bluuebunny/crossref_metadata_2025_split huggingface dataset:
MSC-secreted TGF-β regulates lipopolysaccharide-stimulated macrophage M2-like polarization via the Akt/FoxO1 pathway
Authors: Liu Feng , Qiu Haibo , Xue Ming , Zhang Shi , Zhang Xiwen , Xu Jingyuan , Chen Jianxiao , Yang Yi , Xie Jianfeng 
Published: November 2019

Abstract
Background
An uncontrolled inflammatory response is a critical pathophysiological feature of sepsis. Mesenchymal stem cells (MSCs) induce macrophage phenotype polarization and reduce inflammation in sepsis. MSC-secreted transforming growth factor beta (TGF-β) participated in the immune modulatory function of MSCs. However, the underlying mechanism of MSC-secreted TGF-β was not fully elucidated in regulation macrophage M2-like polarization.

Methods
The paracrine effects of MSCs on macrophage polarization were studied using a co-culture protocol with LPS-stimulated RAW264.7 cells/mouse peritoneal macrophages and MSCs. The effect of TGF-β in the co-culture system was blocked by the TGF-β receptor inhibitor. To determine the role of MSC-secreted TGF-β, we used recombinant TGF-β to culture with LPS-stimulated RAW264.7 cells. In addition, we employed antibody microarray analysis to determine the mechanisms of MSC secreted TGF-β on LPS-stimulated RAW264.7 cell/mouse peritoneal macrophage M2-like polarization. Furthermore, we used an Akt inhibitor and a FoxO1 inhibitor to inhibit the Akt/FoxO1 pathway. The nuclear translocation of FoxO1 was detected by Western blot.

Results
MSCs induced LPS-stimulated RAW264.7 cell/mouse peritoneal macrophage polarization towards the M2-like phenotype and significantly reduced pro-inflammatory cytokine levels via paracrine, which was inhibited by TGF-β receptor inhibitor. Furthermore, we found that MSC-secreted TGF-β enhanced the macrophage phagocytic ability. The antibody microarray analysis and Western blot verified that TGF-β treatment activated the Akt/FoxO1 pathway in LPS-stimulated macrophages, TGF-β-induced FoxO1 nuclear translocation and obviously expressed in the cytoplasm, the effects of TGF-β regulatory effects on LPS-stimulated macrophage were inhibited by pre-treatment with Akt inhibitor and FoxO1 inhibitor.

Conclusions
TGF-β secreted by MSCs could skew LPS-stimulated macrophage polarization towards the M2-like phenotype, reduce inflammatory reactions, and improve the phagocytic ability via the Akt/FoxO1 pathway, providing potential therapeutic strategies for sepsis.
Post-fire fuel succession in a rare California, USA, closed-cone conifer
Authors: McNamara Bret A. , Kane Jeffrey M. , Greene David F. 
Published: November 2019

Abstract
Background
Increasing frequency and size of wildfires over the past few decades have prompted concerns that populations of obligate seeding species may be vulnerable to repeat, short-interval fires that occur prior to these species reaching maturity. The susceptibility of populations to this risk is partially dependent on the amount and characteristics of fuel loading over time and their influence on fire behavior and effects. This study characterized fuel dynamics and modeled fire behavior across a time-since-fire chronosequence in stands of the rare, serotinous conifer, Baker cypress (Hesperocyparis bakeri [Jeps.] Bartel), ranging in age between 3 and 147 years post fire.

Results
Litter and fine woody fuel loading (1- to 100-hour) were highest in the 10-year-old and 147-year-old stands, while coarse fuel loading (1000-hour) peaked in the 10-year-old stand and subsequently decreased with time since fire. Duff loading consistently increased with time since fire. Cone production had not occurred in the first 10 yr of stand development. Foliar moisture content in Baker cypress was inversely correlated with stand age, and older foliage had lower moisture content than younger foliage. Modeled surface fire behavior was highest in the 10-year-old and 107-year-old stands in accordance with higher litter, fine woody fuel, or shrub fuel accumulation. While foliar moisture content was higher in younger stands and influenced the critical fireline intensity, we did not observe changes in fire type.

