bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunotoxin and bcl-2 inhibitor combination therapy targeting chondroitin sulfate proteoglycan 4.
Authors: Yu Xin , Keir Stephen T. , Szafranski Scott , Clayton Steven , Pastan Ira , Bigner Darell D. , Chandramohan Vidyalakshmi 
Published: November 2019

74 Background: Immunotoxins (ITs) are a class of bifunctional chimeric proteins composed of an antibody fragment linked to a toxin. When ITs internalize into target cells, they induce protein synthesis inhibition and apoptosis. While ITs are highly specific and potent, the efficacy of IT-based therapies in some tumor cells is limited by hyperactive anti-apoptotic pathways and inefficient translocation of ITs from the endoplasmic reticulum to the cytosol. Therefore, to improve the efficacy of IT-based therapies, we evaluated a dual-pathway therapy that combines an IT with the ABT-737, ABT-263, or ABT-199 small molecule Bcl-2 inhibitor. Methods: The immunotoxin 9.2.27-PE38KDEL (9.2.27-IT) was generated by fusing a truncated mutant form of Pseudomonas exotoxin A to a single-chain variable fragment antibody. It targets human chondroitin sulfate proteoglycan 4 (CSPG4), an antigen highly expressed in a variety of cancer cells. We screened and identified 3 human glioblastoma xenografts, 3 human melanoma cell lines, and 5 human breast cancer cell lines resistant to the 9.2.27-IT despite their high levels of cell surface expression of CSPG4 (IC50 of IT alone was >100 ng/ml in all cell lines except for one melanoma cell line). In vitro cytotoxicity of the 9.2.27-IT —alone or in combination with the individual Bcl-2 inhibitors ABT-737, ABT-263, or ABT199—was assessed. Concentrations of ABT analogues were chosen so that ABT alone did not induce cytotoxicity. Results: The treatment groups that responded to the combination therapy yielded IC50 values ranging from 0.04 – 9 ng/ml for glioblastoma xenografts, 0.21-15 ng/ml for melanoma cell lines, and 4.5-50 ng/ml for breast cancer cell lines. The most potent combination group showed >1000 fold improvement of IC50 compared to using the immunotoxin alone. ABT-737 produced the strongest synergistic effects among the ABT analogues. Preliminary results from in vivo studies further demonstrated that this approach engendered a synergistic response and delayed tumor growth in immunotoxin-resistant mouse tumor models. Conclusions: This new combinatorial approach will potentially help to overcome immunotoxin resistance in cancer patients and provide better therapeutic outcomes.
Immune monitoring outcomes of patients with stage III/IV melanoma treated with a combination of pembrolizumab and intratumoral plasmid interleukin 12 (pIL-12).
Authors: Algazi Alain Patrick , Tsai Katy K. , Rosenblum Michael , Fox Bernard A. , Andtbacka Robert Hans Ingemar , Li Amy , Takamura Kathryn Toshimi , Dwyer Mary , Browning Erica , Talia Reneta , Twitty Chris , Le Mai H. , Gargosky Sharron , Campbell Jean S. , Ballesteros-Merino Carmen , Bifulco Carlo Bruno , Pierce Robert , Daud Adil 
Published: November 2019

