bluuebunny/crossref_metadata_2025 huggingface dataset:
PB2000 OUTCOME OF PEDIATRIC NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA, IS ABVD THE BEST REGIMEN? 10 YEARS SINGLE CENTER EXPERIENCE, REPORT FROM CHILDREN CANCER HOSPITAL, EGYPT.
Authors: Madney Y. , abdallha A. , Ahmed S. , romeih M. , fikry S. , zaghloul M. , taha H. , Mohammed E. , attia I.
Published: June 2019

Background:

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype of Hodgkin lymphoma (HL) in children and accounts for 5–10% of all pediatric HL.

Aims:

The aim of the study to analyze the clinical characteristics and treatment outcome of Pediatric NLPHL.

Methods:

Retrospective study including all newly diagnosed patients less than 18 years old with NLPHL and treated in children cancer hospital Egypt CCHE between 2007 and 2017.

Results:

Among 43 pediatric NLPHL patients, 29 had early stage (18 with stage I, 11 with stage II). Fourteen patients had advanced stage (7 with stage III & 7 with stage IV). Eleven patients had a mediastinal disease, 8 patients had splenic involvement, 2 patient had bulky disease and 10 patient had B symptoms at diagnosis.

28 Patients with Early‐stage disease treatment; surgery and observation 6 patients, Chemotherapy 6 patients and Combined modality 17 patients. Relapse was seen in 7(25%) patients, 1 observation arm, 3 from chemotherapy arm (ABVD) and 3 from the combined arm (ABVD+IFRTH). 14 advanced stage patients received treatment; Chemotherapy (ABVD) 6 patients, Combined (ABVD+IFRTH) 8 patients, Relapse in 7 (50%) patients (all stage 4 disease), 6 from chemotherapy arm and 1 from the combined arm. 2 patients died (stage IV) from progressive disease and sepsis. B symptoms, mediastinal and splenic involvement had a significant impact on DFS on univariate analysis while combined treatment modality (Chemotherapy and Radiotherapy) had an impact on the outcome of both univariate and multivariate analysis.

5 Years DFS, OS for whole group was 64% and 94% respectively, while 5y DFS for early stage 83% and advanced stage 45% (p‐value = .01) and 5 Years OS for early stage was 100% and advanced stage 87 % (p‐value = .08).

Summary/Conclusion:

Early stage NLPHL had a better outcome but unexpected higher relapse in chemotherapy treatment arm raising a question about the role of radiotherapy while advanced stage disease had poor outcome rising a question of what should be the best chemotherapy regimen for pediatric NLPHL patients.
PB2144 PRESCRIPTION PATTERNS AND OUTCOMES OF FIRST‐LINE THERAPY FOR NON‐TRANSPLANT ELIGIBLE MULTIPLE MYELOMA REAL‐LIFE PATIENTS ACCORDING TO AGE: A RETROSPECTIVE ANALYSIS OF THE 2012‐2016 PERIOD
Authors: Cejalvo M. J. , Sureda A. , González E. , Vázquez‐Álvarez J. , García R. , Ramírez Á. , Pérez‐Persona E. , Abella E. , Garzón S. , García A. , Jarque I. , González M. S. , Sampol A. , Motlló C. , Martí J. M. , Alcalá M. , Duro R. , González Y. , Sastre J. L. , Sarrà J. , Lostaunau G. , López R. , de la Rubia J.
Published: June 2019

Background:

Multiple myeloma (MM) affects elderly individuals with two‐thirds of patients aged >65 years at diagnosis, 35% ≥75 and 10% ≥80. In general, routine clinical practice is based on the results of large, multicenter, randomized clinical trials. However, despite efforts from cooperative groups, patients enrolled in trials are generally younger and presumably healthier than the typical older patient with MM

Aims:

To describe prescription patterns for first‐line treatment of non‐transplant eligible MM patients in the setting of real‐life practice and to analyze treatment outcome according to patients’ age

Methods

Retrospective analysis of newly diagnosed MM patients not eligible for transplantation, who started anti‐myeloma treatment between 2012‐2016 in 20 Spanish hospitals. Variables collected included patients’ characteristics at diagnosis (ECOG, laboratory parameters, ISS, and cytogenetics/fluorescent in situ hybridization), characteristics of first‐line treatment, overall survival (OS), progression‐free survival (PFS), and overall response rate (ORR), defined as partial response or better

Results:

The retrospective cohort included 421 patients with a median age of 76 years (41‐90); 203 (49%), 106 (26%), and 104 (25%) were ≤75, 76‐80, and >80 years old, respectively; 28 (12%) had ECOG >2. ISS staging was I, II, III in 57 (18%), 93 (30%), and 160 (52%) patients, respectively; 73 (25%) patients had high‐risk cytogenetics. The most frequently prescribed regimen was VMP (208 patients), followed by other bortezomib‐based regimens (130 patients) (Table 1). Overall, median treatment duration was 6 months (95%CI 5‐7) and the ORR was 74% (for patients ≤75, 75‐80, and >80 years old: 76%, 80%, and 62%; P = 0.025). Overall, 188 (45%) patients required a dose adjustment and 225 (81%) started second‐line treatment. Median OS and PFS were 32 (95% CI 29‐37) and 15 months (95% CI 14‐17), respectively. OS and PFS of patients ≤75, 75‐80, and >80 years old were 44 and 16 months, 28 and 17 months, and 23 and 12 months (P < 0.01 for age‐group differences in both OS and PFS).

