bluuebunny/crossref_metadata_2025 huggingface dataset:
Transmission of Hepatitis B and D Viruses in an African Rural Community
Authors: Pinho-Nascimento Carlos Augusto , Bratschi Martin W. , Höfer Rene , Soares Caroline Cordeiro , Warryn Louisa , Pečerska Jūlija , Minyem Jacques C. , Paixão Izabel C. N. P. , Baroni de Moraes Marcia Terezinha , Um Boock Alphonse , Niel Christian , Pluschke Gerd , Röltgen Katharina
Published: September 2018

This study revealed that the prevalence of HBV and HDV in a rural area of Cameroon is extremely high, underlining the pressing need for the improvement of control strategies. Systematic serological and phylogenetic analyses of HBV sequences turned out to be useful tools to identify networks of virus transmission within and between households. The high HBsAg carriage rate found among children demonstrates that implementation of the HBV birth dose vaccine and improvement of vaccine coverage will be key elements in preventing both HBV and HDV infections. In addition, the high HBsAg carriage rate in adolescents and adults emphasizes the need for identification of chronically infected individuals and linkage to WHO-recommended treatment to prevent progression to liver cirrhosis and hepatocellular carcinoma.
Neurocognitive and mental health outcomes and association with quality of life among adults living with HIV: a cross-sectional focus on a low-literacy population from coastal Kenya
Authors: Nyongesa Moses Kachama , Mwangala Patrick N , Mwangi Paul , Kombe Martha , Newton Charles R J C , Abubakar Amina A
Published: September 2018

Objectives

Our aim was to compare the neurocognitive performance and mental health outcome of adults living with HIV on antiretroviral therapy with that of community controls, all of low literacy. Furthermore, we also wanted to explore the relationship of these outcomes with quality of life among adults living with HIV.

Study design

This was a descriptive cross-sectional study.

Setting

The study was conducted in Kilifi County, a region located at the Kenyan coast.

Participants

The participants consisted of a consecutive sample of 84 adults living with HIV and 83 randomly selected community controls all with ≤8 years of schooling. All participants were assessed for non-verbal intelligence, verbal working memory and executive functioning. The Major Depression Inventory and a quality of life measure (RAND SF-36) were also administered.

Results

Using analysis of covariance, we found no statistically significant group differences between adults living with HIV and community controls in all the neurocognitive tests except for a marginal difference in the non-verbal intelligence test (F (1, 158)=3.83, p=0.05). However, depressive scores of adults living with HIV were significantly higher than those of controls (F (1, 158)=11.56, p<0.01). Also, quality of life scores of adults living with HIV were significantly lower than those of controls (F (1, 158)=4.62, p=0.03). For the HIV-infected group, results from multivariable linear regression analysis showed that increasing depressive scores were significantly associated with poorer quality of life (β=−1.17, 95% CI −1.55 to –0.80; p<0.01).

Conclusion

Our findings suggest that adults of low-literacy levels living with HIV and on antiretroviral medication at the Kenyan coast do not have significant cognitive deficits compared with their uninfected counterparts. However, their mental health, compared with that of HIV-uninfected adults, remains poorer and their quality of life may deteriorate when HIV and depressive symptoms co-occur.
Atrial fibrillation detection using single lead portable electrocardiographic monitoring: a systematic review and meta-analysis
Authors: Ramkumar Satish , Nerlekar Nitesh , D’Souza Daniel , Pol Derek J , Kalman Jonathan M , Marwick Thomas H
Published: September 2018

Objectives

Recent technology advances have allowed for heart rhythm monitoring using single-lead ECG monitoring devices, which can be used for early diagnosis of atrial fibrillation (AF). We sought to investigate the AF detection rate using portable ECG devices compared with Holter monitoring.

Setting, participants and outcome measures

We searched the Medline, Embase and Scopus databases (conducted on 8 May 2017) using search terms related to AF screening and included studies with adults aged >18 years using portable ECG devices or Holter monitoring for AF detection. We excluded studies using implantable loop recorders and pacemakers. Using a random-effects model we calculated the overall AF detection rate. Meta-regression analysis was performed to explore potential sources for heterogeneity. Quality of reporting was assessed using the tool developed by Downs and Black.

Results

Portable ECG monitoring was used in 18 studies (n=117 436) and Holter monitoring was used in 36 studies (n=8498). The AF detection rate using portable ECG monitoring was 1.7% (95% CI 1.4 to 2.1), with significant heterogeneity between studies (p<0.001). There was a moderate linear relationship between total monitoring time and AF detection rate (r=0.65, p=0.003), and meta-regression identified total monitoring time (p=0.005) and body mass index (p=0.01) as potential contributors to heterogeneity. The detection rate (4.8%, 95% CI 3.6% to 6.0%) in eight studies (n=10 199), which performed multiple ECG recordings was comparable to that with 24 hours Holter (4.6%, 95% CI 3.5% to 5.7%). Intermittent recordings for 19 min total produced similar AF detection to 24 hours Holter monitoring.

Conclusion

Portable ECG devices may offer an efficient screening option for AF compared with 24 hours Holter monitoring.

