bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilaminar Technique with Coronally Advanced Flap and Cryopreserved Human Amniotic Membrane in the Treatment of Gingival Recessions
Authors: Martelloni Mario , Boccaletto Pietro , Montagner Giulia , Trojan Diletta , Abate Roberta
Published: August 2020

Gingival recessions are usually treated with surgical therapies which involve the use of connective tissue autograft in order to thicken the gingival tissue. This has an important biological repercussion on patients since they will have surgical wounds in two different oral cavity sites. In this case report, we offer an alternative technique for the treatment of a Miller class I gingival recession. A 40-year-old female patient has been treated with a combination of bilaminar and coronally advance flap techniques to cover a Miller class I gingival recession with addition of cryopreserved human amniotic membrane. The human amniotic membrane has been employed to thicken the keratinized tissue. The human amniotic membrane in combination with bilaminar and coronally advance flap techniques has produced aesthetically and functionally satisfying results, covering completely the gingival recession and restoring the natural colour and thickness of the gingiva. Bilaminar technique with coronally advanced flap and cryopreserved human amniotic membrane is a valid alternative in treating Miller class I and II gingival recessions and reduce the biological morbidity of a double intervention.
Effectiveness and Safety of Oral Chinese Patent Medicines Combined with Chemotherapy for Gastric Cancer: A Bayesian Network Meta‐Analysis
Authors: Lu Xiaona , Zheng Yawei , Wen Fang , Huang Wenjie , Shu Peng
Published: August 2020

Objectives. This network meta‐analysis (NMA) was designed to assess the comparative effectiveness and safety of oral Chinese patent medicines combined with chemotherapy for gastric cancer on the National Basic Medical Insurance Drugs List of China. Methods. A comprehensive literature search was performed in seven electronic databases from their inception to February 25, 2020, aiming to collect all related randomized controlled trials (RCTs) to evaluate the effectiveness and safety of oral Chinese patent medicines as an adjuvant for gastric cancer. Two researchers independently screened the literature, extracted data, and assessed the risk of bias of included studies using the Cochrane Risk of Bias Scale. NMA was then performed by using STATA 16.0 software and ADDIS 1.16.8 software. Results. Finally, 30 RCTs were included, involving seven kinds of oral Chinese patent medicines, with a total of 2602 patients. For improvement of clinical efficacy, Bazhen granule combined with chemotherapy was ranked first for effectiveness, followed by the Cinobufacin capsule combined with chemotherapy and Xiao’aiping tablet combined with chemotherapy. Meanwhile, Bazhen granules combined with chemotherapy also were ranked first in reducing gastrointestinal reactions. In terms of improving performance status, the Xiao’aiping tablet was the best and significantly better than other oral Chinese patent medicines. Besides, the Zhenqi Fuzheng granule combined with chemotherapy was best for reducing the incidence of leucopenia. Conclusions. Since only one RCT of Bazhen granule was included in this study for analysis, its statistical efficiency is low. Therefore, this study recommends that the Cinobufacin capsule combined with chemotherapy should be a priority in improving clinical efficacy. In terms of improving patients’ quality of life, Xiao’aiping tablet is the best choice. Safety was best for Zhenqi Fuzheng granule and Bazhen granule combined with chemotherapy. Limited by the quantity, quality, and possible bias of included studies, the above conclusions need to be further verified by more high‐quality RCTs.
The Effects of Platelet-Rich and Platelet-Poor Plasma on Biological Characteristics of BM-MSCs In Vitro
Authors: Zhang Jiahui , Zhang Jun , Zhang Nannan , Li Tao , Zhou Xiaohe , Jia Jue , Liang Yingying , Sun Xiaochun , Chen Huabiao
Published: August 2020

Platelet-rich plasma (PRP) and its byproduct platelet-poor plasma (PPP) are rich sources of cytokines in tissue damage repair. Bone marrow-derived mesenchymal stem cells (BM-MSCs) have received more and more attention for their ability to treat multiple diseases. The purpose of our study was to investigate the biologic action of PPP and PRP on BM-MSCs. The adipogenic potential of BM-MSCs revealed no obvious change, but the osteogenic ability of BM-MSCs was enhanced after treated with PRP. CCK8 assays and cell colony formation assays showed that PRP promoted cell proliferation, while this effect of PPP was not obvious. No obvious difference was found in cell cycle and apoptosis of BM-MSCs between PRP and PPP treatment. Expression of β-galactosidase, a biological marker of senescence, was decreased upon PRP treatment which indicated that PRP provided significant protection against cellular senescence. The migratory capacity of BM-MSCs was detected by scratch and transwell assays. The results indicated that PRP could affect the migration ability of BM-MSCs. From immunofluorescence detection and western blot, we demonstrated that the level of epithelial-mesenchymal transition-related proteins was changed and several pluripotency marker genes, including Sox2, Sall4, Oct4, and Nanog, were increased. Finally, the expression of the key signal pathway such as PI3K/AKT was examined. Our findings suggested that PRP promoted cell migration of BM-MSCs via stimulating the signaling pathway of PI3K/AKT.
Evaluation of the Challenges in the Internet of Medical Things with Multicriteria Decision Making (AHP and TOPSIS) to Overcome Its Obstruction under Fuzzy Environment
Authors: Tariq Muhammad Imran , Mian Natash Ali , Sohail Abid , Alyas Tahir , Ahmad Rehan
Published: August 2020