Summary/Conclusion:

In real‐life practice, there is high variability in treatment regimens, being bortezomib‐based the most frequently prescribed regimens in the study period. Besides the clinical characteristics of MM patients, age influenced survival in our cohort of real‐life patients, suggesting that treatment choice for elderly patients should be based on a specific pre‐treatment assessment of risks and benefits.

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PB2172 THE EFFECTS OF CURCUMIN ADDITION ON REMISSION STATUS OF MULTIPLE MYELOMA PATIENTS
Authors: Santosa D. , Suharti C. , Riwanto I. , Dharmana E. , Pangarsa E. Adi , Setiawan B. , Suyono S. , Tobing M. Lumban
Published: June 2019

Background:

The standard treatment for multiple myeloma (MM) which ineligible transplant is melphalan prednisone (MP). Curcumin has anti‐inflamatory, anti angiogenesis, decrease proliferation and delay progression of monoclonal gammopathy undetermined significant or smoldering myeloma. There is no study of curcumin in MM patients

Aims:

To evaluate the effect of curcumin addition to remission status at MM patient with regiment MP

Methods

This experimental study was involved 35 patients which randomly into treatment (n = 17) and control (n = 16). The treatment group was given melphalan 4 mg/m2, prednisone 40 mg/m2 (MP) for 7 days and curcumin 8 gram daily for 28 days. The control group was given MP and placebo. Remision status was evaluated after 4 cycles treatment. The difference between two groups was analysed by Mann‐Whitney U‐Test. Trend analysis was evealuated by Friedman. Remission status was evaluated by Chi‐square. Multivariate analysis was evaluated by multiple logistic regression.

Results:

There was a significant decrease of NF‐KB, VEGF, TNF‐α, LDH levels in the treatment group compared with control. There was a decreasing trend of IL‐6 levels in the treatment group significantly. There was significant difference of remission status beetween the treatment and control group [(75 vs 33.3), X2 = 6.89,df = 1, p = 0.009]. There was significant correlation between TNF‐α levles and remission status [OR = 1.35; (95% CI = 1.03‐1.7.6), p = 0.03].

Summary/Conclusion:

The curcumin addition on MM patient with MP regiment improved the remision status through decreased of TNF‐α levels.
PB2216 ARTERIAL AND VENOUS THROMBOSIS IN TREATED PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS
Authors: Boban A. , Perić M. Morić , Zekanović I. , Horvat I. , Antolić M. Radić , Rončević P. , Zupančić‐Šalek S. , Serventi‐Seiwerth R. , Kinda S. Bašić , Vrhovac R. , Duraković N. , Perić Z. , Sertić D. , Mikulić M. , Pulanić D. , Aurer I.
Published: June 2019

Background:

Cardiovascular and thromboembolic events are the leading causes of morbidity and mortality for patients with myeloproliferative disorders (MPN).

Aims:

This retrospective study aimed to evaluate the incidence and the risk factors for the arterial and venous thrombosis in treated patients with MPN.

Methods:

The study included 329 adult MPN patients, 184 (56%) female, treated at University Hospital Center Zagreb, Department of Internal medicine, Division of Hematology and Zadar General Hospital, Hematology Unit. Patients were aged 24‐85 years (median 68), and were diagnosed as having essential thrombocythemia (ET) (n = 149, 45%), polycythaemia vera (PV)(n = 94, 29%), primary myelofibrosis (PMF)(n = 69, 21%) and unclassifiable MPN (n = 17, 5%). Diagnosis were made according to the 2008 WHO Classification. JAK‐2 mutation status was either established or revised in our center, but was unknown in 55 (17%) patients. Data about treatment and cardiovascular and thromboembolic incidents was retrieved from medical records.

Results:

Forty patients (12%) developed thrombosis after median of 36 (range 1‐240) months from the time of diagnosis. Fifteen (5%) patients developed venous thrombosis, twenty‐four (7%) arterial, while one (0,3%) patient both type of thrombosis. Regarding the disease type, thrombosis was described in 16 patients with ET (11%), 18 with PV (19%) and 6 with PMF (8%). The risk of thrombosis was the highest in patients with previous thrombotic events, but did not correlate with the type of therapy (cytoreductive and/or antiagreggation) nor the JAK‐2 status.

Summary/Conclusion:

The risk of both arterial and venous thrombosis was found to be increased in patients with MPN even after introducing appropriate treatment. The highest risk of post treatment thrombosis was found in patients with previously diagnosed thrombotic events.
PB2231 THE MYELOPROLIFERATIVE NEOPLASMS UNCLASSIFIABLE. OUR EXPERIENCE
Authors: Accurso V. , Santoro M. , Contrino A. D. , Sardo M. , Perez A. , Di Piazza F. , Florena A. M. , Russo A. , Siragusa S.
Published: June 2019

Background:

According to the WHO classification, the designation of myeloproliferative neoplasms unclassifiable (MPN‐U) should be used for cases with clinical, morphologic, and molecular features of MPN failing to meet the diagnostic criteria of a specific entity. Reported incidence of MPN‐U varies significantly in different studies with a range up to > 20%. However, most studies show an incidence of 10–15% or even less. When the 2016 WHO criteria have been applied, the incidence is reduced to <5%.

Aims:

In this report we study the clinical and laboratory characteristics of 31 consecutive cases of unclassifiable myeloproliferative disease afferent to the center for myeloproliferative diseases of our Hematology Unit.

