bluuebunny/crossref_metadata_2025 huggingface dataset:
Leukemia-on-a-chip: Dissecting the chemoresistance mechanisms in B cell acute lymphoblastic leukemia bone marrow niche
Authors: Ma Chao , Witkowski Matthew T. , Harris Jacob , Dolgalev Igor , Sreeram Sheetal , Qian Weiyi , Tong Jie , Chen Xin , Aifantis Iannis , Chen Weiqiang
Published: October 2020

Ma
et al.
dissected the heterogeneous leukemia chemoresistance mechanisms using a leukemia-on-a-chip bone marrow niche model.
Harnessing lipid signaling pathways to target specialized pro-angiogenic neutrophil subsets for regenerative immunotherapy
Authors: Turner T. C. , Sok M. C. P. , Hymel L. A. , Pittman F. S. , York W. Y. , Mac Q. D. , Vyshnya S. , Lim H. S. , Kwong G. A. , Qiu P. , Botchwey E. A.
Published: October 2020

Local delivery of a pro-resolving lipid mediator leads to a shift in the immune microenvironment and improves wound healing.
Bioinspired metagel with broadband tunable impedance matching
Authors: Dong Erqian , Song Zhongchang , Zhang Yu , Ghaffari Mosanenzadeh Shahrzad , He Qi , Zhao Xuanhe , Fang Nicholas X.
Published: October 2020

A bioinspired metagel achieves broadband tunable acoustic impedance matching.
Aerial strategies advance volcanic gas measurements at inaccessible, strongly degassing volcanoes
Authors: Liu E. J. , Aiuppa A. , Alan A. , Arellano S. , Bitetto M. , Bobrowski N. , Carn S. , Clarke R. , Corrales E. , de Moor J. M. , Diaz J. A. , Edmonds M. , Fischer T. P. , Freer J. , Fricke G. M. , Galle B. , Gerdes G. , Giudice G. , Gutmann A. , Hayer C. , Itikarai I. , Jones J. , Mason E. , McCormick Kilbride B. T. , Mulina K. , Nowicki S. , Rahilly K. , Richardson T. , Rüdiger J. , Schipper C. I. , Watson I. M. , Wood K.
Published: October 2020

Aerial measurements using unoccupied aerial systems (UAS) transform our ability to measure and monitor volcanic plumes.
Primary cilia as the nexus of biophysical and hedgehog signaling at the tendon enthesis
Authors: Fang Fei , Schwartz Andrea G. , Moore Emily R. , Sup McKenzie E. , Thomopoulos Stavros
Published: October 2020

Primary cilia at the tendon enthesis serve as mechanosensors and Hh signal transducers.
Viscoelastic properties of biopolymer hydrogels determined by Brillouin spectroscopy: A probe of tissue micromechanics
Authors: Bailey Michelle , Alunni-Cardinali Martina , Correa Noemi , Caponi Silvia , Holsgrove Timothy , Barr Hugh , Stone Nick , Winlove C. Peter , Fioretto Daniele , Palombo Francesca
Published: October 2020

Gelatin hydrogels cover a wide range of microenvironments that are relevant for bioapplications of Brillouin elastography.
K
2P
channel C-type gating involves asymmetric selectivity filter order-disorder transitions
Authors: Lolicato Marco , Natale Andrew M. , Abderemane-Ali Fayal , Crottès David , Capponi Sara , Duman Ramona , Wagner Armin , Rosenberg John M. , Grabe Michael , Minor Daniel L.
Published: October 2020

The innately heterodimeric K
2P
filter permits two C-type gating mechanisms, pinching and dilation, to operate in one channel.
Discovery of a previously unknown biosynthetic capacity of naringenin chalcone synthase by heterologous expression of a tomato gene cluster in yeast
Authors: Kong Deze , Li Sijin , Smolke Christina D.
Published: October 2020

A previously unknown chalcone synthase activity for HCAA synthesis is uncovered via characterization of a tomato gene cluster in yeast.
Fatalities from COVID-19 are reducing Americans’ support for Republicans at every level of federal office
Authors: Warshaw Christopher , Vavreck Lynn , Baxter-King Ryan
Published: October 2020

Increases in COVID-19 fatalities reduce support for the President and other members of his party.
Persistent STAT5 activation reprograms the epigenetic landscape in CD4
+
T cells to drive polyfunctionality and antitumor immunity
Authors: Ding Zhi-Chun , Shi Huidong , Aboelella Nada S. , Fesenkova Kateryna , Park Eun-Jeong , Liu Zhuoqi , Pei Lirong , Li Jiaqi , McIndoe Richard A. , Xu Hongyan , Piazza Gary A. , Blazar Bruce R. , Munn David H. , Zhou Gang
Published: October 2020

Persistent STAT5 activation endows antitumor CD4
+
T cells with desirable functional features that optimize adoptive T cell therapy.
Population Pharmacokinetics and Exposure-Response Analysis of Tribendimidine To Improve Treatment for Children with Hookworm Infection
Authors: Brussee Janneke M. , Hiroshige Noemi , Neodo Anna , Coulibaly Jean T. , Pfister Marc , Keiser Jennifer
Published: October 2020

