bluuebunny/crossref_metadata_2025_split huggingface dataset:
5-Fluorouracil Enhances Protoporphyrin IX Accumulation and Lesion Clearance during Photodynamic Therapy of Actinic Keratoses: A Mechanism-Based Clinical Trial
Authors: Maytin Edward V. , Anand Sanjay , Riha Margo , Lohser Sara , Tellez Alejandra , Ishak Rim , Karpinski Lauren , Sot Janine , Hu Bo , Denisyuk Anton , Davis Scott C. , Kyei Angela , Vidimos Allison 
Published: March 2018

Abstract
Purpose: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK.
Patients and Methods: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminolevulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT.
Results: PpIX levels were increased 2- to 3-fold in 5FU-pretreated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75% versus 45% at 3 months, and 67% versus 39% at 6 months, respectively; these differences were statistically significant.
Conclusions: Serial 5FU and PDT improve AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk. Clin Cancer Res; 24(13); 3026–35. ©2018 AACR.
T-cell Dysfunction in Glioblastoma: Applying a New Framework
Authors: Woroniecka Karolina I. , Rhodin Kristen E. , Chongsathidkiet Pakawat , Keith Kristin A. , Fecci Peter E. 
Published: March 2018

AbstractA functional, replete T-cell repertoire is an integral component to adequate immune surveillance and to the initiation and maintenance of productive antitumor immune responses. Glioblastoma (GBM), however, is particularly adept at sabotaging antitumor immunity, eliciting severe T-cell dysfunction that is both qualitative and quantitative. Understanding and countering such dysfunction are among the keys to harnessing the otherwise stark potential of anticancer immune-based therapies. Although T-cell dysfunction in GBM has been long described, newer immunologic frameworks now exist for reclassifying T-cell deficits in a manner that better permits their study and reversal. Herein, we divide and discuss the various T-cell deficits elicited by GBM within the context of the five relevant categories: senescence, tolerance, anergy, exhaustion, and ignorance. Categorization is appropriately made according to the molecular bases of dysfunction. Likewise, we review the mechanisms by which GBM elicits each mode of T-cell dysfunction and discuss the emerging immunotherapeutic strategies designed to overcome them. Clin Cancer Res; 24(16); 3792–802. ©2018 AACR.
Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting
Authors: Layek Buddhadev , Sadhukha Tanmoy , Panyam Jayanth , Prabha Swayam 
Published: March 2018

AbstractTumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor-targeting strategy that relies on engineering mesenchymal stem cells (MSC) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Furthermore, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count, whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUClung of PTX (1.5 μg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 μg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor-specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Mol Cancer Ther; 17(6); 1196–206. ©2018 AACR.
ABT-165, a Dual Variable Domain Immunoglobulin (DVD-Ig) Targeting DLL4 and VEGF, Demonstrates Superior Efficacy and Favorable Safety Profiles in Preclinical Models
Authors: Li Yingchun , Hickson Jonathan A. , Ambrosi Dominic J. , Haasch Deanna L. , Foster-Duke Kelly D. , Eaton Lucia J. , DiGiammarino Enrico L. , Panchal Sanjay C. , Jiang Fang , Mudd Sarah R. , Zhang Catherine , Akella Surekha S. , Gao Wenqing , Ralston Sherry L. , Naumovski Louie , Gu Jijie , Morgan-Lappe Susan E. 
Published: March 2018

Abstract
Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life &gt; 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment–related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039–50. ©2018 AACR.
Ferroptosis-Induced Endoplasmic Reticulum Stress: Cross-talk between Ferroptosis and Apoptosis
Authors: Lee Young-Sun , Lee Dae-Hee , Choudry Haroon A. , Bartlett David L. , Lee Yong J. 
Published: March 2018

