bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome of renal cell carcinoma in patients on dialysis compared to non‐dialysis patients
Authors: Hayami Noriko , Ubara Yoshifumi , Okaneya Toshikazu , Fujii Takeshi , Nagashima Yoji , Ohashi Kenichi
Published: June 2020

Purpose

To investigate the impact of hemodialysis on survival in renal cell carcinoma (RCC) patients.

Methods

We studied 388 patients who underwent radical or partial nephrectomy for RCC at Toranomon Hospital from 2005 to 2013. Survival curves were drawn according to the Kaplan‐Meier method and compared with the log‐rank test. Multivariate analysis was performed using the Cox proportional hazards regression model to assess the prognostic influence of hemodialysis on cancer‐specific survival.

Result

Of the 388 patients, 66 were on hemodialysis and 322 were not on dialysis. In the hemodialysis patients, incidental diagnosis of RCC was less frequent than in the non‐dialysis patients. In addition, RCC was more likely to be multicentric (41% vs 1.2%), bilateral (14% vs 0.6%), and papillary (18% vs 7%) in hemodialysis patients. Moreover, tumors were smaller, the stage was lower, and the Fuhrman nuclear grade was higher in the patients on hemodialysis. The 5‐year cancer‐specific survival rate was 82.8% for hemodialysis patients and 93.5% for nondialysis patients. Multivariate analysis indicated that hemodialysis, stage, and Fuhrman nuclear grade were independent prognostic factors for RCC.

Conclusions

This study suggested that hemodialysis was an independent prognostic factor for cancer‐specific survival in RCC patients, along with the tumor stage and Fuhrman nuclear grade.
High‐frequency (20 MHz) high‐intensity focused ultrasound: New ablative method for color‐independent tattoo removal in 1‐3 sessions. An open‐label exploratory study
Authors: Serup Jørgen , Bove Torsten , Zawada Tomasz , Jessen Alexander , Poli Mattia
Published: June 2020

Background

High‐intensity focused ultrasound (HIFU) operating at 20 MHz is new and potentially applicable to ablative tattoo removal. The method was documented safe and rational in preclinical testing.

Materials and Methods

High‐intensity focused ultrasound was introduced to subjects when lasers and dermatome shaving had failed or caused side effects. Transducers with focal depths between 1.1 mm and 1.7 mm in the skin were used, and settings of 0.4‐1.2 J/shot at pulse durations of 150 ms were applied. Tattoos were covered with synergistic “shoulder‐by‐shoulder” focused ultrasound shots. Effectiveness and side effects were measured.

Results

Twenty‐two subjects with 67 tattoos were treated. 62% benefitted (19% cleared, 43% partially cleared), and 28% had minor effect. VAS pain was 5‐6 versus 7‐9 with previous lasers removal. Wound healing was longer after HIFU ablation (1‐3 months). 57% of subjects had no scar or minor visible changes of skin surface markings only, while 19% had moderate or major skin thickening. Hypertrophic scar or keloid scars were not observed.

Discussion/Conclusion

High‐intensity focused ultrasound was effective in removal of difficult tattoos of any color where Nd:YAG lasers had failed. The method only needs 1‐3 sessions. As an ablative method, the wound healing period is longer than with laser removal and needs attention. Focused ultrasound can be used as a first‐line treatment of smaller tattoos independent of color, and second line when Nd:YAG lasers have failed or caused problems. The operator shall be qualified, as with lasers.
Reparameterized inverse gamma regression models with varying precision
Authors: Bourguignon Marcelo , Gallardo Diego I.
Published: June 2020

In this article, we propose a mean linear regression model where the response variable is inverse gamma distributed using a new parameterization of this distribution that is indexed by mean and precision parameters. The main advantage of our new parametrization is the straightforward interpretation of the regression coefficients in terms of the expectation of the positive response variable, as usual in the context of generalized linear models. The variance function of the proposed model has a quadratic form. The inverse gamma distribution is a member of the exponential family of distributions and has some distributions commonly used for parametric models in survival analysis as special cases. We compare the proposed model to several alternatives and illustrate its advantages and usefulness. With a generalized linear model approach that takes advantage of exponential family properties, we discuss model estimation (by maximum likelihood), black further inferential quantities and diagnostic tools. A Monte Carlo experiment is conducted to evaluate the performances of these estimators in finite samples with a discussion of the obtained results. A real application using minerals data set collected by Department of Mines of the University of Atacama, Chile, is considered to demonstrate the practical potential of the proposed model.
Homological mirror symmetry for higher-dimensional pairs of pants
Authors: Lekili Yankı , Polishchuk Alexander
Published: June 2020