Methods:

From 2010 to 2018 our center has collected 508 cases of Philadelphia‐negative Myeloproliferative Neoplasms (MPNs). Data from these patients were collected in a specific database and analysed with simple statistic tools.

Results:

Among these 508 patients, 31 (6.2%) had a diagnosis of MPN‐U, 16 male and 14 female. Median age at diagnosis was 60.9 years. 22/31 (70.9%) were JAK2 V617F positive, 3/31 were CALR mutated (0.96%), 2/31 (0.64%) MPL mutated and 6/31 (19.3%) resulted as triple negative (TN) for driver mutations. Data from the other groups of MPNs (PV, ET, overtMF and preMF) were analised as well and compared to the ones from the MPN‐U group.

Summary/Conclusion:

Chronic myeloproliferative diseases unclassifiable (MPN‐U) represent the 6.2% of the cases relating to our center. No significant difference at diagnosis has been highlighted regarding sex, age and mutational status between MPN‐U and MPN classified according to WHO 2016. The exact incidence of MPN‐U is unknown. It is probable that frequency varies significantly according to the experience of the diagnostician and the specific classification system and criteria used. It is possible that careful use of the WHO 2016 classification may significantly reduce the frequency of MPN‐U.
PB2439 CAN THROMBOELASTOGRAPHY (TEG) EFFECTIVELY EVALUATE COAGULATION BALANCE IN PATIENTS WITH ACUTE LEUKAEMIA UNDER CHEMOTHERAPY?
Authors: Raso S. , Napolitano M. , Mancuso S. , Santoro M. , Carlisi M. , Tarantino G. , Franco G. , Lipari M. G. , Siragusa S.
Published: June 2019

Background:

Clinical course of AL may be complicated by thrombosis o major bleeding. Basal coagulation tests and platelet count (PLT) alone have been shown to not adequately identify thrombotic or risk.

Aims:

prospective study investigates the role of TEG, in patients with AL for predicting bleeding or thrombosis either at the presentation o during chemotherapy (CHT).

Methods:

This prospective study was conducted on 11 consecutive patients (PTs) with AL. Assessment of blood count cell (CBC) and conventional coagulation tests (CCT),PT,a‐PTT,DD,FBGandTEG(TEG®5000, Thromboelastograph Haemostasis System) were collected at the diagnosis and during 1 st cycle of CHT. TEG parameters R‐time(min), a‐angle(°), K‐time(min), MA (maximum amplitude) (mm) were recorded and normal ranges were considered as R 9‐27, K 2‐9, a‐angle 22‐58, MA 44‐64.

Results:

Overall, 8 PTs with AML and 3 with ALL were evaluated with a median age of 54 y (range 18 –80). CHT administered were intensive in all but 2 PTs, treated with hypomethylating agent (HP). CCTs resulted normal in all cases with the exception of DD levels that were increased. 6 patients developed blood cloting disorders on CHT:3 thrombotic events [1 portal vein thrombosis,1 thrombosis of the lower limbs, 1 myocardial infarction]; 3 haemorrhages [2 of urinary tract (WHO grade 2) and 1 of central nervous system (WHO grade 3)]. TEG assay at diagnosis resulted normal in 9 patients. In PTs with thrombosis, TEG resulted markedly shortened, with an increased rate of a‐angle and a higher MA, when compared to bleeding PTs and to aymptomatic PTs(Table 1).TEG in PTs receiving HP showed no significant alterations, also in presence of thrombocytopenia.

Summary/Conclusion:

In our cohort, TEG showed a hypercoagulable state, characterized by a reduction of R value during CHT in PTs with thrombosis. MA and a‐angle resulted increased, compared to diagnosis, only in patients with thrombosis, while they were decreased in all the other PTs. These results were no in relationship to PLT or FBG levels. Our findings suggest that TEG may be useful to identify PTs with AL at higher thrombotic risk.

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Angiofibroma of the Eyelid: A Rare Clinical and Histologic Variant
Authors: Charles Norman C. , Jakobiec Frederick A. , Ma Lina , Belinsky Irina
Published: June 2019

A flesh-colored, supraciliary lesion of the left upper eyelid in a 47-year-old man was excised for cosmetic reasons. Histopathology and immunohistochemistry demonstrated CD34-positive benign spindle cells, factor XIIIa-positive dendritic cells, and CD163-positive histiocytes, all dispersed within a diffuse collagenous background. Prominent loose perivascular cuffs of fibroblastic cells and collagen surrounded small blood vessels. Interpreted as an angiofibroma, the histopathology bore resemblance to that of a single previously-reported forearm lesion termed a “dermal fibroma with a distinctive perivascular cell arrangement.” The lesion represents the first eyelid example of an unusual variant of angiofibroma.
Nurse Vigilance
Authors: Zinkan Jerri Lynn , Rutledge Chrystal , Norwood Carrie , Wise Kandi M. , Gaither Stacy , Cameron Brittany , Tofil Nancy M. , Raju Sai Krishna Surapa
Published: June 2019

Early recognition of and prompt intervention for the deteriorating pediatric patient remains paramount in preventing cardiac arrests from occurring outside intensive care units. To decrease these events, we developed a three-part simulation-based blended learning course consisting of a computer-based training module, a simulation scenario, and follow-up in situ scenarios for inpatient nurses. After initiation of the course, our facility has seen a decrease in the number of codes outside critical care areas.
Clinical Performance of Human Papillomavirus Testing and Visual Inspection With Acetic Acid in Primary, Combination, and Sequential Cervical Cancer Screening in China
Authors: Wang Margaret Z. , Feng Rui-mei , Wang Shaoming , Duan Xian-zhi , Li Dong , Zhang Xun , Mu Rong , Qiao Youlin , Smith Jennifer S.
Published: June 2019

Background

World Health Organization guidelines recommend screening with human papillomavirus (HPV) testing followed by either treatment of all HPV-positives, or by visual inspection (VIA) for triage to treatment, citing insufficient evidence to recommend either strategy over the other.

