bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma
Authors: Laubach Jacob P. , Liu Chia-Jen , Raje Noopur S. , Yee Andrew J. , Armand Philippe , Schlossman Robert L. , Rosenblatt Jacalyn , Hedlund Jacquelyn , Martin Michael , Reynolds Craig , Shain Kenneth H. , Zackon Ira , Stampleman Laura , Henrick Patrick , Rivotto Bradley , Hornburg Kalvis T.V. , Dumke Henry J. , Chuma Stacey , Savell Alexandra , Handisides Damian R. , Kroll Stew , Anderson Kenneth C. , Richardson Paul G. , Ghobrial Irene M. 
Published: October 2018

Abstract

Purpose:
The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.

Patients and Methods:
Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2–15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined.

Results:
The MTD was established at 340 mg/m2 evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m2. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months.

Conclusions:
Evofosfamide can be administered at 340 mg/m2 twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.
Age-Related Changes in HAPLN1 Increase Lymphatic Permeability and Affect Routes of Melanoma Metastasis
Authors: Ecker Brett L. , Kaur Amanpreet , Douglass Stephen M. , Webster Marie R. , Almeida Filipe V. , Marino Gloria E. , Sinnamon Andrew J. , Neuwirth Madalyn G. , Alicea Gretchen M. , Ndoye Abibatou , Fane Mitchell , Xu Xiaowei , Sim Myung Shin , Deutsch Gary B. , Faries Mark B. , Karakousis Giorgos C. , Weeraratna Ashani T. 
Published: October 2018

Abstract

Older patients with melanoma have lower rates of sentinel lymph node (LN) metastases yet paradoxically have inferior survival. Patient age correlated with an inability to retain Technetium radiotracer during sentinel LN biopsy in more than 1,000 patients, and high Technetium counts correlated to better survival. We hypothesized that loss of integrity in the lymphatic vasculature due to extracellular matrix (ECM) degradation might play a role. We have implicated HAPLN1 in age-dependent ECM degradation in the dermis. Here, we queried whether HAPLN1 could be altered in the lymphatic ECM. Lymphatic HAPLN1 expression was prognostic of long-term patient survival. Adding recombinant HAPLN1 to aged fibroblast ECMs in vitro reduced endothelial permeability via modulation of VE-cadherin junctions, whereas endothelial permeability was increased following HAPLN1 knockdown in young fibroblasts. In vivo, reconstitution of HAPLN1 in aged mice increased the number of LN metastases, but reduced visceral metastases. These data suggest that age-related changes in ECM can contribute to impaired lymphatics.

Significance:
Our studies reveal that changes in the stroma during aging may influence the way tumor cells traffic through the lymphatic vasculature. Aging may dictate the route of metastatic dissemination of tumor cells, and understanding these changes may help to reveal targetable moieties in the aging tumor microenvironment.
See related commentary by Marie and Merlino, p. 19.
This article is highlighted in the In This Issue feature, p. 1
Shipping Out MEK Inhibitor Resistance with SHP2 Inhibitors
Authors: Torres-Ayuso Pedro , Brognard John 
Published: October 2018

Abstract
Summary: RAS is one of the most frequently altered oncogenes, yet RAS-driven tumors are largely refractory to anticancer therapies. Fedele and colleagues demonstrate that SHP2 inhibitors prevent adaptive MEK inhibitor resistance; therefore, combining MEK and SHP2 inhibitors represents an exciting new therapeutic approach for the treatment of RAS-driven cancers. Cancer Discov; 8(10); 1210–2. ©2018 AACR.
See related article by Fedele et al., p. 1237.
Different Originating Cells Underlie Intertumoral Heterogeneity in Lung Neuroendocrine Tumors
Authors: Pozo Karine , Kelenis Demetra P. , Minna John D. , Johnson Jane E. 
Published: October 2018

Abstract
Summary: Studies in genetically engineered mouse models of neuroendocrine lung cancer suggest that differences in cells of origin underlie subtype variations in this class of cancers. These findings highlight the concept that the same driver mutations introduced into different cells of origin lead to tumors with the same histology but dramatically different metastatic programs and potentially different therapeutic responses. Cancer Discov; 8(10); 1216–8. ©2018 AACR.
See related article by Yang et al., p. 1316.
A Cloud Microphysics Parameterization for Shallow Cumulus Clouds Based on Lagrangian Cloud Model Simulations
Authors: Noh Yign , Oh Donggun , Hoffmann Fabian , Raasch Siegfried 
Published: October 2018

