bluuebunny/crossref_metadata_2025 huggingface dataset:
MRE11-RAD50-NBS1 complex alterations and DNA damage response: implications for cancer treatment
Authors: Bian Lei , Meng Yiling , Zhang Meichao , Li Dong
Published: November 2019

Genome instability is a hallmark of cancer cells and can be accelerated by defects in cellular responses to DNA damage. This feature of malignant cells opens new avenues for tumor targeted therapy. MRE11-RAD50-NBS1 complex plays a crucial role in sensing and repair of DNA damage. Through interacting with other important players of DNA damage response, MRE11-RAD50-NBS1 complex is engaged in various DNA damage repair pathways. Mutations in any member of this complex may lead to hypersensitivity to genotoxic agents and predisposition to malignancy. It is assumed that the defects in the complex may contribute to tumorigenesis and that treatments targeting the defect may be beneficial to cancer patients. Here, we summarized the recent research findings of the role of MRE11-RAD50-NBS1 complex in tumorigenesis, cancer treatment and discussed the potential approaches of targeting this complex to treat cancer.
Pediatric systemic lupus erythematosus patients in South Africa have high prevalence and severity of cardiac and vascular manifestations
Authors: Harrison Michael J. , Zühlke Liesl J. , Lewandowski Laura B. , Scott Christiaan
Published: November 2019

Background

Pediatric onset of systemic lupus erythematosus (SLE) is associated with major organ involvement, and African patients tend to develop more aggressive disease than patients of European descent. Although cardiovascular involvement is common in pediatric SLE, there are few published reports on the subject. This study describes the frequency and characteristics of cardiac and vascular manifestations of pediatric SLE in a multi-ethnic South African cohort.

Methods

Demographic, clinical, and echocardiographic data were collected from pediatric SLE patients at two centers in Cape Town, South Africa. At the time of investigation, this cohort consisted of 93 participants diagnosed with SLE according to international classification criteria prior to the age of 19. Individuals with cardiac and/or vascular involvement were identified by retrospective chart review. Cardiac manifestations were defined as presence of pericardial effusion, myocarditis, cardiomyopathy, cardiac failure, Libman-Sacks endocarditis, myocardial infarction, and arrhythmia. Vascular manifestations included deep vein thrombosis, pulmonary embolism, sinus thrombosis, stroke, critical limb ischemia, cerebral vasculitis and systemic vasculitis. Statistical analysis was performed using R (v3.4.1).

Results

Cardiac and vascular involvement was present in 47% of the cohort. Previous studies have reported prevalence of 5%—50%. Demographic features of those with cardiac/vascular involvement did not differ from the overall cohort. Echocardiographic data were available for 23 participants. The most common cardiac manifestations were pericardial effusion (n = 24) and cardiac failure (n = 8), while the most common vascular manifestations were cerebral vasculitis (n = 9), stroke (n = 7), and pulmonary embolism (n = 7). Cardiovascular manifestations were frequently severe; one third of pericardial effusion cases required intervention, including three cases of cardiac tamponade. Cardiac and vascular involvement conferred an increased risk of mortality (31.1% versus 10.4%).

Conclusions

Cardiac and vascular involvement were highly prevalent in this South African cohort. The mortality rate was high, and severe manifestations were frequent. Prospective research is needed to improve knowledge of pediatric SLE in Africa and to improve outcomes for this high-risk population.
Selective memory and behavioral alterations after ambient ultrafine particulate matter exposure in aged 3xTgAD Alzheimer’s disease mice
Authors: Jew Katrina , Herr Denise , Wong Candace , Kennell Andrea , Morris-Schaffer Keith , Oberdörster Günter , O’Banion M. Kerry , Cory-Slechta Deborah A. , Elder Alison
Published: November 2019

Background

A growing body of epidemiological literature indicates that particulate matter (PM) air pollution exposure is associated with elevated Alzheimer’s disease (AD) risk and may exacerbate AD-related cognitive decline. Of concern is exposure to the ultrafine PM (UFP) fraction (≤100 nm), which deposits efficiently throughout the respiratory tract, has higher rates of translocation to secondary organs, like brain, and may induce inflammatory changes. We, therefore, hypothesize that exposure to UFPs will exacerbate cognitive deficits in a mouse model of AD. The present study assessed alterations in learning and memory behaviors in aged (12.5 months) male 3xTgAD and non-transgenic mice following a 2-week exposure (4-h/day, 4 days/week) to concentrated ambient UFPs using the Harvard ultrafine concentrated ambient particle system (HUCAPS) or filtered air. Beginning one month following exposure, locomotor activity, spatial learning and memory, short-term recognition memory, appetitive motivation, and olfactory discrimination were assessed.

Results

No effects on locomotor activity were found following HUCAPS exposure (number concentration, 1 × 104–4.7 × 105 particles/cm3; mass concentration, 29–132 μg/m3). HUCAPS-exposed mice, independent of AD background, showed a significantly decreased spatial learning, mediated through reference memory deficits, as well as short-term memory deficits in novel object recognition testing. AD mice displayed diminished spatial working memory, potentially a result of olfactory deficits, and short-term memory. AD background modulated HUCAPS-induced changes on appetitive motivation and olfactory discrimination, specifically enhancing olfactory discrimination in NTg mice. Modeling variation in appetitive motivation as a covariate in spatial learning and memory, however, did not support the conclusion that differences in motivation significantly underlie changes in spatial learning and memory.