Methods

We assessed VIA and HPV testing individually, in combination (HPV-VIA cotesting), and as triage models. Three thousand women were screened in Inner Mongolia, China, concurrently with HPV testing and VIA in a real population setting. Screen-positive women underwent colposcopy, and biopsy, if indicated. Accuracy of screening algorithms for cervical intraepithelial neoplasia grade 2 or higher (CIN-2+) was calculated after controlling for verification bias. HPV testing followed by VIA triage for CIN-2+ detection was compared with Hybrid Capture 2 viral loads triage, measured in relative light units/cutoff.

Results

CIN-2+ prevalence was 1.0%. Corrected sensitivity, false negative rate, and specificity for CIN-2+, respectively, for primary HPV testing were 89.7%, 10.3%, and 83.3%; 44.8%, 55.2%, and 92·3% for VIA; 93.1%, 6.9%, and 80.2% for HPV-VIA cotesting; and 41.4%, 58.6, and 95.4% for HPV with VIA triage scenarios. Using relative light units/cutoff of 5 or greater to triage HPV-positive women had twice the sensitivity as VIA triage, with comparable specificity for CIN-2+.

Conclusions

When VIA performs relatively poorly and HPV testing is available, adding VIA to sequential (ie, HPV followed by VIA triage) or primary (HPV-VIA cotesting) screening does not significantly improve CIN-2+ detection beyond primary HPV screening alone. Sequential screening (ie, HPV followed by VIA triage) reduces sensitivity too low for population-based screening programs. The HPV viral loads could offer an alternative low-resource country triage strategy.
Ecological pressures and the contrasting scaling of metabolism and body shape in coexisting taxa: cephalopods versus teleost fish
Authors: Tan Hanrong , Hirst Andrew G. , Glazier Douglas S. , Atkinson David
Published: June 2019

Metabolic rates are fundamental to many biological processes, and commonly scale with body size with an exponent (bR) between 2/3 and 1 for reasons still debated. According to the ‘metabolic-level boundaries hypothesis',bRdepends on the metabolic level (LR). We test this prediction and show that across cephalopod species intraspecificbRcorrelates positively with not onlyLRbut also the scaling of body surface area with body mass. Cephalopod species with highLRmaintain near constant mass-specific metabolic rates, growth and probably inner-mantle surface area for exchange of respiratory gases or wastes throughout their lives. By contrast, teleost fish show a negative correlation betweenbRandLR. We hypothesize that this striking taxonomic difference arises because both resource supply and demand scale differently in fish and cephalopods, as a result of contrasting mortality and energetic pressures, likely related to different locomotion costs and predation pressure. Cephalopods with highLRexhibit relatively steep scaling of growth, locomotion, and resource-exchange surface area, made possible by body-shape shifting. We suggest that differences in lifestyle, growth and body shape with changing water depth may be useful for predicting contrasting metabolic scaling for coexisting animals of similar sizes.

This article is part of the theme issue ‘Physiological diversity, biodiversity patterns and global climate change: testing key hypotheses involving temperature and oxygen’.
Integrating within-species variation in thermal physiology into climate change ecology
Authors: Bennett Scott , Duarte Carlos M. , Marbà Núria , Wernberg Thomas
Published: June 2019

Accurately forecasting the response of global biota to warming is a fundamental challenge for ecology in the Anthropocene. Within-species variation in thermal sensitivity, caused by phenotypic plasticity and local adaptation of thermal limits, is often overlooked in assessments of species responses to warming. Despite this, implicit assumptions of thermal niche conservatism or adaptation and plasticity at the species level permeate the literature with potentially important implications for predictions of warming impacts at the population level. Here we review how these attributes interact with the spatial and temporal context of ocean warming to influence the vulnerability of marine organisms. We identify a broad spectrum of thermal sensitivities among marine organisms, particularly in central and cool-edge populations of species distributions. These are characterized by generally low sensitivity in organisms with conserved thermal niches, to high sensitivity for organisms with locally adapted thermal niches. Important differences in thermal sensitivity among marine taxa suggest that warming could adversely affect benthic primary producers sooner than less vulnerable higher trophic groups. Embracing the spatial, temporal and biological context of within-species variation in thermal physiology helps explain observed impacts of ocean warming and can improve forecasts of climate change vulnerability in marine systems.