Abstract
Cloud microphysics parameterizations for shallow cumulus clouds are analyzed based on Lagrangian cloud model (LCM) data, focusing on autoconversion and accretion. The autoconversion and accretion rates, A and C, respectively, are calculated directly by capturing the moment of the conversion of individual Lagrangian droplets from cloud droplets to raindrops, and it results in the reproduction of the formulas of A and C for the first time. Comparison with various parameterizations reveals the closest agreement with Tripoli and Cotton, such as and , where and are the mixing ratio and the number concentration of cloud droplets, is the mixing ratio of raindrops, is the threshold volume radius, and H is the Heaviside function. Furthermore, it is found that increases linearly with the dissipation rate and the standard deviation of radius and that decreases rapidly with while disappearing at &gt; 3.5 μm. The LCM also reveals that and increase with time during the period of autoconversion, which helps to suppress the early precipitation by reducing A with smaller and larger in the initial stage. Finally, is found to be affected by the accumulated collisional growth, which determines the drop size distribution.
Distinguishing Trends and Shifts from Memory in Climate Data
Authors: Beaulieu Claudie , Killick Rebecca 
Published: October 2018

AbstractThe detection of climate change and its attribution to the corresponding underlying processes is challenging because signals such as trends and shifts are superposed on variability arising from the memory within the climate system. Statistical methods used to characterize change in time series must be flexible enough to distinguish these components. Here we propose an approach tailored to distinguish these different modes of change by fitting a series of models and selecting the most suitable one according to an information criterion. The models involve combinations of a constant mean or a trend superposed to a background of white noise with or without autocorrelation to characterize the memory, and are able to detect multiple changepoints in each model configuration. Through a simulation study on synthetic time series, the approach is shown to be effective in distinguishing abrupt changes from trends and memory by identifying the true number and timing of abrupt changes when they are present. Furthermore, the proposed method is better performing than two commonly used approaches for the detection of abrupt changes in climate time series. Using this approach, the so-called hiatus in recent global mean surface warming fails to be detected as a shift in the rate of temperature rise but is instead consistent with steady increase since the 1960s/1970s. Our method also supports the hypothesis that the Pacific decadal oscillation behaves as a short-memory process rather than forced mean shifts as previously suggested. These examples demonstrate the usefulness of the proposed approach for change detection and for avoiding the most pervasive types of mistake in the detection of climate change.
An Evaluation of SPARC Protein as a Serum Biomarker of Chronic Rhinosinusitis
Authors: Asmar Marc‐Henri , Gaudreau Annie , Maniakas Anastasios , Mfuna Endam Leandra , Desrosiers Martin 
Published: October 2018

ObjectivePrecision medicine initiatives for chronic rhinosinusitis (CRS) management suggest tailoring treatment to the patient's individual disease profile; however, serum biomarkers for evaluation of disease activity or predicting response to therapy are lacking in CRS. Epithelial‐to‐mesenchymal transition (EMT) has been described as a component of barrier dysfunction in CRS. SPARC (secreted protein acidic and rich in cysteine) is a marker of EMT that has previously been identified in sinus epithelium by gene expression profiling. We wished to determine if SPARC could represent a serum biomarker for CRS by verifying (1) if SPARC could be detected in serum, (2) whether levels were sensitive to disease burden reduction following surgery, and (3) if it could predict response to therapy.Study DesignProspective.SettingTertiary care center.SubjectsPatients with CRS undergoing endoscopic sinus surgery (ESS).MethodsTwenty‐six patients undergoing ESS for CRS were prospectively recruited. Serum was collected at the time of surgery and 4 months following ESS and SPARC level measured using enzyme‐linked immunosorbent assay. Postoperative outcome was characterized as “remission” or “unfavorable” based on symptomatology and endoscopy.ResultsSPARC could be detected and measured in serum in all subjects. Following ESS, SPARC levels decreased by 33% (P =. 005) but did not predict evolution at 4 months postsurgery (P =. 94).ConclusionSPARC may be an interesting serum biomarker of disease activity in CRS, as it can be reliably measured and decreases following successful reduction of disease burden after surgery. However, it does not predict post‐ESS evolution, suggesting that the link between EMT and outcome is not linear.
The Expressions of Hope in the Face of Complex Surgery: Experiences of Patients and Their Loved Ones
Authors: Baur Karen M , Chamberlain Jill , Wendler M Cecilia , Harwood Paula , Colle Joni , Yeaman Deb 
Published: October 2018