PROSPERO registration number

CRD42017061021.
What can patients tell us about the quality and safety of hospital care? Findings from a UK multicentre survey study
Authors: O’Hara Jane K , Reynolds Caroline , Moore Sally , Armitage Gerry , Sheard Laura , Marsh Claire , Watt Ian , Wright John , Lawton Rebecca
Published: September 2018

Background

Patient safety measurement remains a global challenge. Patients are an important but neglected source of learning; however, little is known about what patients can add to our understanding of safety. We sought to understand the incidence and nature of patient-reported safety concerns in hospital.

Methods

Feedback about the experience of safety within hospital was gathered from 2471 inpatients as part of a multicentre, waitlist cluster randomised controlled trial of an intervention, undertaken within 33 wards across three English NHS Trusts, between May 2013 and September 2014. Patient volunteers, supported by researchers, developed a classification framework of patient-reported safety concerns from a random sample of 231 reports. All reports were then classified using the patient-developed categories. Following this, all patient-reported safety concerns underwent a two-stage clinical review process for identification of patient safety incidents.

Results

Of the 2471 inpatients recruited, 579 provided 1155 patient-reported incident reports. 14 categories were developed for classification of reports, with communication the most frequently occurring (22%), followed by staffing issues (13%) and problems with the care environment (12%). 406 of the total 1155 patient incident reports (35%) were classified by clinicians as a patient safety incident according to the standard definition. 1 in 10 patients (264 patients) identified a patient safety incident, with medication errors the most frequently reported incident.

Conclusions

Our findings suggest that patients can provide insight about safety that complements existing patient safety measurement, with a frequency of reported patient safety incidents that is similar to those obtained via case note review. However, patients provide a unique perspective about hospital safety which differs from and adds to current definitions of patient safety incidents.

Trial registration number

ISRCTN07689702; pre-results.
Implementing bedside rounds to improve patient-centred outcomes: a systematic review
Authors: Ratelle John T , Sawatsky Adam P , Kashiwagi Deanne T , Schouten Will M , Erwin Patricia J , Gonzalo Jed D , Beckman Thomas J , West Colin P
Published: September 2018

Background

Bedside rounds (BR) have been proposed as an ideal method to promote patient-centred hospital care, but there is substantial variation in their implementation and effects. Our objectives were to describe the implementation of BR in hospital settings and determine their effect on patient-centred outcomes.

Methods

Data sources included Ovid MEDLINE, Ovid Embase, Scopus and Ovid Cochrane Central Registry of Clinical Trials from database inception through 28 July 2017. We included experimental studies comparing BR to another form of rounds in a hospital-based setting (ie, medical/surgical unit, intensive care unit (ICU)) and reporting a quantitative patient-reported or objectively measured clinical outcome. We used random effects models to calculate pooled Cohen's d effect size estimates for the patient knowledge and patient experience outcome domains.

Results

Twenty-nine studies met inclusion criteria, including 20 from adult care (17 non-ICU, 3 ICU), and nine from paediatrics (5 non-ICU, 4 ICU), the majority of which (n=23) were conducted in the USA. Thirteen studies implemented BR with cointerventions as part of a ‘bundle’. Studies most commonly reported outcomes in the domains of patient experience (n=24) and patient knowledge (n=10). We found a small, statistically significant improvement in patient experience with BR (summary Cohen’s d=0.09, 95% CI 0.04 to 0.14, p<0.001, I2=56%), but no significant association between BR and patient knowledge (Cohen’s d=0.21, 95% CI −0.004 to –0.43, p=0.054, I2=92%). Risk of bias was moderate to high, with methodological limitations most often relating to selective reporting, low adherence rates and missing data.

Conclusions

BR have been implemented in a variety of hospital settings, often ‘bundled’ with cointerventions. However, BR have demonstrated limited effect on patient-centred outcomes.
Chromosome painting of the red-handed tamarin (Saguinus midas) compared to other Callitrichinae monkeys
Authors: Stanyon Roscoe , Giusti Dorotea , Araújo Naiara Pereira , Bigoni Francesca , Svartman Marta
Published: September 2018

Here we present, for the first time, the complete chromosome painting map of Saguinus midas, the red-handed tamarin. Chromosome banding and painting with human chromosome-specific probes were used to compare the karyotype of this species with those of four other Neotropical primates of the subfamily Callitrichinae: Leontopithecus rosalia, Callithrix geoffroyi, C. penicillata, and Mico argentatus. The chromosome painting map of S. midas was identical to that of L. rosalia and other previously studied tamarin species (genera Saguinus and Leontopithecus). The three marmoset species studied (genera Callithrix and Mico) differed in the painting pattern of four human probes (chromosomes 1, 2, 10, and 16). These paints identified the presence or absence of chromosome associations HSA 1/10 and 2/16 in these taxa. By integrating our data with those from the literature, we were able to propose an ancestral Callitrichinae karyotype. The genera Saguinus and Leontopithecus (tamarins) conserve the ancestral Callitrichinae karyotype, while Mico and Callithrix (marmosets) show more derived karyotypes due to chromosome translocations and fissions that occurred during the evolution of these taxa.
A note on skeleton groups in coclass graphs
Authors: Dietrich Heiko , Saha Subhrajyoti
Published: September 2018