Using Auroux’s description of Fukaya categories of symmetric products of punctured surfaces, we compute the partially wrapped Fukaya category of the complement of $k+1$ generic hyperplanes in $\mathbb{CP}^{n}$, for $k\geqslant n$, with respect to certain stops in terms of the endomorphism algebra of a generating set of objects. The stops are chosen so that the resulting algebra is formal. In the case of the complement of $n+2$ generic hyperplanes in $\mathbb{C}P^{n}$ ($n$-dimensional pair of pants), we show that our partial wrapped Fukaya category is equivalent to a certain categorical resolution of the derived category of the singular affine variety $x_{1}x_{2}\ldots x_{n+1}=0$. By localizing, we deduce that the (fully) wrapped Fukaya category of the $n$-dimensional pair of pants is equivalent to the derived category of $x_{1}x_{2}\ldots x_{n+1}=0$. We also prove similar equivalences for finite abelian covers of the $n$-dimensional pair of pants.
A kinetic analysis of mouse rod and cone photoreceptor responses
Authors: Reingruber Jürgen , Ingram Norianne T. , Griffis Khris G. , Fain Gordon L.
Published: June 2020

Key points

Most vertebrate eyes have rods for dim‐light vision and cones for brighter light and higher temporal sensitivity.

Rods evolved from cone‐like precursors through expression of different transduction genes or the same genes at different expression levels, but we do not know which molecular differences were most important.

We approached this problem by analysing rod and cone responses with the same model but with different values for model parameters. We showed that, in addition to outer‐segment volume, the most important differences between rods and cones are: (1) decreased transduction gain, reflecting smaller amplification in the G‐protein cascade; (2) a faster rate of turnover of the second messenger cGMP in darkness; and (3) an accelerated rate of decay of the effector enzyme phosphodiesterase and perhaps also of activated visual pigment.

We believe our analysis has identified the principal alterations during evolution responsible for the duplex retina.

Most vertebrates have rod and cone photoreceptors, which differ in their sensitivity and response kinetics. We know that rods evolved from cone‐like precursors through the expression of different transduction genes or the same genes at different levels, but we do not know which molecular differences were most important. We have approached this problem in mouse retina by analysing the kinetic differences between rod flash responses and recent voltage‐clamp recordings of cone flash responses, using a model incorporating the principal features of photoreceptor transduction. We apply a novel method of analysis using the log‐transform of the current, and we ask which of the model's dynamic parameters need be changed to transform the flash response of a rod into that of a cone. The most important changes are a decrease in the gain of the response, reflecting a reduction in amplification of the transduction cascade; an increase in the rate of turnover of cGMP in darkness; and an increase in the rate of decay of activated phosphodiesterase, with perhaps also an increase in the rate of decay of light‐activated visual pigment. Although we cannot exclude other differences, and in particular alterations in the Ca2+ economy of the photoreceptors, we believe that we have identified the kinetic parameters principally responsible for the differences in the flash responses of the two kinds of photoreceptors, which were likely during evolution to have resulted in the duplex retina.
An autocollimator with sub-microradian sensitivity
Authors: Pelle N. , Ehinger L. , Zaug C. R. , Kim W. J.
Published: June 2020

We present a simple autocollimator with sub-microradian sensitivity. To demonstrate the capabilities of our autocollimator, we study the simple harmonic motion of a cantilever beam and apply an external force to affect the cantilever's resonant frequency in the context of dynamic force microscopy. Our setup is ideal for the advanced undergraduate instructional laboratory and allows a variety of high-precision, tabletop experiments.
Investigating a bias for cue preservation in loanword adaptation
Authors: Jaggers Zachary , Baese-Berk Melissa M.
Published: June 2020

Loanword adaptation exhibits a bias favoring sound cue preservation, possibly due to a conservative caution against deleting cues of unsure expendability in a foreign language. This study tests whether listeners are biased to preserve an acoustically ambiguous sound cue in a nonce word framed as originating from a foreign language. Results show the opposite: Listeners are less likely to transcribe an ambiguous sound cue as a phonological segment when the word containing it is framed as a loanword. However, listeners who identify as more open and accommodating to foreign people and languages show relatively more preservation in the loanword condition.
Pandemic vaccines are about to face the real test
Authors: Cohen Jon
Published: June 2020

U.S. and global efforts are taking different approaches to key efficacy trials of candidates.
U.S. academic research funding stays healthy despite pandemic
Authors: Mervis Jeffrey
Published: June 2020

Labs reopening even as campuses struggle.
New tensions dim hopes for salvaging Iran nuclear deal
Authors: Stone Richard
Published: June 2020

Monitoring agency seeks clarity about clandestine R&D.
Meissner corpuscles and their spatially intermingled afferents underlie gentle touch perception
Authors: Neubarth Nicole L. , Emanuel Alan J. , Liu Yin , Springel Mark W. , Handler Annie , Zhang Qiyu , Lehnert Brendan P. , Guo Chong , Orefice Lauren L. , Abdelaziz Amira , DeLisle Michelle M. , Iskols Michael , Rhyins Julia , Kim Soo J. , Cattel Stuart J. , Regehr Wade , Harvey Christopher D. , Drugowitsch Jan , Ginty David D.
Published: June 2020

