mimicry. The objective of this work was to cytogenetically characterize 3 very similar species of the genus Alagoasa (A. pantina, A.areata, and A.scissa). We used classical and molecular cytogenetic as well as molecular genetic techniques. All 3 species showed a diploid chromosome number of 2n = 22 (20+X+y), but differences in the morphology of the chromosomes. All had a meiotic formula of 2n = 10II+X+y and an X+y sex determination system with giant, fully asynaptic sex chromosomes, concordant characteristics observed in the subtribe Oedionychina. FISH demonstrated the presence of 18S and 5S rDNA clusters in 1 pair of autosomes, syntenic and colocalizing in the 3 analyzed species. However, in A. areata, heteromorphism between the cistrons was observed. The telomeric (TTAGG)n probe showed signals in all 3 species, with proximal signals in the X and dispersed signals in the y chromosome of A. areata, and 2 proximal signals in the X chromosome of A. scissa. Molecular analysis of the COI gene indicated that they are 3 distinct species, corroborating the observed cytogenetic characteristics.
Untersuchung der CO2-abhängigen Gefäßregulation in der Netzhaut von Patienten mit Typ-1-Diabetes
Authors: Strauß Olaf
Published: May 2020

Background: Diabetic retinopathy is characterised by morphological lesions in the retina secondary to disturbances in retinal blood flow. Previous studies have shown that the carbonic anhydrase inhibitor (CAI) dorzolamide can induce immediate dilatation of retinal arterioles and a sustained increase in retinal blood flow in primary open-angle glaucoma. However, the effect of sustained treatment with CAI on retinal arterioles in normal persons and in patients with diabetic retinopathy is unknown. Methods: The Dynamic Vessel Analyzer was used to assess the baseline diameter and the diameter response of retinal arterioles during an increase in arterial blood pressure induced by isometric exercise and during flicker stimulation before and 2 h, 24 h and 1 week after onset of topical treatment with dorzolamide. At each examination the diameter responses were studied before and during breathing in of a hypercapnic gas mixture. Results: Treatment with dorzolamide for 1 week significantly increased the diameter of retinal arterioles in normal persons, and breathing in of a hypercapnic gas mixture reduced this response. The pathological vasodilatation and reduced retinal autoregulation in patients with diabetic retinopathy were unaffected by dorzolamide and hypercapnia. Conclusions: The study suggests a lack of relevance of CAI for the treatment of pathological vasodilatation in early diabetic retinopathy.
Critique on the Use of Early Short-Term Dual Antiplatelet Therapy Following Minor Acute Cerebral Ischemic Events
Authors: Moussouttas Michael , Papamitsakis Nikolaos I.H.
Published: May 2020

Background: Two recent cerebrovascular studies, Clopidogrel (Clo) in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT), have purportedly demonstrated the superiority of early dual antiplatelet therapy (DAPT), using aspirin (ASA) plus Clo, in comparison to ASA alone following the occurrence of acute minor cerebral infarction or transient ischemic attack. However, limitations to these trials exist that may not have been adequately explored and presented in the literature, and which may impact the overall efficacy and benefit of DAPT in these situations. Herein we provide a detailed and extensive critique of these 2 trials and of a combined analysis, with particular attention to study data and analyses pertaining to hemorrhagic complications. Summary: DAPT may be superior to ASA alone in preventing recurrent cerebral ischemic events, but exclusively during the first 7–10 days of treatment, and probably only in the presence of acute infarction on cerebral imaging. The impact of minor hemorrhages, which are often clinically consequential and which frequently lead to permanent DAPT discontinuation, has not been adequately considered in the available analyses. Based on data from the trials, DAPT use causes more major and minor hemorrhages than ASA use alone or Clo alone, and Clo use results in fewer hemorrhages than the use of ASA alone. Analyses that include hemorrhage data from the period of Clo alone use as part of the DAPT data may provide inaccurate and erroneous conclusions regarding the relative safety and overall net benefit of DAPT use over ASA alone.
Alcohol Consumption and Cardiovascular Disease
Authors: Larsson Susanna C. , Burgess Stephen , Mason Amy M. , Michaëlsson Karl
Published: May 2020

Background:

The causal role of alcohol consumption for cardiovascular disease remains unclear. We used Mendelian randomization (MR) to predict the effect of alcohol consumption on 8 cardiovascular diseases.

Methods:

Up to 94 single-nucleotide polymorphisms were used as instrumental variables for alcohol consumption. Genetic association estimates for cardiovascular diseases were obtained from large-scale consortia and UK Biobank. Analyses were conducted using the inverse variance–weighted, weighted median, MR-PRESSO, MR-Egger, and multivariable MR methods.