78 Background: Recent publications support the emergence of predictive biomarkers for pembrolizomab in melanoma based on the expression of PD-L1 in the tumor microenvironment (Daud 2016a) or the frequency of PD-1hiCTLA-4hi on CD8+ TIL (Daud 2016b) whereby immunologically inactive tumors show poor response to immune checkpoint inhibition alone. Since intratumoral pIL-12 with electroporation (IT-pIL12-EP) increases TIL in both treated and untreated lesions, we hypothesize that non-response can be rescued with the combination of IT-pIL12-EP and anti-PD-1. Phase II clinical and immunological data are shown. Methods: Melanoma stage III/IV patients were enrolled with CD8+ TIL < 25% PD-1hiCTLA-4+measured by flow cytometry (NCT02493361). PD-L1 IHC (22C3 Ab) was also evaluated. Patients were treated with pembrolizumab (200mg every 3 weeks) and IT-pIL12-EP. Patients were evaluated for ORR every 12 weeks (RECISTv1.1). Pre- and post-treatment blood and tumor specimens were collected, and analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by IHC. Results: TIL assessment for evaluable enrolled patients were < 22% PD-1hiCTLA-4+, a value associated with anti-PD-1 non-response (Daud 2016b). Remarkably, although predicted to be an unresponsive population, the ORR was 40% (4CR/ 2PR) by RECISTv1.1. In patients with CR/PR, analysis of the tumor microenvironment revealed many significant immunological changes not seen in non-responders, including number and ratios of CD8+:PD-L1+by IHC, increased expression of NK, CD8 and ‘adaptive resistance’ markers by NanoString, as well as increased clonality and T cells by TCR sequencing. Conclusions: The excellent safety profile and striking 40% clinical response rate is encouraging as treated patients were predicted to be non-responsive to pembrolizumab. The correlative data shows an immune-directed mechanism that is differentiated between responders and non-responders suggesting the combination can effectively alter the tumor microenviroment to benefit patients otherwise unlikely to respond to anti-PD-1 monotherapy. Clinical trial information: NCT02493361.
Extended survival analysis of ipilimumab for the treatment of advanced malignant melanoma in pretreated patients: Five-year long-term follow-up of the South African expanded access program.
Authors: Rapoport Bernardo Leon , Vorobiof Daniel A. , Dreosti Lydia Mary , Nosworthy Adam L. , McAdam Georgina Laird , Jordaan Johann Petrus , Miller-Janson Helen , de Beer Janetta Catharina , de Necker Margreet 
Published: November 2019

84 Background: Ipilimumab is a human monoclonal IgG1 antibody against CTLA-4 that has been shown to prolong the overall survival of patients with advanced pretreated melanoma. In 2015, a retrospective, multi-centre, non-interventional analysis was performed on data collected from the ipilimumab expanded access programme in South Africa, with last follow-up date (or death) in December 2014. The current study extends this analysis by follow-up on the long-term survival of pre-treated metastatic patients up to September 2016. Methods: Follow-up questions were sent to participating investigators, who had patients who were still alive (29) or for whom it was not known whether they were still alive (11) following the last ipilimumab infusion. Investigators had to confirm whether patients were still alive, the date of death or last contact, clinical response at last contact, and whether the patient was still responding to ipilimumab. Results: Of the 108 patients, 84 (78%) had cutaneous melanoma and 24 patients (22%) had non-cutaneous melanoma, including uveal, mucosal, and melanoma of unknown primary. Twenty patients previously received two or more lines of treatment for metastatic melanoma. The median age was 59 years (range 27 – 86) and there were 73 (68%) males and 35 (32%) females. Baseline ECOG PS was 0 in 33%, PS 1 in 58% and PS 2 in 6% of patients. The longest follow-up time available was 5.4 years. The median OS was 9.36 months (95% CI 7.48 – 11.84). One-year survival was 39% (95% CI 29% - 48%), 2-year survival was 22% (95% CI 15% - 30%), 3-year survival was 19% (95% CI 12% - 27%), 4- and 5-year survival was 15% (95% CI 8% - 21%). In the group of cutaneous melanoma patients, the 4- and 5-year survival was 17% (95% CI 9% - 25%) while in the non-cutaneous group the 4- and 5-year survival was 6% (95% CI 0% - 16%). Conclusions: Ipilimumab at a dose of 3mg/kg is an effective treatment for patients with pre-treated advanced (unresectable or metastatic) melanoma and is associated with durable remissions and long-term survival.
Perspectives from the community setting: A retrospective chart review of nivolumab for previously treated non-small cell lung cancer.
Authors: Nhan Brian Richard , Kulkarni Swati 
Published: November 2019

86 Background: Lung cancer is among the most commonly diagnosed cancers in Canada and is the leading cause of cancer deaths. Non-small cell lung cancer (NSCLC) is one of the most common types representing 85-90% of cases. Compared to other cancers, the five-year survival rate for lung cancer in Canada is among the lowest at 17%. Nivolumab has been in use in the setting of progression of previously treated NSCLC at the Windsor Regional Cancer Center since June 2015. This retrospective chart review abstracts data from 26 patients at WRCC with NSCLC who were treated with nivolumab. Methods: A retrospective chart review of 26 patients treated with nivolumab in the setting of progressive NSCLC. Results: 26 patients were reviewed (1 stage 2a, 2 stage 3a, 3 stage 3b, 20 stage 4 with 12 M1b and 8 M1a). Grade 1-2 side effects were documented in 4 patients treated with monitoring and no discontinuation or dose modification of nivolumab. A grade 3 side effect was documented in 1 patient leading to discontinuation of treatment. 3 living patients discontinued treatment due to progression. 6 patients died while on treatment secondary to disease progression. The remaining patients are on nivolumab with no side effects documented. Conclusions: As the use of immuno-oncology agents use expand in community clinics, opportunities arise from community data to further learn which patients benefit from these treatments, what side effects can occur and how to manage them, and how response to treatment may look. Out of the 26 patients receiving nivolumab, 5 patients had documented side effects resulting in discontinuation of treatment in 1 patient. Overall nivolumab has been well tolerated in patients with NSCLC in this community setting.
Preliminary results from a phase II study of nivolumab for patients with metastatic adrenocortical carcinoma (ACC).
Authors: Cavalcante Ludimila , Carneiro Benedito A. , Costa Ricardo Lima Barros , Chae Young Kwang , Rademaker Alfred , Giles Francis J. 
Published: November 2019