Recent studies of [Formula: see text]-groups of coclass [Formula: see text] concentrate on the coclass graph [Formula: see text]. While the detailed structure of [Formula: see text] is unknown, it is known that its general structure is dominated by the subgraph of ‘skeleton groups’. The original definition of these groups is technical, but some modifications for special cases have been used successfully in the literature. Given their importance, in this paper we define and investigate skeleton groups more rigorously. In particular, we study their isomorphism problem, which is a crucial step towards understanding the skeleton subgraph of [Formula: see text]. During our work we identified erroneous arguments for constructing isomorphisms in a proof of the 2013 paper on [Formula: see text]. We correct these errors here by proving the required results in a more general context.
Fracture Mechanics Assessment of Large Diameter Wind Turbine Bearings
Authors: Dagry François , Mehmanparast Ali , Müller Patrick , Pantke Klaus
Published: September 2018

The structural integrity of large diameter wind turbine bearings have been investigated using the built-in “contour integral” tool in ABAQUS finite element software package by modeling three-dimensional penny-shaped cracks and evaluating the stress intensity factors. In order to sub-model a crack and investigate the fracture mechanics of the rolling contact between the rollers and the raceway, a python script was developed and implemented in the analysis. Important steps to build the crack model are detailed and recommendations are made for further use of the finite element modeling tool in compressive mixed mode fracture mechanics assessment of wind turbine bearings. Moreover, the influence of initial residual stresses due to induction hardening of the raceway is also investigated and discussed in this paper. For frictionless contacts between the two crack faces, “contour integral” in ABAQUS appears to be a suitable method to obtain accurate stress intensity factor solutions for modes II and III. The results from this study are validated through comparison with the analytical solutions available in the literature and are expected to facilitate numerical life assessment of wind turbine bearings.
Recent advances of polar transition-metal sulfides host materials for advanced lithium–sulfur batteries
Authors: Chen Liping , Li Xifei , Xu Yunhua
Published: September 2018

Lithium sulfur batteries (LSBs) have been one of the most promising second batteries for energy storage. However, the commercialization of LSBs is still hindered by low sulfur utilization and poor cycling stability, resulting from shuttle effect and low redox kinetics of lithium polysulfides (LiPSs). Significant progress has been made over the years in enhancing the batteries performances and tap density with the transition-metal sulfides as sulfur host or additive in LSBs. In this review, we present the recent advances in the use of various nanostructured transition-metal sulfides applied in LSBs, and also focus on the interaction mechanisms of polar transition-metal sulfides with LiPSs and its catalysis for the redox of LiPSs. It may provide avenues for the application of transition-metal sulfides in LSBs. The challenges and perspectives of transition-metal sulfides are also addressed.
A treasure chest full of nanogranitoids: an archive to investigate crustal melting in the Bohemian Massif
Authors: Ferrero Silvio , O’Brien Patrick J. , Borghini Alessia , Wunder Bernd , Wälle Markus , Günter Christina , Ziemann Martin A.
Published: September 2018

The central European Bohemian Massif has undergone over two centuries of scientific investigation which has made it a pivotal area for the development and testing of modern geological theories. The discovery of melt inclusions in high-grade rocks, either crystallized as nanogranitoids or as glassy inclusions, prompted the re-evaluation of the area with an ‘inclusionist’ eye. Melt inclusions have been identified in a wide range of rocks, including felsic/perpotassic granulites, migmatites, eclogites and garnet clinopyroxenites, all the result of melting events albeit over a wide range of pressure/temperature conditions (800–1000°C/0.5–5 GPa). This contribution provides an overview of such inclusions and discusses the qualitative and quantitative constraints they provide for melting processes, and the nature of melts and fluids involved in these processes. In particular, data on trace-element signatures of melt inclusions trapped at mantle depths are presented and discussed. Moreover, experimental re-homogenization of nanogranitoids provided microstructural criteria allowing assessment of the conditions at which melt and host are mutually stable during melting. Overall this work aims to provide guidelines and suggestions for petrologists wishing to explore the fascinating field of melt inclusions in metamorphic terranes worldwide, based on the newest discoveries from the still-enigmatic Bohemian Massif.
Organic geochemical research analytics of the petroleum industry: enhanced data density and method flexibility using gas chromatograph multiple detector coupling
Authors: Doerner M. , Berner U. , Erdmann M. , Barth T.
Published: September 2018

In traditional organic geochemical investigations analyses are usually segmented in rather time-consuming single working steps that also require off-line preparation for each analytical instrument which can add to analytical bias. Since industry laboratories need to be precise, as well as cost- and time-efficient, we present a flexible and modular analytical concept which enables the user to perform advanced organic geochemical methods on a single gas chromatograph coupled to multiple detectors. The coupled analytical system can perform analyses of natural gas composition up to
n
-butane, stable carbon isotopes of natural gas compounds up to
n
-butane, identification and quantification of major compounds in oils and extracts, and compound-specific isotopes of oil and extracts. The analytical methodologies are appropriate for enhancement to broaden the application spectrum of coupled detectors.
Network Sparsification for Steiner Problems on Planar and Bounded-Genus Graphs
Authors: Pilipczuk Marcin , Pilipczuk Michał , Sankowski Piotr , Leeuwen Erik Jan Van
Published: September 2018

We propose polynomial-time algorithms that sparsify planar and bounded-genus graphs while preserving optimal or near-optimal solutions to Steiner problems. Our main contribution is a polynomial-time algorithm that, given an unweighted undirected graph
G
embedded on a surface of genus
g
and a designated face
f
bounded by a simple cycle of length
k
, uncovers a set
F
⊆
E
(
G
) of size polynomial in
g
and
k
that contains an optimal Steiner tree for
any
set of terminals that is a subset of the vertices of
f
.