Results:

Genetically predicted alcohol consumption was consistently associated with stroke and peripheral artery disease across the different analyses. The odds ratios (ORs) per 1-SD increase of log-transformed alcoholic drinks per week were 1.27 ([95% CI, 1.12–1.45]
P
=2.87×10
−4
) for stroke and 3.05 ([95% CI, 1.92–4.85]
P
=2.30×10
−6
) for peripheral artery disease in the inverse variance–weighted analysis. There was some evidence for positive associations of genetically predicted alcohol consumption with coronary artery disease (OR, 1.16 [95% CI, 1.00–1.36];
P
=0.052), atrial fibrillation (OR, 1.17 [95% CI, 1.00–1.37];
P
=0.050), and abdominal aortic aneurysm (OR, 2.60 [95% CI, 1.15–5.89];
P
=0.022) in the inverse variance–weighted analysis. These associations were somewhat attenuated in multivariable MR analysis adjusted for smoking initiation. There was no evidence of associations of genetically predicted alcohol consumption with heart failure (OR, 1.00 [95% CI, 0.68–1.47];
P
=0.996), venous thromboembolism (OR, 1.04 [95% CI, 0.77–1.39];
P
=0.810), and aortic valve stenosis (OR, 1.03 [95% CI, 0.56–1.90];
P
=0.926).

Conclusions:

This study provides evidence of a causal relationship between higher alcohol consumption and increased risk of stroke and peripheral artery disease. The causal role of alcohol consumption for other cardiovascular diseases requires further research.
The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction
Authors: Pan Bo , Li Jie , Parajuli Nirmal , Tian Zongwen , Wu Penglong , Lewno Megan T. , Zou Jianqiu , Wang Wenjuan , Bedford Lynn , Mayer R. John , Fang Jing , Liu Jinbao , Cui Taixing , Su Huabo , Wang Xuejun
Published: May 2020

Rationale:

The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Moreover, UPS and autophagic-lysosomal pathway defects are implicated in cardiac pathogenesis. Hence, a better understanding of the cross-talk between the 2 catabolic pathways will help advance cardiac pathophysiology and medicine.

Objective:

Systemic proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. Here we investigate how proteasome malfunction activates cardiac autophagic-lysosomal pathway.

Methods and Results:

Myocardial macroautophagy, TFEB (transcription factor EB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of
Psmc1
(an essential proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted by pharmacological and genetic calcineurin inhibition and by siRNA-mediated
Molcn1
silencing. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null (p62-KO) mice. Bortezomib-induced left ventricular wall thickening and diastolic malfunction was exacerbated by p62 deficiency. In cultured cardiomyocytes from wild type mice but not p62-KO mice, PSMI induced increases in LC3-II flux and the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62-KO mice compared with wild type mice.

Conclusions:

(1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) p62 unexpectedly exerts a feed-forward effect on TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1 (mucolipin1)-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac autophagic-lysosomal pathway activation during proteasome malfunction.
Gut Microbiota‐Dependent Trimethylamine N‐oxide and Cardiovascular Outcomes in Patients With Prior Myocardial Infarction: A Nested Case Control Study From the PEGASUS‐TIMI 54 Trial
Authors: Gencer Baris , Li Xinmin S. , Gurmu Yared , Bonaca Marc P. , Morrow David A. , Cohen Marc , Bhatt Deepak L. , Steg P. Gabriel , Storey Robert F. , Johanson Per , Wang Zeneng , Hazen Stanley L. , Sabatine Marc S.
Published: May 2020

Background

Trimethylamine N‐oxide (
TMAO
) may have prothrombotic properties. We examined the association of
TMAO
quartiles with major adverse cardiovascular events (
MACE
) and the effect of
TMAO
on the efficacy of ticagrelor.