Secrets of Meissner corpuscles

The Meissner corpuscle, a mechanosensory end organ, was discovered more than 165 years ago and has since been found in the glabrous skin of all mammals, including that on human fingertips. Although prominently featured in textbooks, the function of the Meissner corpuscle is unknown. Neubarth
et al.
generated adult mice without Meissner corpuscles and used them to show that these corpuscles alone mediate behavioral responses to, and perception of, gentle forces (see the Perspective by Marshall and Patapoutian). Each Meissner corpuscle is innervated by two molecularly distinct, yet physiologically similar, mechanosensory neurons. These two neuronal subtypes are developmentally interdependent and their endings are intertwined within the corpuscle. Both Meissner mechanosensory neuron subtypes are homotypically tiled, ensuring uniform and complete coverage of the skin, yet their receptive fields are overlapping and offset with respect to each other.

Science
, this issue p.
eabb2751
; see also p.
1311
Direct reversible decarboxylation from stable organic acids in dimethylformamide solution
Authors: Kong Duanyang , Moon Patrick J. , Lui Erica K. J. , Bsharat Odey , Lundgren Rylan J.
Published: June 2020

Simple swaps of CO
2

The loss of carbon dioxide (CO
2
) from carboxylic acids is a common reaction in both biochemical and synthetic contexts, but it has generally involved catalysis or prolonged heating. Kong
et al.
now report that certain polar solvents, such as dimethylformamide, promote reversible CO
2
loss all by themselves from carboxylates bridged by one carbon to aromatic rings. With electron-withdrawing substituents on the ring, isotopically labeled CO
2
can be efficiently swapped in even at room temperature. Alternatively, reaction with aldehydes leads to alcohol formation.

Science
, this issue p.
557
Drug modulation by nuclear condensates
Authors: Viny Aaron D. , Levine Ross L.
Published: June 2020

Concentration of antineoplastic agents into spatial compartments influences activity
COVID-19 and cancer
Authors: Sharpless Norman E.
Published: June 2020

With the spread of coronavirus disease 2019 (COVID-19), countries and states have instituted lockdowns. These decisions have been difficult and are sometimes described as benefiting the public health at the expense of the economy. Fear of contracting the coronavirus in health care settings has dissuaded people from screening, diagnosis, and treatment for non–COVID-19 diseases. The consequences for cancer outcomes, for example, could be substantial. What can be done to minimize this effect?
Microampere Electric Current Causes Bacterial Membrane Damage and Two-Way Leakage in a Short Period of Time
Authors: Krishnamurthi Venkata Rao , Rogers Ariel , Peifer Janet , Niyonshuti Isabelle I. , Chen Jingyi , Wang Yong
Published: June 2020

Although electric voltage and current have been studied for a long time in terms of their ability to suppress the growth of bacteria and to kill bacteria, increasing interest has been aroused more recently due to the prevalence of antibiotic resistance of microbes in past decades. Toward understanding the antimicrobial mechanism of low electric voltage and current, previous studies showed that treating bacteria with milliampere electric currents (≥5 mA) for ≥72 h led to significant damage of the bacterial membrane, which likely resulted in leakage of cellular contents and influx of toxic substances through the damaged membrane. However, it remains unclear to what extent membrane damage and two-way (i.e., inward and outward) leakage are caused by lower (i.e., microampere) electric current in a shorter time frame. In this work, we set out to answer this question. We observed that the membrane damage was caused by microampere electric current in half an hour, which allowed two-way leakage of ions, small molecules, and proteins.
Can the Cecal Ligation and Puncture Model Be Repurposed To Better Inform Therapy in Human Sepsis?
Authors: Alverdy John C. , Keskey Robert , Thewissen Renee
Published: June 2020

A recent report by the National Institutes of Health on sepsis research has implied there is a trend to move away from mouse models of sepsis. The most commonly used animal model to study the pathogenesis of human sepsis is cecal ligation and puncture (CLP) in mice. The model has been the mainstay of sepsis research for decades and continues to be considered the gold standard to inform novel pathways of sepsis physiology and its therapeutic direction. As there have been many criticisms of the model, particularly regarding its relevance to human disease, how this model might be repurposed to be more reflective of the human condition begs discussion.
A Novel Approach To Display Structural Proteins of Hepatitis C Virus Quasispecies in Patients Reveals a Key Role of E2 HVR1 in Viral Evolution
Authors: Tong Yimin , Li Qingchao , Li Rui , Xu Yongfen , Pan Yu , Niu Junqi , Zhong Jin
Published: June 2020