Tribendimidine has been successful in treating hookworm infections and may serve as an alternative to albendazole should resistance arise. Our aims were to (i) characterize the pharmacokinetics (PK) of tribendimidine’s primary metabolite, deacetylated amidantel (dADT), and secondary metabolite, acetylated derivative of amidantel (adADT), in school-aged children and adolescents, (ii) link exposure to efficacy against hookworm, and (iii) evaluate whether tribendimidine pharmacotherapy in children could be further improved.
(p)ppGpp-Dependent Regulation of the Nucleotide Hydrolase PpnN Confers Complement Resistance in Salmonella enterica Serovar Typhimurium
Authors: Chau N. Y Elizabeth , Pérez-Morales Deyanira , Elhenawy Wael , Bustamante Víctor H. , Zhang Yong E. , Coombes Brian K.
Published: October 2020

The stringent response is an essential mechanism of metabolic reprogramming during environmental stress that is mediated by the nucleotide alarmones guanosine tetraphosphate and pentaphosphate [(p)ppGpp]. In addition to physiological adaptations, (p)ppGpp also regulates virulence programs in pathogenic bacteria, including
Salmonella enterica
serovar Typhimurium.
S
. Typhimurium is a common cause of acute gastroenteritis, but it may also spread to systemic tissues, resulting in severe clinical outcomes.
Serum Epitope Repertoire Analysis Enables Early Detection of Lyme Disease with Improved Sensitivity in an Expandable Multiplex Format
Authors: Reifert Jack , Kamath Kathy , Bozekowski Joel , Lis Ewa , Horn Elizabeth J. , Granger Dane , Theel Elitza S. , Shon John , Sawyer Jaymie R. , Daugherty Patrick S.
Published: October 2020

Widely employed diagnostic antibody serology for Lyme disease, known as standard two-tier testing (STTT), exhibits insufficient sensitivity in early Lyme disease, yielding many thousands of false-negative test results each year. Given this problem, we applied serum antibody repertoire analysis (SERA), or next-generation sequencing (NGS)-based serology, to discover IgG and IgM antibody epitope motifs capable of detecting Lyme disease-specific antibodies with high sensitivity and specificity. Iterative motif discovery and bioinformatic analysis of epitope repertoires from subjects with Lyme disease (
n
 = 264) and controls (
n
 = 391) yielded a set of 28 epitope motifs representing 20 distinct IgG antibody epitopes and a set of 38 epitope motifs representing 21 distinct IgM epitopes, which performed equivalently in a large validation cohort of STTT-positive samples.
Acute compartment syndrome of the foot due to a twisting injury while playing sports
Authors: Hijazi Humayun , O'Reilly Marc , Moloney Darren Patrick , Bayer Thomas
Published: October 2020

Acute compartment syndrome (ACS) of the foot is one of the most severe injuries of the foot and typically results from a fracture, crush or vascular injury. ACS, isolated to a single foot compartment, is a rare complication following a simple twisting injury of the ankle. In this article, the authors present the case report of a 25-year-old man who developed ACS, isolated to the lateral compartment of the foot, secondary to rupture of the lateral ligament complex and subsequent haematoma formation. An emergency fasciotomy was performed and the patient had complete resolution of his symptoms. ACS is usually associated with significant trauma, however, there are reported cases in the literature associated with a minor injury. In this case report, the authors describe how ACS developed following a simple ankle sprain playing sports in the absence of a high-energy insult or fracture.
Glandular fever and Epstein-Barr virus-related polyneuropathy: a life-threatening complication
Authors: Dorris Colm Brendan , Gallagher Donna , Black Myles
Published: October 2020

An 18-year-old woman presented with a 1-week history of sore throat, lethargy and fevers. She was subsequently diagnosed with glandular fever and was managed conservatively. Following 1 week of conservative measures, she developed acute upper airway obstruction requiring emergency surgical tracheostomy insertion. Further investigation including electromyography demonstrated multiple cranial nerve neuropathies.
Polycythaemia following treatment of lymphoplasmacytic lymphoma
Authors: Verma Shailendra Prasad , Singh Bhupendra , Kushwaha Rashmi , Pavecha Punita
Published: October 2020

A 61-year-old man presented to the department of clinical haematology in February 2016 with symptomatic anaemia, generalised lymphadenopathy and hepatomegaly. Routine investigations showed severe anaemia with the presence of lymphoplasmacytoid cells in the peripheral smear, and bone marrow examination with IHC and serum protein electrophoresis confirmed diagnosis of lymphoplasmacytic lymphoma. The patient received supportive transfusion therapy and combination chemotherapy. After VI cycles, the patient had a complete haematological response with marrow in remission. Maintenance rituximab was planned every 3 months for 2 years. At the time of first dose of maintenance rituximab, his haemoglobin (Hb) was 189 g/L with low normal erythropoietin level. During the last 3 years follow-up, his Hb ranged between 16.5 and 20.1 g/dL. All causes of secondary polycythaemia were ruled out. Workup for polycythAemia vera (PV), including JAK-2 and bone marrow, was not suggestive of PV. We labelled it as a case of polycythaemia due to undetermined aetiology.
Hypertensive retinopathy in a neonate
Authors: Goyal Prakhar , Agarwal Komal
Published: October 2020

A 23-day-old female child diagnosed as having systemic hypertensive emergency was referred for retinal screening. The fundus examination showed bilateral intraretinal haemorrhages and hard exudates especially at the macula. Venous looping was noted. The ocular features were suggestive of hypertensive retinopathy. Control of systemic hypertension was advised and was managed conservatively with close follow-up. Widefield fundus photography was done at presentation and follow-up to document the change in retinopathy with control of hypertension.

