bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans
Authors: Klämbt Verena , Werth Max , Onuchic-Whitford Ana C , Getwan Maike , Kitzler Thomas M , Buerger Florian , Mao Youying , Deutsch Konstantin , Mann Nina , Majmundar Amar J , Kaminski Michael M , Shen Tian , Schmidt-Ott Kai M , Shalaby Mohamed , El Desoky Sherif , Kari Jameela A , Shril Shirlee , Lienkamp Soeren S , Barasch Jonathan , Hildebrandt Friedhelm 
Published: August 2020

Abstract

Background
An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, &gt;200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis.

Methods
In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD.

Results
We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient’s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.

Conclusion
Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.
11. ASSOCIATION OF TUMOR EXPOSURE TO CEREBROSPINAL FLUID SPACES TO LEPTOMENINGEAL DISEASE IN PATIENTS WITH BRAIN METASTASES
Authors: Patel Kunal , Levin-Epstein Rebecca , Pouratian Nader , Kaprealian Tania , Kim Won 
Published: August 2020

Abstract

BACKGROUND
Development of leptomeningeal disease in patients with brain metastases is associated with extremely poor survival. Identification of the underlying pathogenesis of leptomeningeal disease is unknown.

METHODS
This retrospective case control study included consecutive adult patients with at least one cerebral metastasis from a known extracranial primary solid malignancy and at least 3 month follow up (n=366). Patients were treated with radiotherapy with or without surgical resection and primary outcome was development of leptomeningeal disease.

RESULTS
The overall rate of leptomeningeal disease was 15.0%. Rates of development of leptomeningeal disease correlated with the presence of a dural based lesion (65.7% vs. 9.7%; P&lt;0.0001), intraventricular lesion (29.4% vs. 14.3%; P=0.0897), and with dural based lesions with sulcal or cortical enhancement (100% vs. 12.9%; P&lt;0.0001). Rates of developing leptomeningeal disease were not independently associated with surgical resection (17.2% vs. 14.2%; P=0.4859), however did occur significantly more often with piecemeal, as opposed to en bloc, resection (31.3% vs. 8.1%; P=0.0138) or when the ventricle was entered (61.5% vs. 18.9%; P&lt;0.0001).

CONCLUSIONS
Metastases that are in contact with cerebrospinal fluid spaces are associated with a higher rate of subsequent leptomeningeal disease, with or without surgical resection. Future studies should investigate the use of neoadjuvant radiation, whole brain radiation therapy or adherence to strict surgical technique in high risk brain metastasis patients to mitigate this probability.
20. MELANOMA CELL INTRINSIC GABAA RECEPTOR ENHANCEMENT POTENTIATES RADIATION AND IMMUNE CHECKPOINT INHIBITOR RESPONSE BY PROMOTING DIRECT AND T CELL-MEDIATED ANTI-TUMOR ACTIVITY
Authors: Sengupta Soma , Nasti Tahseen , Kaluzova Milota , Kallay Laura , Melms Johannes , Izar Benjamin , Xu Maxwell , Bhattacharya Debanjan , Burnham Andre , Li Guanguan , Ahmed Taukir , Lawson David , Kowalski Jeanne , Cook James , Medvedovic Mario , Jenkins Andrew , Khan Mohammad , Pomeranz Krummel Daniel 
Published: August 2020