Conclusions

A short-term inhalation exposure of aged mice to ambient UFPs at human-relevant concentrations resulted in protracted (testing spanning 1–6.5 months post-exposure) adverse effects on multiple memory domains (reference and short-term memory) independent of AD background. Impairments in learning and memory were present when accounting for potential covariates like motivational changes and locomotor activity. These results highlight the need for further research into the potential mechanisms underlying the cognitive effects of UFP exposure in adulthood.
Sweden’s engagement in global health: a historical review
Authors: Irwin Rachel
Published: November 2019

Background

Sweden is a long-standing and significant contributor to overseas development aid. This commitment to global health and development is part of Sverigebilden, or the view of Sweden in the world that is formally promoted by the Swedish government. Sweden is seen by many in the global health community as leader on human rights and health and has traditionally been one of the most engaged countries in multilateral affairs more broadly.

Results

This article places Sweden’s engagement in global health within the wider context of domestic changes, as well as transitions within the broader global health landscape in the post-World War Two (WWII)- era. In doing so, it reviews the globalization of health from a Swedish perspective. It also addresses broader questions about what it means for a country to be ‘active’ or ‘engaged’ in global health and responds to recent suggestions that Swedish influence in health has waned. The article finds that in Sweden there is wide political consensus that international development and global health engagement are important, and both are part of the maintenance of Sverigebilen. While there is a not one single Swedish approach to global health, there are norms and values that underpin global health engagement such as human rights, solidarity, equity and gender equality. A sustained focus on key issues, such as sexual and reproductive rights and health (SRHR), creates a tradition which feeds back into Sverigebilden.

Conclusions

The Swedish experience demonstrates the linkages between foreign and domestic policies with regard to international health and development, and to the globalization of public health practice and diplomacy. In global health Sverigebilden is tied to credibility. Sweden is able to exercise influence because of a successful welfare model and strong research traditions; conversely, long-standing and new threats to this credibility and to Sverigebilden pose challenges to Sweden’s future engagement in global health.
A facile and one-pot synthesis of new tetrahydrobenzo[b]pyrans in water under microwave irradiation
Authors: Khumalo Mandlenkosi Robert , Maddila Surya Narayana , Maddila Suresh , Jonnalagadda Sreekantha B.
Published: November 2019

Eleven new tetrahydrobenzo[b]pyran derivatives were synthesized via a three component reaction of different aromatic aldehydes, methyl cyanoacetate and 1,3-cyclohexadione, with water as solvent under catalyst-free microwave irradiation. The structures of all the new molecules were well analysed and their structures established by using various spectral techniques (1H NMR, 13C NMR, 15N NMR and HRMS). Various advantages of reported protocol are the ease of preparation, short reaction times (10 min), aqueous solvent and excellent yields (89–98%). Additionally, this method provides a clean access to the desired products by simple workup.
Effect of mushrooms on obesity in animal models: study protocol for a systematic review and meta-analysis
Authors: Grotto Denise , Camargo Isabella Ferreira , Kodaira Katia , Mazzei Lauren Giustti , Castro Juliana , Vieira Raquel Andrade Leite , Bergamaschi Cristiane de Cásia , Lopes Luciane Cruz
Published: November 2019

Background

Obesity and its consequences are worldwide epidemic problem; therefore, studies with strategies and mechanisms that favor weight loss to improve outcomes in health are necessary. Effects of mushrooms on body weight are uncertain. The aim of this systematic review is to determine the efficacy of mushrooms in weight loss in animal preclinical models.

Method

This is a systematic review of preclinical studies of animal models of obesity (any type of non-aquatic mammal), which were exposed to edible and medicinal mushrooms orally in comparison with the control. The following databases will be used: MEDLINE (PubMed), Web of Science, BIOSIS, SCOPUS, and gray literature. There will be no restriction of language, date, or publication status. The primary outcome will be body weight loss. And the secondary outcomes include the total amount of food consumed by the animals, analysis of metabolic parameters, inflammatory mediators, mortality for any causes, and any adverse effect reported. A team of reviewers will select, in pairs and independently, the titles and abstracts, extract data from qualifying studies, and assess bias risk (using SYstematic Review Centre for Laboratory animal Experimentation SYRCLE’s risk of bias tool and the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist). The standardized mean difference (SMD) will be calculated to measure treatment effect, with 95% confidence intervals (95% CI). The heterogeneity between-study will be calculated by I2 inconsistency values and Cochran’s Q statistical test, where I2 > 50% and/or p < 0.10 suggest high heterogeneity meta-analyses of random effects will be conducted as possible.

Discussion

Although many experimental studies about the effects of mushrooms on obesity have already been published, there is still no consensus in the literature. This study will provide evidences of preclinical research on mushrooms and their relation to body weight loss in animal models of obesity, being non-aquatic mammals. Also, this systematic review will show the limitations and strengths of the studies available in the literature, as well as it will to encourage the financing of new studies by public health managers and governmental entities.