The exponential speed of advancement of innovation has expanded the needs of all users to avail all their information on the Internet 24/7. The Internet of things (IoT) enables smart objects to develop a significant building block in the development of the pervasive framework. The messaging between objects with one another means the least work and least expense for the enterprise. The industry that intends to implement the Internet of medical things (IoMT) in its organizations is still facing difficulties. Recognition and solving of these challenges are a time-consuming task and also need significant expenses if not adequately evaluated and prioritized. The application of the Internet of things is covered in almost every area, including medical/healthcare. In this research, the authors investigated the factors dealing with the Internet of medical things. The outcome of this study is to prioritize the level of significance of the elements causing these challenges, evaluated through fuzzy logic and multicriteria decision-making (MCDM) techniques like Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) and Analytic Hierarchy Process (AHP). It would be beneficial for enterprises to save time and revenue. The main criteria, as well as subcriteria, were determined after due consultation with the Internet of medical things experts. In this study, our goals are to figure out which criteria/factors create hurdles in the adoption of the Internet of medical things. Through the investigation, we figured out 20 criteria ought to be given more importance/preference by the industry that is in the transition phase of the Internet of medical things adoption. The enterprise, with the help of this study, will be enabled to accelerate that adoption by limiting time and fiscal misfortune.
Nonlinear Vibration Analysis of Damaged Microplate considering Size Effect
Authors: Yuan Jihai , Zhang Xiangmin , Chen Changping
Published: August 2020

Since microplates are extensively used in MEMS devices such as microbumps, micromirrors, and microphones, this work aims to study nonlinear vibration of an electrically actuated microplate whose four edges are clamped. Based on the modified couple stress theory (MCST) and strain equivalent assumption, size effect and damage are taken into consideration in the present model. The dynamic governing partial differential equations of the microplate system were obtained using Hamilton’s principle and solved using the harmonic balance method after they are transformed into ordinary differential equation with regard to time. Size effect and damage effect on nonlinear free vibration of the microplate under DC voltage are discussed using frequency-response curve. In the forced vibration analysis, the frequency-response curves were also employed for the purpose of highlighting the influence of different physical parameters such as external excitation, damping coefficient, material length scale parameter, and damage variable when the system is under AC voltage. The results presented in this study may be helpful and useful for the dynamic stability of a electrically actuated microplate system.
Large‐Scale Shaking Table Test of Seismic Response Laws for a Shallow Double‐Arch Tunnel under Unsymmetrical Pressure with a Damping Layer
Authors: Yang Hui , Zhou Wang , Liu Chan , Jiang Xueliang , Yu Lei
Published: August 2020

Based on the similarity theory, a large‐scale shaking table test of a shallow double‐arch tunnel under unsymmetrical pressure with a similarity ratio of 1 : 20 was designed and completed, and a foam concrete damping layer was set in the double‐arch tunnel. The acceleration response, strain response, and crack distribution of double‐arch tunnels under different intensities and different directions of the Wenchuan wave excitation were studied (WC‐X, WC‐Z, and WC‐XZ). The results showed that (1) the bias side (right hole) is greatly affected by the unevenness of the cover soil, and the horizontal acceleration response difference between the two tunnels is large and there is no symmetry. The incident direction of seismic waves has a great influence on the acceleration response of double‐arch tunnels. The amplification factor of WC‐Z is greater than that of WC‐X. (2) On the same horizontal plane, with the vertical centerline of the middle wall as the axis of symmetry, the vertical acceleration amplification factor also has a large difference between the arch foot and the shoulder, but the difference is relatively small at other points. (3) The dynamic strain increases with the increase of seismic intensity, and the tendency is similar under the three different seismic wave excitation directions. The lining is under tensile strain and compressive strain, the strain of the left hole is greater than the strain of the right hole, and severe stress concentration occurs at the top left of the mid partition. (4) The middle partition, shoulder, and vault of the left hole and the shoulder, vault, and foot of the right hole are weak parts of earthquake resistance. Therefore, special attention should be paid to the seismic design.
Cognitive Assessments Used in Occupational Therapy Practice: A Global Perspective
Authors: Manee Fahad S. , Nadar Mohammed Shaban , Alotaibi Naser M. , Rassafiani Mehdi
Published: August 2020