A cell culture model that can recapitulate the diversity of HCV quasispecies in patients is important for analysis of neutralizing epitopes and HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on
trans
-complementation of viral structural proteins (HCVΔS). This system can be used to display structural proteins of HCV strains of multiple genotypes as well as clinical isolates. By using this system, we showed that multiple different HCV structural proteins from a same patient were displayed on HCVΔS. Interestingly, these variant structural proteins within the same patient can be classified according to the sequence of HVR1in E2, which dictates viral sensitivity to nAbs and viral evolution
in vivo
. Our work provided a new tool to study highly divergent HCV quasispecies and shed light on underlying mechanisms driving HCV evolution.
Investigating the formation of the Cretaceous Western Interior Seaway using landscape evolution simulations
Authors: Chang Ching , Liu Lijun
Published: June 2020

Transient intraplate sedimentation like the widespread Late Cretaceous Western Interior Seaway, traditionally considered a flexural foreland basin of the Sevier orogeny, is now generally accepted to be a result of dynamic topography due to the viscous force from mantle downwelling. However, the relative contributions of flexural versus dynamic subsidence are poorly understood. Furthermore, both the detailed subsidence history and the underlying physical mechanisms remain largely unconstrained. Here, we considered both Sevier orogenic loading and three different dynamic topography models that correspond to different geodynamic configurations. We used forward landscape evolution simulations to investigate the surface manifestations of these tectonic scenarios on the regional sedimentation history. We found that surface processes alone are unable to explain Western Interior Seaway sedimentation in a purely orogenic loading system, and that sedimentation increases readily inland with the additional presence of dynamic subsidence. The findings suggest that dynamic subsidence was crucial to Western Interior Seaway formation and that the dominant control on sediment distribution in the Western Interior Seaway transitioned from flexural to dynamic subsidence during 90–84 Ma, coinciding with the proposed emplacement of the conjugate Shatsky oceanic plateau. Importantly, the sedimentation records require the underlying dynamic subsidence to have been landward migratory, which implies that the underlying mechanism was the regional-scale mantle downwelling induced by the sinking Farallon flat slab underneath the westward-moving North American plate. The simulated landscape evolution also implies that prominent regional-scale Laramide uplift in the western United States should have occurred no earlier than the latest Cretaceous.
Electronic symptom monitoring in patients with metastatic lung cancer: a feasibility study
Authors: Friis Rasmus Blechingberg , Hjollund Niels Henrik , Mejdahl Caroline Trillingsgaard , Pappot Helle , Skuladottir Halla
Published: June 2020

Objectives

To design an electronic questionnaire for symptom monitoring and to evaluate the feasibility, usability and acceptability when applied to patients with metastatic lung cancer.

Setting

Single-centre feasibility study.

Participants

Patients with stage IV lung cancer in antineoplastic treatment.

Interventions

This study describes the first three phases of a complex intervention design: phase 1, development of the intervention; phase 2, feasibility testing and phase 3, evaluation of the intervention. In phase 1, items were selected for the questionnaire and adjusted following patient interviews. In phase 2, patients completed the electronic questionnaire weekly during a 3-week feasibility test. In case of symptom deterioration, a nurse was notified with the aim to contact the patient. In phase 3, patients evaluated phase 2 by paper questionnaires, and interviews were conducted with the participating nurses.

Primary outcome measures

The study outcomes: phase 1, usability and relevance; phase 2, recruitment rate, compliance and threshold functionality and phase 3, usability, acceptability and relevance.

Results

In phase 1, a questionnaire was designed and reviewed by patients (n=8). The interviews revealed high usability and relevance of the intervention.

For phases 2 and 3, 20 of 29 approached patients (69%) responded to the questionnaire on a weekly basis. Two patients did not complete any questionnaires (compliance 90%). The remaining 18 patients completed 65 of a total of 72 possible questionnaires (7 missed, 93% completed). Reported symptoms led to a phone call from a nurse in 30% of the responses.

The patients reported high usability and acceptability of questionnaire and software. The substance of the telephonic conversations was relevant, and the study set-up was logistically acceptable.

Conclusions

An electronic questionnaire designed for symptom monitoring revealed high usability, acceptability and relevance in the target population. In conclusion, the study set-up was considered feasible for a randomised controlled trial.

Trial registration number

NCT03529851.
Accuracy of lung ultrasonography in the hands of non-imaging specialists to diagnose and assess the severity of community-acquired pneumonia in adults: a systematic review
Authors: Strøm Julie Jepsen , Haugen Pia Sperling , Hansen Malene Plejdrup , Graumann Ole , Jensen Martin Bach B , Aakjær Andersen Camilla
Published: June 2020

Objectives

We aimed to systematically review the published literature regarding adults with clinical suspicion of pneumonia that compares the accuracy of lung ultrasonography (LUS) performed by non-imaging specialists to other reference standards in diagnosing and evaluating the severity of community-acquired pneumonia. Moreover, we aimed to describe LUS training and the speciality of the physician performing LUS, time spent on the LUS procedure and potential harms to patients.

Materials and methods

We searched MEDLINE, Embase, CINAHL, Web of Science and Cochrane Central Register of Controlled Trials up until May 2019. We included studies that used LUS to diagnose pneumonia, but also confirmed pneumonia by other means. Publications were excluded if LUS was performed by a sonographer or radiologist (imaging specialists) or performed on other indications than suspicion of pneumonia. Two review authors screened and selected articles, extracted data and assessed quality using Quality Assessment of Diagnostic Accuracy Studies 2.