Background: Lung volume reduction surgery (LVRS), a reduction in damaged lung tissue in end-stage chronic obstructive pulmonary disease, is a breakthrough surgical procedure requiring months of rigorous screening, testing, and conditioning. Engaging in this process is prolonged and challenging with no research found exploring patients and loved ones’ experiences through this demanding process. Objective: The purpose was to examine the experience of LVRS for patients and loved ones as they encounter the complex preparation required prior to, during, and throughout the extended convalescence following surgery. Methods: A mixed-methods approach was used, combining health outcomes with interview data. Participants and loved ones were purposefully selected, invited, and consented during the perioperative phase of LVRS. Quantitative data were obtained via chart review, while qualitative data were gathered through a 2-stage interview process, preoperatively and postoperatively. Qualitative data were analyzed using naturalistic inquiry approaches. Results: Patients and loved ones described difficulties of living with illness during the preoperative phase, and expressed relief and joy for an improved quality of life afterward. The overarching theme uncovered was hope. Preoperatively, hope was coupled with anxiety about the upcoming surgery and potential outcomes, whereas the hope expressed after surgery focused on the future, in particular, a shared future. Statistically significant differences were found in the quality of life measures. Conclusion: For both patients and loved ones, LVRS is filled with hope for a more expansive future. Although that future is unclear prior to surgery, clarification and a new normal signals hope for a shared future following LVRS.
The Patient Teacher in General Practice Training: Perspectives of Residents
Authors: Aires Marie José , Gagnayre Rémi , Gross Olivia , Khau Cam-Anh , Haghighi Sophie , Mercier Alain , Ruelle Yannick , Marchand Claire 
Published: October 2018

Background: Patient teachers were involved in training general practice residents (GPRs) to strengthen the patient-centered approach. They teach a course on health democracy by themselves and teach in tandem with a physician teacher during reflective practice-based classes (named GEPRIs). We present the GPRs’ representations of patient teacher characteristics and capacities and their perception of how useful patient teachers are to their professional development. Methods: We administered a questionnaire based on a preliminary qualitative study to 124 GPRs. It explored (a) changes in the GPRs’ representations about patient teacher characteristics and capacities with regard to teaching over the first year of the experiment; (b) GPRs’ perception of patient teacher utility to their training and their contribution to developing patient perspective–related competencies. Results: The response rate was 89.5% (111/124). The majority of GPRs agreed with 17 (before) and 21 (after) of the 23 patient teacher characteristics and with 17 (before) and 19 (after) of the 20 capacities. The agreement rate increased, overall, after patient teacher participation. The GPRs found patient teacher useful to their training in 9 of 11 topics (agreement rate 65%-92%). They felt they had developed the 14 patient knowledge–related competencies (agreement rate 62%-93%), and 52% to 75% of the GPRs rated the patient teachers’ contribution to those competencies “high or very high,” depending on the competency. Conclusion: This study demonstrates the specific contribution of patient teachers to university-level medical training in France. The GPRs recognized that patient teachers helped them develop competencies by providing patient-specific content.
New arsenate minerals from the Arsenatnaya fumarole, Tolbachik volcano, Kamchatka, Russia. X. Edtollite, K2NaCu5Fe3+O2(AsO4)4, and alumoedtollite, K2NaCu5AlO2(AsO4)4
Authors: Pekov Igor V. , Zubkova Natalia V. , Agakhanov Atali A. , Ksenofontov Dmitry A. , Pautov Leonid A. , Sidorov Evgeny G. , Britvin Sergey N. , Vigasina Marina F. , Pushcharovsky Dmitry Y. 
Published: October 2018

