bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1 siRNA Theranostics With a Dextran Nanoparticle Highlights the Importance of Nanoparticle Delivery for Effective Tumor PD-L1 Downregulation
Authors: Pacheco-Torres Jesus , Penet Marie-France , Krishnamachary Balaji , Mironchik Yelena , Chen Zhihang , Bhujwalla Zaver M. 
Published: February 2021

PurposeThe inhibition of immune checkpoints such as programmed cell death ligand-1 (PD-L1/CD274) with antibodies is providing novel opportunities to expose cancer cells to the immune system. Antibody based checkpoint blockade can, however, result in serious autoimmune complications because normal tissues also express immune checkpoints. As sequence-specific gene-silencing agents, the availability of siRNA has significantly expanded the specificity and range of “druggable” targets making them promising agents for precision medicine in cancer. Here, we have demonstrated the ability of a novel biodegradable dextran based theranostic nanoparticle (NP) to deliver siRNA downregulating PD-L1 in tumors. Optical imaging highlighted the importance of NP delivery and accumulation in tumors to achieve effective downregulation with siRNA NPs, and demonstrated low delivery and accumulation in several PD-L1 expressing normal tissues.MethodsThe dextran scaffold was functionalized with small molecules containing amine groups through acetal bonds. The NP was decorated with a Cy5.5 NIR probe allowing visualization of NP delivery, accumulation, and biodistribution. MDA-MB-231 triple negative human breast cancer cells were inoculated orthotopically or subcutaneously to achieve differences in vascular delivery in the tumors. Molecular characterization of PD-L1 mRNA and protein expression in cancer cells and tumors was performed with qRT-PCR and immunoblot analysis.ResultsThe PD-L1 siRNA dextran NPs effectively downregulated PD-L1 in MDA-MB-231 cells. We identified a significant correlation between NP delivery and accumulation, and the extent of PD-L1 downregulation, with in vivo imaging. The size of the NP of ~ 20 nm allowed delivery through leaky tumor vasculature but not through the vasculature of high PD-L1 expressing normal tissue such as the spleen and lungs.ConclusionsHere we have demonstrated, for the first time, the feasibility of downregulating PD-L1 in tumors using siRNA delivered with a biodegradable dextran polymer that was decorated with an imaging reporter. Our data demonstrate the importance of tumor NP delivery and accumulation in achieving effective downregulation, highlighting the importance of imaging in siRNA NP delivery. Effective delivery of these siRNA carrying NPs in the tumor but not in normal tissues may mitigate some of the side-effects of immune checkpoint inhibitors by sparing PD-L1 inhibition in these tissues.
Ten-Year Single Institutional Analysis of Geographic and Demographic Characteristics of Patients Treated With Stereotactic Body Radiation Therapy for Localized Prostate Cancer
Authors: Aghdam Nima , Carrasquilla Michael , Wang Edina , Pepin Abigail N. , Danner Malika , Ayoob Marilyn , Yung Thomas , Collins Brian T. , Kumar Deepak , Suy Simeng , Collins Sean P. , Lischalk Jonathan W. 
Published: February 2021

ObjectivesStereotactic Body Radiation Therapy (SBRT) offers definitive treatment for localized prostate cancer with comparable efficacy and toxicity to conventionally fractionated radiotherapy. Decreasing the number of treatment visits from over 40 to five may ease treatment burden and increase accessibility for logistically challenged patients. Travel distance is one factor that affects a patient’s access to treatment and is often related to geographic location and socioeconomic status. In this study, we review the demographic and geographic factors of patients treated with SBRT for prostate cancer for a single institution with over a decade of experience.MethodsPatient zip codes from one thousand and thirty-five patients were derived from a large, prospectively maintained quality of life database for patients treated for prostate cancer with SBRT from 2008 to 2017. The geospatial distance between the centroid of each zip code to our institution was calculated using the R package Geosphere. Characteristics for seven hundred and twenty-one patients were evaluated at the time of analysis including: race, age, and insurance status. To assess the geographic reach of our institution, we evaluated the demographic features of each zip code using US Census data. Statistical comparisons for these features and their relation to distance traveled for treatment was performed using the Mann-Whitney U test. Finally, an unsupervised learning algorithm was performed to identify distinct clusters of patients with respect to median income, racial makeup, educational level, and rural residency.ResultsPatients traveled from 246 distinct zip codes at a median distance of 11.35 miles. Forty percent of patients were African American, 6.9% resided in a rural region, and 22% were over the age of 75. Using K-means cluster analysis, four distinct patient zip-code groups were identified based on the aforementioned demographic features: Suburban/high-income (45%), Urban (30%), Suburban/low-income (17%), and Rural (8%). For each of the clusters, the average travel distance for SBRT was significantly different at 11.17, 9.26, 11.75, and 40.2 miles, respectively (p-value: &lt;0.001).ConclusionsDistinct demographic features are related to travel distance for prostate SBRT. In our large cohort, travel distance did not prevent uptake of prostate SBRT in African American, elderly or rural patient populations. Prostate SBRT offers a diverse population modern treatment for their localized prostate cancer and particularly for those who live significant distances from a treatment center.
Modulated Electro-Hyperthermia Facilitates NK-Cell Infiltration and Growth Arrest of Human A2058 Melanoma in a Xenograft Model
Authors: Vancsik Tamás , Máthé Domokos , Horváth Ildikó , Várallyaly Anett Anna , Benedek Anett , Bergmann Ralf , Krenács Tibor , Benyó Zoltán , Balogh Andrea 
Published: February 2021