Abstract
Most metastatic melanoma patients exhibit poor and variable response to radiotherapy and targeted therapies, including immune checkpoint inhibitors. There is a need for therapeutics that can potentiate existing treatments to positively impact clinical outcomes of metastatic melanoma patients. We reanalyzed melanoma TCGA transcriptomes and identified, as linked to previously defined molecular subgroups, enhanced expression of genes coding for subunits of the Type A GABA receptor (GABAAR), a chloride ion channel and major inhibitory neurotransmitter receptor. Using whole-cell patch clamp electrophysiology, we find that melanoma cells possess GABAARs that control membrane permeability to anions. Select benzodiazepines, by enhancing GABAAR mediated anion transport, depolarize melanoma cell mitochondrial membrane potential and impair cell viability in vitro. Using a syngeneic melanoma mouse model, we find that a benzodiazepine promotes reduction in tumor volume when administered alone and potentiated radiation or immune checkpoint inhibitor α-PD-L1. When a benzodiazepine is combined with concurrent α-PD-L1 and a sub-lethal radiation dose, there is near complete loss of tumor, beyond what is observed for benzodiazepine with radiation or α-PD-L1. Mechanistically, benzodiazepine with radiation or α-PD-L1 results in ipsilateral and an abscopal tumor volume reduction commensurate with enhanced infiltration into the tumor milieu of polyfunctional CD8 T-cells. There is also an increased expression of genes with roles in the cytokine-cytokine receptor and p53 signaling pathways. This study provides evidence for melanoma cell GABAARs as a therapeutic vulnerability with benzodiazepines promoting both direct and immune-mediated anti-tumor activity.
26. GENETIC CHARACTERIZATION OF SELLAR METASTASIS FROM PRIMARY BRONCHIAL CARCINOID TUMOR OF NEUROENDOCRINE PATHOLOGY
Authors: Hong Christopher , McGuone Declan , Erson-Omay E Zeynep , Bulent Omay Sacit 
Published: August 2020

Abstract
Metastasis to the pituitary gland and surrounding sellar region from systemic tumors is a rare occurrence. Patients may present with signs of endocrine dysfunction secondary to pituitary involvement, as well as mass effect-related symptoms including headaches and visual deficits. Despite a small but accumulating body of literature describing the clinical and histopathological correlates for sellar metastases from systemic tumors, the genetic alterations underlying sellar spread have not been previously described. We describe a 68 year-old female with history of a resected lung carcinoid tumor, followed by chemoradiation, who was diagnosed with a sellar lesion on surveillance PET-CT and subsequent brain MRI. Her tumor was resected via an endoscopic endonasal approach, and final pathology was consistent with neuroendocrine origin, including positive immunohistochemistry for synpatophysin, CK7, TTF-1, and CAM5.2 with a Ki-67 index of 8–12%. Whole-exome sequencing of the sellar specimen demonstrated large-scale deletions of chromosomes 3, 6, and 9 and focal deletions on chromosomes 1,2, 11, 15, and 16. Mutational signature analysis was enriched for COSMIC Signature 4, seen in multiple primary lung cancers. Among 91 total somatic alterations, 7 had been previously associated with oncogenesis (MYO18A, PTCH1, BCOR, CLIC6, TLL2, COL1A1, PTPRK). Notably, mutations in BCOR and PTCH1 have been previously implicated in both systemic neuroendocrine tumors as well as primary tumors of the pituitary gland, while MYO18A, FGF4, and PTPRK mutations had not been reported in systemic neuroendocrine tumors but have been implicated in tumor migration and pituitary adenoma progression. In summary, these data demonstrated an expected mutational pattern indicating a systemic lung neuroendocrine origin but also revealed new mutations previously implicated in primary pituitary pathologies that may have evolutionarily drove divergence from the primary tumor. Further genome studies of these rare lesions may yield further insight into the genetic alterations underlying metastasis to the sellar region.
32. TREATMENT MONITORING OF IMMUNOTHERAPY AND TARGETED THERAPY USING AMINO ACID PET IN PATIENTS WITH BRAIN METASTASES
Authors: Galldiks Norbert , Abdulla Diana , Scheffler Matthias , Wolpert Fabian , Werner Jan-Michael , Hüllner Martin , Stoffels Gabriele , Schweinsberg Viola , Schlaak Max , Kreuzberg Nicole , Landsberg Jennifer , Lohmann Philipp , Ceccon Garry , Baues Christian , Trommer Maike , Celik Eren , Ruge Maximilian , Kocher Martin , Marnitz Simone , Fink Gereon , Tonn Jörg-Christian , Weller Michael , Langen Karl-Josef , Wolf Jürgen , Mauch Cornelia 
Published: August 2020

Abstract

PURPOSE
Recently, the RANO group has analyzed the additional diagnostic value of amino acid PET in patients with primary and secondary brain tumors and recommended the use of this imaging technique in addition to conventional MRI. Here, we investigated the value of PET using the radiolabled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastases (BM) since contrast-enhanced MRI often remains inconclusive.