Conclusions
Fine-fuel loading in Baker cypress stands followed a U-shaped pattern over time (first decreasing, then stable, then increasing), consistent with findings in other forests with stand-replacing fire regimes. Our results indicated that early-successional stages of Baker cypress forests have sufficient fuels to allow for the spread of wildfire and 10-year-old stands could burn with substantive fire behavior prior to cone production. Whenever possible, we recommend suppressing wildfire in stands less than 20 yr old to avoid substantial decreases or local extirpation of these rare Baker cypress populations. Our results highlight the importance of knowing the cone production patterns, fuel dynamics, and corresponding fire behavior over the development of obligate-seeder species to assess the risk of population loss due to short-interval fires.
Uptake and accumulation of di-n-butyl phthalate in six leafy vegetables under hydroponic conditions
Authors: Li Yong , Yan Huang-qian , Yu Xiang-yang 
Published: November 2019

Abstract
The uptake and accumulation of di-n-butyl phthalate (DBP) in six leafy vegetables was investigated under hydroponic conditions. The test vegetables were six varieties of Brassica campestris ssp., including Kangresijiqing (KRSJQ), Xiadiqing (XDQ), Ziyoucai (ZYC), Aijiaohuang (AJH), Shanghaiqing (SHQ) and Gaogengbai (GGB). The root concentration factor (RCF), translocation factor (TF) and transpiration stream concentration factor (TSCF) were calculated in order to compare the difference of uptake and accumulation behaviours of DBP in vegetable varieties. The results showed that DBP was easily concentrated in vegetable roots, but was poorly translocated from the roots to the shoots. Among the six vegetables, the ability of concentrating DBP from the solution to shoots was the highest in GGB, followed by ZYC, KRSJQ, AJH, SHQ and XDQ. High concentrations of DBP (5.0 mg/L) seem to inhibit normal physiological activity in the vegetables, which resulted in a higher RCF and a lower TF and TSCF than in low-concentration treatment. The results will help to evaluate the safety of agricultural products and to provide evidence for screening DBP pollution-safe vegetable cultivars.

Graphical abstract
Preliminary results of the acute Heart Failure registry in the DELTA region of Egypt (DELTA-HF): a database and a quality initiative project
Authors: Elasfar Abdelfatah , Shaheen Sherif , El-Sherbeny Wafaa , Elsokkary Hatem , Elhefnawy Suzan , Al-Setiha Mohammed 
Published: November 2019

Abstract
Background
Data about heart failure in Egypt is scarce. We aimed to describe the clinical characteristics and diagnostic and treatment options in patients with acute heart failure in the Delta region of Egypt and to explore the gap in the management in comparison to the international guidelines.

Results
DELTA-HF is a prospective observational cohort registry for all consecutive patients with acute heart failure (AHF) who were admitted to three tertiary care cardiac centers distributed in the Delta region of Egypt. All patients were recruited in the period from April 2017 to May 2018, during which, data were collected and short-term follow-up was done.
A total of 220 patients (65.5% were males with a median age of 61.5 years and 50.9% had acute decompensation on top of chronic heart failure) was enrolled in our registry. The risk factors for heart failure included rheumatic valvular heart disease (10.9%), smoking (65.3%), hypertension (48.2%), diabetes mellitus (42.7%), and coronary artery disease (28.2%). Left ventricular ejection fraction (LVEF) was less than 40% in 62.6%. Etiologies of heart failure included ischemic heart disease (58.1%), valvular heart disease (16.3%), systemic hypertension (9.1%), and dilated non-ischemic cardiomyopathy (15.5%). Exacerbating factors included infections (28.1%), acute coronary syndromes (25.5%), non-compliance to HF medications (19.6%), and non-compliance to diet (23.2%) in acute decompensated heart failure (ADHF) patients. None of our patients had been offered heart failure device therapy and only 50% were put on beta-blockers upon discharge. In-hospital, 30 days and 90 days all-cause mortality were 18.2%, 20.7%, and 26% respectively.