We apply this general theorem to prove that:

— Given an unweighted graph
G
embedded on a surface of genus
g
and a terminal set
S
⊆
V
(
G
), one can in polynomial time find a set
F
⊆
E
(
G
) that contains an optimal Steiner tree
T
for
S
and that has size polynomial in
g
and |
E
(
T
)|.

— An analogous result holds for an optimal Steiner forest for a set
S
of terminal pairs.

— Given an unweighted planar graph
G
and a terminal set
S
⊆
V
(
G
), one can in polynomial time find a set
F
⊆
E
(
G
) that contains an optimal (edge) multiway cut
C
separating
S
(i.e., a cutset that intersects any path with endpoints in different terminals from
S
) and that has size polynomial in |
C
|.

In the language of parameterized complexity, these results imply the first polynomial kernels for S
teiner
T
ree
and S
teiner
F
orest
on planar and bounded-genus graphs (parameterized by the size of the tree and forest, respectively) and for (E
dge
) M
ultiway
C
ut
on planar graphs (parameterized by the size of the cutset).

Additionally, we obtain a weighted variant of our main contribution: a polynomial-time algorithm that, given an undirected plane graph
G
with positive edge weights, a designated face
f
bounded by a simple cycle of weight
w
(
f
), and an accuracy parameter ε > 0, uncovers a set
F
⊆
E
(
G
) of total weight at most poly(ε
-1
)
w
(
f
) that, for any set of terminal pairs that lie on
f
, contains a Steiner forest within additive error ε
w
(
f
) from the optimal Steiner forest.
A Mazing 2+ε Approximation for Unsplittable Flow on a Path
Authors: Anagnostopoulos Aris , Grandoni Fabrizio , Leonardi Stefano , Wiese Andreas
Published: September 2018

We study the problem of unsplittable flow on a path (UFP), which arises naturally in many applications such as bandwidth allocation, job scheduling, and caching. Here we are given a path with nonnegative edge capacities and a set of tasks, which are characterized by a subpath, a demand, and a profit. The goal is to find the most profitable subset of tasks whose total demand does not violate the edge capacities. Not surprisingly, this problem has received a lot of attention in the research community.

If the demand of each task is at most a small-enough fraction δ of the capacity along its subpath (δ-
small tasks
), then it has been known for a long time [Chekuri et al., ICALP 2003] how to compute a solution of value arbitrarily close to the optimum via LP rounding. However, much remains unknown for the complementary case, that is, when the demand of each task is at least some fraction δ > 0 of the smallest capacity of its subpath (δ-
large tasks
). For this setting, a constant factor approximation is known, improving on an earlier logarithmic approximation [Bonsma et al., FOCS 2011].

In this article, we present a polynomial-time approximation scheme (PTAS) for δ-large tasks, for any constant δ > 0. Key to this result is a complex geometrically inspired dynamic program. Each task is represented as a segment underneath the capacity curve, and we identify a proper maze-like structure so that each
corridor
of the maze is
crossed
by only
O
(1) tasks in the optimal solution. The maze has a tree topology, which guides our dynamic program. Our result implies a 2+ε approximation for UFP, for any constant ε > 0, improving on the previously best 7+ε approximation by Bonsma et al. We remark that our improved approximation algorithm matches the best known approximation ratio for the considerably easier special case of uniform edge capacities.
Online Submodular Maximization with Free Disposal
Authors: Chan T.-H. Hubert , Huang Zhiyi , Jiang Shaofeng H.-C. , Kang Ning , Tang Zhihao Gavin
Published: September 2018

We study the online submodular maximization problem with free disposal under a matroid constraint. Elements from some ground set arrive one by one in rounds, and the algorithm maintains a feasible set that is independent in the underlying matroid. In each round when a new element arrives, the algorithm may accept the new element into its feasible set and possibly remove elements from it, provided that the resulting set is still independent. The goal is to maximize the value of the final feasible set under some monotone submodular function, to which the algorithm has oracle access.

For
k
-uniform matroids, we give a deterministic algorithm with competitive ratio at least 0.2959, and the ratio approaches 1/α
∞
≈ 0.3178 as
k
approaches infinity, improving the previous best ratio of 0.25 by Chakrabarti and Kale (IPCO 2014), Buchbinder et al. (SODA 2015), and Chekuri et al. (ICALP 2015). We also show that our algorithm is optimal among a class of deterministic monotone algorithms that accept a new arriving element only if the objective is strictly increased.