This article is part of the theme issue ‘Physiological diversity, biodiversity patterns and global climate change: testing key hypotheses involving temperature and oxygen’.
ICTV Virus Taxonomy Profile: Artoviridae
Authors: Dietzgen Ralf G. , Jiāng Dàohóng , Kuhn Jens H. , Vasilakis Nikos ,   ICTV Report Consortium
Published: June 2019

The family Artoviridae was created in 2018 for the established monospecific genus Peropuvirus and six new species of invertebrate viruses that had all been discovered by high-throughput sequencing. Artoviruses have negative-sense RNA genomes of about 12 kb and produce enveloped, spherical particles that are 100–130 nm in diameter. Hosts include parasitoid wasps, barnacles, pillworms, woodlice, copepods and odonates. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Artoviridae, which is available at www.ictv.global/report/artoviridae.
Dramatic HIV DNA degradation associated with spontaneous HIV suppression and disease-free outcome in a young seropositive woman following her infection
Authors: Colson Philippe , Dhiver Catherine , Tamalet Catherine , Delerce Jeremy , Glazunova Olga O. , Gaudin Maxime , Levasseur Anthony , Raoult Didier
Published: June 2019

Strategies to cure HIV-infected patients by virus-targeting drugs have failed to date. We identified a HIV-1-seropositive woman who spontaneously suppressed HIV replication and had normal CD4-cell counts, no HIV disease, no replication-competent virus and no cell HIV DNA detected with a routine assay. We suspected that dramatic HIV DNA degradation occurred postinfection. We performed multiple nested-PCRs followed by Sanger sequencing and applied a multiplex-PCR approach. Furthermore, we implemented a new technique based on two hybridization steps on beads prior to next-generation sequencing that removed human DNA then retrieved integrated HIV sequences with HIV-specific probes. We assembled ≈45% of the HIV genome and further analyzed the G-to-A mutations putatively generated by cellular APOBEC3 enzymes that can change tryptophan codons into stop codons. We found more G-to-A mutations in the HIV DNA from the woman than in that of her contaminator. Moreover, 74% of the tryptophan codons were changed to stop codons (25%) or were deleted as a possible consequence of gene inactivation. Finally, we found that this woman’s cells remained HIV-susceptible in vitro. Our findings show that she does not exhibit innate HIV resistance but has been cured of it by extrinsic factors, a plausible candidate for which is the gut microbiota.
PARP1 as a biomarker for early detection and intraoperative tumor delineation in epithelial cancers – first-in-human results
Authors: Kossatz Susanne , Pirovano Giacomo , De Souza França Paula Demétrio , Strome Arianna L. , Sunny Sumsum P. , Zanoni Daniella Karassawa , Mauguen Audrey , Carney Brandon , Brand Christian , Shah Veer , Ramanajinappa Ravindra D. , Hedne Naveen , Birur Praveen , Sihag Smita , Ghossein Ronald A. , Gönen Mithat , Strome Marshall , Suresh Amritha , Molena Daniela , Kuriakose Moni A. , Patel Snehal G. , Reiner Thomas
Published: June 2019

Major determining factors for survival of patients with oral, oropharyngeal, and esophageal cancer are early detection, the quality of surgical margins, and the contemporaneous detection of residual tumor. Intuitively, the exposed location at the epithelial surface qualifies these tumor types for utilization of visual aids to assist in discriminating tumor from healthy surrounding tissue. Here, we explored the DNA repair enzyme PARP1 as imaging biomarker and conducted optical imaging in animal models, human tissues and as part of a first-in-human clinical trial. Our data suggests that PARP1 is a quantitative biomarker for oral, oropharyngeal, and esophageal cancer and can be visualized with PARPi-FL, a fluorescently labeled small molecule contrast agent for topical or intravenous delivery. We show feasibility of PARPi-FL-assisted tumor detection in esophageal cancer, oropharyngeal and oral cancer. We developed a contemporaneous PARPi-FL topical staining protocol for human biospecimens. Using fresh oral cancer tissues within 25 min of biopsy, tumor and margin samples were correctly identified with >95% sensitivity and specificity without terminal processing. PARPi-FL imaging can be integrated into clinical workflows, potentially providing instantaneous assessment of the presence or absence of microscopic disease at the surgical margin. Additionally, we showed first-in-human PARPi-FL imaging in oral cancer. In aggregate, our preclinical and clinical studies have the unifying goal of verifying the clinical value of PARPi-FL-based optical imaging for early detection and intraoperative margin assignment.
Combining weather patterns and cycles of population susceptibility to forecast dengue fever epidemic years in Brazil: a dynamic, ensemble learning approach
Authors: McGough Sarah F. , Clemente Cesar L. , Kutz J. Nathan , Santillana Mauricio
Published: June 2019

Transmission of dengue fever depends on a complex interplay of human, climate, and mosquito dynamics, which often change in time and space. It is well known that disease dynamics are highly influenced by a population’s susceptibility to infection and microclimates, small-area climatic conditions which create environments favorable for the breeding and survival of the mosquito vector. Here, we present a novel machine learning dengue forecasting approach, which, dynamically in time and adaptively in space, identifies local patterns in weather and population susceptibility to make epidemic predictions at the city-level in Brazil, months ahead of the occurrence of disease outbreaks. Weather-based predictions are improved when information on population susceptibility is incorporated, indicating that immunity is an important predictor neglected by most dengue forecast models. Given the generalizability of our methodology, it may prove valuable for public-health decision making aimed at mitigating the effects of seasonal dengue outbreaks in locations globally.
flowEMMi: An automated model-based clustering tool for microbial cytometric data
Authors: Ludwig Joachim , zu Siederdissen Christian Höner , Liu Zishu , Stadler Peter F , Müller Susann
Published: June 2019

Background

Flow cytometry (FCM) is a powerful single-cell based measurement method to ascertain multidimensional optical properties of millions of cells. FCM is widely used in medical diagnostics and health research. There is also a broad range of applications in the analysis of complex microbial communities. The main concern in microbial community analyses is to track the dynamics of microbial subcommunities. So far, this can be achieved with the help of time-consuming manual clustering procedures that require extensive user-dependent input. In addition, several tools have recently been developed by using different approaches which, however, focus mainly on the clustering of medical FCM data or of microbial samples with a well-known background, while much less work has been done on high-throughput, online algorithms for two-channel FCM.