Abstract
Since its discovery in 2012, ferroptosis has been well characterized by the accumulation of lipid peroxides due to the failure of glutathione-dependent antioxidant defenses. It is known as an iron-dependent form of programmed cell death, which is distinct from other forms of cell death such as apoptosis and necrosis. Nonetheless, little is known about the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and its role in cell death. Recent studies reveal that the ferroptotic agent-induced ER stress response plays an important role in the cross-talk between ferroptosis and other types of cell death. Ferroptotic agents induce the unfolded protein response and subsequently ER stress–mediated activation of the PERK–eIF2α–ATF4–CHOP pathway. CHOP (C/EBP homologous protein) signaling pathway–mediated p53-independent PUMA (p53 upregulated modulator of apoptosis) expression is involved in the synergistic interaction between ferroptosis and apoptosis. This review highlights the recent literature on ferroptotic and apoptotic agent interactions through the ER stress–mediated PERK–eIF2α–ATF4–CHOP–PUMA pathway and implicates combined treatment to effectively enhance tumoricidal efficacy as a novel therapeutic strategy for cancer. Mol Cancer Res; 16(7); 1073–6. ©2018 AACR.
Potential Vorticity Dynamics of Forecast Errors: A Quantitative Case Study
Authors: Baumgart Marlene , Riemer Michael , Wirth Volkmar , Teubler Franziska , Lang Simon T. K. 
Published: March 2018

AbstractSynoptic-scale error growth near the tropopause is investigated from a process-based perspective. Following previous work, a potential vorticity (PV) error tendency equation is derived and partitioned into individual contributions to yield insight into the processes governing error growth near the tropopause. Importantly, we focus here on the further amplification of preexisting errors and not on the origin of errors. The individual contributions to error growth are quantified in a case study of a 6-day forecast. In this case, localized mesoscale error maxima have formed by forecast day 2. These maxima organize into a wavelike pattern and reach the Rossby wave scale around forecast day 6. Error growth occurs most prominently within the Atlantic and Pacific Rossby wave patterns. In our PV framework, the error growth is dominated by the contribution of upper-level, near-tropopause PV anomalies (near-tropopause dynamics). Significant contributions from upper-tropospheric divergent flow (prominently associated with latent heat release below) and lower-tropospheric anomalies [tropospheric-deep (i.e., baroclinic) interaction] are associated with a misrepresentation of the surface cyclone development in the forecast. These contributions are, in general, of smaller importance to error growth than near-tropopause dynamics. This result indicates that the mesoscale errors generated near the tropopause do not primarily project on differences in the subsequent baroclinic growth, but instead directly project on the tropopause evolution and amplify because of differences in the nonlinear Rossby wave dynamics.
Self-Monitoring of Fertility Hormones
Authors: Blackwell Leonard , Cooke Delwyn , Brown Simon 
Published: March 2018

Natural family planning (NFP) methods have served many generations well, and in particular, the symptothermal or symptohormonal methods. The comparison of daily mucus and temperature records for individual cycles with daily hormone measurements, which is now possible, shows that some of the assumptions underlying NFP may not be completely accurate. The various methods are inadvertently depending on an element of chance, which, of course, cannot be known by the NFP user. However, it is statistically inevitable that such errors will result eventually in an unexpected pregnancy, and these discrepancies are the likely reason for the method failures. Further research and integration of home hormone measurements with NFP symptoms are needed. Summary: Traditional NFP methods, based on the observations of temperature, mucus, and luteinizing hormone, can work well. However, these data are sometimes difficult to interpret, and significant changes in the variables are sometimes “missing” from some cycles. Changes in these variables are elicited by the estrogen and progesterone released from the ovaries. It follows that the direct measures of events in the ovaries are the levels of estrogen and progesterone or their derivatives in blood or urine. Measurements of urinary derivatives of estrogen and progesterone can be used to monitor the ovaries directly and are clearer indicators than traditional NFP methods.
Infant Male Circumcision
Authors: Jones David Albert 
Published: March 2018