96 Background: ACC is an exceedingly rare malignancy with an estimated incidence of 0.7 cases per million per year. Patients presenting with metastatic disease have an estimated 5-year survival rate of < 15%, without effective standard treatment options. Immunotherapy approaches such as checkpoint inhibitors have emerged as effective therapies for multiple malignancies. Nivolumab, a monoclonal IgG4 antibody against the programmed death-1 (PD-1) receptor on T-cells, acts by inhibiting the interaction with PD-L1 and PD-L2 and thus eliciting an increased anti-tumor immune response. This phase II study will assess the efficacy of nivolumab monotherapy according to objective response rate (ORR) in patients with advanced ACC – the study is currently in the patient enrollment phase. Methods: Patients with metastatic or locally advanced ACC with disease progression after treatment with ≥ 1 line of therapy (including mitotane and/or chemotherapy), or not eligible for first-line chemotherapy are currently being enrolled on this phase II study. Nivolumab is given at a fixed dose of 240mg IV q2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. Planned accrual of up to 33 patients will follow a Simon two stage design with interim analysis for efficacy after 10 evaluable patients are enrolled. Results: This is an initial report of the first 7 evaluable patients enrolled on study. Median age 57 years; female (4/7); endocrine hyperfunction (2/7); prior chemotherapy with EDP +/- mitotane (5/7). Patients were treated with a median of 4 doses of nivolumab. Median time to progression of 8 weeks. Best overall response rate thus far has been progression of disease in 5 pts, with 2 pts pending evaluation. Grade 3 or 4 adverse events (AEs) at least possibly related to nivolumab: tremor, hypokalemia (1 pt each). Reported grade 1 and 2 AEs: LFT elevation (3 pts), lower extremity edema (2 pts), lymphopenia, urinary frequency and fatigue (1 pt each). Conclusions: Nivolumab has been well tolerated in this population of patients with metastatic ACC. Clinical trial information: NCT02720484.
Effect of exogenous interferon-gamma (IFN-gamma) on peripheral blood immune markers as part of a phase I clinical trial of combined IFN-gamma with nivolumab (Nivo) in patients (pts) with select solid tumors.
Authors: Zibelman Matthew R. , Macfarlane Alexander , Alpaugh R. Katherine , Dulaimi Essel , Costello Kim , O'Neill John , Borghaei Hossein , Denlinger Crystal Shereen , Geynisman Daniel M. , Dotan Efrat , Jain Angela , Martin Lainie P. , Obeid Elias , Nieves Jeffery A. , Crouteau David , Grahn Amy Y. , Campbell Kerry , Plimack Elizabeth R. 
Published: November 2019