Results

We bridge this gap with flowEMMi, a model-based clustering tool based on multivariate Gaussian mixture models with subsampling and foreground/background separation. These extensions provide a fast and accurate identification of cell clusters in FCM data, in particular for microbial community FCM data that are often affected by irrelevant information like technical noise, beads or cell debris. flowEMMi outperforms other available tools with regard to running time and information content of the clustering results and provides near-online results and optional heuristics to reduce the running-time further.

Conclusions

flowEMMi is a useful tool for the automated cluster analysis of microbial FCM data. It overcomes the user-dependent and time-consuming manual clustering procedure and provides consistent results with ancillary information and statistical proof.
Spectral Hallmark of Auditory-Tactile Interactions in the Mouse Somatosensory Cortex
Authors: Zhang Manning , Kwon Sung Eun , Ben-Johny Manu , O’Connor Daniel H. , Issa John B.
Published: June 2019

To synthesize a coherent representation of the external world, the brain must integrate inputs across stimulus modalities. Yet the mechanistic basis of this computation at the level of neuronal populations remains obscure. Here, we investigate tactile-auditory integration using two-photon Ca2+ imaging in the mouse primary (S1) and secondary (S2) somatosensory cortices. Pairing sound with whisker stimulation modulates tactile responses in both S1 and S2, with the most prominent modulation being robust inhibition in S2. The degree of inhibition depends on tactile stimulation frequency, with lower frequency responses the most severely attenuated. Alongside these neurons, we identify sound-selective neurons in S2 whose responses are inhibited by high tactile frequencies. These results are consistent with a hypothesized local mutually-inhibitory S2 circuit that spectrally selects tactile versus auditory inputs. Our findings enrich mechanistic understanding of multisensory integration and suggest a key role for S2 in combining auditory and tactile information.
A Novel PHOX/CD38/MCOLN1/TFEB Axis Important For Macrophage Activation During Bacterial Phagocytosis
Authors: Najibi Mehran , Moreau Joseph A. , Honwad Havisha H. , Irazoqui Javier E.
Published: June 2019

Macrophages are a key and heterogenous class of phagocytic cells of the innate immune system, which act as sentinels in peripheral tissues and are mobilized during infection. Macrophage activation in the presence of bacterial cells and molecules entails specific and complex programs of gene expression. How such triggers elicit the gene expression programs is incompletely understood. We previously discovered that transcription factor TFEB is a key contributor to macrophage activation during bacterial phagocytosis. However, the mechanism linking phagocytosis of bacterial cells to TFEB activation remained unknown. In this article, we describe a previously unknown pathway that links phagocytosis with the activation of TFEB and related transcription factor TFE3 in macrophages. We find that phagocytosis of bacterial cells causes an NADPH oxidase (PHOX)-dependent oxidative burst, which activates enzyme CD38 and generates NAADP in the maturing phagosome. Phago-lysosome fusion brings Ca2+ channel TRPML1/MCOLN1 in contact with NAADP, causing Ca2+ efflux from the lysosome, calcineurin activation, and TFEB nuclear import. This drives TFEB-dependent expression of important pro-inflammatory cytokines, such as IL-1α, IL-1β, and IL-6. Thus, our findings reveal that TFEB activation is a key regulatory event for the activation of macrophages. These findings have important implications for infections, cancer, obesity, and atherosclerosis.
Osteopontin and iCD8α cells promote intestinal intraepithelial lymphocyte homeostasis
Authors: Nazmi Ali , Greer Michael J. , Hoek Kristen L. , Piazuelo M. Blanca , Weitkamp Joern-Hendrik , Olivares-Villagómez Danyvid
Published: June 2019

Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses such as survival of Th17 cells and homeostasis of NK cells, among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. Here, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ+, TCRβ+CD4+, TCRβ+CD4+CD8α+and TCRβ+CD8αα+cells in comparison to wild-type mice. For some IEL subpopulations the decrease in cells numbers could be attributed to apoptosis and reduced cell division. Moreover, we showin vitrothat exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL, but not TCRγδ+IEL, TCRβ+IEL or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL.

Key Points

Osteopontin promotes homeostasis of mouse and human IEL, mediated by its ligand CD44

iCD8α cells produce osteopontin which impacts the survival of other IEL

Lack of osteopontin renders mice susceptible to intestinal inflammation
Clinicopathological characteristics and survival of lymphoepithelial carcinoma of the oral cavity and pharynx: a population-based study
Authors: Bai Jinbo , Zhao Fen , Pan Shuang
Published: June 2019