Results

We included 17 studies. The sensitivity of LUS to diagnose pneumonia ranged from 0.68 to 1.00; however, in 14 studies, sensitivity was ≥0.91. Specificities varied from 0.57 to 1.00. We found no obvious differences between studies with low and high diagnostic accuracy. The non-imaging specialists were emergency physicians, internal medicine physicians, intensivists or ‘speciality not described’. Five studies described LUS training, which varied from a 1-hour course to fully credentialed ultrasound education. In general, the methodological quality of studies was good, though, some studies had a high risk of bias.

Conclusion

We found significant heterogeneity across studies. In the majority of studies, LUS in the hands of the non-imaging specialists demonstrated high sensitivities and specificities in diagnosing pneumonia. However, due to problems with methodology and heterogeneity there is a need for larger studies with uniform and clearly established criteria for diagnosis and blinding.

PROSPERO registration number

Prospectively registered in PROSPERO (CRD42017057804).
Compliance of smokeless tobacco supply chain actors and products with tobacco control laws in Bangladesh, India and Pakistan: protocol for a multicentre sequential mixed-methods study
Authors: Khan Zohaib , Huque Rumana , Sheikh Aziz , Readshaw Anne , Eckhardt Jappe , Jackson Cath , Kanaan Mona , Iqbal Romaina , Akhter Zohaib , Garg Suneela , Singh Mongjam Meghachandra , Ahmad Fayaz , Abdullah S M , Javaid Arshad , A Khan Javaid , Han Lu , Rahman Aziz , Siddiqi Kamran
Published: June 2020

Introduction

South Asia is home to more than 300 million smokeless tobacco (ST) users. Bangladesh, India and Pakistan as signatories to the Framework Convention for Tobacco Control (FCTC) have developed policies aimed at curbing the use of tobacco. The objective of this study is to assess the compliance of ST point-of-sale (POS) vendors and the supply chain with the articles of the FCTC and specifically with national tobacco control laws. We also aim to assess disparities in compliance with tobacco control laws between ST and smoked tobacco products.

Methods and analysis

The study will be carried out at two sites each in Bangladesh, India and Pakistan. We will conduct a sequential mixed-methods study with five components: (1) mapping of ST POS, (2) analyses of ST samples packaging, (3) observation, (4) survey interviews of POS and (5) in-depth interviews with wholesale dealers/suppliers/manufacturers of ST. We aim to conduct at least 300 POS survey interviews and observations, and 6–10 in-depth interviews in each of the three countries. Data collection will be done by trained data collectors. The main statistical analysis will report the frequencies and proportions of shops that comply with the FCTC and local tobacco control policies, and provide a 95% CI of these estimates. The qualitative in-depth interview data will be analysed using the framework approach. The findings will be connected, each component informing the focus and/or design of the next component.

Ethics and dissemination

Ethical approvals for the study have been received from the Health Sciences Research Governance Committee at the University of York, UK. In-country approvals were taken from the National Bioethics Committee in Pakistan, the Bangladesh Medical Research Council and the Indian Medical Research Council. Our results will be disseminated via scientific conferences, peer-reviewed research publications and press releases.
FcγRII (CD32) modulates antibody clearance in NOD SCID mice leading to impaired antibody-mediated tumor cell deletion
Authors: Oldham Robert J , Mockridge C Ian , James Sonya , Duriez Patrick J , Chan H T Claude , Cox Kerry L , Pitic Vicentiu A , Glennie Martin J , Cragg Mark S
Published: June 2020

Background

Immune compromised mice are increasingly used for the preclinical development of monoclonal antibodies (mAb). Most common are non-obese diabetic (NOD) severe combined immunodeficient (SCID) and their derivatives such as NOD SCID interleukin-2 γ-/- (NSG), which are attractive hosts for patient-derived xenografts. Despite their widespread use, the relative biological performance of mAb in these strains has not been extensively studied.

Methods

Clinically relevant mAb of various isotypes were administered to tumor and non-tumor-bearing SCID and NOD SCID mice and the mAb clearance monitored by ELISA. Expression analysis of surface proteins in both strains was carried out by flow cytometry and immunofluorescence microscopy. Further analysis was performed in vitro by surface plasmon resonance to assess mAb affinity for Fcγ receptors (FcγR) at pH 6 and pH 7.4. NOD SCID mice genetically deficient in different FcγR were used to delineate their involvement.