Modulated electro-hyperthermia (mEHT), induced by 13.56 MHz radiofrequency, has been demonstrated both in preclinical and clinical studies to efficiently induce tumor damage and complement other treatment modalities. Here, we used a mouse xenograft model of human melanoma (A2058) to test mEHT (~42°C) both alone and combined with NK-cell immunotherapy. A single 30 min shot of mEHT resulted in significant tumor damage due to induced stress, marked by high hsp70 expression followed by significant upregulation of cleaved/activated caspase-3 and p53. When mEHT was combined with either primary human NK cells or the IL-2 independent NK-92MI cell line injected subcutaneously, the accumulation of NK cells was observed at the mEHT pretreated melanoma nodules but not at the untreated controls. mEHT induced the upregulation of the chemoattractant CXCL11 and increased the expression of the matrix metalloproteinase MMP2 which could account for the NK-cell attraction into the treated melanoma. In conclusion, mEHT monotherapy of melanoma xenograft tumors induced irreversible heat and cell stress leading to caspase dependent apoptosis to be driven by p53. mEHT could support the intratumoral attraction of distantly injected NK-cells, contributed by CXCL11 and MMP2 upregulation, resulting in an additive tumor destruction and growth inhibition. Therefore, mEHT may offer itself as a good partner for immunotherapy.
Clinical Characteristics and Prognostic Factors of Testicular Sarcoma: A Population-Based Study
Authors: Wang Xingyuan , Chen Zeyu , Qiu Shi , Cao Dehong , Jin Kun , Li Jin , Chen Bo , Lei Haoran , Huang Yin , Bao Yige , Yang Lu , Liu Liangren , Wei Qiang 
Published: February 2021

ObjectivesTo study clinical characteristics and factors that may affect the prognosis of testicular sarcoma patients.Patients and MethodsIn the Surveillance Epidemiology and End Results database (2006–2016), people with testicular sarcoma were enrolled in our research. Multivariable Cox proportional hazard model and Multivariable Logistic regression model were used to compare the impact of different factors on cancer-specific survival, localized metastasis, and distant metastasis.ResultsThis research was based on the registry information of 158 testicular sarcoma patients. All patients with a median age of 17.00 (1.00–93.00) years were pathologically diagnosed with orchiectomy or needle biopsy specimens. Patients with Grade I, II, III, and IV testicular sarcoma accounted for 34.29% (n = 24), 10.10% (n = 7), 22.86% (n = 16), and 32.86% (n = 23) of all patients, respectively. There were 42 (30.43%), 53 (38.41%), 15 (10.87%), 20 (14.49%), 5 (3.62%), 3 (2.17%) patients with Tis, T1, T2, T3, T4, and &gt;T4 (the invasion degree exceeded the staging system of testicular cancer) disease respectively. Among all included patients, localized metastasis occurred in 31 (20.13%) patients, distant metastasis was found in 28 (18.18%) patients during observation, and 61.69% (n = 95) had no metastasis. Thirty-two (20.25%) patients died of this cancer. According to our study, patients with distant metastasis [OR = 17.86, 95% CI (4.63–68.84), p &lt; 0.0001] and T3 disease [OR = 4.13, 95% CI (1.10–15.53), p = 0.0359] were more likely to die of this cancer. Patients with advanced T stage were more likely to occur distant metastasis, [OR = 13.91, 95% CI (1.80–107.54), p = 0.0116] for T3 and [OR = 16.36, 95% CI (1.36–196.21), p = 0.0275] for T4.ConclusionsAccording to our research, factors including metastasis and higher T stage were significantly related with poorer prognosis of testicular sarcoma. Higher T stage was also found to be a risk factor of distant metastasis. The recognization of these poor prognostic factors may allow physicians to make comprehensive and appropriate management decision for testicular sarcoma patients.
The Most Efficacious Induction Chemotherapy Regimen for Locoregionally Advanced Nasopharyngeal Carcinoma: A Network Meta-Analysis
Authors: Choi Horace Cheuk-Wai , Chan Sik-Kwan , Lam Ka-On , Chan Sum-Yin , Chau Sze-Chun , Kwong Dora Lai-Wan , Leung To-Wai , Luk Mai-Yee , Lee Anne Wing-Mui , Lee Victor Ho-Fun 
Published: February 2021