Methods and Results

PEGASUS
‐
TIMI
54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin ‐ Thrombolysis in Myocardial Infarction 54) randomized patients with prior myocardial infarction to ticagrelor or placebo (median follow‐up 33 months). Baseline plasma concentrations of
TMAO
were measured in a nested case‐control study of 597 cases with cardiovascular death, myocardial infarction, or stroke (
MACE
) and 1206 controls matched for age, sex, and estimated glomerular filtration rate [
eGFR
]. Odds ratios (
OR
) were used for the association between
TMAO
quartiles and
MACE
, adjusting for baseline clinical characteristics (age, sex,
eGFR
, region, body mass index, hypertension, hypercholesterolemia, diabetes mellitus, smoking, peripheral artery disease, index event, aspirin dosage and treatment arm), and cardiovascular biomarkers (hs‐TnT [high‐sensitivity troponin T], hs‐
CRP
[high‐sensitivity C‐reactive protein],
NT
‐pro
BNP
[N‐terminal‐pro‐B‐type natriuretic peptide]). Higher
TMAO
quartiles were associated with risk of
MACE
(
OR
for quartile 4 versus quartile 1, 1.43, 95% CI, 1.06–1.93,
P
trend=0.015). The association was driven by cardiovascular death (
OR
2.25, 95% CI, 1.28–3.96,
P
trend=0.003) and stroke (
OR
2.68, 95% CI, 1.39–5.17,
P
trend<0.001). After adjustment for clinical factors, the association persisted for cardiovascular death (
OR
adj
1.89, 95% CI, 1.03–3.45,
P
trend=0.027) and stroke (
OR
adj
2.01, 95% CI, 1.01–4.01,
P
trend=0.022), but was slightly attenuated after adjustment for cardiovascular biomarkers (cardiovascular death:
OR
adj
1.74, 95% CI, 0.88–3.45,
P
trend=0.079; and stroke:
OR
adj
1.82, 95% CI, 0.88–3.78,
P
trend=0.056). The reduction in
MACE
with ticagrelor was consistent across
TMAO
quartiles (
P
interaction=0.92).

Conclusions

Among patients with prior myocardial infarction, higher
TMAO
levels were associated with cardiovascular death and stroke but not with recurrent myocardial infarction. The efficacy of ticagrelor was consistent regardless of
TMAO
levels.

Registration

URL
:
https://www.clini​caltr​ials.gov
; Unique identifiers:
PEGASUS
‐
TIMI
54,
NCT
01225562.
The liverwort genus Metzgeria (Metzgeriaceae, Marchantiophyta) in Thailand

Authors: SUKKHARAK PHIANGPHAK , CHANTANAORRAPINT SAHUT
Published: May 2020

The taxonomic account of the genus Metzgeria in Thailand is presented based on herbarium specimens and recent collections from field surveys. Five species of Metzgeria including M. consanguinea, M. furcata, M. kinabaluensis, M. leptoneura, and M. lindbergii are recognized. Of these, M. kinabaluensis is newly reported to Thailand. A key to the species, descriptions and illustrations of each species are provided. Ecology and geographical distribution of the species are noted. In addition, M. pubescens is excluded from the country.
Differentiation of external morphology of Oribatulidae (Acari: Oribatida) in light of the ontogeny of three species
Authors: SENICZAK STANISŁAW , SENICZAK ANNA
Published: May 2020

In this paper the differentiation of external morphology and ontogeny of Oribatulidae were investigated, on the basis ofPhauloppia lucorum (C. L. Koch, 1841), Lucoppia burrowsi (Michael, 1890), and Oribatula tibialis (Nicolet, 1855),which ontogeny is described and illustrated here for the first time. The juveniles of these species have smooth cuticle, aclavate sensillus with barbed head, and similar formulae of coxisternal, genital and aggenital setae, but differ mainly inbody size, formulae of gastronotal setae, number of setal excentrosclerites on the gastronotum, and shape of some setae.The number of setal excentrosclerites and presence of seta h 3 in larva differ the juveniles of Ph. lucorum and L. burrowsifrom those of O. tibialis, and seem to have generic value, and are also associated with the number of notogastral setae inadults (14 pairs in two former species, 13 pairs in latter species). The juveniles of O. tibialis lack excentrosclerite at setalm, comparing to those of Ph. lucorum and L. burrowsi, and this morphological character is shared with ScheloribatesBerlese, 1908 and Liebstadia Oudemans, 1906 from the family Scheloribatidae. The larva of O. tibialis lacks seta h 3 , sim-ilarly as that of Scheloribates, while the larvae of Ph. lucorum, L. burrowsi, and Liebstadia have this seta. Presence ofsetal pair c 3 in adult of Zygoribatula cf. frisiae (Oudemans, 1900) is recorded here for the first time, which indicates the order of loss of setae of c-series in Oribatulidae according to Grandjean (1951, 1958, 1968).
A synopsis of catalogs and checklists of harvestmen (Arachnida, Opiliones)
Authors: KURY ADRIANO B.
Published: May 2020

