bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preexisting Commensal Dysbiosis Is a Host-Intrinsic Regulator of Tissue Inflammation and Tumor Cell Dissemination in Hormone Receptor–Positive Breast Cancer
Authors: Buchta Rosean Claire , Bostic Raegan R. , Ferey Joshua C.M. , Feng Tzu-Yu , Azar Francesca N. , Tung Kenneth S. , Dozmorov Mikhail G. , Smirnova Ekaterina , Bos Paula D. , Rutkowski Melanie R. 
Published: May 2019

Abstract

It is unknown why some patients with hormone receptor–positive (HR+) breast cancer present with more aggressive and invasive disease. Metastatic dissemination occurs early in disease and is facilitated by cross-talk between the tumor and tissue environment, suggesting that undefined host-intrinsic factors enhance early dissemination and the probability of developing metastatic disease. Here, we have identified commensal dysbiosis as a host-intrinsic factor associated with metastatic dissemination. Using a mouse model of HR+ mammary cancer, we demonstrate that a preestablished disruption of commensal homeostasis results in enhanced circulating tumor cells and subsequent dissemination to the tumor-draining lymph nodes and lungs. Commensal dysbiosis promoted early inflammation within the mammary gland that was sustained during HR+ mammary tumor progression. Furthermore, dysbiosis enhanced fibrosis and collagen deposition both systemically and locally within the tumor microenvironment and induced significant myeloid infiltration into the mammary gland and breast tumor. These effects were recapitulated both by directly targeting gut microbes using nonabsorbable antibiotics and by fecal microbiota transplantation of dysbiotic cecal contents, demonstrating the direct impact of gut dysbiosis on mammary tumor dissemination. This study identifies dysbiosis as a preexisting, host-intrinsic regulator of tissue inflammation, myeloid recruitment, fibrosis, and dissemination of tumor cells in HR+ breast cancer.

Significance:
Identification of commensal dysbiosis as a host-intrinsic factor mediating evolution of metastatic breast cancer allows for development of interventions or diagnostic tools for patients at highest risk for developing metastatic disease.
See related commentary by Ingman, p. 3539
Discovery and Characterization of SY-1365, a Selective, Covalent Inhibitor of CDK7
Authors: Hu Shanhu , Marineau Jason J. , Rajagopal Nisha , Hamman Kristin B. , Choi Yoon Jong , Schmidt Darby R. , Ke Nan , Johannessen Liv , Bradley Michael J. , Orlando David A. , Alnemy Sydney R. , Ren Yixuan , Ciblat Stephane , Winter Dana K. , Kabro Anzhelika , Sprott Kevin T. , Hodgson J. Graeme , Fritz Christian C. , Carulli John P. , di Tomaso Emmanuelle , Olson Eric R. 
Published: May 2019

Abstract

Recent studies suggest that targeting transcriptional machinery can lead to potent and selective anticancer effects in cancers dependent on high and constant expression of certain transcription factors for growth and survival. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of the CDK-activating kinase complex. Its function is required for both cell-cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive cancer target because its inhibition leads to decreased transcript levels of oncogenic transcription factors, especially those associated with super-enhancers. Here, we describe a selective CDK7 inhibitor SY-1365, which is currently in clinical trials in populations of patients with ovarian and breast cancer (NCT03134638). In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL2L1 (BCL-XL) expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial antitumor effects in multiple AML xenograft models as a single agent; SY-1365–induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Antitumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematologic and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers.