Lymphoepithelial carcinoma (LEC) of the oral cavity and pharynx is uncommon, and the characteristics and survival remains unclear. The present study aims to describe the clinicopathological characteristics and determine the factors associated with survival of this uncommon cancer. A population-based study was carried out to investigate clinical characteristics and prognosis of LEC of the oral cavity and pharynx using the data from Surveillance, Epidemiology and End Results (SEER) database between 1988 and 2013. The propensity-matched analysis was conducted for prognostic analysis, and a prognostic nomogram was also constructed. Totally, 1025 patients with LEC of the oral cavity and pharynx were identified, including 769 nasopharyngeal LEC patients and 256 non-nasopharyngeal LEC patients. The median OS of all LEC patients was 232.0m (95% CI 169.0-258.0). The 1-, 5-, 10- and 20-year survival rates were 92.9%, 72.9%, 59.3%, and 46.8%, respectively. Surgery could significantly prolong the survival time of LEC patients (P<0.01, mOS: 190m vs. 255m). Radiotherapy, as well as radiotherapy after surgery, could prolong the mOS (P<0.01 for both). The survival analysis demonstrated that old age (>60 years), lymph node (N3) and distant metastases were independent factors for poor survival, whereas radiotherapy and surgery were independent factors for favorable survival. No significant differences in survival time between nasopharyngeal LEC and non-nasopharyngeal LEC patients were observed. The prognostic nomogram was established base on five independent prognostic factors (C-index=0.70; 95% CI 0.66-0.74). In conclusion, LEC of the oral cavity and pharynx is a rare disease, and old age, lymph node and distant metastases, surgery and radiotherapy were significantly associated with prognosis. The prognostic nomogram could be used to make individual predictions of OS.
Genomic structure ofHstx2modifier ofPrdm9-dependent hybrid male sterility in mice
Authors: Lustyk Diana , Kinský Slavomír , Ullrich Kristian Karsten , Yancoskie Michelle , Kašíková Lenka , Gergelits Václav , Sedláček Radislav , Chan Yingguang Frank , Odenthal-Hesse Linda , Forejt Jiří , Jansa Petr
Published: June 2019

F1 hybrids between mouse inbred strains PWD and C57BL/6 represent the most thoroughly genetically defined model of hybrid sterility in vertebrates. Hybrid male sterility can be fully reconstituted from three components of this model, namely thePrdm9hybrid sterility gene, intersubspecific homeology ofMus musculus musculusandMus musculus domesticusautosomes, and the X-linkedHstx2locus.Hstx2modulates the extent ofPrdm9-dependent meiotic arrest and harbors two additional genetic factors responsible for intersubspecific introgression-induced oligospermia (Hstx1) and reduced global meiotic recombination rate (Meir1). To facilitate positional cloning and to overcome the recombination suppression within the 4.3 Mb genomicDob interval encompassing theHstx2locus we designedHstx2-CRISPR and SPO11/Cas9 transgenes aimed to induce DNA double-strand breaks specifically within theHstx2locus. The resulting recombinant reduced theHstx2locus to 2.70 Mb (Chr X:66.51-69.21 Mb). The newly definedHstx2still operates as the major X-linked factor of the F1 hybrid sterility, controls meiotic chromosome synapsis, and modifies meiotic recombination rate. Despite extensive further crosses, the 2.70 MbHstx2interval behaved as a recombination cold spot with reduced PRDM9-mediated H3K4 hotspots and absence of DMC1-defined DNA DSB hotspots. To search for structural anomalies as a possible cause of recombination suppression we used optical mapping of theHstx2interval and observed high incidence of subspecies-specific structural variants along the X chromosome, with a striking copy number polymorphism of the microRNAMir465cluster. Finally, we analyzed the role of one of theHstx2candidate genes, the Fmr1 neighbor (Fmr1nb) gene in male fertility.

Article summary

Early meiotic arrest of mouse intersubspecific hybrids depends on the interaction between thePrdm9gene and Hybrid sterility X2 (Hstx2) locus on chromosome X. Lustyk et al. conducted high-resolution genetic and physical mapping of theHstx2locus, reduced it to 2.7 Mb interval within a constitutive recombination cold spot and found that the newly definedHstx2still operates as the X-linked hybrid sterility factor, controls meiotic chromosome synapsis, and modifies recombination rate. Optical mapping of theHstx2genomic region excluded inversion as a cause of recombination suppression and revealed a striking copy number polymorphism of the microRNAMir465cluster.
A Comprehensive Genome-wide and Phenome-wide Examination of BMI and Obesity in a Northern Nevadan Cohort
Authors: Schlauch Karen A. , Read Robert W. , Lombardi Vincent C. , Elhanan Gai , Metcalf William J , Slonim Anthony D. ,   the 23andMe Research Team, Grzymski Joseph J.
Published: June 2019

The aggregation of Election Health Records (EHR) and personalized genetics leads to powerful discoveries relevant to population health. Here we perform genome-wide association studies (GWAS) and accompanying phenome-wide association studies (PheWAS) to validate phenotype-genotype associations of BMI, and to a greater extent, severe Class 2 obesity, using comprehensive diagnostic and clinical data from the EHR database of our cohort. Three GWASs of 500,000 variants on the Illumina platform of 6,645 Healthy Nevada participants identified several published and novel variants that affect BMI and obesity. Each GWAS was followed with two independent PheWASs to examine associations between extensive phenotypes (incidence of diagnoses, condition, or disease), significant SNPs, BMI, and incidence of extreme obesity. The first GWAS excludes DM2-diagnosed individuals and focuses on associations with BMI exclusively. The second GWAS examines the interplay between Type 2 Diabetes (DM2) and BMI. The intersection of significant variants of these two studies is surprising. The third complementary case-control GWAS, with cases defined as extremely obese (Class 2 or 3 obesity), identifies strong associations with extreme obesity, including established variants in theFTOandNEGR1genes, as well as loci not yet linked to obesity. The PheWASs validate published associations between BMI and extreme obesity and incidence of specific diagnoses and conditions, yet also highlight novel links. This study emphasizes the importance of our extensive longitudinal EHR database to validate known associations and identify putative novel links with BMI and obesity.
Extensive Evaluation of Weighted Ensemble Strategies for Calculating Rate Constants and Binding Affinities of Molecular Association/Dissociation Processes
Authors: Pratt A. J. , Suárez Ernesto , Zuckerman Daniel M. , Chong Lillian T.
Published: June 2019

