bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping Urban-Rural Linkage in Promoting Sustainable Regional Development to Support Rural Creative Economy Entrepreneurs
Authors: Azmi H. N. H. , Wijaya B. , Wijaya M. I. H. , Novandaya Z. , Kurniawati H.
Published: November 2021

Strong rural-urban linkages are one of the supports for sustainable regional development. With the potential of the creative economy in the rural area owned by Temanggung Regency, the creative economy sector can be a driving force for rural-urban linkages. One of the actors that can drive the strengthening of rural-urban linkages is creative economy entrepreneurs, who have the potential to eliminate the boundaries of rural-urban linkages through good capacity in accessing various advantages that exist in the city such as knowledge and market share while optimizing the advantages of rural locations. This study aims to examine the role of rural creative economy actors in Temanggung Regency in encouraging the strengthening of existing rural-urban linkages based on the flow of people/labor, production, commodities, capital and information. The research method used in this study is descriptive qualitative with the support of data obtained through interviews and FGDs of creative economy actors in Temanggung Regency. The result of this research is that rural creative economy actors in Temanggung Regency have the potential to strengthen rural-urban relations, especially in the aspects of capital, information, and commodities.
Implementation of Klassen Typology in Mapping of Superior Commodities of Food Crops in The Malolo Agropolitan Area
Authors: Siradjuddin H. , Anshar M. , Asman A. I.
Published: November 2021

The Malolo agropolitan area is a strategic food crop production center in Takalar. The implementation of klassen tipology is used to identify superior commodities with export value from food plants cultivated by farmers in the area. This study aims to determine the superior commodities of food crops using klassen typology and to map these superior commodities in the Malolo Agropolitan Area. The analytical methods used were klassen typology and Ar-GIS mapping. The results showed that the implementation of klassen typology on food commodities in the Agropolitan Malolo area resulted in maize as the only superior commodity out of 4 other food commodities. Maize is a leading commodity in 4 areas, that is Massamaturu, Timbuseng, Barugaya, and Towata. Mapping results show that 4 areas are superior commodity development, 11 areas for mainstay commodity development, 37 areas for prospective commodity development, and 38 areas for slow commodity development. The number of areas for slow commodity development shows that the production of food commodities in the Malolo agropolitan area is less able to compete with food commodity production in other areas in a larger area.
Equi-Lipschitz minimizing trajectories for non coercive, discontinuous, non convex Bolza controlled-linear optimal control problems
Authors: Mariconda Carlo
Published: November 2021

This article deals with the Lipschitz regularity of the “approximate” minimizers for the Bolza type control functional of the form
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper J Subscript t Baseline left-parenthesis y comma u right-parenthesis colon-equal integral Subscript t Superscript upper T Baseline normal upper Lamda left-parenthesis s comma y left-parenthesis s right-parenthesis comma u left-parenthesis s right-parenthesis right-parenthesis d s plus g left-parenthesis y left-parenthesis upper T right-parenthesis right-parenthesis">

J
t

(
y
,
u
)
≔

∫
t
T

Λ
(
s
,
y
(
s
)
,
u
(
s
)
)

d
s
+
g
(
y
(
T
)
)

J_t(y,u)≔\int _t^T\Lambda (s,y(s), u(s))\,ds+g(y(T))

\]
among the pairs

(
y
,
u
)

(y,u)

satisfying a prescribed initial condition

y
(
t
)
=
x

y(t)=x

, where the state

y
y

is absolutely continuous, the control

u
u

is summable and the dynamic is controlled-linear of the form

y
′

=
b
(
y
)
u

y’=b(y)u

. For

b
≡
1

b\equiv 1

the above becomes a problem of the calculus of variations. The Lagrangian

Λ
(
s
,
y
,
u
)

\Lambda (s,y,u)

is assumed to be either convex in the variable

u
u

on every half-line from the origin (radial convexity in

u
u

), or partial differentiable in the control variable and satisfies a local Lipschitz regularity on the time variable, named Condition (S). It is allowed to be extended valued, discontinuous in

y
y

or in

u
u

, and non convex in

u
u

. We assume a very mild growth condition, actually a violation of the Du Bois-Reymond–Erdmann equation for high values of the control, that is fulfilled if the Lagrangian is coercive as well as in some almost linear cases. The main result states that, given any admissible pair

(
y
,
u
)

(y,u)

, there exists a more convenient admissible pair

(

y
¯

,

u
¯

)