The haemorrhages and exudates resolved on follow-up but significant retinal pigment epithelium changes with beaten bronze appearance were noted at the area of previous oedema. Presence of hypertensive retinopathy in a neonate is rare and has long-term effects on visual development. This report describes the course of hypertensive retinopathy in a neonate.
Postnephrectomy diaphragmatic hernia presenting as progressive dyspnoea
Authors: Azam Aqeem , Michael Kirolos
Published: October 2020

The diagnosis of diaphragmatic hernia (DH) in adults is rare and may be due to missed congenital DH or acquired DH from trauma or as a postoperative complication of certain thoracic and abdominal surgeries. We present a case of a patient with well-controlled chronic obstructive pulmonary disease who presented to the hospital with progressive dyspnoea, 6 months after laparoscopic nephrectomy. The patient was initially misdiagnosed and treated for empyema after plain radiographic images were reported as consolidation with gas locules. Multislice CT imaging undertaken before diagnostic thoracocentesis confirmed the presence of a right-sided DH, which was subsequently surgically repaired in the outpatient setting, given her haemodynamic stability. As patients with DH usually present in the emergency setting, requiring urgent inpatient surgical repair, there are currently no guidelines on the method and urgency of management of asymptomatic or mildly symptomatic, stable patients. Furthermore, while plain radiography is the usual first-line imaging modality used, misdiagnosis of DH as pleural effusion or empyema can lead to unnecessary and potentially harmful procedures such as diagnostic thoracocentesis. These risks can potentially be minimised with early utilisation of multislice CT imaging in patients with high clinical suspicion.
Sternal metastatectomy in a case of papillary thyroid carcinoma
Authors: Pradeep Sivakumar , Hedne Naveen , Vidhyadharan Sivakumar , Rajiv Santosham
Published: October 2020

Thyroid cancer is the most common among endocrine cancers. Over 90% of all thyroid malignancies are differentiated thyroid carcinomas (DTC). However, only 2%–13% of DTC present with bone metastasis. Radioactive iodine ablation (RAI) is the treatment of choice for metastatic DTC. However, RAI therapy is not as effective in bone metastasis as it is in lung and visceral metastases. Only few cases of surgical management of bone metastasis in DTC have been reported in the literature. Here, we report a case of follicular variant of papillary thyroid carcinoma with sternal and lung metastases, for which sternal metastatectomy was performed.
Lemierre’s syndrome: a forgotten life-threatening entity
Authors: Gama Rita , Sousa Manuel , Castro Fernanda , Condé Artur
Published: October 2020

Lemierre’s syndrome is a very rare but potentially fatal condition. It mainly affects adolescents and young adult males, and usually arises as a serious complication of pharyngitis or peritonsillar abscess. It is characterised by the triad of internal jugular vein septic thrombophlebitis, septic emboli (mostly pulmonary) and the isolation of the agent ‘Fusobacterium necrophorum’in sterile fluids. In this report, it is described a case in which the nonspecific and subtle clinic made the diagnosis difficult to reach. In fact, only the dissociation between flu-like symptoms and the presence of significant changes in the blood tests (suggestive of acute bacterial infection), led to the request for imaging tests, which proved to be essential for the final diagnosis and subsequent control of the disease. This case report aims to increase the awareness among Ear, Nose and Throat (ENT) residents, paediatricians and family doctors about the existence of this entity and its potential life-threatening nature.
Oropharyngeal Kimura’s disease: a diagnostic dilemma and therapeutic challenge
Authors: Saravanam Prasanna Kumar , Gajendran Aishwarya , Dinakaran Nethra , Jayaraman Dhaarani
Published: October 2020

Kimura’s disease is a chronic inflammatory disorder involving subcutaneous tissue and locoregional lymph nodes of head and neck region, characterised by angiolymphoid proliferation. It is typically associated with peripheral eosinophilia, increased serum IgE and lymphadenopathy. Diagnosis is usually based on histopathological examination. Though various treatment modalities have been put forward, surgical management remains the first line of treatment, followed by systemic steroids application. This case report discusses the diagnostic dilemma and therapeutic management of a rare clinical presentation and management of oropharyngeal Kimura’s disease in a young immunocompetent woman.
Pleomorphic carcinoma of the trachea after chemoradiotherapy for laryngeal cancer
Authors: Saikawa Hirotaka , Uesugi Noriyuki , Sugai Tamotsu , Maemondo Makoto
Published: October 2020