The weighted ensemble (WE) path sampling strategy is highly efficient in generating pathways and rate constants for rare events using atomistic molecular dynamics simulations. Here we extensively evaluated the impact of several advances to the WE strategy on the efficiency of computing association and dissociation rate constants (kon, koff) as well as binding affinities (KD) for a set of benchmark systems, listed in order of increasing timescales of molecular association/dissociation processes: methane/methane, Na+/Cl-, and K+/18-crown-6 ether. In particular, we assessed the advantages of carrying out (i) a large set of “light-weight” WE simulations that each consist of a small number of trajectories vs. a single “heavy-weight” WE simulation that consists of a relatively large number of trajectories, (ii) equilibrium vs. steady-state WE simulations, (iii) history augmented Markov State Model (haMSM) post-simulation analysis of equilibrium sets of trajectories, and (iv) tracking of trajectory history (the state last visited) during the dynamics propagation of equilibrium WE simulations. Provided that state definitions are known in advance, our results reveal that heavy-weight, steady-state WE simulations are the most efficient protocol for calculating kon, koff, and KD values. If states are not strictly defined in advance, heavy-weight, equilibrium WE simulations are the most efficient protocol. This efficiency can be further improved with the inclusion of trajectory history during dynamics propagation. In addition, applying the haMSM post-simulation analysis enhances the efficiency of both steady-state and equilibrium WE simulations. Recommendations of appropriate WE protocols are made according to the goals of the simulations (e.g. to efficiently calculate rate constants and/or generate a diverse set of pathways).
Occurrence of cross-resistance and beta-lactam seesaw effect in glycopeptide, lipopeptide, and lipoglycopeptide-resistant MRSA correlates with membrane phosphatidylglycerol levels
Authors: Hines Kelly M. , Shen Tianwei , Ashford Nate K. , Waalkes Adam , Penewit Kelsi , Holmes Elizabeth A. , McLean Kathryn , Salipante Stephen J. , Werth Brian J. , Xu Libin
Published: June 2019

Treatment of methicillin-resistantStaphylococcus aureus(MRSA) infections is challenging and is associated with high rates of therapeutic failure. The glycopeptide (GP) vancomycin and the lipopeptide (LP) daptomycin are still relied upon to manage invasive MRSA infections; however, resistance to these antibiotics has emerged and there is evidence of cross-resistance between them. It has been observed that the susceptibility of MRSA to beta-lactams increases as susceptibility to GPs and LPs decreases, a phenomenon termed the seesaw effect. Recent efforts to understand the mechanism underlying the seesaw effect have focused on the penicillin binding proteins (PBPs). However, while daptomycin resistance is largely mediated by remodeling of membrane lipid composition, the role of membrane lipids in producing cross-resistance and the seesaw effect has not yet been investigated. Here, we evaluate the lipid profiles, cross susceptibilities, and beta-lactam susceptibilities of a collection of isogenic MRSA strains selected against daptomycin, vancomycin or dalbavancin (a lipoglycopeptide; LGP) to assess the relationship between membrane composition, cross-resistance, and the seesaw effect. We found that modification of membrane composition occurs not only in daptomycin-selected strains, but also vancomycin- and dalbavancin-selected strains. Significantly, we observed that typically the levels of short-chain phosphatidylglycerols (PGs) negatively correlate with MICs of GP/LP/LGP and positively correlate with MIC of certain beta-lactams, the latter being dependent on the primary PBP target of the particular beta-lactam. Furthermore, changes to certain PGs with long-chain fatty acids correlate well with presence of the seesaw effect. These studies demonstrate a major association between membrane remodeling and the seesaw effect.
Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels
Authors: Heyne Henrike O. , Baez-Nieto David , Iqbal Sumaiya , Palmer Duncan , Brunklaus Andreas ,   the Epi25 Collaborative, Johannesen Katrine M. , Lauxmann Stephan , Lemke Johannes R. , Møller Rikke S. , Pérez-Palma Eduardo , Scholl Ute , Syrbe Steffen , Lerche Holger , May Patrick , Lal Dennis , Campbell Arthur J. , Pan Jen , Wang Hao-Ran , Daly Mark J.
Published: June 2019

Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) which is not only corresponding to clinical disease manifestations, but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. Based on known gene-disease-mechanisms, we here infer LOF (518 variants) and GOF (309 variants) of likely pathogenic variants from disease phenotypes of variant carriers. We show regional clustering of inferred GOF and LOF variants, respectively, across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCN/CACNA1 genes. By training a machine learning model on sequence- and structure-based features we predict LOF- or GOF- associated disease phenotypes (ROC = 0.85) of likely pathogenic missense variants. We then successfully validate the GOF versus LOF prediction on 87 functionally tested variants inSCN1/2/8AandCACNA1I(ROC = 0.73) and in exome-wide data from > 100.000 cases and controls. Ultimately, functional prediction of missense variants in clinically relevant genes will facilitate precision medicine in clinical practice.