Results

Here, we show that strains on the NOD SCID background have significantly faster antibody clearance than other strains leading to reduced antitumor efficacy of clinically relevant mAb. This rapid clearance is dependent on antibody isotype, the presence of Fc glycosylation (at N297) and expression of FcγRII. Comparable effects were not seen in the parental NOD or SCID strains, demonstrating the presence of a compound defect requiring both genotypes. The absence of endogenous IgG was the key parameter transferred from the SCID as reconstituting NOD SCID or NSG mice with exogenous IgG overcame the rapid clearance and recovered antitumor efficacy. In contrast, the NOD strain was associated with reduced expression of the neonatal Fc Receptor (FcRn). We propose a novel mechanism for the rapid clearance of certain mAb isotypes in NOD SCID mouse strains, based on their interaction with FcγRII in the context of reduced FcRn.

Conclusions

This study highlights the importance of understanding the limitation of the mouse strain being used for preclinical evaluation, and demonstrates that NOD SCID strains of mice should be reconstituted with IgG prior to studies of mAb efficacy.
Distinctive germline expression of class I human leukocyte antigen (HLA) alleles and DRB1 heterozygosis predict the outcome of patients with non-small cell lung cancer receiving PD-1/PD-L1 immune checkpoint blockade
Authors: Correale Pierpaolo , Saladino Rita Emilena , Giannarelli Diana , Giannicola Rocco , Agostino Rita , Staropoli Nicoletta , Strangio Alessandra , Del Giudice Teresa , Nardone Valerio , Altomonte Maria , Pastina Pierpaolo , Tini Paolo , Falzea Antonia Consuelo , Imbesi Natale , Arcati Valentina , Romeo Giuseppa , Caracciolo Daniele , Luce Amalia , Caraglia Michele , Giordano Antonio , Pirtoli Luigi , Necas Alois , Amler Evzen , Barbieri Vito , Tassone Pierfrancesco , Tagliaferri Pierosandro
Published: June 2020

Background

Nivolumab is a human monoclonal antibody against programmed cell death receptor-1 (PD-1) able to rescue quiescent tumor infiltrating cytotoxic T lymphocytes (CTLs) restoring their ability to kill target cells expressing specific tumor antigen-derived epitope peptides bound to homologue human leukocyte antigen (HLA) molecules. Nivolumab is currently an active but expensive therapeutic agent for metastatic non-small cell lung cancer (mNSCLC), producing, in some cases, immune-related adverse events (irAEs). At the present, no reliable biomarkers have been validated to predict either treatment response or adverse events in treated patients.

Methods

We performed a retrospective multi-institutional analysis including 119 patients with mNSCLC who received PD-1 blockade since November 2015 to investigate the predictive role of germinal class I HLA and DRB1 genotype. We investigated the correlation among patients’ outcome and irAEs frequency with specific HLA A, B, C and DRB1 alleles by reverse sequence-specific oligonucleotide (SSO) DNA typing.

Results

A poor outcome in patients negative for the expression of two most frequent HLA-A alleles was detected (HLA: HLA-A*01 and or A*02; progression-free survival (PFS): 7.5 (2.8 to 12.2) vs 15.9 (0 to 39.2) months, p=0.01). In particular, HLA-A*01-positive patients showed a prolonged PFS of 22.6 (10.2 to 35.0) and overall survival (OS) of 30.8 (7.7 to 53.9) months, respectively. We also reported that HLA-A and DRB1 locus heterozygosis (het) were correlated to a worse OS if we considered het in the locus A; in reverse, long survival was correlated to het in DRB1.

Conclusions

This study demonstrate that class I and II HLA allele characterization to define tumor immunogenicity has relevant implications in predicting nivolumab efficacy in mNSCLC and provide the rationale for further prospective trials of cancer immunotherapy.
Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing
Authors: Rischin Danny , Migden Michael R , Lim Annette M , Schmults Chrysalyne D , Khushalani Nikhil I , Hughes Brett G M , Schadendorf Dirk , Dunn Lara A , Hernandez-Aya Leonel , Chang Anne Lynn S , Modi Badri , Hauschild Axel , Ulrich Claas , Eigentler Thomas , Stein Brian , Pavlick Anna C , Geiger Jessica L , Gutzmer Ralf , Alam Murad , Okoye Emmanuel , Mathias Melissa , Jankovic Vladimir , Stankevich Elizabeth , Booth Jocelyn , Li Siyu , Lowy Israel , Fury Matthew G , Guminski Alexander
Published: June 2020

Background

Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498).

Methods

The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability.

Results

For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%).

Conclusion

In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses.