METHODS
We retrospectively identified 40 patients with 107 BM secondary to melanoma (n=29 with 75 BM) or non-small cell lung cancer (n=11 with 32 BM) treated with ICI or TT who had FET PET (n=60 scans) for treatment monitoring from 2015–2019. The majority of patients (n=37; 92.5%) had radiotherapy during the course of disease. In 27 patients, FET PET was used for the differentiation of treatment-related changes from BM relapse following ICI or TT. In 13 patients, FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 months). In all lesions, static and dynamic FET PET parameters were obtained (i.e., mean tumour-to-brain ratios (TBR), time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathological findings as reference.

RESULTS
A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P=0.003). Metabolic Responders to ICI or TT on FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P=0.004). Furthermore, at follow-up, time-to-peak values in metabolic responders increased significantly (P=0.019).

CONCLUSIONS
FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.
38. INNOVATIVE USE OF A CUSTOM MOBILE APPLICATION (APP) BY A BRAIN METASTASES PROGRAM FACILITATES MULTIDISCIPLINARY MANAGEMENT OF PATIENTS AND DECREASED LENGTH OF HOSPITAL STAY (LOS)
Authors: Bovi Joseph , Lindstedt Jennifer , Santos-Pinheiro Fernando , Mueller Wade , Michael Straza , Puckett Lindsay , Thompson Jonathon , Nelson Ariel , Peltier Wendy , Brausch Carolyn , Erlitz Tracy , Meerstein Heather , Atkinson David , Crabb Marianne , Leuck Julianne , Roller-Voigt Kimberly , Schultz Christopher 
Published: August 2020

Abstract

INTRODUCTION
Patients with Brain Metastases (BM) are complex, mandating multidisciplinary care. Our BM patients are discussed at in-person, weekly Brain Tumor Boards (BTB). However, BM patients diagnosed outside weekly BTBs wait several days for the next BTB, causing delays in generating multidisciplinary plans-of-care, prolonging LOS. We created a custom mobile app for our Brain Metastases Program to have a ‘Brain Metastases Virtual Tumor Board’ (BMVTB) discussion, in real-time, resulting in faster plans-of-care, decreasing LOS.

METHODS
The current pathway for navigating multidisciplinary discussions for patients with BM was examined by members of our Brain Metastases Program. We identified the need for all disciplines to participate in a BMVTB, outside of our in-person, weekly BTB. We developed a secure app that can be downloaded on any provider’s mobile device. The app includes a digital BM treatment algorithm for providers to understand comprehensive, data-driven, BM management. The app also gives our multidisciplinary Brain Metastases Program access to a BMVTB messenging tool to securely communicate and generate real-time consensus plans-of-care. Using a Vizient Clinical Database, we retrospectively calculated LOS index (observed LOS/expected LOS) for 184 BM patients over 21 months, creating a baseline. After launching our app and BMVTB workflow we prospectively evaluated LOS index in 45 BM patients over 6 months.

RESULTS
Over 21-months, 184 patients demonstrated baseline LOS index of 1.073. After launching our mobile app and BMVTB workflow, 45 patient admissions over 6-months demonstrated LOS index of 0.850. Using Levene’s test for equal variances, LOS variance with the app and BMVTB was lower than LOS variance at baseline (p = 0.049). This demonstrates a 38% reduction in LOS when the app and BMVTB generated real-time plans-of-care.

CONCLUSION
We demonstrated utility of a custom BM app coupled with a BMVTB to generate real-time plans-of-care for BM patients, reducing LOS.
64. AN ENT2-DEPENDENT, CELL-PENETRATING, AND DNA-DAMAGING LUPUS AUTOANTIBODY CROSSES THE BLOOD-BRAIN BARRIER TO TARGET BRAIN TUMORS
Authors: Rattray Zahra , Deng Gang , Zhang Shenqi , Shirali Anupama , May Christopher , Liu Jun , Zou Pan , Cuffari Benedette , Rattray Nicholas , Johnson Caroline , Dubljevic Valentina , Campbell James , Huttner Anita , Baehring Joachim , Zhou Jiangbing , Hansen James 
Published: August 2020