An annotated synopsis is presented of the publications which offer species checklists and catalogs of the arachnid orderOpiliones. Catalogs and checklists are included if they cover both (1) a suprafamilial group and (2) a country, continentalor zoogeographical region. Standardized information is given on the number of species treated and the taxonomic and geo-graphic scope. A total of 100 catalog works (7 of which are online only) are listed. They record from 4 to 6125 species,and they are classified into 3 categories: (1) manuals, which contain diagnoses and keys, (2) catalogs, which contain no-menclatural acts and synonymic literature headings and (3) checklists, which contain only a species list. Finally, a synopsisof key systematic works for each area in each zoogeographical region is given, and a species count is provided for all zogeographical regions of the world.
Fahimi’s racerunner, a new species of the genus Eremias Fitzinger, 1834 (Sauria: Lacertidae) from Iran
Authors: MOZAFFARI OMID , AHMADZADEH FARAHAM , SABERI-PIROOZ REIHANEH
Published: May 2020

We describe a new species of Lacertid lizard of the genus Eremias from the border of the northeastern side of Markazi Province to the western side of Tehran Province in Iran. Eremias fahimii sp. nov. is part of the Eremias subgenus (or morphotype) by virtue of lacking lateral fringes on the fourth toe, having movable eyelids, a lower nasal shield that rests on two supralabials, and ventral plates arranged in oblique longitudinal rows. It can be further differentiated from previously described species assigned to this morphotype by the absence of distinctly keeled upper caudal scales, gular scales that do not extend to the second inframaxiallary scales, shape and relative size of frontoparietals, parietal and parietals, scale counts and absence of lateral color ocellus. In addition, the molecular phylogeny of the most common Iranian racerunners including Eremias fahimii sp. nov. was studied using mitochondrial Cytochrome b (Cyt b) and 12S ribosomal RNA (12S) genes. Our results support the validation of the new species which depicts a sister group relationship to E. persica. Of the 20 species of Eremias known from Iran, E. fahimii sp. nov. is the seventh endemic species along with E. andersoni, E. isfahanica, E. lalezharica, E. kavirensis, E. montana and E. papenfussi. Despite the fact that up to now E. fahimii sp. nov. is only known from the type locality, it is highly probable that it also occurs in Tehran, Alborz, Qom, Qazvin and Zanjan Provinces due to topological characteristics and habitat similarities in these areas.
Description of larva and pupa of Phylloicus cressae Prather 2003 (Trichoptera: Calamoceratidae) from a montane forest stream in the peri-urban area of Caracas, Venezuela
Authors: BARRIOS MARGENNY C. , MENDOZA MARÍA D. , MONTOYA JOSÉ V.
Published: May 2020

Phylloicus is the most species-rich genus of the Neotropical Calamoceratidae. In Venezuela, twelve species are known from the adult stage and, from those, only one has its larval and pupal stages described. Here, we describe and illustrate the larva, pupa, and case of Phylloicus cressae, from a first order stream of the heavily disturbed Tuy River watershed in the peri-urban area of Caracas, northcentral Venezuela.
Estimating and Modeling the Effects of Grass Growth on Surface Runoff through a Rainfall Simulator on Field Plots
Authors: Montaldo Nicola , Curreli Matteo , Corona Roberto , Saba Andrea , Albertson John D.
Published: May 2020

Seasonal changes in grass cover impact the generation of surface runoff due to the effects of grass roots on soil hydrologic properties and processes (i.e., infiltration). Using a rainfall simulator in a grass field site, we broadly investigated the influence of different initial conditions of soil moisture and grass growth stages on rainfall–runoff transformations. To parameterize the stages of grass growth, we used the height of the vegetation hveg, which is related to the leaf area index. Surprisingly, typical characteristics of runoff formation (peak flow and time to peak flow) were conditioned mainly by hveg. The runoff coefficient decreased about 40% when grass reached its maximum growth and was inversely and significantly related to the height of grass in general. Using the rainfall simulator experiments, we estimated the saturated soil hydraulic conductivity ks, a key parameter of infiltration models. We found strong relationships between ks and hveg when the Philip infiltration model was used, and we proposed a linear relationship between ks and hveg, making ks vary in time with grass growth (i.e., hveg). We compared predictions of hydrologic models at plot scale using ks varying with grass growth with predictions using a constant ks, as hydrological models commonly assume. Neglecting ks variability with grass growth can lead to errors up to 100% in surface runoff predictions at an event time scale and up to 87% at a monthly time scale. Ecohydrological models for runoff predictions should take into account the influence of grass growth dynamics on soil infiltration parameters.