Trial registration number

Clinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498
Cancer Moonshot Immuno-Oncology Translational Network (IOTN): accelerating the clinical translation of basic discoveries for improving immunotherapy and immunoprevention of cancer
Authors: Annapragada Ananth , Sikora Andrew , Bollard Catherine , Conejo-Garcia Jose , Cruz Conrad Russell , Demehri Shadmehr , Demetriou Michael , Demirdjian Levon , Fong Lawrence , Horowitz Mary , Hutson Alan , Kadash-Edmondson Kathryn , Kufe Donald , Lipkin Steven , Liu Song , McCarthy Claire , Morgan Martin , Morris Zachary , Pan Yang , Pasquini Marcelo , Schoenberger Stephen , Van Allen Eliezer , Vilar Eduardo , Xing Yi , Zha Wenjuan ,   the IOTN Consortium, Odunsi Adekunle
Published: June 2020

Despite regulatory approval of several immune-based treatments for cancer in the past decade, a number of barriers remain to be addressed in order to fully harness the therapeutic potential of the immune system and provide benefits for patients with cancer. As part of the Cancer Moonshot initiative, the Immuno-Oncology Translational Network (IOTN) was established to accelerate the translation of basic discoveries to improve immunotherapy outcomes across the spectrum of adult cancers and to develop immune-based approaches that prevent cancers before they occur. The IOTN currently consists of 32 academic institutions in the USA. By leveraging cutting-edge preclinical research in immunotherapy and immunoprevention, open data and resource sharing, and fostering highly collaborative team science across the immuno-oncology ecosystem, the IOTN is designed to accelerate the generation of novel mechanism-driven immune-based cancer prevention and therapies, and the development of safe and effective personalized immuno-oncology approaches.
Chronic immune checkpoint inhibitor pneumonitis
Authors: Naidoo Jarushka , Cottrell Tricia R , Lipson Evan J , Forde Patrick M , Illei Peter B , Yarmus Lonny B , Voong K Ranh , Feller-Kopman David , Lee Hans , Riemer Joanne , Wang Daphne , Taube Janis M , Brahmer Julie R , Lin Cheng Ting , Danoff Sonye K , D'Alessio Franco R , Suresh Karthik
Published: June 2020

Background

Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4–6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression.

Methods

Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available.

Results

Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0–50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3–12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16–43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper.

Conclusions

A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.
Smouldering ashes: burning questions after the outbreak of electronic cigarette or vaping-associated lung injury (EVALI)
Authors: Xantus Gabor Zoltan , Gyarmathy Anna V , Johnson Carole Ann
Published: June 2020

In the summer of 2019, the Center for Disease Control and Prevention (CDC) declared an emergency of electronic cigarettes and/or vaping (vaping)-associated lung injury (EVALI) in the USA. The outbreak abated by January 2020, which the CDC attributed to heightened public awareness, ‘user actions to reduce risk’ and potentially the removal of vitamin E acetate (VEA) from vaping products (VEA is an oily chemical cutting agent, strongly associated with the disease). Even though the EVALI outbreak appears to be over, numerous epidemiological and medical questions are left still open. First, why were there practically no cases outside the USA, which represents nearly a quarter of the global vaping market? Comparative studies to map the differences in device/fluids/user habits between countries might be needed urgently. Second, what is the pathomechanism that sickens vapers irrespective of VEA exposure? VEA was only confirmed in about half of the cases and the presumed toxicity is yet to be determined. Aetiology/epidemiology focused research is needed to investigate/interpret the broader context to explain the outbreak. Third, could any socioeconomic/environmental factors have influenced the course of the outbreak? Finally, what should we expect in the years to come? Was EVALI a serious but reversible emergency medicine condition or is vaping as detrimental to long-term health as smoking? Besides the complex legislative, regulatory, ethical aspects of EVALI, biomedical research is also difficult: in-vitro experiments have limited inferential value to real real-life vaping due to its complexity; user habits are self-reported and under-researched; there is an active black market pouring unknown quality counterfeit products and, in the USA, federal restrictions limit cannabis research. Vaping is a toxicological, multidimensional conundrum; therefore, stringent quality control, transparent legal/ethical boundaries, meticulous international research and user education are paramount to prevent potential future outbreaks and determine the parameters safe vaping (if these exist).
Cosmological constant, Planck mass, Hubble mass, and axion: a relation through higher-order loops Coleman–Weinberg potential with Weinberg–Landau gauge
Authors: El-Nabulsi Rami Ahmad
Published: June 2020

In this communication, a conformal coupling gravity is discussed in the presence of a complex Coleman–Weinberg potential, which is generated from the contributions from first-, second-, and all higher-order loops. A relation between the cosmological constant, the Hubble mass, and the Higgs vacuum energy is obtained in particular when Weinberg–Landau gauge is used. Moreover, it was observed that the removal of the logarithmic mass boosts the scalar mass from Hubble mass of order 10–33 eV to 2.47 × 10–3 eV, which is comparable to the mass of non-baryonic cold dark matter or axion based on recent observations and which constitutes about 84% of all matter in the Universe.
A first assessment of microplastics and other anthropogenic particles in Hudson Bay and the surrounding eastern Canadian Arctic waters of Nunavut
Authors: Huntington Aimee , Corcoran Patricia L. , Jantunen Liisa , Thaysen Clara , Bernstein Sarah , Stern Gary A. , Rochman Chelsea M.
Published: June 2020