Abstract
The blood-brain barrier (BBB) limits conventional antibody-based approaches to brain tumors. ENT2, an equilibrative nucleoside transporter, facilitates penetration of autoantibodies into live cells and is expressed in the BBB. PAT-DX1 (also known as Deoxymab-1 or DX1) is an ENT2-dependent, cell-penetrating, and DNA-damaging lupus autoantibody that is synthetically lethal to cancer cells with defects in the DNA damage response. PTEN loss renders sensitivity to DX1 and is common in primary and metastatic brain tumors. We show that DX1 is toxic to spheroids derived from primary PTEN-deficient glioblastoma (GBM), and crosses the BBB to suppress the growth of orthotopic GBM and breast cancer brain metastases. Mechanistically, we find the ENT2 inhibitor dipyridamole blocks DX1 penetration into brain endothelial cells and transport across the BBB in vitro and in vivo, consistent with ENT2-mediated uptake of DX1 into brain tumors. Autoantibodies that hijack nucleoside transporters to cross cell membranes may open new frontiers in brain tumor therapy.
75. PROGRAMMED DEATH RECEPTOR LIGAND ONE EXPRESSION MAY INDEPENDENTLY PREDICT SURVIVAL IN NON-SMALL CELL LUNG CARCINOMA BRAIN METASTASES PATIENTS RECEIVING IMMUNOTHERAPY
Authors: Hulsbergen Alexander , Mammi Marco , Nagtegaal Steven , Malk Asad , Kavouridis Vasileios , Smith Timothy , Iorgulescu Bryan , Mekary Rania , Verhoeff Joost , Broekman Marike , Phillips John 
Published: August 2020

Abstract

BACKGROUND
Programmed death receptor ligand one (PD-L1) expression is known to predict response to PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). However, the predictive role of this biomarker in brain metastases (BMs) is unknown. The aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with PD-1/PD-L1 inhibitors, after adjusting for established prognostic models.

METHODS
In this multi-institutional retrospective cohort study, we identified NSCLC-BM patients treated with PD-1/PD-L1 inhibitors after local BM treatment (radiotherapy or neurosurgery) but before intracranial progression. Cox proportional hazards models were used to assess predictive value PD-L1 expression for overall survival (OS) and intracranial progression free survival (IC-PFS).

RESULTS
Forty-eight BM patients with available PD-L1 expression were identified. PD-L1 expression was positive in 33 patients (69%). Median survival was 26 months. In univariable analysis, PD-L1 predicted favorable OS (HR = 0.44; 95% CI 0.19 – 1.02; p = 0.055). This effect persisted after correcting for lung-graded prognostic assessment (lung-GPA) and other identified potential confounders (HR = 0.24; 95% CI = 0.10 – 0.61; p = 0.002). Moreover, when modeled as a continuous variable, there appeared to be a proportional relationship between percentage of PD-L1 expression and survival (HR = 0.86 per 10% expression, 95% CI 0.77 – 0.98, p = 0.02). In contrast, PD-L1 expression did not predict IC-PFS in uni- or multivariable analysis (adjusted HR = 0.54, 95% CI 0.26 – 1.14, p = 0.11).

CONCLUSIONS
In patients with NSCLC-BMs treated with PD-1/PD-L1 checkpoint inhibitors and local treatment, PD-L1 expression may predict OS independent of lung-GPA. IC-PFS did not show association with PD-L1 expression, although the present analysis may lack power to assess this. Larger studies are required to validate these findings.
Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to the glo Tobacco Heating Product: A Randomized, Controlled Ambulatory Study
Authors: Gale Nathan , McEwan Michael , Camacho Oscar M , Hardie George , Murphy James , Proctor Christopher J 
Published: August 2020

Abstract

Introduction
Tobacco heating products (THPs) generate lower machine yields of toxicants compared to those found in conventional cigarette smoke. During use, these products are likely to expose users to lower levels of particulate matter and harmful and potentially harmful compounds compared with smoking cigarettes.