Infant male circumcision (IMC) has become controversial among Catholics, and many have criticized the practice of routine IMC, still widely performed in the United States. Others have gone further, claiming that circumcision has been condemned explicitly by the Church and criticizing IMC as “mutilation” and, hence, prohibited implicitly by Catholic moral principles. However, closer examination of the Catholic tradition shows that the Church regards IMC as having been a means of grace under the Old Covenant and, more importantly, in the flesh of Jesus. This positive theological account of IMC cannot be evaded by invoking a supposed historical distinction between milah (a token cut) and periah (the complete removal of the foreskin). The Church has never condemned IMC as mutilation, and while IMC carries some risk, there is no evidence that it inflicts per se disabling mutilation. A reasonable body of medical opinion regards IMC as conferring net health benefits. Summary: This paper concerns the ethics of infant male circumcision especially, though not only, as this is practiced within contemporary Judaism. This topic is examined from a Catholic ethical and theological perspective. It is found that the Church has never sought to restrict Jews from practicing circumcision and has never condemned circumcision as “mutilation.” Current evidence suggests that infant male circumcision confers net health benefits. Catholic theology since the Second Vatican Council has increasingly emphasized that God’s covenant with the Jewish people remains valid. It has never been revoked. This covenant includes infant male circumcision.
Use of Aborted Fetal Tissue in Vaccines and Medical Research Obscures the Value of All Human Life
Authors: McKenna Kyle Christopher 
Published: March 2018

This opinion addresses the licitness, quasi-benefits, and consequences of using aborted fetal tissue in vaccines and in medical research. The Catholic Church permits temporary use of vaccines generated using aborted fetal tissue to protect children from preventable diseases until alternative vaccines that do not use aborted fetal tissue are available. In medical research, cell lines that were generated from elective abortions should be avoided and alternative cell lines of licit origin utilized. The association between in utero Zika virus infections and microcephaly has increased the demand for fetal tissue to establish causality and to understand disease progression. These studies require extensive oversight as they could directly encourage elective abortions. The consequence of the use of fetal tissue from elective abortions is desensitization of beneficiaries to the original illicit act of abortion thereby obscuring the value of all human life and potentially leading to scandal. Summary: The use of fetal tissue from elective abortions is commonplace in the pharmaceutical industry and in medical research. This opinion addresses the licitness, quasi-benefits, and consequences of using fetal tissue from elective abortions in vaccines and in medical research. All people of good conscience have the responsibility to voice opposition to the use of fetal tissue from elective abortions in order to promote development of alternatives, affirm the value of all human life and limit scandal.
Surgical treatment of pulmonary metastasis: report from a tertiary care center
Authors: Saleh Waleed , AlShammari Abdullah , Sarraj Jumana , AlAshgar Omniyah , Ahmed Mohamed Hussein , AlKattan Khaled 
Published: March 2018

Objective This retrospective analysis aimed to determine the factors influencing prognosis in adult patients who presented to our thoracic surgery service with lung metastases and were eligible for pulmonary metastasectomy. Methods We retrospectively reviewed the data of 296 patients who underwent resection of 575 lung metastases from January 2000 to January 2016. Univariate and multivariate analyses were performed based on age, sex, histology of the primary tumor, disease-free interval, number and size of metastases. Results Sixty-eight (22.97%) patients developed lung metastases from bone sarcoma, 68 (22.97%) from soft-tissue sarcoma, 56 (18.9%) from head and neck cancers, 46 (15.5%) from colorectal cancer, and 58 (19.6%) from other epithelial tumors. The mean size of the lung nodules was 2.48 cm. Open surgical resection was performed in 217 (73.3%) patients. After a mean follow-up of 43 months, 120 (40.7%) patients had died or were lost to follow-up. Univariate analysis confirmed that patients with bone cancer, soft tissue sarcoma, or colorectal carcinoma had a worse prognosis ( p = 0.0003). Moreover, those with a disease-free interval >24 months had a better 5-year survival ( p = 0.0001). The number and size of metastases, age, and sex had no effect on prognosis. The actuarial survival after complete metastasectomy was 71.6% (95% confidence interval: 66–75) at 2 years and 59.3% (95% confidence interval: 56–64) at 5 years. Conclusions Pulmonary metastasectomy provides good long-term survival. The type of primary tumor and disease-free interval are independent prognostic factors for survival.
Open Latarjet Procedures Produce Better Outcomes in Competitive Athletes Compared With Recreational Athletes: A Clinical Comparative Study of 106 Athletes Aged Under 30 Years
Authors: Baverel Laurent , Colle Pierre-Emmanuel , Saffarini Mo , Anthony Odri Guillaume , Barth Johannes 
Published: March 2018