(\overline y, \overline u)

for

J
t

J_t

where

u
¯

\overline u

is bounded,

y
¯

\overline y

is Lipschitz, with bounds and ranks that are uniform with respect to

t
,
x

t,x

in the compact subsets of

[
0
,
T
[
×

R

n

[0,T[\times \mathbb {R}^n

. The result is new even in the superlinear case. As a consequence, there are minimizing sequences that are formed by pairs of equi-Lipschitz trajectories and equi-bounded controls. A new existence and regularity result follows without assuming any kind of Lipschitzianity in the state variable. We deduce, without any need of growth conditions, the nonoccurrence of the Lavrentiev phenomenon for a wide class of Lagrangians containing those that satisfy Condition (S), are bounded on bounded sets “well” inside the effective domain and are radially convex in the control variable. The methods are based on a reparametrization technique and do not involve the Maximum Principle.
Potato tuber-inducing activities of jasmonic acid and related-compounds (II)
Authors: Miyawaki Kanji , Inoue Shiro , Kitaoka Naoki , Matsuura Hideyuki
Published: November 2021

New information is being accumulated for plant-derived oxylipins, such as jasmonic acid (JA) amino acid conjugates. However, these compounds have not being examined for their activity in promoting potato tuber formation. It was found that (−)-JA had the highest activity followed cis-(−)-OPDA, (+)-4, 5-didehydroJA, cis-(+)-OPDA-l-Ile, and (−)-JA-l-Ile, -Leu, -Phe, -Val, although iso-OPDA and 3,7-didehydroJA did not exhibit activity.
Regulation of mouse primordial follicle formation by signaling through the PI3K pathway
Authors: Burton Joshua J N , Luke Amanda J , Pepling Melissa E
Published: November 2021

Cell signaling mediated by the KIT receptor is critical for many aspects of oogenesis including the proliferation and migration of primordial germ cells, as well as the survival, growth, and maturation of ovarian follicles. We previously showed that KIT regulates cyst breakdown and primordial follicle formation, and in this study, have investigated the mechanisms downstream of the receptor by modulating the activity of two downstream signaling cascades: the phosphoinositide 3-kinase (PI3K) and the mitogen-activated protein kinase pathways. E17.5 ovaries were cultured for 5 days with a daily dose of media supplemented with either the PI3K inhibitor LY294002, the MEK inhibitor U0126, or a DMSO vehicle control. Our histological observations aligned with the established role of PI3K in oocyte growth and primordial follicle activation but also revealed that LY294002 treatment delayed the processes of cyst breakdown and primordial follicle formation. U0126 treatment also led to a reduction in oocyte growth and follicle development but did not appear to affect cyst breakdown. The delay in cyst breakdown was mitigated when ovaries were dually dosed with LY294002 and KITL, suggesting that while KIT may signal through PI3K to promote cyst breakdown, other signaling networks downstream of the receptor could compensate. These observations unearth a role for PI3K signaling in the establishment of the ovarian reserve and suggest that PI3K might be the primary mediator of KIT-induced cyst breakdown and primordial follicle formation in the mouse ovary.
Do coping strategies really affect cardiovascular events? The Isfahan cohort study of adults in Eastern Mediterranean Regional Office
Authors: Roohafza Hamidreza , Askari Mozhde , Nouri Fatemeh , Talaei Mohammad , Sarrafzadegan Nizal , Sadeghi Masoumeh
Published: November 2021

Aims

Psychological factors are among the most suspected indicators which may cause atherosclerosis. Coping strategies modifying psychological stress may be significantly associated with health outcomes. However, little is known about the influence of adaptive and maladaptive coping strategies on major adverse cardiovascular disease (CVD) events. The purpose of this study is to examine this idea among a sample of adults. Design: cohort study.

Methods and results

The Isfahan cohort study (ICS) is a longitudinal population-based, prospective study. Participants (N=6323 individuals aged 35 years or greater at baseline) were selected by multistage random sampling with 6-year intervals (i.e. 2001: 6323 individuals, 2007: 3296 individuals, and 2013: 1706 individuals). Adaptive and maladaptive coping strategies were evaluated by a multicomponent self-administered stress management paper-based questionnaire. All CVD events were confirmed by a blinded panel of experts and a marginal cox regression model was used to model the survival data. Adaptive coping strategies could be protective against CVD events with hazard ratios (95% confidence interval) [0.97 (0.95–0.99)] and maladaptive coping strategies seem to be a risk factor, 1.02 (1.01–1.04) in the whole population. Individuals younger than 60 showed similar results, with 0.96 (0.93–0.98) and 1.04 (1.01–1.07) for adaptive and maladaptive coping strategies, respectively. However, these findings were not replicated among seniors older than age 60.