Systematic review registration

PROSPERO (CRD42019125299).
Measuring informal STEM learning supports across contexts and time
Authors: Morris Bradley J. , Owens Whitney , Ellenbogen Kirsten , Erduran Sibel , Dunlosky John
Published: November 2019

Background

Informal science activities are critical for supporting long-term learning in STEM fields. However, little is known about the kinds of activities children and their families engage in outside of formal settings and how such activities foster long-term STEM engagement. One gap in the literature is the lack of data that document self-designated STEM activities and measure their impact on later engagement with learning opportunities that are distributed over time and contexts (i.e., the informal learning ecology). One reason for this gap is that there has been little measurement during the events, because using only a few measures (which can be completed briefly) may reduce psychometric validity. We developed an instrument, the STEMwhere app, to measure four informal science learning supports (interest, engagement, identity, and goal setting), across the informal learning ecology. For a period of 2 months, 26 children ages 7–14 used the app to check-in during STEM activities and answer eight questions about each activity.

Results

The results demonstrated that most STEM activities occurred in the home, often consisted of hands-on activities, suggesting that the family home provides more opportunity for engagement than other locations. Child interest and engagement ratings were high in all settings and activities suggesting that high situational interest was relatively common during these activities. Further, user ratings suggested relations between different learning supports. For example, increases in interest were related to increases in subsequent engagement and “fun” goals, while increases in engagement were related to increases in learning goals. By collecting participant-generated check-ins, we identified periods of increasing activity and their likely triggers, which is a novel measure we refer to as topical runs. We operationally defined a run as a pattern of check-ins that were unlikely to occur by chance and shared a topic or location.

Conclusions

Our results serve as both a proof-of-concept for a novel tool for measuring informal STEM activity in the wild that provides data consistent with existing measures and provide novel findings that contribute to our understanding of where and how informal science activity occurs.
Travel medicine, coca and cocaine: demystifying and rehabilitating Erythroxylum – a comprehensive review
Authors: Bauer Irmgard
Published: November 2019

Few travel health measures are as controversial as the use of coca leaves at high altitude; yet, there appears widespread ignorance among health professionals and the general public about coca, its origins as well as its interesting and often flamboyant history. Equally, the cultural and traditional significance to Andean people is not recognised. The coca leaves contain many alkaloids, one of which, cocaine, has gained notoriety as a narcotic, leading to the mistaken idea that coca equals cocaine. This article contrasts coca with cocaine in an attempt to explain the differences but also the reasons for this widespread misconception. By its very nature, there may never be scientific ‘proof’ that coca leaves do or do not work for travellers at altitude, but at least a solid knowledge of coca, and how it differs from cocaine, provides a platform for informed opinions and appropriate critical views on the current confusing and contradictory legal situation.
Change of the upper airway after mandibular setback surgery in patients with mandibular prognathism and anterior open bite
Authors: Lee Kyungjin , Hwang Soon Jung
Published: November 2019

Purpose

It has been reported before that the amount of pharyngeal airway space (PAS) significantly decreases following mandibular setback (MS) surgery in patients with mandibular prognathism (MP). Further, MP patients with an anterior open-bite (AOB) presentation may show a larger decrease in PAS compared with those without AOB. However, studies on postoperative PAS changes in MP patients with AOB remain rare. This study sought to evaluate changes in PAS and hyoid bone positioning following MS surgery in MP patients with and without AOB.

Patients and methods

Twenty patients who underwent two jaw surgery involving MS movement were included. Patients were divided into a non-AOB group (n = 10; overbite > 2 mm) and an AOB group (n = 10; overbite < − 4 mm). Three-dimensional changes in PAS and hyoid bone positioning were compared and statistically evaluated pre- and postoperatively using computed tomography (CT).

Results

The mean magnitude of MS was 6.0 ± 2.8 mm and 5.6 ± 3.2 mm in the non-AOB group and AOB group, respectively. The oropharyngeal volume and upper hypopharyngeal volume were significantly reduced after surgery in both the groups (p = 0.006 and p = 0.003), while the retroglossal cross-sectional area was significantly reduced only in the AOB group (p = 0.028). Although the AOB group showed a larger decrease in PAS, the difference was not statistically significant between the groups. The position of the hyoid bone showed significant posterior and inferior displacement only in the AOB group, while the vertical displacement of the hyoid bone showed a statistically significant difference between the two groups.

Conclusion

PAS was significantly decreased after MS in both the groups, while only the AOB group presented a statistically significant reduction in the retroglossal cross-sectional area. Vertical displacement of the hyoid bone showed a statistically significant difference between the groups, while the PAS change was not. Surgeons should be aware of potential postoperative airway problems that may arise when performing MS surgeries.
Six-year epidemiological analysis of post traumatic endophthalmitis in a Brazilian hospital
Authors: Nakayama Luis Filipe , Bergamo Vinicius Campos , de Moraes Nilva Simeren Bueno
Published: November 2019

Background

To evaluate the epidemiology of endophthalmitis cases related to ocular trauma, including visual acuity during and 1 year after trauma, source of trauma and method of treatment.

Methods

A retrospective study analyzed the epidemiological data of patients with a clinical presentation of endophthalmitis after ocular penetrating trauma between January 2012 and January 2017 at Escola Paulista de Medicina/UNIFESP, a hospital in São Paulo, SP, Brazil.