Aims and Methods
This randomized, controlled study is investigating whether biomarkers of exposure (BoE) to smoke toxicants are reduced when smokers switch from smoking cigarettes to using the glo THP in a naturalistic, ambulatory setting. Control groups include smokers who are abstaining from cigarette smoking and never-smokers. At a baseline study visit, 24-hour urine samples and spot blood samples were taken for BoE analysis, and exhaled carbon monoxide was also measured. N-(2-cyanoethyl) valine (CEVal) was used as a marker of compliance in subjects asked to refrain from combustible cigarette smoking. Subjects are being followed up at periodic intervals for 360 days; this article presents data following a planned interim analysis at day 90.

Results
In continuing smokers, BoE remained stable between baseline (day 1) and day 90. In both per-protocol and CEVal-compliant analysis populations, reductions in BoE were observed in subjects switching to using glo or undergoing smoking cessation. These reductions were statistically significant for a number of BoE when switching to glo was compared with continued smoking. Furthermore, in both populations, reductions observed in subjects switching to using glo were comparable to those seen with smoking cessation and were also to levels similar to those seen in never-smokers.

Conclusion
glo is a reduced-exposure tobacco product.

Implications
This clinical study builds on a previous 5-day confinement study and demonstrates that when smokers switched from smoking combustible cigarettes to using the glo THP in a naturalistic, ambulatory setting, their exposure to tobacco smoke toxicants was significantly decreased. For most BoE examined, this was to the same extent as that seen when a control group of smokers ceased cigarette smoking, or even to levels seen in never-smoker controls. This indicates that glo is a reduced-exposure product with the potential to be a reduced-risk tobacco product, when used by smokers whose cigarette consumption is displaced completely.

Clinical trial registration
ISRCTN81075760.
Nicotine, Cotinine, and Tobacco-Specific Nitrosamines Measured in Children’s Silicone Wristbands in Relation to Secondhand Smoke and E-cigarette Vapor Exposure
Authors: Quintana Penelope J E , Lopez-Galvez Nicolas , Dodder Nathan G , Hoh Eunha , Matt Georg E , Zakarian Joy M , Vyas Mansi , Chu Linda , Akins Brittany , Padilla Samuel , Anderson Kim A , Hovell Melbourne F 
Published: August 2020

Abstract

Introduction
Simple silicone wristbands (WB) hold promise for exposure assessment in children. We previously reported strong correlations between nicotine in WB worn by children and urinary cotinine (UC). Here, we investigated differences in WB chemical concentrations among children exposed to secondhand smoke from conventional cigarettes (CC) or secondhand vapor from electronic cigarettes (EC), and children living with nonusers of either product (NS).

Methods
Children (n = 53) wore three WB and a passive nicotine air sampler for 7 days and one WB for 2 days, and gave a urine sample on day 7. Caregivers reported daily exposures during the 7-day period. We determined nicotine, cotinine, and tobacco–specific nitrosamines (TSNAs) concentrations in WB, nicotine in air samplers, and UC through isotope-dilution liquid chromatography with triple-quadrupole mass spectrometry.

Results
Nicotine and cotinine levels in WB in children differentiated between groups of children recruited into NS, EC exposed, and CC exposed groups in a similar manner to UC. WB levels were significantly higher in the CC group (WB nicotine median 233.8 ng/g silicone, UC median 3.6 ng/mL, n = 15) than the EC group (WB nicotine median: 28.9 ng/g, UC 0.5 ng/mL, n = 19), and both CC and EC group levels were higher than the NS group (WB nicotine median: 3.7 ng/g, UC 0.1 ng/mL, n = 19). TSNAs, including the known carcinogen NNK, were detected in 39% of WB.

Conclusions
Silicone WB show promise for sensitive detection of exposure to tobacco-related contaminants from traditional and electronic cigarettes and have potential for tobacco control efforts.

Implications
Silicone WB worn by children can absorb nicotine, cotinine, and tobacco-specific nitrosamines, and amounts of these compounds are closely related to the child’s urinary cotinine. Levels of tobacco-specific compounds in the silicone WB can distinguish patterns of children’s exposure to secondhand smoke and e-cigarette vapor. Silicone WB are simple to use and acceptable to children and, therefore, may be useful for tobacco control activities such as parental awareness and behavior change, and effects of smoke-free policy implementation.