AbstractTwo new isostructural minerals edtollite K2NaCu5Fe3+O2(AsO4)4and alumoedtollite K2NaCu5AlO2(AsO4)4have been found in the Arsenatnaya fumarole, Second scoria cone of the Northern Breakthrough of the Great Tolbachik Fissure Eruption, Tolbachik volcano, Kamchatka, Russia. They are associated with sylvite, tenorite, dmisokolovite, shchurovskyite, johillerite, bradaczekite, and orthoclase. Edtollite forms prismatic crystals up to 0.02 mm × 0.1 mm; alumoedtollite forms long-prismatic crystals up to 0.01 mm × 0.1 mm. Both minerals have a semi-metallic lustre. Edtollite is brown–black to black and alumoedtollite is bronze coloured.Dcalc.= 4.26 (edtollite) and 4.28 (alumoedtollite) g cm–3. In reflected light, both minerals are grey, with distinct anisotropy. Reflectance values [edtollite/alumoedtollite:R1–R2, % (λ, nm)] are: 8.3–8.2/8.7–7.7 (470); 7.7–7.4/8.3–7.4 (546); 7.1–6.9/8.3–7.4 (589); and 6.3–6.3/7.6–7.2 (650). Chemical data are: (edtollite/alumoedtollite, wt.%, electron-microprobe): Na2O 3.13/2.58, K2O 8.12/9.09, Rb2O 0.00/0.11, CaO 0.00/0.52, CuO 36.55/38.35, ZnO 0.46/0.00, Al2O30.00/3.48, Fe2O37.34/1.79, TiO20.27/0.00, As2O543.57/43.66, total 99.44/99.58. The empirical formulae, based on 18 O apfu, for edtollite is: K1.83Na1.07Cu4.88Zn0.06Fe3+0.98Ti0.04As4.03O18; and for alumoedtollite is: K2.02Rb0.01Na0.87Ca0.10Cu5.06Al0.72Fe3+0.24As3.99O18. Both minerals are triclinic,P$\bar{1}$; unit-cell parameters (edtollite/alumoedtollite) are:a= 5.1168(6)/5.0904(11),b= 9.1241(12)/9.0778(14),c= 9.6979(14)/9.6658(2) Å, α = 110.117(13)/110.334(17), β = 102.454(12)/102.461(19), γ = 92.852(11)/92.788(15)°,V= 411.32(9)/404.88(14) Å3andZ= 1/1. The strongest reflections in the powder X-ray diffraction pattern [d,Å(I)(hkl)] are for edtollite: 8.79(92)(001), 7.63(41)(0$\bar{1}$1), 5.22(44)(011), 3.427(100)(012), 3.148(64)(0$\bar{1}$3), 2.851(65)($\bar{1}$03) and 2.551(40)($\bar{2}$01); and for alumoedtollite: 8.78(81)(001), 7.62(67)(0$\bar{1}$1), 3.418(100)(012), 3.147(52)(0$\bar{1}$3), 2.558(58)($\bar{1}$22), 2.544(65)($\bar{2}$01) and 2.528(52)($\bar{1}\bar{3}$2). The crystal structures [single-crystal X-ray diffraction,R= 0.0773 (edtollite) and 0.0826 (alumoedtollite); 1504 and 1046 unique reflections, respectively] represent a novel structure type. It is based upon a heteropolyhedral pseudo-framework with the column formed by Cu2+-centred octahedra and square pyramids, octahedraMO6(M= Fe3+, Al3+or Cu2+) and AsO4tetrahedra as the main building unit. K+and Na+are located in wide and narrow channels, respectively. Edtollite is named after the Russian geologist and Arctic explorer Eduard Vasilievich Toll (1858–1902), alumoedtollite is its analogue with Al prevailing among trivalent cations.
Brain and Spinal Epidural Abscess
Authors: Chow Felicia 
Published: October 2018

ABSTRACT

PURPOSE OF REVIEW
Brain abscesses and spinal epidural abscesses are serious, potentially life-threatening infections of the central nervous system. This article outlines the clinical presentation, evaluation, and management of brain abscesses and spinal epidural abscesses, with a specific focus on bacterial infections.