Results

A total of 453 patients with antecedent open globe trauma were evaluated, among these, 30 patients with suspected endophthalmitis. All patients were male. The time interval between trauma and ophthalmological evaluation and collection of vitreous and aqueous material was 1 day in 36.66%, 2–7 days in 43.44%, 7–14 days in 10% and more than 15 days in 10% of patients; 66.66% had positive cultures. 11 patients had intraocular foreign body. One year after trauma, visual acuity was classified as no light perception (NLP) in 33.33%, light perception in 6.66%, hand motion in 13.33%, counting fingers in 13.33%, and better than 20/400 in 20% of patients. Considering presence of intraocular foreign body, initial visual acuity and symptoms onset time, only initial visual acuity showed as better prognostic factor in final visual acuity.

Conclusion

Endophthalmitis is a severe ocular inflammatory condition that may lead to irreversible vision loss. Initially only one patient had visual acuity of NLP, but after 1 year, 33% showed visual acuity of NLP, and only 20% had visual acuity better than 20/400, what is consistent with a severe infection with a guarded prognosis. The high incidence of endophthalmitis after ocular penetrant trauma justifies distinct treatment and greater attention.
Anodal tDCS over left parietal cortex expedites recovery from stroke-induced apraxic imitation deficits: a pilot study
Authors: Ant Jana M. , Niessen Eva , Achilles Elisabeth I. S. , Saliger Jochen , Karbe Hans , Weiss Peter H. , Fink Gereon R.
Published: November 2019

Background

To date, specific therapeutic approaches to expedite recovery from apraxic deficits after left hemisphere (LH) stroke remain sparse. Thus, in this pilot study we evaluated the effect of anodal transcranial direct current stimulation (tDCS) in addition to a standardized motor training on apraxic imitation deficits.

Methods

In a rehabilitation hospital, we assessed apraxic, aphasic, and motor deficits in 30 LH stroke patients before and after a five-day standard programme of motor training combined with either anodal (10 min, 2 mA; n = 14) or sham (10 min, 0 mA, n = 16) tDCS applied in a double-blind fashion over left posterior parietal cortex (PPC). Where appropriate, data were analyzed with either t-test, Fisher’s exact test, or univariate/ repeated measures ANOVA.

Results

Compared to sham tDCS, five sessions of anodal tDCS expedited recovery from apraxic imitation deficits (p < 0.05): Already after 5 days, the anodal tDCS group showed levels of imitation performance that were achieved in the sham tDCS group after 3 months. However, the primary outcome of the study (i.e., anodal tDCS induced improvement of the total apraxia score) failed significance, and there was no significant tDCS effect on apraxia after 3 months. Anodal tDCS improved grip force (of the contra-lesional, i.e., right hand), but had no effect on aphasia.

Conclusions

Data from this pilot study show that repetitive, anodal tDCS over left PPC combined with a standardized motor training expedites recovery from imitation deficits in LH stroke patients with apraxia (relative to sham stimulation). Results suggest that in patients suffering from apraxic imitation deficits a randomized controlled trial (RCT) is warranted that investigates the effects of tDCS applied over PPC in addition to a standardized motor training.
Indoor versus outdoor scene recognition for navigation of a micro aerial vehicle using spatial color gist wavelet descriptors
Authors: Ganesan Anitha , Balasubramanian Anbarasu
Published: November 2019

In the context of improved navigation for micro aerial vehicles, a new scene recognition visual descriptor, called spatial color gist wavelet descriptor (SCGWD), is proposed. SCGWD was developed by combining proposed Ohta color-GIST wavelet descriptors with census transform histogram (CENTRIST) spatial pyramid representation descriptors for categorizing indoor versus outdoor scenes. A binary and multiclass support vector machine (SVM) classifier with linear and non-linear kernels was used to classify indoor versus outdoor scenes and indoor scenes, respectively. In this paper, we have also discussed the feature extraction methodology of several, state-of-the-art visual descriptors, and four proposed visual descriptors (Ohta color-GIST descriptors, Ohta color-GIST wavelet descriptors, enhanced Ohta color histogram descriptors, and SCGWDs), in terms of experimental perspectives. The proposed enhanced Ohta color histogram descriptors, Ohta color-GIST descriptors, Ohta color-GIST wavelet descriptors, SCGWD, and state-of-the-art visual descriptors were evaluated, using the Indian Institute of Technology Madras Scene Classification Image Database two, an Indoor-Outdoor Dataset, and the Massachusetts Institute of Technology indoor scene classification dataset [(MIT)-67]. Experimental results showed that the indoor versus outdoor scene recognition algorithm, employing SVM with SCGWDs, produced the highest classification rates (CRs)—95.48% and 99.82% using radial basis function kernel (RBF) kernel and 95.29% and 99.45% using linear kernel for the IITM SCID2 and Indoor-Outdoor datasets, respectively. The lowest CRs—2.08% and 4.92%, respectively—were obtained when RBF and linear kernels were used with the MIT-67 dataset. In addition, higher CRs, precision, recall, and area under the receiver operating characteristic curve values were obtained for the proposed SCGWDs, in comparison with state-of-the-art visual descriptors.
Incidental findings in lumbar spine MRI: their prevalence and potential impact on patient management
Authors: Ibrahim Heba , Elsadawy Momena Essam Ibrahim
Published: November 2019

Background

To document the prevalence of extra spinal findings in lumbar MRI

Results

Among the scanned 400 patients, 90 cases had incidental non-spinal findings, and in 30 out of these 90 patients, the finding was the only reason for their complaint.