A 66-year-old male patient who had received chemoradiotherapy (CRT) for laryngeal cancer 2 years ago visited a local doctor complaining of dyspnoea and wheezing. CT scan showed narrowing of the trachea caused by a tumour. We intubated the trachea over the tumour using a bronchoscope. A week later, the truncated tracheal tumour obstructed the tracheal tube, compromising the patient’s breathing. We removed the obstructed tube and inserted a new one. We submitted the tissue from the tube to a pathologist. Histopathological diagnosis was pleomorphic carcinoma, a subtype of sarcomatoid carcinoma. The mechanism of epithelial–mesenchymal transition (EMT) occurring after CRT was detected in the tumour. Because he had undergone CRT for laryngeal cancer, surgery was not indicated, and we started radiation therapy. Sarcomatoid carcinomas including pleomorphic carcinoma of the trachea are extremely rare, with few reported cases, and EMT is associated with this histological type and CRT.
Mandibular odontogenic myxoma in a paediatric patient
Authors: Shupak Raymond Patrick , Cho Jason J
Published: October 2020

Odontogenic myxoma (OM) are benign, locally aggressive tumours that are rarely found in the paediatric maxillofacial region. OMs derive from mesenchymal odontogenic tissue. We describe the management of a 3-year-old girl who presented with a large right-sided mandibular lesion. Her treatment included conservative excision, curettage and peripheral ostectomy. A literature review was performed which calls into question the dogmatic practice of resection with 1 to 1.5 cm margins. Treatment approaches to the OM could potentially be altered in the paediatric patient.
Prognostic value of TERT promoter mutations in conjunctival melanomas in addition to clinicopathological features
Authors: van Ipenburg J A , Naus N C , Dubbink H J , van Ginderdeuren R , Missotten G S , Paridaens D , Verdijk R M
Published: October 2020

Aims

To evaluate the prognostic value of clinical, histopathological and molecular features and to relate different treatment modalities to clinical outcome in conjunctival melanomas (CM).

Methods

Retrospective review of clinical, histopathological and BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutation status and treatment modalities, correlated to recurrence and metastasis in 79 patients with CM, diagnosed between 1987 and 2015 in three tertiary referral centres in the Netherlands and Belgium.

Results

Out of 78 evaluable patients, recurrences occurred in 16 patients and metastasis in 12 patients (median follow-up time 35 months (0–260 months)). Tumour thickness >2 mm, pT status, the presence of epithelioid cells, ulceration and mitoses was significantly correlated with metastasis (p value 0.046, 0.01, 0.02, 0.001 and 0.003, respectively). Furthermore, CM frequently harbour BRAF V600E and TERT promoter mutations (29% and 43%, respectively). TERT promoter mutations were correlated to shorter metastasis-free survival (p value 0.002). No significant correlation was found for clinical parameters and metastatic disease. Palpebral, forniceal and caruncular melanomas were more prone to develop recurrences (p value: 0.03). Most CM were treated with excision with adjuvant therapy.

Conclusion

In line with the recommendations in the Eighth Edition of the American Joint Committee on Cancer Staging for CM, the pathology report should include information about pT status, tumour thickness, presence of epithelioid cells, ulceration and mitoses. Furthermore, information about the presence of a TERT promoter mutation and BRAF V600E mutation is of interest for therapeutic decision making. The presence of a TERT promoter mutation is correlated to metastatic disease.
Employing body-fixed sensors and machine learning to predict physical activity in military personnel
Authors: Papadakis Nikolaos , Havenetidis K , Papadopoulos D , Bissas A
Published: October 2020

Introduction

This was a feasibility pilot study aiming to develop and validate an activity recognition system based on a custom-made body-fixed sensor and driven by an algorithm for recognising basic kinetic movements in military personnel. The findings of this study are deemed essential in informing our development process and contributing to our ultimate aim which is to develop a low-cost and easy-to-use body-fixed sensor for military applications.

Methods

Fifty military participants performed a series of trials involving walking, running and jumping under laboratory conditions in order to determine the optimal, among five machine learning (ML), classifiers. Thereafter, the accuracy of the classifier was tested towards the prediction of these movements (15 183 measurements) and in relation to participants’ gender and fitness level.

Results

Random forest classifier showed the highest training and validation accuracy (98.5% and 92.9%, respectively) and classified participants with differences in type of activity, gender and fitness level with an accuracy level of 83.6%, 70.0% and 62.2%, respectively.

Conclusions

The study showed that accurate prediction of various dynamic activities can be achieved with high sensitivity using a low-cost easy-to-use sensor and a specific ML model. While this technique is in a development stage, our findings demonstrate that our body-fixed sensor prototype alongside a fully trained validated algorithm can strategically support military operations and offer valuable information to commanders controlling operations remotely. Further stages of our developments include the validation of our refined technique on a larger range of military activities and groups by combining activity data with physiological variables to predict phenomena relating to the onset of fatigue and performance decline.
Proposal of a clinical care pathway for quality and safe management of headache patients: a consensus study report
Authors: Pascual Julio , Pozo-Rosich Patricia , Carrillo Irene , Rodríguez-Justo Sandra , Jiménez-Hernández Dolores , Layos-Romero Almudena , Bailón-Santamaría Cristina , Torres Antonio , Martínez-García Alba , Ignacio Emilio , Mira José Joaquín
Published: October 2020

Background

Headache is one of the most prevalent and disabling conditions. Its optimal management requires a coordinated and comprehensive response by health systems, but there is still a wide variability that compromises the quality and safety of the care process.

Purpose

To establish the basis for designing a care pathway for headache patients through identifying key subpathways in the care process and setting out quality and clinical safety standards that contribute to providing comprehensive, adequate and safe healthcare.