Conclusion

Based on our results, coping strategies have an important role in cardiovascular events, particularly among young adults. According to the results, informing patients about adaptive stress management may promote primary prevention of CVD events.
Effects of temperature, moisture content and storage on dormancy release and germination of European hornbeam (Carpinus betulusL.) seeds
Authors: Suszka Jan , Bujarska-Borkowska Barbara , Tylkowski Tadeusz , Wawrzyniak Mikołaj Krzysztof
Published: November 2021

Mature seeds of European hornbeam (Carpinus betulus L.) are characterized by deep physical and morphological dormancy. Although a procedure for their stratification is well developed, secondary dormancy prevents many healthy seeds from germinating, and this affects the productivity of the specie’s nursery material. The objective of this work was to determine optimal conditions for germination of European hornbeam seeds, and how to avoid the induction of their secondary dormancy. We also aimed at establishing methods for controlling the seed germination prior to sowing. Harvested nuts were stratified in a substrate at 20°/3°C for 4 + 16–18 weeks. Following stratification, the seeds were dried up to 25, 20, 15 and 10 per cent moisture content or frozen in the substrate at −3°C for 8, 16 or 32 weeks. The seeds dried up to 10 and 15 per cent moisture content were also stored at −3°C for 8, 16 and 32 weeks. After stratification, drying, storing and freezing, the seeds were germinated at the laboratory at 20°C and 3/20°C (16 + 8 h). However, reliable germination results were only achieved when the seeds not germinating at the above listed temperatures were additionally germinated at 3°C. Poor germination at 20° and 3/20°C was due to the induction of secondary dormancy. Stratified seeds of European hornbeam were found sensitive to dehydration. Their viability decreased considerably, particularly after drying up to 10 per cent moisture content, and in the seeds dried to 15 per cent the viability further decreased during storage. The seeds that were not dried but frozen at −3°C after stratification retained their germination ability for at least 16 weeks. Our results shows dual effects of temperature on germination control of hornbeam seeds. In laboratory practice applying temperature cycles of 3°/20°C at 16/8 h intervals is recommended to avoid the induction of secondary dormancy.
Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: Novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy
Authors: Logli Elena , Marzuolo Elisa , D’Agostino Marco , Conti Libenzio Adrian , Lena Anna Maria , Diociaiuti Andrea , Dellambra Elena , Has Cristina , Cianfanelli Valentina , Zambruno Giovanna , El Hachem May , Magenta Alessandra , Candi Eleonora , Condorelli Angelo Giuseppe
Published: November 2021

Epidermolysis bullosa simplex (EBS) with cardiomyopathy (EBS-KLHL24) is an EBS subtype caused by dominantly inherited, gain-of-function mutations in the gene encoding for the ubiquitin-ligase KLHL24, which addresses specific proteins to proteasomal degradation. EBS-KLHL24 patients are born with extensive denuded skin areas and skin fragility. Whilst skin fragility rapidly ameliorates, atrophy and scarring develop over time, accompanied by life-threatening cardiomyopathy. To date, pathogenetic mechanisms underlying such a unique disease phenotype are not fully characterized. The basal keratin 14 (K14) has been indicated as a KLHL24 substrate in keratinocytes. However, EBS-KLHL24 pathobiology cannot be determined by the mutation-enhanced disruption of K14 alone, as K14 is similarly expressed in foetal and postnatal epidermis and its protein levels are preserved both in vivo and in vitro disease models. In this study, we focused on foetal keratins as additional KLHL24 substrates. We showed that K7, K8, K17 and K18 protein levels are markedly reduced via proteasome degradation in normal foetal keratinocytes transduced with the mutant KLHL24 protein (ΔN28-KLHL24) as compared to control cells expressing the wild-type form. In addition, heat stress led to keratin network defects and decreased resilience in ΔN28-KLHL24 cells. The KLHL24-mediated degradation of foetal keratins could contribute to congenital skin defects in EBS-KLHL24. Furthermore, we observed that primary keratinocytes from EBS-KLHL24 patients undergo accelerated clonal conversion with reduced colony forming efficiency (CFE) and early replicative senescence. Finally, our findings pointed out a reduced CFE in ΔN28-KLHL24-transduced foetal keratinocytes as compared to controls, suggesting that mutant KLHL24 contributes to patients’ keratinocyte clonogenicity impairment.
Drug resistance profiles and influencing factors among HIV-infected children and adolescents receiving long-term ART: a multicentre observational study in China
Authors: Yan Liting , Yu Fengting , Liang Jiangming , Cheng Yuewu , Li Huiqin , Zhao Qingxia , Chen Jinfeng , Chen Meiling , Guo Jing , Zhao Hongxin , Zhang Fujie
Published: November 2021