Further, we prove that no deterministic monotone algorithm can be strictly better than 0.25-competitive even for partition matroids, the most modest generalization of
k
-uniform matroids, matching the competitive ratio by Chakrabarti and Kale (IPCO 2014) and Chekuri et al. (ICALP 2015). Interestingly, we show that randomized algorithms are strictly more powerful by giving a (non-monotone) randomized algorithm for partition matroids with ratio 1/α
∞
≈ 0.3178.
Simultaneous Feedback Vertex Set
Authors: Agrawal Akanksha , Lokshtanov Daniel , Mouawad Amer E. , Saurabh Saket
Published: September 2018

For a family
F
of graphs, a graph
G
, and a positive integer
k
, the
F
-D
eletion
problem asks whether we can delete at most
k
vertices from
G
to obtain a graph in
F
.
F
-D
eletion
generalizes many classical graph problems such as V
ertex
C
over
, F
eedback
V
ertex
S
et
, and O
dd
C
ycle
T
ransversal
. For an integer α ≥ 1, an
n
-vertex (multi) graph
G
= (
V
, ⋃
i=1
α
E
i
), where the edge set of
G
is partitioned into α color classes, is called an α-edge-colored (multi) graph. A natural extension of the
F
-D
eletion
problem to edge-colored graphs is the S
imultaneous
F
-D
eletion
problem. In the latter problem, we are given an α-edge-colored graph
G
and the goal is to find a set
S
of at most
k
vertices such that each graph

G
i

−
S
, where

G
i

= (
V
,

E
i

) and 1 ≤
i
≤ α, is in
F
. In this work, we study S
imultaneous
F
-D
eletion
for
F
being the family of forests. In other words, we focus on the S
imultaneous
F
eedback
V
ertex
S
et
(S
im
FVS) problem. Algorithmically, we show that, like its classical counterpart, S
im
FVS parameterized by
k
is fixed-parameter tractable (FPT) and admits a polynomial kernel, for any fixed constant α. In particular, we give an algorithm running in 2

O
(
α k
)

n

O
(1)

time and a kernel with
O
(α
k
3(α+1)
) vertices. The running time of our algorithm implies that S
im
FVS is FPT even when α ∈
o
(log
n
). We complement this positive result by showing that if we allow α to be in
O
(log
n
), where
n
is the number of vertices in the input graph, then S
im
FVS becomes W[1]-hard. In particular, when α is roughly equal to
c
log
n
, for a non-zero positive constant
c
, the problem becomes W[1]-hard. Our positive results answer one of the open problems posed by Cai and Ye (MFCS 2014).
[WITHDRAWN] Retinal Vasculature in Development and Diseases
Authors: Sun Ye , Smith Lois E.H.
Published: September 2018

This article was withdrawn on October 15, 2020, at the request of the journal editors, with agreement from the authors, owing to a substantial amount of unattributed or improperly cited text overlap with other sources. In accordance with Annual Reviews' commitment to transparency, the original PDF of the article remains available for download at https://www.annualreviews.org/doi/pdf/10.1146/annurev-vision-091517-034018 .
NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263
Authors: Dastur Anahita , Choi AHyun , Costa Carlotta , Yin Xunqin , Williams August , McClanaghan Joseph , Greenberg Max , Roderick Justine , Patel Neha U. , Boisvert Jessica , McDermott Ultan , Garnett Mathew J. , Almenara Jorge , Grant Steven , Rizzo Kathryn , Engelman Jeffrey A. , Kelliher Michelle , Faber Anthony C. , Benes Cyril H.
Published: September 2018

Purpose:

Effective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL.

Experimental Design:

We performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both in vitro experiments and in vivo studies on patient-derived xenograft models.

Results:

We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax in vitro and leads to tumor regressions in vivo.

Conclusions:

Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.
MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer
Authors: Parikh Aparna R. , Lee Fa-Chyi , Yau Linda , Koh Han , Knost James , Mitchell Edith P. , Bosanac Ivan , Choong Nicholas , Scappaticci Frank , Mancao Christoph , Lenz Heinz-Josef
Published: September 2018

Purpose:

MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC).

Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/β-actin mRNA expression level and region.

Results:

Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61–1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56–1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56–1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51–1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93–1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20–2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously.

Conclusions:

First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.
A Novel Approach for Image-Guided 131I Therapy of Pancreatic Ductal Adenocarcinoma Using Mesenchymal Stem Cell-Mediated NIS Gene Delivery
Authors: Schug Christina , Gupta Aayush , Urnauer Sarah , Steiger Katja , Cheung Phyllis Fung-Yi , Neander Christian , Savvatakis Konstantinos , Schmohl Kathrin A. , Trajkovic-Arsic Marija , Schwenk Nathalie , Schwaiger Markus , Nelson Peter J. , Siveke Jens T. , Spitzweg Christine
Published: September 2018