Conclusions
There is a clear gap in the management of patients with acute heart failure in the Delta region of Egypt with confirmed under-utilization of heart failure device therapy and under-prescription of guideline-directed medical therapies particularly beta-blockers. The short-term mortality is high if compared with Western and other local registries. This could be attributed mainly to the low-resource health care system in this region and the lack of formal heart failure management programs.
Postoperative 320 multi-slice computed tomography in assessment of pedicle screw insertion in thoraco-lumbar fixation
Authors: Salama Alsiagy A. , Amin Mohamed A. , Soliman Ahmed Y. , El-Tantaway Ahmed 
Published: November 2019

Abstract
Background
Pedicle screw instrumentation is used widely in lumbar spine for stabilization to enhance arthrodesis and has been accepted in the thoracic spine in recent years. The purpose of this study was to assess the value of postoperative 320 multi-slice computed tomography (MSCT) in assessment of pedicle screw placement in patients with spinal fixation with clinical and surgical correlation.

Results
A total of 340 pedicular screws were inserted to 70 cases. 286 (84.12%) were in, 54 screws (15.88%) were violated, and revision surgeries were required for 5 displaced screws. On axial, coronal reconstruction and three-dimensional (3D) reformatted CT images 36, 47, and 54 displaced screws were detected, respectively. Both sensitivity and specificity for 3D reformatted images were 100%. For axial image, they were 97.6% and 89.4%, respectively, compared with surgical findings in 5 revised screws.

Conclusion
Multi-slice CT scan is a valuable and valid postoperative assessment tool of accuracy of spinal pedicle screw placement.
Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia: Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age
Authors: Rank Cecilie U. , Wolthers Benjamin O. , Grell Kathrine , Albertsen Birgitte K. , Frandsen Thomas L. , Overgaard Ulrik M. , Toft Nina , Nielsen Ove J. , Wehner Peder S. , Harila-Saari Arja , Heyman Mats M. , Malmros Johan , Abrahamsson Jonas , Norén-Nyström Ulrika , Tomaszewska-Toporska Beata , Lund Bendik , Jarvis Kirsten B. , Quist-Paulsen Petter , Vaitkevičienė Goda E. , Griškevičius Laimonas , Taskinen Mervi , Wartiovaara-Kautto Ulla , Lepik Kristi , Punab Mari , Jónsson Ólafur G. , Schmiegelow Kjeld 
Published: November 2019

PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.
Radiotherapy to enhance T-cell infiltration and efficacy of PD-L1 blockade in murine orthotopic models of head and neck cancer.
Authors: Oweida Ayman , Lennon Shelby , Calame Dylan , Bhatia Shilpa , Raben David , Heasley Lynn , Nemenoff Raphael , Karam Sana 
Published: November 2019

101 Background: Cancers of the head and neck (HNC) represent some of the most debilitating and aggressive tumors. Radiotherapy (RT) is the primary treatment modality for locally advanced HNC, but less than 50% of patients treated with RT survive to 5 years. Clinical trials with the immune checkpoint inhibitor PD-L1 have shown considerable promise, but on its own has only yielded a 20% response rate. RT has the potential to transform the tumor microenvironment promoting infiltration of T-cells in poorly immunogenic tumors and activating T-cells in tumors with pre-existing T-cell populations. We hypothesized that the combination of PD-L1 inhibition with radiation can enhance therapeutic efficacy through re-invigoration of exhausted T-cells. Methods: Tumor cells were injected into the right buccal mucosa. Treatment was initiated when established tumors were observed. Forty mice per tumor model were randomized to IgG2b control, anti PD-L1, RT alone or RT+anti PD-L1. Anti PD-L1 was started 3 days before RT (single dose of 10Gy) and maintained for 3 weeks. For mechanistic studies, mice received the same treatment but were euthanized 72 hours after RT. Flow cytometric analysis of T-cell expression of PD-1, CTLA-4, FOXP3, CD44 and IFNG was performed on freshly harvested tumors and regional lymph nodes. Results: Tumor-bearing mice formed aggressive tumors with regional lymph node metastasis. Mice treated with RT or anti PD-L1 had slightly improved survival whereas mice treated with RT+anti-PD-L1 had significantly improved survival (p = 0.0007). Tumor control was significantly improved in the RT+anti-PD-L1 group compared to other groups. Anti PD-L1 alone did not improve tumor control. Average tumor volume on day 23 was 175±60.1 mm3 in the RT+anti-PD-L1 group compared to 623±91.0 mm3 in the PD-L1 group. Flow cytometric analysis revealed that this is mediated by enhancement in T-cell infiltration. Analysis of T-cell activation showed increased expression of CD44 and IFNG. Conclusions: Our results show a critical role for RT in mediating sensitivity to PD-L1 inhibition in HNC. In combination with anti PD-L1, RT significantly increased survival and tumor control compared to either modality alone.
Targeting the TNFR2 oncogene on tumor cells and tregs of the tumor microenvironment via dominant TNFR2 antagonism.
Authors: Faustman Denise L. , Torrey Heather , Butterworth John , Mera Toshi , Okubo Yoshiaki , Wang Limei , Baum Danielle , Warden Sara , Plager Sarah , Huang Daniel , Vanamee Eva , Foster Rosemary 
Published: November 2019