Conclusions

Radiologists should give attention to the non-spinal findings in lumbar spine MRI, as the detected pathology could be the source of pain or could potential life-threatening conditions.
Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma
Authors: Paiva Bruno , Puig Noemi , Cedena Maria-Teresa , Rosiñol Laura , Cordón Lourdes , Vidriales María-Belén , Burgos Leire , Flores-Montero Juan , Sanoja-Flores Luzalba , Lopez-Anglada Lucia , Maldonado Roberto , de la Cruz Javier , Gutierrez Norma C. , Calasanz Maria-Jose , Martin-Ramos Maria-Luisa , Garcia-Sanz Ramón , Martinez-Lopez Joaquin , Oriol Albert , Blanchard María-Jesús , Rios Rafael , Martin Jesus , Martinez-Martinez Rafael , Sureda Anna , Hernandez Miguel-Teodoro , de la Rubia Javier , Krsnik Isabel , Moraleda Jose-Maria , Palomera Luis , Bargay Joan , Van Dongen Jacques J.M. , Orfao Alberto , Mateos Maria-Victoria , Blade Joan , San-Miguel Jesús F. , Lahuerta Juan-José ,   on behalf of the GEM (Grupo Español de Mieloma)/PETHEMA (Programa Para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group
Published: November 2019

PURPOSE

Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG).

PATIENTS AND METHODS

In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10−6. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial.

RESULTS

Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%.

CONCLUSION

The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.
Effect of MMP9 inhibition on effector T-cell responses in a PD1-axis refractory model.
Authors: Smith Victoria , Juric Vladi , Mikels-Vigdal Amanda , O'Sullivan Chris , Kovalenko Maria , Degenhardt Jeremiah , Yue Peng , Sriram Venkataraman
Published: November 2019

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Background: Matrix metalloproteinase 9 (MMP9) acts via diverse mechanisms to promote tumor growth and metastasis, and is a key component of the immune-suppressive myeloid inflammatory milieu. We developed a monoclonal antibody (AB0046) that inhibits murine MMP9 and assessed its mechanism of action in immunocompetent mice as a single agent, or in combination with a murine anti-PDL1 antibody. Methods: An orthotopic, syngeneic tumor model (NeuT), which models MMP9-positive myeloid infiltrate, was utilized for efficacy and pharmacodynamic studies involving RNA and T cell receptor (TCR) sequencing, and flow cytometry. Enzymatic analyses were performed on T cell chemoattractant CXCR3 ligands (CXCL9, CXCL10, and CXCL11) which were subsequently evaluated in chemotaxis assays. Results: Anti-MMP9 treatment alone or in combination with an anti-PDL1 antibody decreased primary tumor growth as compared to IgG control-treated animals (56% vs 335% tumor growth increase, p = 0.0005) or anti-PDL1 alone. Profiling of tumors by RNA sequencing revealed that inhibition of MMP9 resulted in elevated expression of genes associated with immune cell activation pathways (Hallmark Interferon Gamma Response, FDR p < 0.001). Treatment with anti-MMP9 and anti-PDL1 antibodies decreased TCR clonality, with evidence of a more diverse TCR repertoire (p = 0.005). Immunophenotyping of tumor-associated T cells by flow cytometry showed that anti-MMP9 and anti-PDL1 co-treatment promoted a 2.8-fold increase in CD3+ cells in tumors (p = 0.01), which was associated with an increase in CD4+ T cells (3.2-fold increase; p = 0.006) and CD8+ T cells (2.8-fold increase; p = 0.013). In contrast, anti-MMP9 and combination treatment resulted in a decrease in tumor-associated regulatory T cells (CD25+ FoxP3+ cells, p = 0.04). MMP9 cleavage of T cell chemoattractant ligands in vitro rendered them functionally inactive for recruitment of activated primary human effector T cells. Conclusions: Inhibition of MMP9 reduces tumor burden and promotes cytotoxic T cell infiltration in a PD1-axis refractory mouse model. The combination of nivolumab and GS-5745, a humanized anti-MMP9 inhibitory antibody, is currently being evaluated in gastric cancer (NCT02864381).
Planning of dosing regimen and schedule of assessments for first in human oncology clinical trials for therapeutic monoclonal antibodies.
Authors: Bernstein Galina , Oldenhof John
Published: November 2019