The sodium iodide symporter (SLC5A5/NIS) as theranostic gene would allow for non-invasive imaging of functional NIS expression and therapeutic radioiodine application. Genetically engineered mesenchymal stem cells (MSC), based on their tumor-homing abilities, show great promise as tumor-selective NIS gene delivery vehicles for non-thyroidal tumors. As a next step towards clinical application, tumor specificity and efficacy of MSCs were investigated in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC). Syngeneic murine MSCs were stably transfected with a NIS-expressing plasmid driven by the CMV-promoter (NIS-MSC). In vivo 123I-scintigraphy and 124I-PET revealed significant perchlorate-sensitive NIS-mediated radioiodide accumulation in PDAC after systemic injection of NIS-MSCs. Active MSC recruitment into the tumor stroma was confirmed using NIS immunohistochemistry (IHC). A therapeutic strategy, consisting of three cycles of systemic MSC-mediated NIS delivery, followed by 131I application, resulted in a significant delay and reduction in tumor growth as compared to controls. Furthermore, IHC analysis of α-SMA and Ki67 revealed differences in the amount and behavior of activated fibroblasts in tumors of mice injected with NIS-MSCs as compared with saline-treated mice. Taken together, MSCs as NIS gene delivery vehicles in this advanced endogenous PDAC mouse model demonstrated high stromal targeting of NIS by selective recruitment of NIS-MSCs after systemic application resulting in an impressive 131I therapeutic effect.

Implications:

These data expand the prospect of MSC-mediated radioiodine imaging-guided therapy of pancreatic cancer using the sodium iodide symporter as a theranostic gene in a clinical setting.
Lung-Enriched Mutations in the p53 Tumor Suppressor: A Paradigm for Tissue-Specific Gain of Oncogenic Function
Authors: Barta Julie A. , McMahon Steven B.
Published: September 2018

Lung cancer, the leading cause of cancer-related mortality in the United States, occurs primarily due to prolonged exposure to an array of carcinogenic compounds in cigarette smoke. These carcinogens create bulky DNA adducts, inducing alterations including missense mutations in the tumor suppressor gene TP53. TP53 is the most commonly mutated gene in many human cancers, and a specific set of these variants are enriched in lung cancer (at amino acid residues V157, R158, and A159). This perspective postulates that lung-enriched mutations can be explained, in part, by biological selection for oncogenic gain-of-function (GOF) mutant p53 alleles at V157, R158, and A159. This hypothesis explaining tissue-specific TP53 mutations is further supported by mouse model studies of the canonical TP53 hotspots showing that tumor spectra and GOF activities are altered with mutation type. Therefore, although smoking-related lung cancer unequivocally arises due to the mutagenic environment induced by tobacco carcinogens, this perspective provides a rationale for the preferential selection of lung-enriched V157, R158, and A159 mutant p53.
Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer
Authors: Rafiei Shahrzad , Gui Bin , Wu Jiaxin , Liu X. Shirley , Kibel Adam S. , Jia Li
Published: September 2018

Although androgen deprivation therapy (ADT) is an effective treatment for metastatic prostate cancer, incurable castration-resistant prostate cancer (CRPC) inevitably develops. Importantly, androgen receptor (AR) continues to be critical for prostate cancer growth and progression after ADT. One of the underlying molecular mechanisms is derepression of AR-repressed genes involved in cell cycle and proliferation after ADT. Here, the data demonstrate that C-X-C chemokine receptor type 7 (CXCR7), a seven-transmembrane G-protein–coupled chemokine receptor, is an AR-repressed gene and is upregulated after ADT. AR directly regulates CXCR7 using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Macrophage migration inhibitory factor (MIF) was identified as a ligand for CXCR7, which induces expression of cell-cycle genes through activating AKT signaling pathway. Previous studies have been focused on chemokine CXCL12 and its receptor CXCR4 in mediating metastasis of various cancer types, including prostate cancer. The critical roles of CXCL12/CXCR4 axis in the interaction between cancer cells and their microenvironment render it a promising therapeutic target in cancer treatment. The data suggest that the MIF/CXCR7/AKT pathway drives CRPC growth and metastasis independent of the CXCL12/CXCR4 axis. Furthermore, CXCR7 blockade in combination with anti-androgen enzalutamide inhibits CRPC tumor growth and potentially prevents metastasis. Notably, both MIF and CXCR7 are overexpressed in CRPC patient specimens and therefore are attractive therapeutic targets for these patients.

Implications:

This work suggests that CXCR7 plays more important roles than CXCR4 in CRPC progression; thus, targeting CXCR7 in combination with anti-androgen is a promising therapeutic approach for metastatic CRPC.
The Role of Alcohol-Induced Golgi Fragmentation for Androgen Receptor Signaling in Prostate Cancer
Authors: Manca Sonia , Frisbie Cole P. , LaGrange Chad A. , Casey Carol A. , Riethoven Jean-Jack M. , Petrosyan Armen
Published: September 2018

Multiple epidemiologic observations and meta-analysis clearly indicate the link between alcohol abuse and the incidence and progression of prostate cancer; however, the mechanism remains enigmatic. Recently, it was found that ethanol (EtOH) induces disorganization of the Golgi complex caused by impaired function of the largest Golgi matrix protein, giantin (GOLGB1), which, in turn, alters the Golgi docking of resident Golgi proteins. Here, it is determined that in normal prostate cells, histone deacetylase 6 (HDAC6), the known regulator of androgen receptor (AR) signaling, localizes in the cytoplasm and nucleus, while its kinase, glycogen synthase kinase β (GSK3β), primarily resides in the Golgi. Progression of prostate cancer is accompanied by Golgi scattering, translocation of GSK3β from the Golgi to the cytoplasm, and the cytoplasmic shift in HDAC6 localization. Alcohol dehydrogenase–generated metabolites induces Golgi disorganization in androgen-responsive LNCaP and 22Rv1 cells, facilitates tumor growth in a mouse xenograft model and activates anchorage-independent proliferation, migration, and cell adhesion. EtOH-treated cells demonstrate reduced giantin and subsequent cytoplasmic GSK3β; this phenomenon was validated in giantin-depleted cells. Redistribution of GSK3β to the cytoplasm results in phosphorylation of HDAC6 and its retention in the cytoplasm, which, in turn, stimulates deacetylation of HSP90, AR import into the nucleus, and secretion of prostate-specific antigen (PSA). Finally, the relationship between Golgi morphology, HDAC6 cytoplasmic content, and clinicopathologic features was assessed in human prostate cancer patient specimens with and without a history of alcohol dependence.