RECENT FINDINGS
The overall incidence of brain abscesses has declined, in part because of fewer brain abscesses associated with otogenic infections. However, emerging patient populations at high risk for brain abscess include those with a history of penetrating head trauma, neurosurgery, or immunodeficiency. Improved mortality rates for brain abscess are attributable to modern diagnostic imaging, stereotactic-guided aspiration, and newer antimicrobials that readily penetrate into the central nervous system and abscesses. Brain MRI is more sensitive than CT for brain abscess, particularly in the early stages, but CT remains more widely available and can adequately identify potential abscesses and confirm response to treatment. With the advent of minimally invasive neurosurgical techniques, surgical excision is often employed only for posterior fossa, multiloculated, or superficial well-circumscribed abscesses. In select clinical scenarios, conservative medical management may be a safe alternative to a combined surgical and medical approach. Unlike brain abscess, the incidence of spinal epidural abscess is on the rise and has been attributed to higher prevalence of predisposing factors, including spinal procedures and instrumentation.

SUMMARY
Successful diagnosis and management of brain abscess and spinal epidural abscess requires a collaborative approach among neurologists, neurosurgeons, radiologists, and infectious disease physicians. The foundation of management of brain abscess includes surgical intervention for diagnostic purposes if a pathogen has not been identified or for decompression of larger abscesses or those with mass effect and significant surrounding edema; appropriate dosing and adequate duration of an antimicrobial regimen tailored to the presumptive source of infection and available culture data, and eradication of the primary source of infection. For spinal epidural abscesses, neurologic status at the time of presentation is directly related to outcomes, underscoring the importance of prompt recognition and intervention.
Tetanus, Botulism, and Diphtheria
Authors: Berkowitz Aaron L. 
Published: October 2018

ABSTRACT

PURPOSE OF REVIEW
This article reviews the pathophysiology, epidemiology, clinical manifestations, diagnosis, and treatment of tetanus, botulism, and diphtheric neuropathy.

RECENT FINDINGS
Tetanus is most common in lower-income settings, but rare cases are seen in higher-income settings because of the inadequate maintenance of vaccination status. Foodborne botulism remains rare, but botulism can also be caused by IV drug use (wound botulism) and medical use of botulinum toxin (iatrogenic botulism); botulinum toxin has also been considered a potential agent of bioterrorism. Diphtheric neuropathy is rare but has been seen in recent epidemics in the former Soviet Union, and vaccination status is inadequate in a significant proportion of older individuals, creating the potential for subsequent epidemics.

SUMMARY
Tetanus, botulism, and diphtheric neuropathy are rare in higher-resource settings where most neurologists practice; however, familiarity with the unique clinical manifestations of and laboratory evaluation for these disorders is essential for the rapid diagnosis and treatment of patients with these conditions.
Zika Virus and Other Emerging Arboviral Central Nervous System Infections
Authors: Sejvar James J. 
Published: October 2018

ABSTRACT

PURPOSE OF REVIEW
In recent years, we have observed the emergence and reemergence of a number of arthropod-borne viruses (arboviruses). Zika virus is the most recent addition to this group, first causing sporadic cases of uncomplicated febrile illness followed by sizeable outbreaks in the Pacific. However, the epidemiology and clinical features of Zika virus infection have changed rapidly and dramatically; it is now recognized as causing Guillain-Barré syndrome (GBS) in children and adults and congenital abnormalities in infected fetuses. This article reviews the epidemiology, clinical features, and diagnosis of Zika virus–associated neurologic illness and briefly reviews features of West Nile virus and Japanese encephalitis virus.

RECENT FINDINGS
Zika virus has emerged as a significant human pathogen in recent years. In 2015, it began to cause large outbreaks of febrile rash illness in South America and the Caribbean. During these large Zika virus outbreaks, a significant increase in the incidence of GBS was also observed in multiple countries/territories. Zika virus–associated GBS has several unique features, including a relatively short interval between febrile illness and GBS onset, an unusually high incidence among older people, and prominent cranial nerve abnormalities. Congenital Zika syndrome includes a myriad of abnormalities, including microcephaly, lissencephaly, hydrocephalus, arthrogryposis, and parenchymal calcifications. Currently, no treatment has been identified for Zika virus, although work on vaccines is under way.

SUMMARY
Arboviruses continue to surprise us with unexpected emergence in various locations, the nature of clinical illness, and outcomes. Zika virus presents a classic example of this type of emergence. Ongoing surveillance will be needed to evaluate the long-term pattern of Zika virus and related arboviruses.