Method

A qualitative research study based on the consensus conference technique. Eleven professionals from the Spanish National Health System participated, seven of them with clinical experience in headache and four specialists in healthcare management and quality. First, identification of the key subpathways in the care process for headache, barriers/limitations for optimal quality of care, and quality and safety standards applied in each subpathway. Second, two consecutive consensus rounds were carried out to assess the content of the subpathway level descriptors, until the expert agreement was reached. Third, findings were assessed by 17 external healthcare professionals to determine their understanding, adequacy and usefulness.

Results

Seven key subpathways were identified: (1) primary care, (2) emergency department, (3) neurology department, (4) specialised headache unit, (5) hospitalisation, (6) outpatients and (7) governance and management. Sixty-seventh barriers were identified, the most frequent being related to diagnostic errors (36,1%), resource deficiency (25%), treatment errors (19,4%), lack of health literacy (13,9%) and inadequate communications with care transitions (5,6%). Fifty-nine quality and 31 safety standards were defined. They were related to evaluation (23.3%), patient safety (21.1%), comprehensive care (12.2%), treatment (12.2%), clinical practice guidelines (7.8%), counselling (6.7%), training (4.4%) and patient satisfaction (3.3%).

Conclusions

This proposal incorporates a set of indicators and standards, which can be used to define a pathway for headache patients and determine the levels of quality.
Impact of transition programmes for students and new graduate nurses on workplace bullying, violence, stress and resilience: a scoping review protocol
Authors: Alshawush Khadijah Ali , Hallett Nutmeg , Bradbury-Jones Caroline
Published: October 2020

Introduction

The shortage of nurses is projected to grow, and the number of new graduate nurses (NGNs) who are predicted to replace expert nurses has increased. Meanwhile, those NGNs leaving their job within the first year, give various reasons for leaving, including workplace bullying and violence. In response, some hospitals and universities have developed nurse transition programmes such as nurse residency programmes and nurse internship programmes to attract NGNs and to assist in their changing status from education to practice. Although these programmes have been successful in decreasing the turnover rate for new nurses and are cost-effective, their impact on workplace bullying and violence has not been systematically reviewed and is yet to be determined. A scoping review will be conducted to address this gap. The aim is to identify current knowledge regarding the content of transition programmes and their impact in supporting NGNs dealing with workplace violence, bullying and stress.

Methods and analysis

Arksey and O’Malley’s scoping framework and the Joanna Briggs Institute scoping review guidance will guide the methodology process of the review. Published studies, with no date limit, will be identified through the electronic databases (CINAHL, Scopus, MEDLINE, Web of Science, ASSIA, PsycINFO, Embase, PROSPERO and ProQuest Dissertation) and reference lists. Primary key terms will be ‘novice nurse’, ‘new graduate nurses’ and ‘transition programmes’. Two reviewers, guided by standardised procedures, will perform the study selection process independently. Data from the selected studies will be extracted using a data extraction form. Thematic analysis (for qualitative papers) and descriptive summary of the results (for quantitative papers) will be performed.

Ethics and dissemination

Ethical approval is not required for this review. Findings will be used to inform future study designs to evaluate the transition programmes and disseminated via peer-reviewed journals and conferences.
CAR-T cells and TRUCKs that recognize an EBNA-3C-derived epitope presented on HLA-B*35 control Epstein-Barr virus-associated lymphoproliferation
Authors: Dragon Anna Christina , Zimmermann Katharina , Nerreter Thomas , Sandfort Deborah , Lahrberg Julia , Klöß Stephan , Kloth Christina , Mangare Caroline , Bonifacius Agnes , Tischer-Zimmermann Sabine , Blasczyk Rainer , Maecker-Kolhoff Britta , Uchanska-Ziegler Barbara , Abken Hinrich , Schambach Axel , Hudecek Michael , Eiz-Vesper Britta
Published: October 2020

Background

Immunosuppressive therapy or T-cell depletion in transplant patients can cause uncontrolled growth of Epstein-Barr virus (EBV)-infected B cells resulting in post-transplant lymphoproliferative disease (PTLD). Current treatment options do not distinguish between healthy and malignant B cells and are thereby often limited by severe side effects in the already immunocompromised patients. To specifically target EBV-infected B cells, we developed a novel peptide-selective chimeric antigen receptor (CAR) based on the monoclonal antibody TÜ165 which recognizes an Epstein-Barr nuclear antigen (EBNA)−3C-derived peptide in HLA-B*35 context in a T-cell receptor (TCR)-like manner. In order to attract additional immune cells to proximity of PTLD cells, based on the TÜ165 CAR, we moreover generated T cells redirected for universal cytokine-mediated killing (TRUCKs), which induce interleukin (IL)-12 release on target contact.

Methods

TÜ165-based CAR-T cells (CAR-Ts) and TRUCKs with inducible IL-12 expression in an all-in-one construct were generated. Functionality of the engineered cells was assessed in co-cultures with EBNA-3C-peptide-loaded, HLA-B*35-expressing K562 cells and EBV-infected B cells as PTLD model. IL-12, secreted by TRUCKs on target contact, was further tested for its chemoattractive and activating potential towards monocytes and natural killer (NK) cells.