Implications:

This study demonstrates the importance of alcohol-induced Golgi fragmentation in the activation of AR-mediated proliferation.
Chronic Maternal Hyperoxygenation and Effect on Cerebral and Placental Vasoregulation and Neurodevelopment in Fetuses with Left Heart Hypoplasia
Authors: Edwards Lindsay A. , Lara Diego A. , Sanz Cortes Magdalena , Hunter Jill V. , Andreas Shelley , Nguyen Magnolia J. , Schoppe Lacey J. , Zhang Jianhong , Smith Eboni M. , Maskatia Shiraz A. , Sexson-Tejtel S. Kristen , Lopez Keila N. , Lawrence Emily J. , Wang Yunfei , Challman Melissa , Ayres Nancy A. , Altman Carolyn A. , Aagaard Kjersti , Becker Judith A. , Morris Shaine A.
Published: September 2018

Introduction: In a pilot study of chronic maternal hyperoxygenation (CMH) in left heart hypoplasia (LHH), we sought to determine effect estimates of CMH on head size, vascular resistance indices, and neurodevelopment compared to controls. Material and Methods: Nine gravidae meeting the inclusion criteria (fetal LHH, ≥25.9 weeks’ gestation, and ≥10% increase in percent aortic flow after acute hyperoxygenation) were prospectively enrolled. Controls were 9 contemporary gravidae with fetal LHH without CMH. Brain growth and Doppler-derived estimates of fetal cerebrovascular and placental resistance were blindly evaluated and compared using longitudinal regression. Postnatal anthropomorphic and neurodevelopmental assessments were compared. Results: There was no difference in baseline fetal measures between groups. There was significantly slower biparietal diameter (BPD) growth in the CMH group (z-score change –0.03 ± 0.02 vs. +0.09 ± 0.05 units/week, p = 0.02). At 6 months postnatal age, the mean head circumference z-score in the CMH group was smaller than that of controls (–0.20 ± 0.58 vs. +0.85 ± 1.11, p = 0.048). There were no differences in neurodevelopmental testing at 6 and 12 months. Discussion: In this pilot study, relatively diminished fetal BPD growth and smaller infant head circumference z-scores at 6 months were noted with in utero CMH exposure.
Application of the Milan System for Risk Stratification and Its Comparison with a Previous Reporting System of Parotid Gland Cytopathology in a Tertiary Care Centre
Authors: Vallonthaiel Archana George , Kaushal Seema , Jangir Hemlata , Rajendran Hemanth Kumar
Published: September 2018

Objective: To compare the recently proposed Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) with the four-tiered reporting system (FTRS) followed at our institute. Methods: Parotid gland fine-needle aspirates reported over a period of 5 years were analysed. These aspirates had been placed into 4 categories according to the FTRS: unsatisfactory (UNS), no evidence of malignancy/negative (NEG), inconclusive for malignancy (INC), and diagnostic for malignancy/positive (POS). Aspirates with follow-up histopathology were then categorized according to the MSRSGC as follows: non-diagnostic, non-neoplastic, atypia of unde­termined significance (AUS), neoplasm, suspicious for malignancy, and malignant. The risk of malignancy (ROM) was calculated. Results: A total of 893 parotid region aspirates were evaluated and histopathology was available for 190 cases (21%). ROM in MSRSGC groups, namely non-diagnostic, non-neoplastic, AUS, neoplasm, suspicious for malignant neoplasm, and malignant, was 44, 8, 0, 12, 81 and 100%, respectively. ROM in FTRS groups, namely UNS, NEG, INC, and POS, was 45, 13, 67 and 100%, respectively. Conclusions: MSRGC and FTRS are comparable with respect to the ROM across groups. Compared to FTRS, the further subcategorisation of the non-malignant group, the use of specific nomenclature, and the reproducibility of MSRGC provide proper risk stratification, thereby guiding better management and resulting in improved patient care.
Is There a Role for Primary Care in the Follow-Up of Colorectal Cancer Patients? The Case of a Portuguese University Hospital
Authors: Costa Ferreira Bandarra Maria Margarida , Escoval Ana , Marques da Costa Luís
Published: September 2018