Significance:
These findings demonstrate the molecular mechanism of action and potent antitumor activity of SY-1365, the first selective CDK7 inhibitor to enter clinical investigation.
Imaging of Activated T Cells as an Early Predictor of Immune Response to Anti-PD-1 Therapy
Authors: Levi Jelena , Lam Tina , Goth Samuel R. , Yaghoubi Shahriar , Bates Jennifer , Ren Gang , Jivan Salma , Huynh Tony L. , Blecha Joseph E. , Khattri Roli , Schmidt Karl F. , Jennings Dominique , VanBrocklin Henry 
Published: May 2019

Abstract

Compelling evidence points to immune cell infiltration as a critical component of successful immunotherapy. However, there are currently no clinically available, noninvasive methods capable of evaluating immune contexture prior to or during immunotherapy. In this study, we evaluate a T-cell–specific PET agent, [18F]F-AraG, as an imaging biomarker predictive of response to checkpoint inhibitor therapy. We determined the specificity of the tracer for activated T cells in vitro and in a virally induced model of rhabdomyosarcoma. Of all immune cells tested, activated human CD8+ effector cells showed the highest accumulation of [18F]F-AraG. Isolation of lymphocytes from the rhabdomyosarcoma tumors showed that more than 80% of the intratumoral signal came from accumulation of [18F]F-AraG in immune cells, primarily CD8+ and CD4+. Longitudinal monitoring of MC38 tumor-bearing mice undergoing anti-PD-1 treatment revealed differences in signal between PD-1 and isotype antibody–treated mice early into treatment. The differences in [18F]F-AraG signal were also apparent between responders and nonresponders to anti-PD-1 therapy. Importantly, we found that the signal in the tumor-draining lymph nodes provides key information about response to anti-PD-1 therapy. Overall, [18F]F-AraG has potential to serve as a much needed immunomonitoring clinical tool for timely evaluation of immunotherapy.

Significance:
These findings reveal differences in T-cell activation between responders and nonresponders early into anti-PD-1 treatment, which may impact many facets of immuno-oncology, including patient selection, management, and development of novel combinatorial approaches.
Targeting the High-Mobility Group Box 3 Protein Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin
Authors: Mukherjee Anirban , Huynh Van , Gaines Kailee , Reh Wade Alan , Vasquez Karen M. 
Published: May 2019

Abstract

Chemotherapeutic regimens for ovarian cancer often include the use of DNA interstrand crosslink–inducing agents (e.g., platinum drugs) or DNA double-strand break–inducing agents. Unfortunately, the majority of patients fail to maintain a durable response to treatment, in part, due to drug resistance, contributing to a poor survival rate. In this study, we report that cisplatin sensitivity can be restored in cisplatin-resistant ovarian cancer cells by targeting the chromatin-associated high-mobility group box 3 (HMGB3) protein. HMGB proteins have been implicated in the pathogenesis and prognosis of ovarian cancer, and HMGB3 is often upregulated in cancer cells, making it a potential selective target for therapeutic intervention. Depletion of HMGB3 in cisplatin-sensitive and cisplatin-resistant cells resulted in transcriptional downregulation of the kinases ATR and CHK1, which attenuated the ATR/CHK1/p-CHK1 DNA damage signaling pathway. HMGB3 was associated with the promoter regions of ATR and CHK1, suggesting a new role for HMGB3 in transcriptional regulation. Furthermore, HMGB3 depletion significantly increased apoptosis in cisplatin-resistant A2780/CP70 cells after cisplatin treatment. Taken together, our results indicate that targeted depletion of HMGB3 attenuates cisplatin resistance in human ovarian cancer cells, increasing tumor cell sensitivity to platinum drugs.

Significance:
This study shows that targeting HMGB3 is a potential therapeutic strategy to overcome chemoresistance in ovarian cancer.
Intratumoral Adaptive Immunosuppression and Type 17 Immunity in Mismatch Repair Proficient Colorectal Tumors
Authors: Llosa Nicolas J. , Luber Brandon , Tam Ada J. , Smith Kellie N. , Siegel Nicholas , Awan Anas H. , Fan Hongni , Oke Teniola , Zhang JiaJia , Domingue Jada , Engle Elizabeth L. , Roberts Charles A. , Bartlett Bjarne R. , Aulakh Laveet K. , Thompson Elizabeth D. , Taube Janis M. , Durham Jennifer N. , Sears Cynthia L. , Le Dung T. , Diaz Luis A. , Pardoll Drew M. , Wang Hao , Anders Robert A. , Housseau Franck 
Published: May 2019

Abstract

Purpose:
Approximately 10% of patients with mismatch repair–proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer.