Results

After co-cultivation with EBV target cells, TÜ165 CAR-Ts and TRUCKs showed an increased activation marker expression (CD137, CD25) and release of proinflammatory cytokines (interferon-γ and tumor necrosis factor-α). Moreover, TÜ165 CAR-Ts and TRUCKs released apoptosis-inducing mediators (granzyme B and perforin) and were capable to specifically lyse EBV-positive target cells. Live cell imaging revealed a specific attraction of TÜ165 CAR-Ts around EBNA-3C-peptide-loaded target cells. Of note, TÜ165 TRUCKs with inducible IL-12 showed highly improved effector functions and additionally led to recruitment of monocyte and NK cell lines.

Conclusions

Our results demonstrate that TÜ165 CAR-Ts recognize EBV peptide/HLA complexes in a TCR-like manner and thereby allow for recognizing an intracellular EBV target. TÜ165 TRUCKs equipped with inducible IL-12 expression responded even more effectively and released IL-12 recruited additional immune cells which are generally missing in proximity of lymphoproliferation in immunocompromised PTLD patients. This suggests a new and promising strategy to specifically target EBV-infected cells while sparing and mobilizing healthy immune cells and thereby enable control of EBV-associated lymphoproliferation.
Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor
Authors: Zhang Boning , Napoleon John Victor , Liu Xin , Luo Qian , Srinivasarao Madduri , Low Philip S
Published: October 2020

Background

Most adoptive cell therapies (ACTs) suffer from an inability to control the therapeutic cell’s behavior following its transplantation into a patient. Thus, efforts to inhibit, activate, differentiate or terminate an ACT after patient reinfusion can be futile, because the required drug adversely affects other cells in the patient.

Methods

We describe here a two domain fusion receptor composed of a ligand-binding domain linked to a recycling domain that allows constitutive internalization and trafficking of the fusion receptor back to the cell surface. Because the ligand-binding domain is designed to bind a ligand not normally present in humans, any drug conjugated to this ligand will bind and endocytose selectively into the ACT.

Results

In two embodiments of our strategy, we fuse the chronically endocytosing domain of human folate receptor alpha to either a murine scFv that binds fluorescein or human FK506 binding protein that binds FK506, thereby creating a fusion receptor composed of largely human components. We then create the ligand-targeted drug by conjugating any desired drug to either fluorescein or FK506, thereby generating a ligand-drug conjugate with ~10-9M affinity for its fusion receptor. Using these tools, we demonstrate that CAR T cell activities can be sensitively tuned down or turned off in vitro as well as tightly controlled following their reinfusion into tumor-bearing mice.

Conclusions

We suggest this ‘chimeric endocytosing receptor’ can be exploited to manipulate not only CAR T cells but other ACTs following their reinfusion into patients. With efforts to develop ACTs to treat diseases including diabetes, heart failure, osteoarthritis, cancer and sickle cell anemia accelerating, we argue an ability to manipulate ACT activities postinfusion will be important.
Society for Immunotherapy of Cancer clinical and biomarkers data sharing resource document: Volume I—conceptual challenges
Authors: Rutella Sergio , Cannarile Michael A , Gnjatic Sacha , Gomes Bruno , Guinney Justin , Karanikas Vaios , Karkada Mohan , Kirkwood John M , Kotlan Beatrix , Masucci Giuseppe V , Meeusen Els , Monette Anne , Naing Aung , Thorsson Vésteinn , Tschernia Nicholas , Wang Ena , Wells Daniel K , Wyant Timothy L , Cesano Alessandra
Published: October 2020

The sharing of clinical trial data and biomarker data sets among the scientific community, whether the data originates from pharmaceutical companies or academic institutions, is of critical importance to enable the development of new and improved cancer immunotherapy modalities. Through data sharing, a better understanding of current therapies in terms of their efficacy, safety and biomarker data profiles can be achieved. However, the sharing of these data sets involves a number of stakeholder groups including patients, researchers, private industry, scientific journals and professional societies. Each of these stakeholder groups has differing interests in the use and sharing of clinical trial and biomarker data, and the conflicts caused by these differing interests represent significant obstacles to effective, widespread sharing of data. Thus, the Society for Immunotherapy of Cancer (SITC) Biomarkers Committee convened to identify the current barriers to biomarker data sharing in immuno-oncology (IO) and to help in establishing professional standards for the responsible sharing of clinical trial data. The conclusions of the committee are described in two position papers: Volume I—conceptual challenges and Volume II—practical challenges, the first of which is presented in this manuscript. Additionally, the committee suggests actions by key stakeholders in the field (including organizations and professional societies) as the best path forward, encouraging the cultural shift needed to ensure responsible data sharing in the IO research setting.
Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy
Authors: Cubas Rafael , Khan Zia , Gong Qian , Moskalenko Marina , Xiong Huizhong , Ou Qinglin , Pai Christine , Rodriguez Ryan , Cheung Jeanne , Chan Andrew C
Published: October 2020

Background

Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.

Results

Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors inPtpn22-/-mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibilityPtpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.

Conclusions

Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.
Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions
Authors: Bauché David , Mauze Smita , Kochel Christina , Grein Jeff , Sawant Anandi , Zybina Yulia , Blumenschein Wendy , Yang Peng , Annamalai Lakshmanan , Yearley Jennifer H , Punnonen Juha , Bowman Edward P , Chackerian Alissa , Laface Drake
Published: October 2020

Background

Programmed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events.