Objectives

To analyse the characteristics and determinants of drug resistance mutations (DRMs) in HIV-infected children and adolescents on long-term ART in China.

Methods

An observational cohort study was conducted in five centres. All participants younger than 15 years at ART initiation were screened, and those identified as having virological failure (VF) with viral load (VL) ≥ 400 copies/mL were included for genotypic resistance testing. Logistic regression analysis was performed and the accumulation of major mutations was analysed in a subgroup of resistant individuals with complete VL results since HIV diagnosis.

Results

Among 562 eligible participants, protease and RT regions were successfully amplified for 93 who failed treatment with a median of 10.0 years ART. Sixty-eight (73.1%) harboured ≥1 major mutations. NRTI, NNRTI and dual-class resistance accounted for 48.4%, 63.4% and 38.7%, respectively. Only 3.2% were resistant to PIs. Age at ART initiation [adjusted OR (aOR) = 0.813, 95% CI 0.690–0.957], subtype B (aOR = 4.378, 95% CI 1.414–13.560) and an initial NNRTI-based regimen (aOR = 3.331, 95% CI 1.180–9.402) were independently associated with DRMs. Among 40 resistant participants with additional VL data, 55.0% had continued VF on a suboptimal regimen and the estimated duration of VF was positively correlated with the total number of major mutations (r = 0.504, P = 0.001).

Conclusions

The development of DRMs was common in children and adolescents receiving long-term treatment, and continued VF was prevalent in those with resistance. Timely genotypic testing and new child-friendly formulations are therefore urgently required.
Characteristics of elastic wave dispersion and attenuation induced by microcracks in complex anisotropic media
Authors: Li Xiaobin , Yan Jianguo , Qi Qiaomu , Xie Rui
Published: November 2021

The mechanism of dispersion and attenuation induced by fluid flow among pores and microcracks in rocks is an important research topic in geophysical domain. A generalised frequency-dependent fourth-rank tensor is proposed and derived herein by combining Sayers's discontinuity tensor formula and Gurevich's squirt flow model. Furthermore, a proposed method for establishing a cracked model with cracks embedded in a transversely isotropic (TI) background medium is developed. Based on the new formulation, we investigate the characteristics of dispersion, attenuation and azimuthal anisotropy of three commonly encountered vertical crack distributions, including aligned cracks, monoclinic cracks and cracks with partial random orientations. We validate the developed model by comparing its predictions with those of the classic anisotropic squirt flow model for an aligned crack. The numerical analyses indicate that the azimuth is independent of frequency when the maximum attenuation is observed for all three crack distributions. In a low-frequency range in the case of an anisotropic background, the attenuation of the qP-wave is inversely proportional to velocity, whereas the attenuation of the qSV-wave is proportional to velocity. In addition, the inherent anisotropy of the rock does not significantly affect the dispersion and attenuation owing to squirt flow. Finally, to investigate the applicability of the theory, we model laboratory data of a synthetic porous sandstone with aligned cracks. Overall, the models agree well with laboratory data. The complex characteristics determined through this study may be useful for the seismic characterisation of fractured reservoirs.
The Effect of Streaming Chat on Perceptions of Political Debates
Authors: Asbury-Kimmel Victoria , Chang Keng-Chi , McCabe Katherine T , Munger Kevin , Ventura Tiago
Published: November 2021