97 Background: IFN-gamma is a known activator of PD-L1 expression and plays a key role in immune activation. We present initial correlative peripheral blood findings after the first 2 cohorts of pts enrolled in a phase I trial of combined IFN-gamma/Nivo in pts with various solid tumors. Methods: Pts with advanced solid tumors who had progressed after at least 1 prior therapy were recruited. An induction phase of IFN-gamma (50 or 75 mcg/m2 subq every other day for 1 week) preceded the combination of Nivo (3 mg/kg IV every 2 weeks) with continuation of IFN-gamma at same dose and schedule for 3 months. Pts with clinical benefit could remain on Nivo alone for up to 1 year. Peripheral blood was analyzed via flow cytometry at baseline, after IFN-gamma induction (prior to Nivo start), and after 6 weeks of combo treatment. Results: 13 pts have been accrued. Pre and post induction samples were collected on all pts. Nine pts had available on-treatment samples at time of data analysis. Comparing blood collections from baseline to post-IFN-gamma induction revealed a substantial expansion of the CD14high, CD16+ monocyte population (p=0.001) and a statistically significant increase in MHC class II expression on all monocyte populations (p≤ 0.002 for all types). Natural killer (NK) cells demonstrated greater numbers of cells per ml of blood (p=0.03) and increased NKp30 expression, an important receptor mediating tumor cell lysis (p= 0.005 for CD56dim; p= 0.03 for CD56bright). With the addition of Nivo, evidence for activation of CD56dim NK cells was detected as increased CD69 expression compared to post-induction (p=0.02). PD-1 expression on T-cells showed reduced expression in most comparators after initiation of Nivo (p=0.055 CD8+; p=0.008 CD4+). Conclusions: Early correlative peripheral blood data demonstrate expected systemic IFN-gamma effect as measured by monocyte activation and increased MHC II expression. Evidence of NK cell activation and proliferation was also observed. Decreased PD-1 expression on T-cells may reflect down-regulation in response to PD-1 blockade. Correlations with biopsy specimens and clinical response are planned. Clinical trial information: NCT02614456.
Mutations in LAMB2 Are Associated With Albuminuria and Optic Nerve Hypoplasia With Hypopituitarism
Authors: Tahoun Mona , Chandler Jennifer C , Ashton Emma , Haston Scott , Hannan Athia , Kim Ji Soo , D’Arco Felipe , Bockenhauer D , Anderson G , Lin Meei-Hua , Marzouk Salah , Saied Marwa H , Miner Jeffrey H , Dattani Mehul T , Waters Aoife M 
Published: November 2019

Abstract

Context
Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic syndrome, ocular abnormalities, and neurodevelopmental delay (Pierson syndrome).

Case description
This report describes a 12-year-old boy with short stature, visual impairment, and developmental delay who presented with macroscopic hematuria and albuminuria. He had isolated growth hormone deficiency, optic nerve hypoplasia, and a small anterior pituitary with corpus callosum dysgenesis on his cranial magnetic resonance imaging, thereby supporting a diagnosis of optic nerve hypoplasia syndrome. Renal histopathology revealed focal segmental glomerulosclerosis. Using next-generation sequencing on a targeted gene panel for steroid-resistant nephrotic syndrome, compound heterozygous missense mutations were identified in LAMB2 (c.737G&gt;A p.Arg246Gln, c.3982G&gt;C p.Gly1328Arg). Immunohistochemical analysis revealed reduced glomerular laminin β2 expression compared to control kidney and a thin basement membrane on electron microscopy. Laminin β2 is expressed during pituitary development and Lamb2–/– mice exhibit stunted growth, abnormal neural retinae, and here we show, abnormal parenchyma of the anterior pituitary gland.

Conclusion
We propose that patients with genetically undefined optic nerve hypoplasia syndrome should be screened for albuminuria and, if present, screened for mutations in LAMB2.
“The Languo of Flows”
Authors: Brannigan John , Ryfield Frances , Crowe Tasman , Cabana David 
Published: November 2019

Abstract“Flow” is a key concept in our era of liquid modernity, across a broad range of ecological, economic, and cultural discourses. In this essay, we examine the material flows integral to naturecultures through the specific case study of Seascale on the Cumbria coast in the UK. Through an analysis of cultural representations, we show the construction of Seascale as a seaside resort in the nineteenth and early twentieth centuries, and the rapid and irrevocable sinking of its cultural value since the commissioning of the nuclear power and reprocessing plant at Sellafield in 1947. By following the “flows” of pleasure, emotion, energy, and waste through Seascale, we explore the legacies of nuclear contamination for coastal communities, within a broader regime of the commodification of nature. This essay emerges from a transdisciplinary research project to investigate the cultural influences and impacts of ecosystem change in coastal environments around the Irish Sea. A collaboration between environmental humanities and ecological sciences, the project sought a materialist intervention in the conceptualization and practice of ecosystem assessment so as to capture and map a more inclusive and multidirectional sense of the flows that are integral to ecosystems, and to move beyond the limitations of dominant models of environmental stewardship. In contrast to the ways in which flow metaphors have been employed in contemporary economic and environmental discourse, the project attempts to analyze the material flows integral to naturecultures through particular places, perspectives, and agencies.
Chronophilia; or, Biding Time in a Solar System
Authors: Hall Marcus 
Published: November 2019