This exploratory study was aimed at evaluating the current status of global occupational therapy practice on the use of assessments for clients with cognitive impairments and providing recommendations for ongoing evidence. We targeted international occupational therapy clinicians working with clients experiencing neurocognitive impairments. 323 occupational therapists from a wide range of clinical practice areas participated in the study. A large number of therapists used noncognitive specific assessments with a focus on functional approaches. The most commonly used standardized assessments were the COPM (56.7%), followed by MMSE (54.2%) and MoCA (45.5%), while the nonstandardized assessments were clinical observation (38.4%) and generic ADL assessment (34.1%). The use of main assessments was significantly different across world regions (p<0.05), as were the reasons for choosing them (p<0.05). The occupational therapists’ use of assessment tools with clients suffering from neurocognitive impairments is inconsistent across the globe. The identification of international best practices for selecting and implementing proper outcome measures is warranted. It is essential to promote the development of an occupational therapy initiative to support the use of appropriate assessments at the international levels to facilitate consistent best practice.
Characteristics and Outcomes for Secondary Breast Cancer in Childhood, Adolescent, and Young Adult Cancer Survivors Treated with Radiation
Authors: Sauder Candice A.M. , Li Qian , Othieno Alisha , Cruz Daisy , Arora Mili , Bold Richard J. , Meyers Fredrick J. , Keegan Theresa H.M.
Published: August 2020

Background:

Radiotherapy is used to treat many adolescent and young adult (AYA) and childhood cancer patients and is a risk factor for secondary breast cancer. While premenopausal breast cancer is inherently more aggressive, no studies to date have evaluated the characteristics and breast cancer–specific survival (BCSS) of premenopausal secondary breast cancer after radiotherapy in AYA and childhood cancer survivors.

Methods:

Female patients ages 12 to 50 diagnosed with primary breast cancer from 1988 to 2014 (n = 107,751) were obtained from the California Cancer Registry and compared with similar aged patients with secondary breast cancer who were treated with radiotherapy for their primary tumor (n = 1,147) from ages 12 to 39. We examined BCSS using multivariable Cox proportional hazards regression.

Results:

The secondary breast cancer cohort was more likely to be Hispanic or Black, be 35 to 45 years of age, have earlier stage tumors, be higher grade, have no lymph node involvement, and be hormone receptor negative. All women showed worse BCSS for large tumor size, lymph node involvement, and hormone receptor–negative status. BCSS was worse for women with secondary breast cancer both overall (hazard ratio, 1.98; 95% confidence interval, 1.77–2.23) and in all subgroups considered. Associations were most pronounced in Hispanics, Asian/Pacific Islanders, and younger women, as well as those with earlier stage, lymph node–negative, and hormone receptor–positive disease.

Conclusions:

BCSS is significantly decreased among all survivors of childhood and AYA cancer treated with radiotherapy that develop a secondary breast cancer, including women with good prognostic features.

Impact:

Therefore, we may need to consider alternative and even more aggressive treatment in what were considered low-risk populations previously.
Immunomodulatory Activity of a Colony-stimulating Factor-1 Receptor Inhibitor in Patients with Advanced Refractory Breast or Prostate Cancer: A Phase I Study
Authors: Autio Karen A. , Klebanoff Christopher A. , Schaer David , Kauh John Sae Wook , Slovin Susan F. , Adamow Matthew , Blinder Victoria S. , Brahmachary Manisha , Carlsen Michelle , Comen Elizabeth , Danila Daniel C. , Doman Thompson N. , Durack Jeremy C. , Fox Josef J. , Gluskin Jill S. , Hoffman David M. , Kang Suhyun , Kang Praneet , Landa Jonathan , McAndrew Philomena F. , Modi Shanu , Morris Michael J. , Novosiadly Ruslan , Rathkopf Dana E. , Sanford Rachel , Chapman Sonya C. , Tate Courtney M. , Yu Danni , Wong Phillip , McArthur Heather L.
Published: August 2020

Purpose:

Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855.

Patients and Methods:

Patients with advanced refractory metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) were treated with LY3022855 intravenously in 6-week cycles in cohorts: (A) 1.25 mg/kg every 2 weeks (Q2W); (B) 1.0 mg/kg on weeks 1, 2, 4, and 5; (C) 100 mg once weekly; (D)100 mg Q2W. mCRPC patients were enrolled in cohorts A and B; patients with MBC were enrolled in all cohorts. Efficacy was assessed by RECIST and Prostate Cancer Clinical Trials Working Group 2 criteria.

Results:

Thirty-four patients (22 MBC; 12 mCRPC) received ≥1 dose of LY3022855. At day 8, circulating CSF-1 levels increased and proinflammatory monocytes CD14DIMCD16BRIGHT decreased. Best RECIST response was stable disease in five patients with MBC (23%; duration, 82–302 days) and three patients with mCRPC (25%; duration, 50–124 days). Two patients with MBC (cohort A) had durable stable disease >9 months and a third patient with MBC had palpable reduction in a nontarget neck mass. Immune-related gene activation in tumor biopsies posttreatment was observed. Common any grade treatment-related adverse events were fatigue, decreased appetite, nausea, asymptomatic increased lipase, and creatine phosphokinase.