11

Background: Planning of the dosing regimen for oncology therapeutics, based on the pre-clinical information about the monoclonal antibody, is an important step in the development of a clinical program. Accumulated material about previously developed monoclonal antibodies allows for the rational approach to plan a dosing regimen and the assessments of biomarkers based on structural similarities and the mode of action. Methods: The structural approach to predict the elimination half-life and related frequency of dosing was applied to plan first in human clinical trials for monoclonal therapeutics. The following attributes were taken into account: glycosylation content and related affinity to Fcγ receptors (t1/2 ↑), glycosylation and affinity to non-specific receptors – asialoglycoprotein receptor and mannose receptor (t1/2 ↓), oxidation of hinge Met and affinity to FcRn receptor(t1/2 ↑), immunogenicity (t1/2 ↓), mechanism of action – binding to solid or soluble target, ADCC, CDC, aggregate state and impurities. Literature data on monoclonal antibodies with similar qualities, attributes, and mechanism of action were used as input for the predictive estimates. The schedule of biomarker assessments was developed on a similar approach. The structural characterization was aided by the data on the pharmacokinetics in animal species. Results: A risk-based approach, taking into account estimates of effective elimination half-life, was used to determine an optimal dosing regimen for either IV infusion or SC injection. The interim PK analyses completed early in the conduct of the study aided in study planning and conduct to ensure balanced concentration of the drug without excessive accumulation. Conclusions: The knowledge acquired in the field of immune-oncology allows for effective planning of dosing regimen and schedule of biomarker assessments for novel monoclonal antibodies. The results of the predictive estimates were used in the clinical studies protocol with follow-up interim PK analysis. The results of the study will be published at a later presentation.
Interleukin 17 in the tumor microenvironment: A potent target for anticancer immunotherapy?
Authors: Fabre Joseph , Giustiniani Jérôme , Servagi-Vernat Stéphanie , Garbar Christian , Merrouche Yacine , Antonicelli Frank , Bensussan Armand
Published: November 2019

115

Background: Inflammation has been known to play a critical role in cancer for decades. Tumors build up on the “inflammatory soup” in the surrounding microenvironment to progress, grow, metastasize and evade immune response. Since its discovery in the nineties, interleukin-17 (IL-17A), a proinflammatory cytokine mainly secreted by T helper 17 cells, has been extensively studied in chronic inflammatory diseases like psoriasis or rheumatoid arthritis. In solid malignancies, there is growing evidence that IL-17 enhances cancer cells’ capacity of division, invasion and chemotherapy resistance. Methods: Based on our team's experience and publications, we systematically reviewed the existing literature about the role of IL-17 in cancers, in aim to discuss if developing IL-17 pathway-targeting strategies could be effective. Results: Data from several preclinical studies indicated tumor-promoting effects of IL-17 on diverse cancer models, cellular or murine. In clinical studies, detection of high levels of IL-17 in patients’ blood or tumors was correlated to bad prognosis. Concordantly, we reported recently in triple negative breast cancer cell lines that IL-17A and IL-17E promoted resistance to Docetaxel and failed to induce apoptosis as previously observed for IL-17E by other authors. Interestingly, we also revealed that both cytokines induced the generation of tumorigenic low molecular weight forms of cyclin E (LMW-E), which high levels correlated strongly with a poor survival in breast cancer patients. Lastly, we reported a crosstalk between IL-17E and epidermal growth factor signaling, which confers in vitro resistance to EGFR-targeted therapies. In opposition, a few studies observed that IL-17 inhibited tumor grafts development and metastasis in rodent possibly through the expression of other proinflammatory mediators such as IL-1β, TNFα, IL-6 or GM-CSF and the recruitment of neutrophils to the tumor site. Conclusions: Most of the literature supports a critical role of IL-17 in cancer promotion and development. These results encourage us to present the IL-17 family members and their receptors as potent targets for anticancer biotherapy.
Expansion of Lox-1+CD15+ myeloid-derived suppressor cells in hepatocellular carcinoma patients.
Authors: Li Xing , Ye Qing-Jian , Xing Yan-Fang , Lin Jin-Xiang , Lin Qu , Wu Xiang-yuan
Published: November 2019

124

Background: The top issue in the field of myeloid deprived suppressor cell (MDSC) was lack of specific markers. Lox-1 was reported to be a novel marker for polymorphonuclear MDSC (PMN-MDSC) in whole blood of head and neck cancer and lung cancer patients. The present study is aimed to detecting the lox-1 PMN-MDSC in whole blood. Methods: In the present study, a series of 24 hepatocellular carcinoma (HCC) patients and 12 healthy donors were analyzed investigating frequencies of PMN-MDSC (Lox-1+CD15+) in whole blood. The immunosuppressive function of MDSC were evaluated using T cell proliferation and activation tests. The underly mechnisms were determined using inhibitors, genes expression and activity tests. The association between MDSC and clinical parameters were determined retrospectively. Results: Patients presented significantly higher level of PMN-MDSCs. In order to confirm immune suppressive capacity of PMN-MDSCs in HCC patients, circulative PMN-MDSCs and T cells were purified using flow sorting and cocultured. T cell proliferation was abrogated by the addition of PMN-MDSC with a dosage dependent manner, as well as the production of IFN-γ. Besides, the suppression on T cell proliferation and IFN-γ production was partially reversed by reactive oxygen species (ROS) inhibitor and Arginase inhibitor. The ROS level were higher in PMN-MDSC than their normal controls. The mRNA level of NOX2, the key protein complex responsible for ROS productin in MDSC, and Arginase I were higher in PMN-MDSCs. Finally, the frequencies of PMN-MDSCs was positively associated with tumor volume. Conclusions: The present study found that Lox-1+CD15+ were novel markers for PMN-MDSCs in whole blood and very easily to be standardized between institutions.
Formation of FcRγ-deficient NK cell subset associated with HCMV-reactivation in hematopoietic cell transplant recipients.
Authors: Lee Jaewon , Kim Sungjin , Scott Jeannine , Al-Homsi A. Samer , Williams Stephanie F. , Muilenburg Marlee , Hong Suyeon , Esselman Walter J
Published: November 2019