106 Background: A major barrier to cancer immunotherapy is lack of selective inhibitors of the regulatory T cells (Tregs) of the cancer microenvironment and methods to directly kill tumors through novel surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is a target protein with restricted expression on the most potent Tregs of the tumor infiltrate and newly identified as a broadly expressed oncogene on human tumors. Methods: We characterized the effect of TNFR2 antibody antagonists via TNFR2 in human samples from ovarian ascites compared to healthy controls. Results: TNFR2 antagonists potently inhibited Treg proliferation with exponential potency and selectivity for tumor microenvironment Tregs. Furthermore, common ovarian cancer cell lines such as OVCAR3 expressed the TNFR2 oncogene and were rapidly and completely killed by TNFR2 antagonistic antibodies. TNFR2 antagonistic antibodies were dominant because they succeeded even in the presence of TNF agonism. Remarkably, these antibodies worked as well in killing Treg cells as F(ab’)2 fragments, but not as well as Fc fragments. TNFF2 antagonists were not dependent on ADCC mechanisms for activity. Conclusions: Dominant TNFR2 antagonistic antibodies demonstrate tumor-specific Treg depletion. Blocking TNFR2 signaling with antagonist antibodies also creates a novel tool to possibly eliminate tumors expressing the TNFR2 oncogene and to more potently suppress Tregs of the tumor microenvironment.
The effect on quality of life via bio-mimetic hormone replacement therapy for breast cancer patients.
Authors: Wiley TS , Haraldsen Jason T. 
Published: November 2019

113 Background: Many treatments for breast cancer block the estrogen receptors to reduce the risk of relapse. However, this treatment results in massive changes to the normal hormonal milieu. When the normal rhythmic hormonal patterns are disrupted, either through treatment or normal menopause, women typically experience a multitude of harsh symptoms with little affect on relapse rate. We set out to examine and evaluate the effects of estrogen (E2) and progesterone (P4) treatments via a bio-mimetic bio-identical hormone replacement therapy (BBHRT). We theorized, through the analysis of physiological and clinical literature, that the use BBHRT in the normal physiological pattern of reproductive women will lead to an increase of overall well-being and better quality of life for post-treatment and menopausal women, but does not increase their risk of breast cancer. Methods: E2 and P4 control over 9,000 different gene products and a disruption of these processes can lead to an increase in illnesses of aging including cancer. Through an evaluation of current literature, we theorize that a BBHRT approach utilizing E2 and P4 in a bio-mimetic manner to restore a woman’s body to normal hormonal levels can be achieved through twice-daily transdermal applications of hormonal creams with peaks in serum levels on days 12 and 21. The proposed method uses compounded, bio-identical hormones dosed to mimic the female reproductive cycle. Results: While this is a proposed clinical study, it is expected that women will experience resolution of menopausal and post-treatment symptoms, including better sleep, decreased migraines and incontinence, increased focus, and increased libido. By restoring the normal hormonal rhythm, it is anticipated that the body’s natural response elements will help restore both quality of life and well being, while also protecting from possible relapse. Conclusions: We propose a method to provide better quality of life and well being for women through BHRT that combines the use of E2 and P4 in a manner that mimics a woman’s normal reproductive levels. While a small long-term study of this method has shown promising results, we conclude that further, most detailed studies are still needed.
TLR9 triggering/STAT3 inhibition to reprogram leukemic cells into antigen-presenting cells and trigger T-cell responses.
Authors: Gupta Priyanka Dutta , Lu Brandon , Li Haiqing , Li Zhou , Zhao Xingli , Kuo Ya-Huei , Kortylewski Marcin 
Published: November 2019