Conclusions:

LY3022855 was well tolerated and showed evidence of immune modulation. Clinically meaningful stable disease >9 months was observed in two patients with MBC.
Concentration-dependent Early Antivascular and Antitumor Effects of Itraconazole in Non–Small Cell Lung Cancer
Authors: Gerber David E. , Putnam William C. , Fattah Farjana J. , Kernstine Kemp H. , Brekken Rolf A. , Pedrosa Ivan , Skelton Rachael , Saltarski Jessica M. , Lenkinski Robert E. , Leff Richard D. , Ahn Chul , Padmanabhan Chyndhri , Chembukar Vaidehi , Kasiri Sahba , Kallem Raja Reddy , Subramaniyan Indhumathy , Yuan Qing , Do Quyen N. , Xi Yin , Reznik Scott I. , Pelosof Lorraine , Faubert Brandon , DeBerardinis Ralph J. , Kim James
Published: August 2020

Purpose:

Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients.

Experimental Design:

Patients with non–small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10–14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers.

Results:

Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, −0.71; P = 0.05) and tumor perfusion (Ktrans; Spearman correlation, −0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, −0.73; P = 0.01) and GM-CSF (Spearman correlation, −1.00; P < 0.001), and reduction in tumor microvessel density (Spearman correlation, −0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations.

Conclusions:

Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.
Calcium Channel Blockers Impair the Antitumor Activity of Anti-CD20 Monoclonal Antibodies by Blocking EGR-1 Induction
Authors: Spasevska Ivana , Matera Eva Laure , Chettab Kamel , Ville Jade , Potier-Cartereau Marie , Jordheim Lars Petter , Thieblemont Catherine , Sahin Denis , Klein Christian , Dumontet Charles
Published: August 2020

Direct cell death induction, in addition to immune-effector cell-mediated mechanisms, is one of the key mechanisms of action of anti-CD20 antibodies, and yet the signaling pathways implicated remain poorly investigated. Here we show that the transcription factor EGR-1 is rapidly induced by anti-CD20 antibodies and is a key mediator for CD20-induced cell death. EGR-1 induction results from an increased calcium influx induced by anti-CD20 antibodies. We show that both rituximab and obinutuzumab induce calcium influx, albeit through different mechanisms, and this influx is crucial for cell death induction. Inhibition of the calcium flux with calcium channel blockers (CCB) abolished EGR-1 induction and impaired the efficacy of anti-CD20 antibodies in preclinical in vitro and in vivo models. Finally, we investigated the impact of CCBs in patients treated with anti-CD20 antibodies included in the clinical trials GOYA and REMARC, and found that patients simultaneously receiving CCBs and anti-CD20 therapy have a shorter progression-free survival and overall survival. These results reveal EGR-1 as a key mediator of the direct cytotoxic activity of anti-CD20 antibodies and provide a rationale to evaluate EGR-1 expression as a new biomarker to predict response to anti-CD20 treatment. In addition, our findings show that calcium influx is required for anti-CD20–mediated tumor cell death and suggest that simultaneous administration of calcium channel blocking agents could be deleterious in patients receiving anti-CD20–based immunotherapy.
Dysregulation of EAAT2 and VGLUT2 Spinal Glutamate Transports via Histone Deacetylase 2 (HDAC2) Contributes to Paclitaxel-induced Painful Neuropathy
Authors: Wang Xiao-Min , Gu Pan , Saligan Leorey , Iadarola Michael , Wong Stanley Sau Ching , Ti Lian Kah , Cheung Chi Wai
Published: August 2020

Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel (2 mg/kg, i.p., cumulative dose 8 mg/kg) induced long-lasting mechanical allodynia (>28 days) with increased glutamate concentration and decreased EAAT2 expression with no changes in GABA/glycine or VGAT (vesicular GABA transporter) in rat spinal dorsal horn. VGLUT2 expression was upregulated and coexpressed with enhanced synaptophysin, characterizing nociceptive afferent sprouting and new synapse formation of glutamatergic neurons in the spinal cord dorsal horn. HDAC2 and transcription factor YY1 were also upregulated, and their interaction and colocalization were confirmed following paclitaxel treatment using co-immunoprecipitation. Inhibition or knockdown of HDAC2 expression by valproic acid, BRD6688, or HDAC2 siRNA not only attenuated paclitaxel-induced mechanical allodynia but also suppressed HDAC2 upregulation, glutamate accumulation, and the corresponding changes in EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction. These findings indicate that loss of the balance between glutamate release and reuptake due to dysregulation EAAT2/VGLUT2/synaptophysin cascade in the spinal dorsal horn plays an important role in the development of paclitaxel-induced neuropathic pain. HDAC2/YY1 interaction as a complex appears essential in regulating this pathway, which can potentially be a therapeutic target to relieve CIPN by reversing central sensitization of spinal nociceptive neurons.
Concurrent Targeting of Potential Cancer Stem Cells Regulating Pathways Sensitizes Lung Adenocarcinoma to Standard Chemotherapy
Authors: Shibata Masahiro , Ooki Akira , Inokawa Yoshikuni , Sadhukhan Pritam , Ugurlu M. Talha , Izumchenko Evgeny , Munari Enrico , Bogina Giuseppe , Rudin Charles M. , Gabrielson Edward , Singh Anju , Hoque Mohammad O.
Published: August 2020

Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined with chemotherapy in lung adenocarcinoma. Here, we showed that YAP1 contributes to CSC regulation and enhances tumor formation while suppressing apoptosis. Mechanistically, YAP1 promotes phosphorylation of STAT3 by upregulating IL6. In lung adenocarcinoma clinical specimens, YAP1 expression correlated with that of IL6 (P < 0.01). More importantly, YAP1 and phosphorylated STAT3 (pSTAT3) protein expressions were significantly correlated (P < 0.0001) in primary lung adenocarcinoma as determined by IHC. Immunoblotting of 13 lung adenocarcinoma patient-derived xenografts (PDX) showed that all YAP1-expressing PDXs also exhibited pSTAT3. Additional investigations revealed that chemotherapy resistance and malignant stemness were influenced by upregulating NANOG, OCT4, and SOX2, and the expression of these targets significantly attenuated by genetically and pharmacologically hindering the activities of YAP1 and STAT3 in vivo and in vitro. Therapeutically, the dual inhibition of YAP1 and STAT3 elicits a long-lasting therapeutic response by limiting CSC expansion following chemotherapy in cell line xenograft and PDX models of lung adenocarcinoma. Collectively, these findings provide a conceptual framework to target the YAP1 and STAT3 pathways concurrently with systemic chemotherapy to improve the clinical management of lung adenocarcinoma, based on evidence that these two pathways expand CSC populations that mediate resistance to chemotherapy.
Dual Epitope Targeting and Enhanced Hexamerization by DR5 Antibodies as a Novel Approach to Induce Potent Antitumor Activity Through DR5 Agonism
Authors: Overdijk Marije B. , Strumane Kristin , Beurskens Frank J. , Ortiz Buijsse Antonio , Vermot-Desroches Claudine , Vuillermoz Boris S. , Kroes Thessa , de Jong Bart , Hoevenaars Naomi , Hibbert Richard G. , Lingnau Andreas , Forssmann Ulf , Schuurman Janine , Parren Paul W.H.I. , de Jong Rob N. , Breij Esther C.W.
Published: August 2020

Higher-order death receptor 5 (DR5) clustering can induce tumor cell death; however, therapeutic compounds targeting DR5 have achieved limited clinical efficacy. We describe HexaBody-DR5/DR5, an equimolar mixture of two DR5-specific IgG1 antibodies with an Fc-domain mutation that augments antibody hexamerization after cell surface target binding. The two antibodies do not compete for binding to DR5 as demonstrated using binding competition studies, and binding to distinct epitopes in the DR5 extracellular domain was confirmed by crystallography. The unique combination of dual epitope targeting and increased IgG hexamerization resulted in potent DR5 agonist activity by inducing efficient DR5 outside-in signaling and caspase-mediated cell death. Preclinical studies in vitro and in vivo demonstrated that maximal DR5 agonist activity could be achieved independent of Fc gamma receptor–mediated antibody crosslinking. Most optimal agonism was observed in the presence of complement complex C1, although without inducing complement-dependent cytotoxicity. It is hypothesized that C1 may stabilize IgG hexamers that are formed after binding of HexaBody-DR5/DR5 to DR5 on the plasma membrane, thereby strengthening DR5 clustering and subsequent outside-in signaling. We observed potent antitumor activity in vitro and in vivo in large panels of patient-derived xenograft models representing various solid cancers. The results of our preclinical studies provided the basis for an ongoing clinical trial exploring the activity of HexaBody-DR5/DR5 (GEN1029) in patients with malignant solid tumors.
Retargeted and Stealth-Modified Oncolytic Measles Viruses for Systemic Cancer Therapy in Measles Immune Patients
Authors: Bah Eugene S. , Nace Rebecca A. , Peng Kah Whye , Muñoz-Alía Miguel Ángel , Russell Stephen J.
Published: August 2020

Measles viruses (MV) are rapidly inactivated by anti-measles neutralizing antibodies, which has limited their clinical performance as oncolytic agents. Here, by substituting the H and F surface glycoproteins of MV with those from the homologous canine distemper virus (CDV) and engineering the CDV H attachment protein to target EGFR or CD38, we generated a fully retargeted MV capable of resisting neutralization by measles-immune human serum. The resultant recombinant MVs encoding retargeted CDV envelope glycoproteins had similar growth kinetics as the control MV, showed the expected engineered receptor specificities for cell entry, intercellular fusion, and target cell killing, and were blind to native CDV receptors. In contrast to the control MV, recombinant MVs incorporating CDV F and H glycoproteins retained full infectivity when exposed to high concentrations of pooled measles-immune human serum. Comparing viruses bearing MV or CDV glycoproteins in the SKOV3ip.1 model, only the virus bearing an EGFR-retargeted CDV envelope glycoprotein complex was capable of limiting tumor growth and extending the survival in measles immune mice. MV, “stealthed” and retargeted using engineered CDV surface glycoproteins, may be a promising platform to advance for systemic cancer therapy in measles immune patients.
Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody–Drug Conjugate
Authors: Anderson Mark G. , Falls Hugh D. , Mitten Michael J. , Oleksijew Anatol , Vaidya Kedar S. , Boghaert Erwin R. , Gao Wenqing , Palma Joann P. , Cao Diana , Chia Puey-Ling , John Thomas , Gan Hui K. , Scott Andrew M. , Reilly Edward B.
Published: August 2020

ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody–drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or amplification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and in vivo studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.
Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors
Authors: Chiorean E. Gabriela , Perkins Susan M. , Strother R. Matthew , Younger Anne , Funke Jennifer M. , Shahda Safi G. , Hahn Noah M. , Sandrasegaran Kumar , Jones David R. , Skaar Todd C. , Schneider Bryan P. , Sweeney Christopher J. , Matei Daniela E.
Published: August 2020

VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).
An IL6–Adenosine Positive Feedback Loop between CD73+ γδTregs and CAFs Promotes Tumor Progression in Human Breast Cancer
Authors: Hu Guoming , Cheng Pu , Pan Jun , Wang Shimin , Ding Qiannan , Jiang Zhou , Cheng Lu , Shao Xuan , Huang Liming , Huang Jian
Published: August 2020

The tumor microenvironment induces immunosuppression via recruiting and expanding suppressive immune cells such as regulatory T cells (Treg) to promote cancer progression. In this study, we documented that tumor-infiltrating CD73+ γδTregs were the predominant Tregs in human breast cancer and exerted more potent immunosuppressive activity than CD4+ or CD8+ Tregs. We further demonstrated that cancer-associated fibroblast (CAF)–derived IL6, rather than TGFβ1, induced CD73+ γδTreg differentiation from paired normal breast tissues via the IL6/STAT3 pathway to produce more adenosine and become potent immunosuppressive T cells. CD73+ γδTregs could in turn promote IL6 secretion by CAFs through adenosine/A2BR/p38MAPK signaling, thereby forming an IL6–adenosine positive feedback loop. CD73+ γδTreg infiltration also impaired the tumoricidal functions of CD8+ T cells and significantly correlated with worse prognosis of patients. The data indicate that the IL6–adenosine loop between CD73+ γδTregs and CAFs is important to promote immunosuppression and tumor progression in human breast cancer, which may be critical for tumor immunotherapy.
A Ingratidão: o diabo alegórico de José de Anchieta
Authors: Domene Marina Gialluca
Published: August 2020

Não há como se compreender uma narrativa - seja ela em prosa, em verso ou em cena - sem olhar para suas personagens. E a frequência com que um tipo de personagem figura na obra de um autor pode dizer muito sobre a visão de mundo que ele ou ela busca imprimir em seus textos, sobretudo quando se trata de autores com um objetivo específico. No caso do teatro do padre José de Anchieta, que buscava a catequese tanto de ameríndios quanto de colonos no Brasil do século XVI, a frequência com que o Diabo se apresenta em cena é muito significativa. De todos os demônios que ele apresenta, todos eles carregando pecados que o padre-dramaturgo vê cometidos ao seu redor, tanto por brancos quanto por ameríndios, um se destaca. A Ingratidão, em Na vila de Vitória, é o único diabo de gênero feminino, mas também é o único diabo que carrega, em si, a carga de uma alegoria. Isso a torna única dentro do contexto da obra do jesuíta, e digna de um estudo mais aprofundado, que é o objetivo deste artigo, produto da minha pesquisa de mestrado.
Linhas para o Interior de uma igreja, de Pieter Neeffs
Authors: Oliveira Pedro Furtado de
Published: August 2020

Poema sobre uma pintura de Pieter Neeffs.
Palavra colônia
Authors: Diniz Liana Ferraz
Published: August 2020

'Palavra Colônia' é uma poesia escrita em um fluxo de pensamento que revela caoticamente o sentido de insignificância de uma pesquisadora brasileira.
Um útero como máquina performática: uma leitura de Um útero é do tamanho de um punho no mundo
Authors: Beraldo Juliana de Assis
Published: August 2020