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Background: We have previously identified a novel subset of human NK cells that lacks FcRγ, a transmembrane signaling adaptor associated with CD16, the Fc receptor for IgG. These FcRγ-deficient NK cells (termed g-NK cells) display enhanced functional activity against target cells, including virus-infected cells, in concert with target-specific antibody molecules. The presence of g-NK cells in humans is associated with prior infection by human cytomegalovirus (HCMV). Additionally, g-NK cells are activated and expand robustly against HCMV-infected cells in the presence of HCMV-specific antibodies, consistent with predicted features of memory-like or adaptive NK cells. Recent studies have reported that expansion of a specific subset of NK cells with an adaptive phenotype can occur in response to HCMV reactivation after hematopoietic cell transplantation. Remarkably, patients with the expanded subset of NK cells showed reduced incidence of leukemia relapse and improved disease-free survival. Methods: Using blood samples obtained from BMT patients pre- and post-transplant, we have performed FACS-based phenotyping and ELISA-based serotyping analyses to explore whether HCMV-reactivation correlates with the generation of FcRγ-deficient NK cells in a bone marrow transplantation (BMT) setting. Results: Our data demonstrate that FcRγ-deficient NK cells appear in transplant patients following HCMV-reactivation, but not in the BMT patients without HCMV-reactivation. Phenotypic analysis indicates that these FcRγ-deficient NK cells display characteristics consistent with those observed in g-NK cells obtained from healthy HCMV-seropositive individuals, e.g. decreased expression of tyrosine kinase SYK. Conclusions: These results provide evidence in support of a causal relationship between HCMV infection and the generation of g-NK cells. Given the enhanced functional capability of g-NK cells against HCMV-infected target cells, the formation and functional activity of g-NK cells within BMT patients may contribute to the control of HCMV infection during the transplant procedure, and impact recovery from other diseases.
Combination of TLR9 agonists EnanDIM with checkpoint inhibitors for cancer immunotherapy.
Authors: Schmidt Manuel , Kapp Kerstin , Oswald Detlef , Wittig Burghardt , Volz Barbara
Published: November 2019

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Background: TLR9 agonists have shown anti-tumor effects by modulating the innate and adaptive immune system. Ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. The new family of TLR9 agonists, EnanDIM, consists of linear single-stranded ODN synthesized using L-deoxyribonucleotides (natural enantiomers of D-deoxyribonucleotides) at their 3’-ends to prevent degradation. Therefore, EnanDIM does not own the off-target effects of PTO-modified CpG-ODN. Methods: EnanDIM with varying nucleotid sequences were compared for IFN-alpha response from human peripheral blood mononuclear cells and those molecules inducing the stronges response were selected. A maximum feasible dose (MFD) approach was employed to evaluate their acute toxicity and immunomodulatory properties. In addition, a combinatory approach with aPD-1 was evaluated in an syngeneic colon carcinoma CT26 mouse tumor model. Results: EnanDIM581 and EnanDIM532 were selected due to their pronounced activation of the IFN-alpha pathway in vitro. Safety assessments throughout and a gross necropsy at the end of the study revealed no signs of toxicity despite extremely high doses (300 - 1700 mg/kg). Dose-dependent increase of IP-10 levels in serum was observed between 6 and 24 hours after injection. In the colon carcinoma CT26 model subcutaneous injection of EnanDIM532 and intraperitoneal injection of aPD-1 had a moderate effect on the tumor growth when used in monotherapy (28.3% and 57.0% tumor growth inhibition, TGI). Notably, a combination of EnanDIM532 and aPD-1 further reduced tumor growth (74.7% TGI) and thus prolonged survival of the mice. Conclusions: In conclusion, EnanDIM, a new family of TLR9 agonists and immune surveillance reactivators (ISR), broadly activates the immune system, shows no toxicity in an MFD study and enhances the anti-tumor effects of the aPD-1 checkpoint inhibitor in a pilot study of a murine colon carcinoma tumor model. These data show the promising potential of EnanDIM not only for monotherapeutic but also combinatory approaches.
Intratumoral (i.t.) IMO-2125 (IMO), a TLR9 agonist, in combination with ipilimumab (ipi) in PD-(L)1 refractory melanoma (RM).
Authors: Uemura Marc Isamu , Haymaker Cara L. , Murthy Ravi , James Marihella , Cornfeld Mark , Chunduru Srinivas , Agrawal Sudhir , Yee Cassian , Wargo Jennifer A. , Amaria Rodabe Navroze , Patel Sapna Pradyuman , Tawbi Hussein Abdul-Hassan , Glitza Isabella Claudia , Woodman Scott Eric , Hwu Wen-Jen , Davies Michael A. , Hwu Patrick , Overwijk Willem W , Bernatchez Chantale , Diab Adi
Published: November 2019