Methods

We have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody.

Results

Sustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit.

Conclusion

These data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.
Toward a more inclusive paradigm: thrombectomy for stroke patients with pre-existing disabilities
Authors: Regenhardt Robert W , Young Michael J , Etherton Mark R , Das Alvin S , Stapleton Christopher J , Patel Aman B , Lev Michael H , Hirsch Joshua A , Rost Natalia S , Leslie-Mazwi Thabele M
Published: October 2020

Background

Persons with pre-existing disabilities represent over one-third of acute stroke presentations, but account for a far smaller proportion of those receiving endovascular thrombectomy (EVT) and thrombolysis. This is despite existing ethical, economic, legal, and social directives to maximize equity for this vulnerable population. We sought to determine associations between baseline modified Rankin Scale (mRS) and outcomes after EVT.

Methods

Individuals who underwent EVT were identified from a prospectively maintained database. Demographics, medical history, presentations, treatments, and outcomes were recorded. Baseline disability was defined as baseline mRS≥2. Accumulated disability was defined as the delta between baseline mRS and absolute 90-day mRS.

Results

Of 381 individuals, 49 had baseline disability (five with mRS=4, 23 mRS=3, 21 mRS=2). Those with baseline disability were older (81 vs 68 years, P<0.0001), more likely female (65% vs 49%, P=0.032), had more coronary disease (39% vs 20%, P=0.006), stroke/TIA history (35% vs 15%, P=0.002), and higher NIH Stroke Scale (19 vs 16, P=0.001). Baseline mRS was associated with absolute 90-day mRS ≤2 (OR=0.509, 95%CI=0.370–0.700). However, baseline mRS bore no association with accumulated disability by delta mRS ≤0 (ie, return to baseline, OR=1.247, 95%CI=0.943–1.648), delta mRS ≤1 (OR=1.149, 95%CI=0.906–1.458), delta mRS ≤2 (OR 1.097, 95% CI 0.869–1.386), TICI 2b–3 reperfusion (OR=0.914, 95%CI=0.712–1.173), final infarct size (P=0.853, β=−0.014), or intracerebral hemorrhage (OR=0.521, 95%CI=0.244–1.112).

Conclusions

While baseline mRS was associated with absolute 90-day disability, there was no association with accumulated disability or other outcomes. Patients with baseline disability should not be routinely excluded from EVT based on baseline mRS alone.
Association between SARS-CoV-2 infection, exposure risk and mental health among a cohort of essential retail workers in the USA
Authors: Lan Fan-Yun , Suharlim Christian , Kales Stefanos N , Yang Justin
Published: October 2020

Objectives

To investigate SARS-CoV-2 (the virus causing COVID-19) infection and exposure risks among grocery retail workers, and to investigate their mental health state during the pandemic.

Methods

This cross-sectional study was conducted in May 2020 in a single grocery retail store in Massachusetts, USA. We assessed workers’ personal/occupational history and perception of COVID-19 by questionnaire. The health outcomes were measured by nasopharyngeal SARS-CoV-2 reverse transcriptase PCR (RT-PCR) results, General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9).

Results

Among 104 workers tested, 21 (20%) had positive viral assays. Seventy-six per cent positive cases were asymptomatic. Employees with direct customer exposure had an odds of 5.1 (95% CI 1.1 to 24.8) being tested positive for SARS-CoV-2 after adjustments. As to mental health, the prevalence of anxiety and depression (ie, GAD-7 score >4 or PHQ-9 score >4) was 24% and 8%, respectively. After adjusting for potential confounders, those able to practice social distancing consistently at work had odds of 0.3 (95% CI 0.1 to 0.9) and 0.2 (95% CI 0.03 to 0.99) screening positive for anxiety and depression, respectively. Workers commuting by foot, bike or private cars were less likely to screen positive for depression (OR 0.1, 95% CI 0.02 to 0.7).

Conclusions

In this single store sample, we found a considerable asymptomatic SARS-CoV-2 infection rate among grocery workers. Employees with direct customer exposure were five times more likely to test positive for SARS-CoV-2. Those able to practice social distancing consistently at work had significantly lower risk of anxiety or depression.
Depression and anxiety in an early rheumatoid arthritis inception cohort. associations with demographic, socioeconomic and disease features
Authors: Fragoulis George E , Cavanagh Jonathan , Tindell Alistair , Derakhshan Mohammad , Paterson Caron , Porter Duncan , McInnes Iain B , Siebert Stefan
Published: October 2020

Objective

Depression and anxiety are not uncommon in Rheumatoid arthritis (RA). It is increasingly recognised that they are associated with high disease activity and worse disease outcomes. We aimed to examine the frequency of depression and anxiety in an early RA inception cohort and to explore associations with disease-related measures.

Methods

The Scottish Early Rheumatoid Arthritis inception cohort recruited newly diagnosed RA patients followed-up 6-monthly. Anxiety and depression were assessed using the hospital anxiety and depression scale. Associations with demographic characteristics and disease-related measures were examined at baseline, 6 months and 12 months.