Background: In Portugal, colorectal cancer is the second most common type of cancer. With the increasing number of cancer survivors, follow-up is perceived as a chronic disease, with a significant impact on hospital care. Objective: To characterize colorectal patients in follow-up at Centro Hospitalar Lisboa Norte, EPE, and to determine the profile of economic resources consumed as well as the consultation workload. Materials and Methods: We characterized colorectal patients in follow-up at Centro Hospitalar Lisboa Norte, EPE, registered from 2008 until 2013 and the profile of economic resources consumed. Results: The Department of Oncology is responsible for 56.2% of colorectal patients’ follow-up. In this study, only 0.4% of cases had follow-up secured in primary care, which translates to a significant impact in terms of resources allocation and consultation management, especially if we consider that 41% of patients are in follow-up for longer than 3 years. The average annual adjusted cost of follow-up per patient is EUR 539.09. Patients who were alive on 31 January 2014 had generated 2,930 follow-up hospital appointments per year, representing 12% of the total number of oncology appointments reported in 2013. Discussion and Conclusions: The follow-up of colorectal cancer patients is associated with significant hospital resource allocation and physicians’ time consumption. Other follow-up models might emerge as an alternative to traditional hospital-centered follow-up, such as the shared-care follow-up, which requires a multidisciplinary and survivor-centered approach, ensuring that information and communication are shared between settings with a clear definition of responsibilities, a survivor care plan, and mechanisms for future referencing when justified.
Airway-Centered Pleuroparenchymal Fibroelastosis Associated with Non-Necrotizing Granulomas: A Rare New Entity
Authors: Bargagli Elena , Rottoli Paola , Torricelli Elena , Allegrini Chiara , Dubini Alessandra , Bennett David , Luzzi Luca , Spina Donatella , Poletti Venerino , Tomassetti Sara
Published: September 2018

Pleuroparenchymal fibroelastosis is a rare form of upper-lobe-dominant progressive pulmonary fibrosis characterized histologically by visceral pleural thickening with collagenous fibrosis, subpleural elastosis, and intra-alveolar collagenous fibrosis. It was first described 25 years ago by Amitani et al. This report firstly describes a new variant or rare phenotype of PPFE with airway involvement, minimal pleuroparenchymal connections, and non-necrotizing granulomas.
Association of the Polymorphisms and Plasma Level of CHI3L1 with Alzheimer’s Disease in the Chinese Han Population: A Case-Control Study
Authors: Dai Qi-He  , Gong  Dao-Kai 
Published: September 2018

Objective: To investigate whether the polymorphisms and plasma level of chitinase-3-like protein 1 (CHI3L1) are associated with Alzheimer’s disease (AD) in the Chinese Han population. Methods: A total of 166 patients who were initially diagnosed with AD were enrolled as the case group, and 184 healthy subjects were recruited as the healthy controls. TaqMan® SNP genotyping assays were applied for the genotyping of rs4950928, rs10399931 and rs6691378. The plasma level of CHI3L1 was determined by enzyme-linked immunosorbent assay. Results: The CG+GG genotype of rs4950928 C>G is a protective factor for AD and could effectively reduce the severity of AD. Patients with the CT+TT genotype of rs10399931 C>T had a significantly increased risk of AD, and it apparently aggravated the severity of AD. Moreover, the plasma CHI3L1 level in AD patients was significantly higher than that in healthy controls, which was increased with the severity of AD. A Kaplan-Meier survival curve showed that significant differences in 5-year survival rates were found in AD patients in different genotypes of CHI3L1 rs4950928 C>G and rs10399931 C>T. The AD patients and healthy controls who carried the CG+GG genotype of rs4950928 C>G had lower plasma CHI3L1 levels than CC genotype carriers. However, the CT+TT genotype of rs10399931 in the AD patients had an elevated plasma level of CHI3L1 as compared with the CC genotype. Binary logistic regression analysis showed that the plasma level of CHI3L1, the CC genotype of rs4950928 C>G and the CT+TT genotype of rs10399931 C>T were risk factors for AD. Conclusion: Polymorphisms of the CHI3L1 gene (rs4950928 C>G and rs10399931 C>T) are associated with the risk and prognosis of AD and can affect the expression of CHI3L1 in plasma.
Hepatorenal Syndrome or Hepatocardiorenal Syndrome: Revisiting Basic Concepts in View of Emerging Data
Authors: Kazory Amir , Ronco Claudio
Published: September 2018

Background: Accumulating evidence on the pathophysiology of hepatorenal syndrome has challenged the conventional model of liver-kidney connection. While liver cirrhosis is traditionally considered the origin of a cascade of pathophysiologic mechanisms directly affecting other organs such as the kidney, emerging data point to the heart as the potential mediator of the untoward renal effects. Summary: Herein, we briefly review the often-overlooked contribution of the heart to circulatory dysfunction in hepatorenal syndrome and put forward evidence arguing for the involvement of systemic inflammation and endothelial dysfunction in this setting. The temporality of cardiorenal interactions in hepatorenal syndrome and the observed beneficial effects of portosystemic shunting on these pathways lend further support to the notion that cardiac involvement plays a key role in the development of renal dysfunction in severe cirrhosis. Key Messages: The disturbances traditionally bundled within hepatorenal syndrome could represent a hepatic form of cardiorenal syndrome whereby the liver affects the kidney in part through cardiorenal pathways. This new model has practical implications and calls for a shift in the focus of diagnostic and therapeutic approaches to renal dysfunction in advanced cirrhosis.