Experimental Design:
We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n = 13) versus those who did not (n = 6) to anti-PD-1 therapy (NCT01876511). We define a 10 gene–based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n = 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors.

Results:
Although both IL17Low and IL17High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/IFNγ and PD-L1/IDO1 colocalization), only IL17Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment.

Conclusions:
The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy.
See related commentary by Willis et al., p. 5185
FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia
Authors: Norsworthy Kelly J. , By Kunthel , Subramaniam Sriram , Zhuang Luning , Del Valle Pedro L. , Przepiorka Donna , Shen Yuan-Li , Sheth Christopher M. , Liu Chao , Leong Ruby , Goldberg Kirsten B. , Farrell Ann T. , Pazdur Richard 
Published: May 2019

Abstract
On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30–0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval.
See related commentary by Fathi, p. 6015
Timing and Predictors of Recurrence of Dyspepsia Symptoms after Cessation of Acotiamide Therapy for Functional Dyspepsia: A Long-Term Observational Study
Authors: Shinozaki Satoshi , Osawa Hiroyuki , Sakamoto Hirotsugu , Hayashi Yoshikazu , Kobayashi Yasutoshi , Miura Yoshimasa , Lefor Alan Kawarai , Yamamoto Hironori 
Published: May 2019

Background/Aims: The long-term outcomes of patients after cessation of acotiamide therapy in patients with functional dyspepsia remains unclear. The aim of this study is to investigate the timing and predictors of recurrence of dyspepsia symptoms after cessation of acotiamide therapy for functional dyspepsia. Methods: Seventy patients treated with acotiamide for functional dyspepsia who then ceased treatment were enrolled. Changes in dyspepsia symptoms were evaluated using the Izumo scale, a self-reporting questionnaire of abdominal symptom-related quality of life. Patients were subclassified into epigastric pain, postprandial distress, and overlapped types. Results: The mean follow-up after cessation of acotiamide was 1.9 years. After cessation of acotiamide, 39 patients (56%) had recurrence. Kaplan-Meier analysis revealed a recurrence-free rate of 51% at 1 year. Predictors of recurrence evaluated with a Cox proportional hazards model showed that overlapped-type dyspepsia and consultation with the treating physician before cessation were identified as significant positive and negative predictors, respectively (p < 0.05). The resumption of acotiamide significantly decreased the score for dyspepsia symptoms at 1 month. Conclusions: Dyspepsia symptoms recur about one year after cessation of acotiamide therapy. Patients with overlapped-type dyspepsia should be carefully followed after cessation. Patients should consult their treating physician before stopping acotiamide.
An Overview of Using Weather Radar for Climatological Studies: Successes, Challenges, and Potential
Authors: Saltikoff Elena , Friedrich Katja , Soderholm Joshua , Lengfeld Katharina , Nelson Brian , Becker Andreas , Hollmann Rainer , Urban Bernard , Heistermann Maik , Tassone Caterina 
Published: May 2019

AbstractWeather radars have been widely used to detect and quantify precipitation and nowcast severe weather for more than 50 years. Operational weather radars generate huge three-dimensional datasets that can accumulate to terabytes per day. So it is essential to review what can be done with existing vast amounts of data, and how we should manage the present datasets for the future climatologists. All weather radars provide the reflectivity factor, and this is the main parameter to be archived. Saving reflectivity as volumetric data in the original spherical coordinates allows for studies of the three-dimensional structure of precipitation, which can be applied to understand a number of processes, for example, analyzing hail or thunderstorm modes. Doppler velocity and polarimetric moments also have numerous applications for climate studies, for example, quality improvement of reflectivity and rain rate retrievals, and for interrogating microphysical and dynamical processes. However, observational data alone are not useful if they are not accompanied by sufficient metadata. Since the lifetime of a radar ranges between 10 and 20 years, instruments are typically replaced or upgraded during climatologically relevant time periods. As a result, present metadata often do not apply to past data. This paper outlines the work of the Radar Task Team set by the Atmospheric Observation Panel for Climate (AOPC) and summarizes results from a recent survey on the existence and availability of long time series. We also provide recommendations for archiving current and future data and examples of climatological studies in which radar data have already been used.
Incarceration, HIV Risk–Related Behaviors, and Partner Characteristics Among Heterosexual Men at Increased Risk of HIV Infection, 20 US Cities
Authors: Wise Akilah , Finlayson Teresa , Sionean Catlainn , Paz-Bailey Gabriela 
Published: May 2019