Um útero é do tamanho de um punho (2012), de Angélica Freitas, apresenta lugares comuns do discurso sobre mulheres usando diferentes procedimentos. O livro obteve uma recepção significativa e a partir dele se articularam leituras que focalizaram tanto aspectos poéticos como políticos. Este artigo possui como interesse central o mapeamento de alguns dos desdobramentos e modos de funcionamentos deste livro em diferentes esferas: desde o contexto de sua própria produção e inquietações primeiras, até a percepção de como estabelece relações com outras produções contemporâneas. A proposta é refletir sobre o livro como uma máquina performática, seguindo as discussões de Aguilar e Cámara (2017). Trata-se de uma abordagem que pretende analisar os mais diversos signos que compõem o campo dos poemas permitindo por em discussão noções de literário, estético e político. Assim, este trabalho deseja impulsionar estudos sobre as políticas da poesia e da crítica, entendendo a literatura como campo expandido (KRAUSS, 1979) e buscando possibilidades e experimentações no método de crítica por meio de uma experiência de desierarquização dos signos. Portanto, incentiva-se a refletir sobre a forma com que os poemas circulam e impactam a sociedade promovendo outras configurações políticas.
O absurdo impertinente: intersecções filosóficas e fantásticas na obra de José J. Veiga
Authors: Corrêa Rafael Vinicius Costa
Published: August 2020

Esse artigo visa apresentar duas concepções que apresentam possíveis encontros na análise da narrativa do escritor brasileiro José J. Veiga. Primeiramente, demonstraremos como se desenvolve uma das teorias de análise contemporâneas do fantástico na literatura sob a perspectiva do professor David Roas (2011, 2014). A seguir, através do estudo da obra do filósofo e escritor argelino Albert Camus, em especial seu livro O mito de Sísifo (2019), iremos apontar em linhas gerais as características mais discutidas da chamada filosofia do absurdo defendida pelo escritor. A partir dessas comparações iremos apontar as semelhanças entre os estudos filosóficos de Camus e a teoria da literatura fantástica desenvolvida por Roas e apontar como ambas apresentam pontos de intersecção na literatura do autor brasileiro José J. Veiga, em especial em dois de seus contos “O galo impertinente” e “ Onde andam os didangos?”, ambos do livro A estranha máquina extraviada (2010), conduzindo a uma leitura fantástica-absurda da obra do autor em conexão com uma possível ontologia de mundo.
Entre a performance e a escrita: um olhar sobre a literatura expandida contemporânea na poesia marginal-periférica de Nívea Sabino
Authors: Souza Luiz Eduardo Rodrigues de Almeida , Coelho Rogério Meira
Published: August 2020

Pretende-se nesse artigo construir uma leitura analítica sobre as vozes, corpos e espaços entre a performance e a escrita da poeta Nívea Sabino, que participa da cena/movimento/circuito dos saraus e slams marginais-periféricos de Belo Horizonte (MG). Para isso, apresentamos uma breve incursão pelas estéticas do marginal e do periférico em contraponto ao espaço/lugar da literatura contemporânea contestada, relacionando o contexto sociocultural dessa produção literária à margem com as vozes, escritas e performances do movimento e circuito de saraus e slams. Da produção escrita de Nívea, teremos como base um dos poemas do livro Interiorana, como suporte, para entendermos uma literatura que nasce e é criada no “entre” a performance e a escrita.
Silentium
Authors: Geraldo Vitor Hugo Luís
Published: August 2020

Criação literária.
A importância da viagem: uma correspondência poética entre poetas e caraíbas
Authors: Coroa Leila Melo , Guimarães Mayara Ribeiro
Published: August 2020

Este trabalho se dispôs a interpretar as longas peregrinações realizadas pelos tupis-guaranis de modo a estabelecer relação com uma noção de viagem que é muito cara à linguagem poética, aliás, própria do estatuto do poeta, ou seja, daquele que se lança no fazer poético; assim como a imagem ascética e errante do caraíba, enquanto designação também do poeta. Deste modo, pensar nesta correspondência entre o ritual indígena em busca de um território sagrado para refletir no próprio expediente poético, e em como ambos dialogam, ao entenderem, cada um à sua maneira, a importância da viagem, de sua trajetória e errância, mas também da figura do profeta-poeta, ou seja, daquele que se dispõe obstinada e religiosamente, no sentido da busca pelo sagrado, nesta perquirição. Para estabelecer tal correspondência, usaremos a trajetória poética de Max Martins, pois ele incorporou tais aspectos. Entre os teóricos que direcionaram este trabalho estão Maurice Blanchot, Martin Heidegger, Benedito Nunes, Edmond Jabès, entre outros.
Spatial aggregation and specificity of incidents with wildlife make tea plantations in southern India potential buffers with protected areas
Authors: Kalam Tamanna , Puttaveeraswamy Tejesvini A. , Srivastava Rajeev K. , Puyravaud Jean-Philippe , Davidar Priya
Published: August 2020