BackgroundInduction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) for non-metastatic locoregionally advanced nasopharyngeal carcinoma (NPC) has gained considerable attention. However, the most efficacious IC regimens remain investigational. We aimed to compare the survival benefits of all available IC regimens followed by CCRT in this network meta-analysis.MethodsAll randomized-controlled trials of CCRT with or without IC in non-metastatic locoregionally advanced NPC were included, with an overall nine trials of 2,705 patients counted in the analysis. CCRT alone was the reference category. Eight IC regimens followed by CCRT were analyzed: docetaxel + cisplatin (DC), gemcitabine + carboplatin + paclitaxel (GCP), gemcitabine + cisplatin (GP), mitomycin + epirubicin + cisplatin + fluorouracil + leucovorin (MEPFL), cisplatin + epirubicin + paclitaxel (PET), cisplatin + fluorouracil (PF), cisplatin + capecitabine (PX) and cisplatin + fluorouracil (PF), cisplatin + capecitabine (PX). Fixed-effects frequentist network meta-analysis models was applied and P-score was used to rank the treatments.ResultsDC, GP, and PX were the top three IC regimens with the highest probability of benefit on overall survival (OS). Their corresponding hazard ratios (HRs) (95% CIs) compared with CCRT alone were of 0.24 (0.08–0.73), 0.43 (0.24–0.77), and 0.54 (0.27–1.09) and the respective P-scores were 94%, 82%, and 68%. The first three IC regimens showing significantly improved progression-free survival (PFS) were PX, followed by GP and DC with respective HRs of 0.46 (0.24–0.88), 0.51 (0.34–0.77), and 0.49 (0.20–1.20), and P-scores of 82%, 78%, and 74%. Among the studies in the intensity-modulated radiation therapy (IMRT) era, GP and PX were the best performed IC regimens, whilst DC performed the best among non-IMRT studies. Doublet and gemcitabine-based IC regimens had better survival benefits compared to triplet and taxane-based IC regimens, respectively.ConclusionsGiven its consistent superiority in both OS and PFS, DC, GP, and PX ranked among the three most efficacious IC regimens in both the overall and subgroup analysis of IMRT or non-IMRT studies. Exploratory analyses suggested that doublet and gemcitabine-based IC regimens showed better survival performance.
Clinician Emotions Surrounding Pediatric Oncology Patient Deterioration
Authors: Graetz Dylan E. , Giannars Emily , Kaye Erica C. , Garza Marcela , Ferrara Gia , Rodriguez Mario , Soberanis Vasquez Dora Judith , Mendez Aceituno Alejandra , Antillon-Klussmann Federico , Gattuso Jami S. , Andes Karen L. , Mandrell Belinda N. , Baker Justin N. , Rodriguez-Galindo Carlos , Agulnik Asya 
Published: February 2021