Objectives: The effect of incarceration on HIV risk–related behaviors among at-risk heterosexual men is understudied. The objective of our study was to examine the association between incarceration and HIV risk–related behaviors among a sample of predominantly non-Hispanic black and Hispanic heterosexual men residing in urban areas in the United States with a high prevalence of AIDS. Methods: We analyzed data from the 2013 National HIV Behavioral Surveillance system on 5321 at-risk heterosexual men using log-linked Poisson regression models, adjusted for demographic characteristics and clustered on city. Results: Of 5321 men, 1417 (26.6%) had recently been incarcerated (in the past 12 months), 2781 (52.3%) had ever been incarcerated but not in the past 12 months, and 1123 (21.1%) had never been incarcerated. Recent incarceration was associated with multiple casual female sexual partners (adjusted prevalence ratio [aPR] = 1.23; 95% confidence interval [CI], 1.05-1.44), condomless sex with multiple female sexual partners (aPR = 1.32; 95% CI, 1.06-1.66), injection drug use (aPR = 3.75; 95% CI, 2.64-5.32), and having sexual partners who were more likely to have ever injected drugs (aPR = 1.84; 95% CI, 1.48-2.28), been incarcerated (aPR = 2.28; 95% CI, 2.01-2.59), or had a concurrent sexual partner (aPR = 1.08; 95% CI, 1.05-1.11), as compared with never-incarcerated men. Conclusions: Incarceration history was associated with HIV risk–related behaviors among heterosexual men from urban areas in the United States. Correctional rehabilitation initiatives are needed to promote strategies that mitigate HIV risk–related behaviors and promote healthy reentry into communities among heterosexual men at high risk for HIV.
The clinical spectrum of reversible cerebral vasoconstriction syndrome: The Italian Project on Stroke at Young Age (IPSYS)
Authors: Caria Filomena , Zedde Marialuisa , Gamba Massimo , Bersano Anna , Rasura Maurizia , Adami Alessandro , Piantadosi Carlo , Quartuccio Luca , Azzini Cristiano , Melis Maurizio , Luisa Delodovici Maria , Dallocchio Carlo , Gandolfo Carlo , Cerrato Paolo , Motto Cristina , Melis Fabio , Chiti Alberto , Gentile Mauro , Bignamini Valeria , Morotti Andrea , Maria Lotti Enrico , Toriello Antonella , Costa Paolo , Silvestrelli Giorgio , Zini Andrea , De Giuli Valeria , Poli Loris , Paciaroni Maurizio , Lodigiani Corrado , Marcheselli Simona , Sanguigni Sandro , Del Sette Massimo , Monaco Serena , Lochner Piergiorgio , Zanferrari Carla , Anticoli Sabrina , Padovani Alessandro , Pezzini Alessandro ,   on behalf of the Italian Project on Stroke at Young Age (IPSYS) Investigators
Published: May 2019