Broadcast media consumption is becoming more social. Many online video “livestreams” come with embedded livestreaming chatboxes, uniting the on-screen and social components. We investigate how streaming chat shapes perceptions of political events. We conducted a field experiment during the September 2019 Democratic Primary Debate where subjects were assigned to view the debate with or without streaming chat. We use text analyses to characterize the frequency, toxicity, and tone of comments in the chat. Our experimental findings indicate that Democratic subjects assigned to the Facebook (social) chat condition reported lower affect toward Democrats and a worse viewing experience, aligned with the toxic and overwhelming nature of the chat. The polarity of candidate-directed comments also influenced candidate evaluations and perceived performance in the polls. This suggests that consumers of mass media will be both more immediately affected by social feedback and likely to make inferences about the experiences of their fellow consumers.
Spectrophotometric azole and amphotericin B MIC readings against Aspergillus fumigatus sensu lato using the EUCAST 9.3.2 methodology. Are ≥90 and ≥95% fungal growth inhibition endpoints equally suitable?
Authors: Serrano-Lobo Julia , Gómez Ana , Muñoz Patricia , Escribano Pilar , Guinea Jesús
Published: November 2021

We recently reported high essential (97.1%) and categorical (99.6%) agreements between azole and amphotericin B MICs against Aspergillus fumigatus sensu lato obtained by visual and spectrophotometric readings using a ≥ 95% fungal growth endpoint and following the EUCAST methodology (doi: 10.1128/AAC.01693-20). Here, we compared the aforementioned MICs against spectrophotometric MIC readings obtained using a ≥ 90% inhibition endpoint. Spectrophotometric readings using either ≥ 90% or ≥ 95% fungal growth inhibition resulted in high categorical (>99.9%) agreements with visual MIC readings against A. fumigatus sensu stricto. In contrast, agreements with visual MICs against cryptic species were higher with the use of a ≥ 95% fungal growth inhibition endpoint.

Lay Summary

Spectrophotometrically obtained MIC readings using either ≥ 90% or ≥ 95% fungal growth inhibition endpoints and following the EUCAST methodology are suitable against A. fumigatus sensu stricto. However, the ≥ 95% fungal growth inhibition endpoint is preferred against cryptic species.
Rotation and deformation of strangeon stars in the Lennard-Jones model
Authors: Gao Yong , Lai Xiao-Yu , Shao Lijing , Xu Ren-Xin
Published: November 2021

The strong interactions at low energy scales determine the state of the supranuclear matter in the pulsar-like compact objects. It is proposed that the bulk strong matter could be composed of strangeons, which are quark clusters with a nearly equal number of three light-flavor quarks. In this work, to characterize the strong-repulsive interactions at short distances and the non-relativistic nature of the strangeons, the Lennard-Jones model is used to describe the equation of state (EoS) of strangeon stars (SSs). We investigate the static, the slowly rotating, and the tidally deformed SSs in detail. The corrections resulted from the finite surface densities are considered crucially in the perturbative approaches. We also study the universal relations between the moments of inertia, the tidal deformabilities, and the quadrupole moments. Those results are ready to be used for various purposes in astrophysics, and possible constraints from contemporary observations on the parameter space of the Lennard-Jones model are discussed. Future observations of the pulsars’ radio signals, the X-ray emissions from the hot spots on the surface of the stars, and the gravitational waves (GWs) from binary mergers can give tighter constraints or even verify or falsify the existence of SSs.
Model-independent reconstruction of cosmological accelerated–decelerated phase
Authors: Capozziello Salvatore , Dunsby Peter K S , Luongo Orlando
Published: November 2021

We propose two model-independent methods to obtain constraints on the transition and equivalence redshifts, ztr and zeq, respectively. In particular, we consider ztr as the onset of cosmic acceleration, whereas zeq the redshift at which the densities of dark energy and pressureless matter are equated. With this prescription, we expand the Hubble and deceleration parameters up to two hierarchical orders and show a linear correlation between transition and equivalence, from which we propose exclusion plots where zeq is not allowed to span. To this end, we discuss how to build up cosmographic expansions in terms of ztr and compute the corresponding observable quantities by directly fitting the luminosity and angular distances and the Hubble rate with cosmic data. We make our computations through Monte Carlo fits involving Type Ia supernova, baryonic acoustic oscillation, and Hubble most recent data catalogues. We show that at 1σ confidence level the Lambda cold dark matter predictions on ztr and zeq are slightly confirmed, although at 2σ confidence level dark energy expectations cannot be excluded. Finally, we theoretically interpret our outcomes and discuss possible limitations of our overall approach.
The complex intracluster medium of Abell 1569 and its interaction with central radio galaxies
Authors: Tiwari Juhi , Singh Kulinder Pal
Published: November 2021