118 Background: Clinical studies demonstrated potential of cancer immunotherapies while underscoring the need to block immune checkpoints shielding tumors from immune attack. We recently generated a strategy to target STAT3 transcription factor, critical immune checkpoint regulator, using TLR9-targeted delivery of STAT3 decoy inhibitor (CpG-STAT3dODN) targeting TLR9+ immune cells and all subsets of leukemic cells, including leukemic progenitor/stem cells in vitro and in vivo experiments in murine and human AML cells. Methods: Studies were conducted using mouse Cbfb/MYH11/Mpl and C1498 models of AML and acombination of flow cytometry, electron microscopy, and sequencing techniques were used to define changes in the AML cells after CpG-STAT3dODN treatment. Results: Intravenous injections of CpG-STAT3dODN into engrafted mice, led to significant changes in CD11b/CD11c expression, cell morphology, mitochondrial shape and number within the first 5 days of treatment. RNA-sequencing studies indicated increased expression of genes regulating differentiation and antigen presentation such as IRF8, GADD45A, CIITA, IL-12A, IFNγ. These effects associated with increased number of activated T cells in the leukemic microenvironment, thereby resulting in regression of AML in majority of treated mice. Two week CpG-STAT3dODN treatment was sufficient to generate protective antitumor immunity as demonstrated in rechallenge experiments. Conclusions: Our studies suggested that concurrent TLR9-stimulation and STAT3 inhibition trigger potent immunogenicity of AML cells sufficient to drive effector and memory T cell responses. We hypothesize that STAT3-inhibition can unleash immune-stimulation downstream of TLR9 signaling transforming leukemic cells into antigen-presenting cells Our further studies will dissect role of STAT3 and TLR9-induced signaling mediators (IRF, NF-κB) in regulation of the process.This information should support the design of new therapeutic regimens for AML immunotherapy using CpG-STAT3dODN alone or in combination with T cell-based therapies.
A novel therapeutic to enhance the immunogenicity of breast cancer cells.
Authors: Vishnubhotla Priya , Khaled Amr , Showalter Anne , Oyer Jeremiah , Igarshi Robert , Copik Alicja , Khalid Annette 
Published: November 2019

119 Background: Breast cancer is a challenge for immunotherapy because of its inherent genetic heterogeneity and decreased immunogenicity. A possible solution is to generate dying breast cancer cells that operate like a vaccine to stimulate tumor-specific immunity. This is termed immunogenic cell death (ICD) and is characterized by a unique molecular signature, involving the release of molecules that attract and stimulate phagocytes and sensitize tumor cells to killing by natural killer (NK) cells. However, the current doses of drugs used to induce ICD may be too high to translate into clinically relevant regimens. Methods: Our group discovered a novel peptide, CT20p, that is effective at nanomolar concentrations and can be delivered to breast tumors using targeted nanoparticles. CT20p works by inhibiting a unique protein folding complex, called chaperonin-containing TCP-1 (CCT), which is highly expressed in cancer cells but not normal cells. Using triple negative breast cancer (TNBC) and normal cell lines as well as patient-derived tumor cells, we examined the biological consequences of CCT inhibition by CT20p in terms of the induction of endoplasmic reticulum (ER) stress, through the accumulation of unfolded proteins, and the release of the danger signals associate with ICD that could stimulate innate immunity. Results: Dying TNBC cells treated with CT20p displayed alterations in PERK, a mediator of the unfolded protein response (UPR), which resulted in the membrane translocation of calreticulin (Crt), an “eat me”’ signal and a key marker of ICD. CT20p-killed TNBC cells were more readily phagocytosed, and NK cells more effectively killed remaining cancer cells. In our experiments normal breast epithelial cells, macrophages or NK cells were unaffected by CT20p. Conclusions: Our study suggests that inhibition of CCT by CT20p generates dying cancer cells that stimulate innate immune responses, through the release of signals like Crt, to attract phagocytes and promote NK cell cytotoxicity. By enhancing the immunogenicity of breast cancer cells, CT20p could increase responsiveness to to checkpoint inhibitors or cellular immunotherapy, hence providing more complete protection from breast cancer recurrence and metastasis.