BackgroundPediatric oncology patients have a high rate of clinical deterioration frequently requiring critical care. Patient deterioration events are distressing for clinicians, but little is known about how Pediatric Early Warning Systems (PEWS) impact clinicians’ emotional responses to deterioration events.MethodsSemi-structured interviews were conducted with 83 nurses, pediatricians, oncologists, and intensive care clinicians who had recently participated in a patient deterioration event at two pediatric oncology hospitals of different resource-levels: St. Jude Children’s Research Hospital (N = 42 participants) in Memphis, Tennessee or Unidad Nacional de Oncología Pediátrica (N = 41 participants) in Guatemala City, Guatemala. Interviews were conducted in the participants’ native language (English or Spanish), transcribed, and translated into English. Each transcript was coded by two researchers and analyzed for thematic content.ResultsEmotions around patient deterioration including concern, fear, and frustration were reported across all disciplines at both hospitals. Concern was often triggered by an elevated PEWS score and usually resulted in increased attention, which reassured bedside clinicians that patients were receiving necessary interventions. However, persistently elevated PEWS scores, particularly at St. Jude Children’s Research Hospital, occasionally resulted in a false sense of relief, diminishing clinician attention and negatively impacting patient care. Nurses at both institutions described how PEWS amplified their voices, engendering confidence and empowerment, two of the only positive emotions described in the study.ConclusionClinicians experienced a range of emotions while caring for high-risk patients in the setting of clinical deterioration. These emotions have the potential to contribute to compassion fatigue and burnout, or to resilience. Acknowledgment and further investigation of the complex interplay between PEWS and clinician emotions are necessary to maximize the impact of PEWS on patient safety while simultaneously supporting staff wellbeing.
Microscopic Invasion of Nerve Is Associated With Aggressive Behaviors in Pancreatic Neuroendocrine Tumors
Authors: Zhou Hao , Wang Yajie , Guo Chuangen , Li Xiaoshuang , Cui Wenjing , Wang Zhongqiu , Chen Xiao 
Published: February 2021

ObjectivesThe role of neural invasion has been reported in cancers. Few studies also showed that neural invasion was related to survival rate in patients with pancreatic neuroendocrine tumor (PNET). The aim of this study is to explore the association between neural invasion and aggressive behaviors in PNET.MethodsAfter excluding those patients with biopsy and with missing histological data, a total 197 patients with PNET who underwent surgery were retrospectively analyzed. The demographic data and histological data were obtained. Aggressive behavior was defined based on extra-pancreatic extension including vascular invasion, organ invasion and lymph node metastases. Logistic regression analyses were used to identify risk factor for aggressive behavior. Receiver operating characteristic (ROC) curves were performed to show the performance of nomograms in evaluating aggressive behavior of PNET.ResultsThe prevalence of neural invasion in the cohort was 10.1% (n = 20). The prevalence of lymph node metastasis, organ invasion, and vascular invasion in PNET patients with neural invasion was higher than those in patients without neural invasion (p &lt; 0.05). Neural invasion was more common in grade 3 (G3) tumors than G1/G2 (p &lt; 0.01). Tumor size, tumor grade, and neural invasion were independent associated factors of aggressive behavior (p &lt; 0.05) after adjusting for possible cofounders in total tumors and G1/G2 tumors. Two nomograms were developed to predict the aggressive behavior. The area under the ROC curve was 0.84 (95% confidence interval (CI): 0.77–0.90) for total population and was 0.84 (95% CI: 0.78–0.89) for patients with G1/G2 PNET respectively.ConclusionsNeural invasion is associated with aggressive behavior in PNET. Nomograms based on tumor size, grade and neural invasion show acceptable performances in predicting aggressive behavior in PNET.
Effectiveness of One-Stop Screening for Colorectal, Breast, and Prostate Cancers: A Population-Based Feasibility Study
Authors: Sung Joseph J. Y. , Luk Arthur K. C. , Ng Simon S. M. , Ng Anthony C. F. , Chiu Peter K. F. , Chan Emily Y. Y. , Cheung Polly S. Y. , Chu Winnie C. W. , Wong Sunny H. , Lam Thomas Y. T. , Wong Samuel Y. S. 
Published: February 2021