Abstract
Having evolved in a dynamic solar system, all life on earth has adapted to and depends on recurring and repeating cycles of light, heat, and gravity. Our sleep cycles, reproductive cycles, and emotional cycles are all linked in varying ways to planetary motion even though we continually disrupt, modify, or extend these cycles to go about our personal and collective business. This essay explores how our sense of time is both physiological and cultural, with deep ramifications for confronting such challenges as jet lag, navigation, calendar construction, shift work, and even life span. Although chronobiologists have posited the existence of a Zeitgeber, or external master clock that serves to reset our internal clocks, it has become clear that any master clock relies as much on natural elements (such as a rising sun) as cultural elements (such as an alarm clock). Moreover the “circa” of circadian rhythms, suggests that our activities and emotions recur, not in exact twenty-four-hour cycles, but in more plastic and approximate cycles that, according to circumstance and individual, may span somewhat longer or shorter periods than one earthly rotation. Or as one chronobiologist explains, “Any one physiologic variable is characterized by a spectrum of rhythms that are genetically anchored, sociologically synchronized . . . and influenced by heliogeophysical effects.” As we contemplate faster and further travel and other activities that disrupt our biorhythms, we need to develop greater awareness of chronophilia, our attachment to rhythm, our love of familiar time.
Self-Assembly of Radially π-Extended Tetrathiafulvalene Tetramers for Visible and Near Infrared Electrochromic Nanofiber
Authors: Hasegawa Masashi , Iyoda Masahiko 
Published: November 2019

Abstract
The self-assembly and electrochromic nanofiber formation of radially π-extended tetrathiafulvalene (TTF) tetramers anchored to 1,2,4,5-tetraethynylbenzene were investigated. The tetramer with SBu-substituents underwent self-assembly in solution. Cationic species of the tetramer, obtained by chemical oxidation with Fe(ClO4)3, exhibited a marked electrochromism in the solution. Their electronic spectra revealed absorption bands corresponding to intermolecular mixed-valence aggregation based on (TTF//TTF)•+, and π-aggregation based on (TTF•+//TTF•+) due to the strong molecular association in the cationic species. Furthermore, the tetramer formed an entangled nanoscale fibrous material from CHCl3–hexane. Electrochemical oxidation of the nanofiber on an indium tin oxide electrode revealed a repeatable redox profile. The nanofiber displayed remarkable electrochromic behavior: the color of the fiber changed from purple (neutral) to brown/brownish green (dication and trication) and green (tetracation). These color changes of the nanofiber are similar to those in solution, and the electronic spectra of the oxidized nanofibers reflected the stacked TTF units in the cationic nanofibers.
Force-sharing within the Triceps Surae: An Achilles Heel in Achilles Tendinopathy
Authors: CROUZIER MARION , TUCKER KYLIE , LACOURPAILLE LILIAN , DOGUET VALENTIN , FAYET GUILLEMETTE , DAUTY MARC , HUG FRANÇOIS 
Published: November 2019

ABSTRACT

Purpose
The primary aim of this study was to determine whether the distribution of force between the three heads of the triceps surae differs between people with Achilles tendinopathy and controls. We also aimed to determine the effect of this force distribution on subtendon strain.

Methods
Data were collected for 21 participants with Achilles tendinopathy and 21, case-wise paired, asymptomatic controls. Ultrasonography was used to measure muscle volume, fascicle length, pennation angle and subtendon length at rest. Muscle activation was estimated using surface electromyography during maximal and submaximal isometric plantarflexion tasks. The product of normalized activation, physiological cross-sectional area, and the cosine of the pennation angle was considered as an index of individual muscle force. Displacement of the distal myotendinous junction of each muscle was measured during the submaximal contractions.

Results
The contribution of the gastrocnemius lateralis to the overall triceps surae physiological cross-sectional area and activation was 8.5% (P = 0.047, d = 0.75) and 24.7% lower (main effect group P = 0.009, d = 0.67) in people with Achilles tendinopathy than in the controls, respectively. Consequently, gastrocnemius lateralis contributed approximately 28% less (main effect group P = 0.025, d = 0.62) of the triceps surae force in people with Achilles tendinopathy. The contribution of gastrocnemius medialis and soleus was not different between groups. Subtendon strain was not different between groups (P = 0.835).

Conclusions
These results provide evidence for a difference in force-sharing strategy within the triceps surae in people with Achilles tendinopathy compared with the controls. Whether this altered strategy is a cause or a consequence of Achilles tendinopathy should be explored further.