Results

848 RA patients were included. The prevalence of anxiety and depression at baseline was 19.0% and 12.2%, respectively. Depression and anxiety scores correlated with DAS28 at all time-points (all p<0.0001). In multivariable linear regression, anxiety score at baseline was associated with younger age and Health Assessment Questionnaire (HAQ) score. Anxiety scores at 6 months and 12 months were associated with low body mass index (BMI), baseline anxiety score and current patient global score and HAQ. Depression score at baseline was associated with younger age, being single and HAQ, while depression scores at 6 months and 12 months were associated with male gender (only at 6 months), baseline anxiety and depression scores and current patient global score, HAQ and C-reactive protein (CRP) levels.

Conclusion

Depression and anxiety are associated with disease activity, worse functional status and other variables in early RA. There is a close relationship between CRP and depression but not anxiety.
Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme
Authors: Cohen Stanley B , Tanaka Yoshiya , Mariette Xavier , Curtis Jeffrey R , Lee Eun Bong , Nash Peter , Winthrop Kevin L , Charles-Schoeman Christina , Wang Lisy , Chen Connie , Kwok Kenneth , Biswas Pinaki , Shapiro Andrea , Madsen Ann , Wollenhaupt Jürgen
Published: October 2020

Objective

Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). We report the largest integrated safety analysis of tofacitinib, as of March 2017, using data from phase I, II, III, IIIb/IV and long-term extension studies in adult patients with RA.

Methods

Data were pooled for patients with RA who received ≥1 tofacitinib dose. Incidence rates (IRs; patients with events/100 patient-years [PY]; 95% CIs) of first-time occurrences were obtained for adverse events (AEs) of interest.

Results

7061 patients received tofacitinib (total exposure: 22 875 PY; median [range] exposure: 3.1 [0 to 9.6] years). IRs (95% CI) for serious AEs, serious infections, herpes zoster (all), opportunistic infections (excluding tuberculosis [TB]) and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5) and 0.2 (0.1 to 0.2), respectively. IRs (95% CI) for malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC and lymphomas were 0.8 (0.7 to 0.9), 0.6 (0.5 to 0.7) and 0.1 (0.0 to 0.1), respectively. IRs (95% CI) for gastrointestinal perforations, deep vein thrombosis, pulmonary embolism, venous thromboembolism, arterial thromboembolism and major adverse cardiovascular events were 0.1 (0.1 to 0.2), 0.2 (0.1 to 0.2), 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.3), 0.4 (0.3 to 0.5) and 0.4 (0.3 to 0.5), respectively. IR (95% CI) for mortality was 0.3 (0.2 to 0.3). IRs generally remained consistent across 6-month intervals to >78 months.

Conclusion

This represents the largest clinical dataset for a JAK inhibitor in RA to date. IRs remained consistent with previous reports from the tofacitinib RA clinical development programme, and stable over time.

Trial registration numbers

NCT01262118;NCT01484561;NCT00147498;NCT00413660;NCT00550446;NCT00603512;NCT00687193;NCT01164579;NCT00976599;NCT01059864;NCT01359150;NCT02147587;NCT00960440;NCT00847613;NCT00814307;NCT00856544;NCT00853385;NCT01039688;NCT02187055;NCT00413699;NCT00661661.

For summary of phase I, phase II, phase III, phase IIIb/IV and LTE studies included in the integrated safety analysis, see online supplemental table 1.
Threat of exotic worms in dogs imported from Romania
Authors: Wright Ian , Collins Marisol , McGarry John , Teodoru Soare , Constantin Stoian Andrei , Corfield Emma Lesley , Harding Isabella
Published: October 2020

More and more dogs are legally entering the UK from overseas, bringing with them the risk of importing unusual parasites, some of which are zoonotic. Here, Ian Wright and colleagues describe three cases of parasitic worms found in Romanian dogs.
Spermidine is not an independent factor regulating limb muscle mass in mice following androgen deprivation
Authors: Gordon Bradley S. , Rossetti Michael L. , Casero Robert A.
Published: October 2020

Maintaining a critical amount of skeletal muscle mass is linked to reduced morbidity and mortality. In males, testicular androgens regulate muscle mass with a loss of androgens being critical as it is associated with muscle atrophy. Atrophy of the limb muscles is particularly important, but the pathways by which androgens regulate limb muscle mass remain equivocal. We used microarray analysis to identify changes to genes involved with polyamine metabolism in the tibialis anterior (TA) muscle of castrated mice. Of the polyamines, the concentration of spermidine (SPD) was significantly reduced in the TA of castrated mice. To assess whether SPD was an independent factor by which androgens regulate limb muscle mass, we treated castrated mice with SPD for 8 weeks and compared them with sham operated mice. Though this treatment paradigm effectively restored SPD concentrations in the TA muscles of castrated mice, mass of the limb muscles (i.e., TA, gastrocnemius, plantaris, and soleus) were not increased to the levels observed in sham animals. Consistent with those findings, muscle force production was also not increased by SPD treatment. Overall, these data demonstrate for the first time that SPD is not an independent factor by which androgens regulate limb skeletal muscle mass.

Novelty: Polyamines regulate growth in various cells/tissues. Spermidine concentrations are reduced in the limb skeletal muscle following androgen depletion. Restoring spermidine concentrations in the limb skeletal muscle does not increase limb muscle mass or force production.