Background: In cases of shoulder stabilization for anterior instability, the main goals of the surgery are a rapid and efficient return to sports and excellent long-term outcomes without recurrence of dislocation, particularly in young and competitive athletes. Purpose: To determine whether outcomes of open Latarjet procedure (OLPs) depend on the level of sports practiced by patients and to report clinical scores and complication rates for OLP at a minimum follow-up of 2 years. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective comparative study was conducted for all patients who underwent OLP by the senior author (J.B.) between July 2007 and December 2012. The indication for OLP at the authors’ institution was a minimum of 2 episodes of dislocation and/or subluxation, a positive apprehension test result in the cocking position, an Instability Severity Index Score more than 2, and evidence of anterior instability lesions on computed tomography arthrograms. The 106 included patients (110 shoulders) with a mean follow-up of 46 months were compared in 2 groups depending on sport activities: 57 (54%) competitive athletes and 49 (46%) recreational athletes. The principal outcome measure was evidence of recurrent instability. The secondary outcome measures were clinical scores related to anterior instability and related to sport practice: Rowe score, Oxford Shoulder Instability Score (OSIS), Western Ontario Shoulder Instability Index, and level of satisfaction. Results: Of the 106 patients, 3 reported recurrence of shoulder dislocation: 2 competitive athletes (3.5%; 95% CI, 0.9%-11.2%) and 1 recreational athlete (2%; 95% CI, 0.4%-10.7%) ( P = .684). The persistent apprehension test result was positive in 7 competitive athletes (11.5%) and in 5 recreational athletes (10%) ( P = .566). The Rowe scores improved from 56.3 ± 13.2 (range, 30-80) preoperatively to 84.2 ± 16.4 (range, 30-100) postoperatively in competitive athletes and from 55.0 ± 11.0 (range, 35-80) to 69.5 ± 22.0 (range, 15-100) in recreational athletes ( P < .001). The net improvement in Rowe scores was significantly greater in competitive athletes (27.9 ± 21.7) compared with recreational athletes (14.5 ± 24.4) ( P = .006). The scores unrelated to sport activity (Oxford Shoulder Instability Score and Simple Shoulder Test) were similar for the 2 groups. All 57 (100%) competitive athletes and 34 (69.4%) recreational athletes resumed their previous sports practice, at the same level or higher than before their injury (respectively, 78.9% and 42.9%; P = .004). Conclusion: The OLP could be considered for primary shoulder stabilization, particularly in competitive athletes, who have high functional demands and great risks of redislocation.
Le Fort III Distraction With Internal vs External Distractors
Authors: Robertson Kevin J. , Mendez Bernardino M. , Bruce William J. , McDonnell Brendan D. , Chiodo Michael V. , Patel Parit A. 
Published: March 2018

Objective: This study compares the change in midface position following Le Fort III advancement using either rigid external distraction (group 1) or internal distraction (group 2). We hypothesized that, with reference to right-facing cephalometry, internal distraction would result in increased clockwise rotation and inferior displacement of the midface. Design: Le Fort III osteotomies and standardized distraction protocols were performed on 10 cadaveric specimens per group. Right-facing lateral cephalograms were traced and compared across time points to determine change in position at points orbitale, anterior nasal spine (ANS), A-point, and angle ANB. Setting: Institutional. Patients, Participants: Twenty cadaveric head specimens. Interventions: Standard subcranial Le Fort III osteotomies were performed from a coronal approach and adequately mobilized. The specified distraction mechanism was applied and advanced by 15 mm. Main Outcome Measure(s): Changes of position were calculated at various skeletal landmarks: orbitale, ANS, A-point, and ANB. Results: Group 1 demonstrated relatively uniform x-axis advancement with minimal inferior repositioning at the A-point, ANS, and orbitale. Group 2 demonstrated marked variation in x-axis advancement among the 3 points, along with a significant inferior repositioning and clockwise rotation of the midface ( P < .0001). Conclusion: External distraction resulted in more uniform advancement of the midface, whereas internal distraction resulted in greater clockwise rotation and inferior displacement. External distraction appears to provide increased vector control of the midface, which is important in creating a customized distraction plan based on the patient’s individual occlusal and skeletal needs.