Abstract: Many wildlife species survive in human-modified landscapes and understanding the opinions of those who share space with wildlife will aid conservation efforts.  Using a questionnaire, we assessed the presence of 12 mammal species in 78 tea plantations in the Nilgiris, southern India.  We obtained data on (i) plantation size, location, and elevation, (ii) species presence over a year, (iii) type and number of wildlife incidents caused, (iv) financial cost of wildlife damage, and (v) support for wildlife conservation.  We used a generalized linear model to assess whether the distance to protected areas, elevation, and plantation size influenced species presence and the effect of these variables and wildlife incidents on support for conservation.  Among all species reported, Bonnet Macaque, Wild Boar, and Porcupine were the most widespread, and the former two and the Gaur reportedly caused >50% of damages.  Crop damage was the most frequent (74%, n = 244), whereas livestock predation, attacks on people, and infrastructure damage constituted <10% of incidents reported.  The cost of wildlife damage was negligible for 72 estates and significant for six.  The number of species increased with proximity to protected areas, with increasing elevation and plantation area. Plantation management (62%) supported wildlife conservation, and support increased with decreasing plantation size, increasing distance to protected areas, and with a higher number of species reported, but decreased with increasing incidents of wildlife damage.  Mitigating impacts of a few widely distributed species that cause disproportionate damage and compensating those that incur disproportionately high costs could increase support for conservation.  Education and awareness programs for the plantation community can further help increase support and participation in wildlife conservation activities.  Plantations can thus serve as supplementary habitats for wildlife in regions where hard boundaries between protected areas and human settlements prevail.
Innovative way of human-elephant competition mitigation
Authors: Sanjit Kumar Saha
Published: August 2020

Abstract: The negative interaction between humans and elephants is often referred to as conflict, however it is also seen as competition.  Human-elephant competition (HEC) is a major protection threat in the fringe villages of the Jaldapara National Park (JPNP) of West Bengal, India.  JPNP is facing challenges from the highly populated fringe villages, which exist in elephant corridors.  Between 2015 and 2018 there were 12 elephant deaths.  During the same period elephants caused 34 human deaths.  As per data, most of the elephant interactions occurred in the fringe villages of Madarihat and Jaldapara North Range.  Per reports of human deaths, Chekamari and Khairbari villages of Madarihat Range are in the most vulnerable list.  Most of the human deaths occurred in the early morning (05.00–06.00 h) and in the evening, when people are going outside for open defecation (OD).  On a pilot basis Chekamari and Khairbari villages of Madarihat Range were selected for a door to door household survey with the objective to develop an innovative strategy as a mitigation measure of HEC.  The results of the survey show that both villages are tribal and minority population, the socio-economic condition of the people is very poor, on an average 5–6 members are in each household, the source of drinking water is a community well for most of the households, and 50 households are devoid of toilet facilities so automatically the members of those households go outside for OD.  Out of the total human deaths, 16 occurred in the Madarihat area; out of these 16 cases, six were from the Chekamari and Khairbari villages.  For this reason, between April 2019 to September 2019, with available funds 20 toilets with tube-well were built in the 20 neediest households of these two villages.  Due to the communication with the community, behavioural changes were made and their participation for 100% usage of those toilets was assured.  After the construction of the toilets until now, no human death cases have been reported.
First record of a morphologically abnormal and highly metal-contaminated Spotback Skate Atlantoraja castelnaui (Rajiformes: Arhynchobatidae) from southeastern Rio de Janeiro, Brazil
Authors: Rachel Ann Hauser-Davis  , Márcio L.V. Barbosa-Filho  , Lucia Helena S. de S. Pereira  , Catarina A. Lopes  , Sérgio C. Moreira  , Rafael C.C. Rocha  , Tatiana D. Saint’Pierre  , Paula Baldassin  , Salvatore Siciliano
Published: August 2020

This paper reports the first record of a morphologically abnormal and highly metal-contaminated Spotback Skate Atlantoraja castelnaui (Ribeiro, 1907) (Elasmobranchii, Rajidae) in Rio de Janeiro, Brazil. Incomplete fusion of the right pectoral fin with the head was observed, while a radiography indicated muscle sheaf discontinuity near the rostrum.  Extremely high contamination by several elements, including teratogenic As, Hg and Cd in the individual was detected.  The observed morphological deformity may be due to high concentrations of teratogenic elements in the environment, possibly playing a role in abnormal embryonic development in egg cases exposed to high environmental concentrations of these contaminants.  Atlantoraja castelnaui is the least biologically understood member of the genus Atlantoraja, and this paper furthers both morphological observations and ecotoxicological assessments on this species.
Preliminary checklist of spider fauna (Araneae: Arachnida) of Chandranath Hill, Goa, India
Authors: Pandit Rupali , Dharwadkar Mangirish
Published: August 2020

The present investigation is a very first attempt to generate the checklist of spiders from Chandranath Hill, Paroda, Quepem, Goa.  A preliminary study was conducted from June 2018 to March 2020 to document the spider diversity from the region.  In all, 125 species of spiders belonging to 102 genera from 19 families were identified.  The dominant families were Salticidae followed by Araneidae.  Guild structure analysis revealed six feeding guilds, namely, orb weavers, foliage runners, ground runners, stalkers, space-web builders and ambushers.  This study has not only highlighted the need for conservation of this ecosystem due to the significant species diversity and endemic species but has also filled the lacuna of spider study in Goa to form the foundation for further investigation.  Extensive research on the spiders from Chandranath Hill in the future can certainly expect further new discoveries.