Microplastics are a globally ubiquitous contaminant, invading the most remote regions, including the Arctic. To date, our understanding of the distribution and sources of microplastics in the Arctic is limited but growing. This study aims to advance our understanding of microplastics in the Arctic. Surface water, zooplankton, sediment, and snow samples were collected from Hudson Bay to north Baffin Bay onboard the CCGS Amundsen from July to August 2017. Samples were examined for microplastics, which were chemically identified via Raman spectroscopy for surface water and zooplankton and Fourier transform infrared spectroscopy for sediment. We found that 90% of surface water and zooplankton samples, and 85% of sediment samples, contained microplastics or other anthropogenic particles. Mean anthropogenic particle concentrations, which includes microplastics, were 0.22 ± 0.23 (per litre) for surface water, 3.51 ± 4.00 (per gram) for zooplankton, and 1.94 ± 4.12 (per gram) for sediment. These concentrations were not related to the human populations upstream, suggesting that microplastic contamination in the Arctic is from long-range transport. Overall, this study highlights the presence of microplastics across the eastern Canadian Arctic, in multiple media, and offers evidence of long-range transport via ocean and atmospheric currents. Further research is needed to better understand sources, distribution, and effects to Arctic ecosystems.
Recollements of stable categories of Gorenstein injective modules
Authors: Wang Zhanping , Mu Ting , Wang Xiaomei
Published: June 2020

Let [Formula: see text] and [Formula: see text] be rings, [Formula: see text] a [Formula: see text]-bimodule and [Formula: see text] be a triangular matrix ring. We first give an explicit description for Gorenstein injective [Formula: see text]-modules over the triangular matrix ring [Formula: see text], and then construct a (right) recollement of stable categories of Gorenstein injective modules.
A domain-specific supercomputer for training deep neural networks
Authors: Jouppi Norman P. , Yoon Doe Hyun , Kurian George , Li Sheng , Patil Nishant , Laudon James , Young Cliff , Patterson David
Published: June 2020

Google's TPU supercomputers train deep neural networks 50x faster than general-purpose supercomputers running a high-performance computing benchmark.
Destruction, Catharsis, and Emotional Release in Human-Robot Interaction
Authors: Luria Michal , Sheriff Ophir , Boo Marian , Forlizzi Jodi , Zoran Amit
Published: June 2020

The intersection between social, technical, and economic factors biases new product development to focus on utilitarian value. However, objects that serve alternative goals, behaviors and emotions have accompanied humankind for millennia. This article speculates about robotic objects for one non-utilitarian behavior and its implications: destruction. Robots and objects for destruction have a shared history of embodiment and heavily rely on their embodiment for interaction. Yet the topic of destruction is not very common in the field of human-robot interaction (HRI). Thus, we (1) present a survey of ethnographic investigations that show modes of HRI related to destruction, and (2) develop speculative concepts of interaction that demonstrate these ideas in HRI. By exemplifying a broad range of speculative uses of destruction in HRI and grounding it in literature, we hope this theoretical and conceptual article will bring a fresh perspective on alternative interactions with robots.
Personalized Query Auto-Completion for Large-Scale POI Search at Baidu Maps
Authors: Li Ying , Huang Jizhou , Fan Miao , Lei Jinyi , Wang Haifeng , Chen Enhong
Published: June 2020

Query auto-completion (QAC) is a featured function that has been widely adopted by many sub-domains of search. It can dramatically reduce the number of typed characters and avoid spelling mistakes. These merits of QAC are highlighted to improve user satisfaction, especially when users intend to type in a query on mobile devices. In this article, we will present our industrial solution to the personalized QAC for the point of interest (POI) search at Baidu Maps, a well-known Web mapping service on mobiles in China. The industrial solution makes a good tradeoff between the offline effectiveness of a novel neural learning model that we devised for feature generation and the online efficiency of an off-the-shelf learning to rank (LTR) approach for the real-time suggestion. Besides some practical lessons from how a real-world QAC system is built and deployed in Baidu Maps to facilitate a large number of users in searching tens of millions of POIs, we mainly explore two specific features for the personalized QAC function of the POI search engine:
the spatial-temporal characteristics of POIs
and
the historically queried POIs of individual users
.

We leverage the large-volume POI search logs in Baidu Maps to conduct offline evaluations of our personalized QAC model measured by multiple metrics, including Mean Reciprocal Rank (MRR), Success Rate (SR), and normalized Discounted Cumulative Gain (nDCG). Extensive experimental results demonstrate that the personalized model enhanced by the proposed features can achieve substantial improvements (i.e., +3.29% MRR, +3.78% SR@1, +5.17% SR@3, +1.96% SR@5, and +3.62% nDCG@5). After deploying this upgraded model into the POI search engine at Baidu Maps for A/B testing online, we observe that some other critical indicators, such as the average number of keystrokes and the average typing speed at keystrokes in a QAC session, which are also related to user satisfaction, decrease as well by 1.37% and 1.69%, respectively. So the conclusion is that the two kinds of features contributed by us are quite helpful in personalized mapping services for industrial practice.