Colorectal cancer (CRC), prostate cancer (PC) and breast cancer (BC) are among the most common cancers worldwide with well-established screening strategies. We aim to investigate the effectiveness and compliance of a one-stop screening service for CRC, PC and BC. Asymptomatic subjects aged 50–75 years were invited. Eligible subjects were offered fecal immunochemical test (FIT) for CRC screening. Serum prostate specific antigen (PSA) and Prostate Health Index (PHI) were offered for male PC screening and mammogram (MMG) for female BC screening as a one-stop service. Colonoscopy was offered to FIT+ subjects, prostate biopsy to PSA/PHI+ (PSA&gt;10/PHI≥35) males and breast biopsy to MMG+ (Breast Imaging-Reporting and Data System, BI-RADS≥4) females. From August 2018 to April 2020, 3165 subjects were recruited. All participants (1372 men and 1793 women) were willing to accept FIT for CRC screening, and PSA/PHI test or MMG as second cancer screening. 102 subjects diagnosed advanced neoplasms after colonoscopy. Thirty-three males diagnosed PC after prostate biopsy and 15 females diagnosed BC after breast biopsy. No major complication reported in first tier screening tests. Subjects who were willing to undergo CRC screening were highly likely to accept other cancer screening when offered in a one-stop program. In conclusion, the effectiveness and compliance of a one-stop service for CRC, PC, and BC screening among asymptomatic subjects were high. Future studies should be conducted to test various ways of integrating cancer screening programs.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04034953.
Vitamin D Deficiency and Vasovagal Syncope in Children and Adolescents
Authors: Zhang Qingyou , Sun Yan , Zhang Chunyu , Qi Jianguang , Du Junbao 
Published: February 2021

Aims: To investigate the association of vitamin D deficiency with cardiovascular autonomic nervous system function in children and adolescents with vasovagal syncope (VVS).Methods: This study recruited 76 pediatric patients with VVS and 15 healthy children. The 25-hydroxyvitamin D levels in serum among the participants were evaluated. Heart rate variability analysis including SDNN, rMSSD, and SDANN was tested in patients with VVS. The correlation between indices of time-domain analysis and serum vitamin D status of the children with VVS was investigated.Results: In this work, 25-hydroxyvitamin D levels in serum among VVS cases remarkably decreased compared with those among healthy controls (48.76 ± 19.25 vs. 67.62 ± 15.46 nmol/L, p &lt; 0.01). The vitamin D deficient patients with VVS exhibited a lower rMSDD value compared to the non-deficient group with VVS (45.56 ± 16.87 vs. 61.90 ± 20.38 ms, p &lt; 0.001, respectively). Pearson correlation analysis indicated that serum 25-hydroxyvitamin D levels had positive correlation with rMSDD values (r = 0.466, p &lt; 0.001).Conclusions: As suggested by our data, VVS children and adolescents with vitamin D deficiency may have cardiac autonomic dysfunction and cardiac vagal tone decreases with the reduction in vitamin D level.
Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner
Authors: Föhr Karl Josef , Nastos Ariadni , Fauler Michael , Zimmer Thomas , Jungwirth Bettina , Messerer David Alexander Christian 
Published: February 2021

Atomoxetine, a neuroactive drug, is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is primarily known as a high affinity blocker of the noradrenaline transporter, whereby its application leads to an increased level of the corresponding neurotransmitter in different brain regions. However, the concentrations used to obtain clinical effects are much higher than those which are required to block the transporter system. Thus, off-target effects are likely to occur. In this way, we previously identified atomoxetine as blocker of NMDA receptors. As many psychotropic drugs give rise to sudden death of cardiac origin, we now tested the hypothesis whether atomoxetine also interacts with voltage-gated sodium channels of heart muscle type in clinically relevant concentrations. Electrophysiological experiments were performed by means of the patch-clamp technique at human heart muscle sodium channels (hNav1.5) heterogeneously expressed in human embryonic kidney cells. Atomoxetine inhibited sodium channels in a state- and use-dependent manner. Atomoxetine had only a weak affinity for the resting state of the hNav1.5 (Kr: ∼ 120 µM). The efficacy of atomoxetine strongly increased with membrane depolarization, indicating that the inactivated state is an important target. A hallmark of this drug was its slow interaction. By use of different experimental settings, we concluded that the interaction occurs with the slow inactivated state as well as by slow kinetics with the fast-inactivated state. Half-maximal effective concentrations (2–3 µM) were well within the concentration range found in plasma of treated patients. Atomoxetine also interacted with the open channel. However, the interaction was not fast enough to accelerate the time constant of fast inactivation. Nevertheless, when using the inactivation-deficient hNav1.5_I408W_L409C_A410W mutant, we found that the persistent late current was blocked half maximal at about 3 µM atomoxetine. The interaction most probably occurred via the local anesthetic binding site. Atomoxetine inhibited sodium channels at a similar concentration as it is used for the treatment of ADHD. Due to its slow interaction and by inhibiting the late current, it potentially exerts antiarrhythmic properties.