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Background: Checkpoint inhibitors (CPI) have transformed melanoma treatment but many patients remain refractory. CPI plus i.t. IMO may improve response by activating innate immune function. Based on this we initiated a trial of IMO in combination with ipi or pembrolizumab (pem) in RM. Methods: Adults with RM that progressed during or after ≥ 12 weeks of PD-1 therapy are eligible. IMO, 4 – 32 mg, is given i.t. for 6 doses, along with either ipi or pem. Endpoints are safety, response, biomarkers, and PK. Injected and distant tumors are biopsied pre-treatment and again at 24 hrs (injected tumor), weeks 8 and 13 for immune analyses. Results: As of October 7, 2016, 10 pts have been treated; median age 55 (range: 39-76), 8 with visceral and 1 with brain metastases. Two pts have mucosal histology. 60% have BRAF mutations. Prior duration of anti-PD-(L)1 therapy ranges from 8 to 63 weeks and median time from last PD-1 therapy to onset of study treatment is 6 (4,57) weeks. IMO has been administered at 4, 8, and 16 mg. No DLTs have been observed and there have been no treatment-related discontinuations or deaths. Ipi was discontinued after the second dose in one subject with previous ipi-related hepatitis for recurrent transaminase elevations (grade 4). Grade 3 hypophysitis is the only other immune-related AE (2 pts). Most frequent TEAE (N > 2) are nausea, vomiting, anemia, diarrhea, increases in ALT/AST/GGT/triglycerides, chills, fatigue, pyrexia, and leukopenia; the majority are low-grade. 6 patients are evaluable for response - CR (1), PR (2), SD (2), PD (1) by RECIST1.1. Tumor biopsies show consistent maturation of the myeloid DC1 subset in IMO injected tumors at 24 hrs. Week 8 results are consistent with a higher rate of proliferative (Ki67) effector CD4+ and CD8+ T-cells in responders. Circulating IFNγ shows 2-3 fold increase in responders. Conclusions: The combination of IMO and ipi is tolerable and has activity in PD-1 refractory melanoma. Dose escalation is ongoing and a Phase 2 expansion with both combinations is planned. Updated safety, antitumor activity, PK, and biomarker data will be presented at the meeting. Clinical trial information: NCT02644967.
Effect of dendritic cells (DC) transduced with chimeric antigen receptor (CAR) on CAR T-cell cytotoxicity.
Authors: Suh Hyung Chan , Pohl Katherine , Javier Anna Patricia L. , Slamon Dennis J. , Chute John P
Published: November 2019

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Background: T cells interacting DC could be superior in T cell cytotoxicity. CD141+/Cleg9a+ intra-tumoral DC play a critical role in tumor cytotoxicity. Therefore, combining intra-tumoral DC in CAR T cell would safely increase localized CAR T cell cytotoxicity. We hypothesized that bioengineered DC compartment could be an excellent source for enhanced CAR T cell cytotoxicity. Methods: DC precursors and T cells of PBMC were transduced with a CAR (pCCL-anti-CD33-4-1BB-CD3z-T2A-GFP; CAR-DC or CAR T). For comparison, additional DC were transduced with 4-1BB cDNA (pCCL-4-1BB-T2A-GFP; 4-1BB-DC) or mock control (pCCL-eGFP). In addition to lentivirus transduction, differentiation of DC in vitro employed Flt3L/GM-CSF/IL-4. Transduced CAR T and CAR-DC were sorted by GFP expression at day 5. After further 10 days of culture, cells were harvested and analyzed for phenotype. An acute myeloid leukemia (AML) cell line (Kasumi-1) was treated with CAR T +/- CAR-DC, 4-1BB-DC, or mock control for functional assays. Results: Frequencies of cells expressing CD141+/Cleg9a+ were higher in 4-1BB-DC vs. control DC (33% vs. 1.5%). After mixing CAR T and CAR-DC (5X105) with Kasumi-1 (1X105) for 6 hours, CAR T/CAR-DC showed 100% Kasumi-1 cell cytotoxicity compared to 70% of CAR T by trypan blue. CAR T/CAR-DC also demonstrated higher Annexin V positive Kasumi-1 cells compared with CAR-T (91% vs. 52%). CAR T with or without CAR-DC were also assessed with multiplex immunoassays. CAR T cells mixed with CAR-DC induced higher level of IFN-gamma (10,316 vs. 6,186 pg/ml), IL-2 (68,840 vs. 64,708 pg/ml), and TNFalpha (1,361 vs. 905 pg/ml) (Kasumi-1 cells mixed with CAR-T cells of 10 E/T ratio) than CAR T cells. CAR-DC produced significantly higher IL-12 cytokine production (1,352 vs. 161 pg/ml) than CAR T cells in response to CD33 but independent to T cells, confirmed by comparing IL-12 production with CAR T/4-1BB-DC. Conclusions: These data show that in vitro differentiation of DC bearing 4-1BB increases CD141+/Cleg9a+ DC population and that interaction with CAR-DC to CAR T cells enhances anti-AML cytotoxicity. Our finding may implicate the development of CAR-DC therapy combined to CAR T cells to increase the efficiency of cancer immunotherapy.