Introduction To describe clinical, neuroimaging, and laboratory features of a large cohort of Italian patients with reversible cerebral vasoconstriction syndrome. Methods In the setting of the multicenter Italian Project on Stroke at Young Age (IPSYS), we retrospectively enrolled patients with a diagnosis of definite reversible cerebral vasoconstriction syndrome according to the International Classification of Headache Disorders (ICHD)-3 beta criteria (6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome, imaging-proven). Clinical manifestations, neuroimaging, treatment, and clinical outcomes were evaluated in all patients. Characteristics of reversible cerebral vasoconstriction syndrome without typical causes (“idiopathic reversible cerebral vasoconstriction syndrome”) were compared with those of reversible cerebral vasoconstriction syndrome related to putative causative factors (“secondary reversible cerebral vasoconstriction syndrome”). Results A total of 102 patients (mean age, 47.2 ± 13.9 years; females, 85 [83.3%]) qualified for the analysis. Thunderclap headache at presentation was reported in 69 (67.6%) patients, and it typically recurred in 42 (60.9%). Compared to reversible cerebral vasoconstriction syndrome cases related to putative etiologic conditions (n = 21 [20.6%]), patients with idiopathic reversible cerebral vasoconstriction syndrome (n = 81 [79.4%]) were significantly older (49.2 ± 13.9 vs. 39.5 ± 11.4 years), had more frequently typical thunderclap headache (77.8% vs. 28.6%) and less frequently neurological complications (epileptic seizures, 11.1% vs. 38.1%; cerebral infarction, 6.1% vs. 33.3%), as well as concomitant reversible brain edema (25.9% vs. 47.6%). Conclusions Clinical manifestations and putative etiologies of reversible cerebral vasoconstriction syndrome in our series are slightly different from those observed in previous cohorts. This variability might be partly related to the coexistence of precipitating conditions with a putative etiologic role on disease occurrence.
Involving hybrid professionals in top management decision-making: How managerial training can make the difference
Authors: Giacomelli Giorgio , Ferré Francesca , Furlan Manuela , Nuti Sabina 
Published: May 2019

Hybrid professionals have a two-fold – professional and managerial – role, which requires appropriate management skills. Investing on managerial training programs aims to empower professionals with managerial skills and competencies. Does this pay back? Assessing the impact of such training programs is still a limited practice. This paper explores whether participation in managerial training programs in healthcare can enhance the involvement of hybrid professionals (namely, clinical directors) in top management decision-making. The mediational effects of knowledge of performance information and its use are explored. Survey data were collected from more than 3000 clinical directors of 69 public health authorities from five regional healthcare systems in Italy. Relationships between participation in managerial training programs, performance management practices (i.e., knowledge and use of performance information) and the level of clinicians’ involvement by the top management were studied using a three-path mediation analysis with structural equation modelling. Propensity score matching was also performed to mitigate selection bias. Knowledge and use of performance information positively mediate, both independently and sequentially, the relationship between clinical directors' participation in managerial training programs and the level of their involvement in decision-making. The results of the study suggest that managerial training can support hybrid professionals in engaging with managerialism and playing upward influence on top management decision-making.
Cryoprobe biopsy for the diagnosis of acute hypoxemic respiratory failure of undetermined origin
Authors: Heras Marcos J Las , Dianti Jose , Tisminetzky Manuel , Svetliza Graciela , Giannasi Sergio E , Roman Eduardo San 
Published: May 2019

Rationale Acute hypoxemic respiratory failure is a condition that comprises a wide array of entities. Obtaining a histological lung sample might help reach a diagnosis and direct an appropriate treatment in a select group of patients. Objective To describe our experience in the use of cryobiopsy for the diagnosis of acute hypoxemic respiratory failure of undetermined origin. Methods Retrospective analysis of case series of patients with acute hypoxemic respiratory failure who underwent lung cryobiopsy at the Intensive Care Unit of the Hospital Italiano de Buenos Aires, Argentina. Results Cryobiopsy yielded a histological diagnosis in all patients ( n = 10, 100%). This led to either a change in therapy or continuation of a specific treatment in eight of these patients. Cryobiopsy was found to be contributive in all the patients who did not meet Berlin criteria for acute respiratory distress syndrome. No major complications were associated with the procedure. Conclusions Cryobiopsy is a safe procedure with a high diagnostic yield in a selected group of patients.