We present the first in-depth study of X-ray emission from a nearby (z ∼ 0.0784) galaxy cluster Abell 1569 using an archival Chandra observation. A1569 consists of two unbound subclusters – a northern subcluster (A1569N) hosting a double-lobed radio galaxy 1233+169 at its centre, and a southern subcluster (A1569S) harbouring a wide-angle-tailed (WAT) radio source 1233+168. X-ray emission from A1569N and A1569S extends to a radius r ∼248 kpc and r ∼370 kpc, respectively, indicating that the two gas clumps are group-scale systems. The two subclusters have low X-ray luminosities (∼1042–43 erg s−1), average elemental abundances ∼1/4 Z⊙, low average temperatures (∼2 keV), and lack large (r ≳ 40–50 kpc) cool cores associated with the intracluster gas. We detect a pair of cavities coincident with the radio lobes of 1233+169 in A1569N. The total mechanical power associated with the cavity pair is an order of magnitude larger than the X-ray radiative loss in the cavity-occupied region, providing corroborating evidence for cavity-induced heating of the intragroup gas in A1569N. A1569S exhibits possible evidence for a small-scale cluster-subcluster merger, as indicated by its high central entropy, and the presence of local gas elongation and a density discontinuity in between the bent radio tails of 1233+168. The discontinuity is indicative of a weak merger shock with Mach Number, M ∼ 1.7. The most plausible geometry for the ongoing interaction is a head-on merger occurring between A1569S and a subcluster falling in from the west along the line bisecting the WAT tails.
Management of heterogeneous tumor response patterns to immunotherapy in patients with metastatic melanoma
Authors: Jan Willem Rauwerdink Daan , van Persijn van Meerten Els , van der Hage Jos , Kapiteijn Ellen
Published: November 2021

Immunotherapy has revolutionized the treatment of metastatic melanoma. Response to therapy can be complex to evaluate, as Response Evaluation Criteria in Solid Tumor (RECIST) does not capture heterogeneous responses. In this retrospective single-institution analysis, we describe the management, clinicopathological characteristics, RECIST and disease course of metastatic melanoma patients with a heterogeneous response to first-line anti-CLTA-4 and/or anti-PD-1 between September 2011 and September 2020. In 196 patients, 37 had a heterogeneous response to immunotherapy (19%). Distinct identified responses included a mixed response (MR) (15%), pseudoprogressive disease (PP) (3%), and a sarcoid-like reaction (2%). Patients with a MR and possibly no response to therapy (MR-NR) had a higher median lactic acid dehydrogenase (LDH) (P = 0.01), were more often male (P = 0.04), had more involved disease sites (P = 0.01), and had brain metastasis more frequently (P = 0.02). MR patients with later response to therapy (MR-R) and PP patients had a longer overall survival of 1.7 [95% confidence interval (CI), 1.1–2.7] and 1.6 years (95% CI, 1.3–2.0) versus MR-NR 1.2 (0.7–1.7) (P < 0.01). In this cohort study, we identified prognostic clinical characteristics that can contribute to clinical decision-making for patients with a MR. Additionally, patients with pseudoprogression had benefited from therapy continuation, suggesting the importance of not halting therapy early in case of suspected PP. The male sex, more involved disease sites, brain metastasis and had a higher median LDH were associated with a poor survival for patients with a MR, suggesting that these clinical variables could be used to predict whether a mixed responder will possibly respond to therapy.
Merkel Cell Carcinoma In Situ: No More Serendipity?
Authors: Brem Candice E. , Wolpowitz Deon , Chang Kyung Hee , Bhawan Jag
Published: November 2021

A 50-year-old man, with a history of extensive sun exposure and multiple previous non-melanoma skin cancers, presented with an asymptomatic 8-× 10-millimeter scaly, skin-colored papule on his right shoulder. Subsequent biopsy and excision revealed epidermal hyperplasia containing large atypical basaloid cells with pagetoid spread. Immunoperoxidase staining for cytokeratin-20 demonstrated a focal perinuclear dot-like pattern, and after excluding other in situ entities, a diagnosis of Merkel cell carcinoma In Situ (MCCIS) was rendered. MCCIS is a very rare entity. Although approximately 18% of Merkel cell carcinomas have epidermal involvement, currently only 17 cases of MCCIS have been reported, of which only 7 had no associated neoplasm. Previously, MCCIS was considered a serendipitous or incidental finding, as most cases co-existed with squamous cell carcinoma in situ. This case is unique in that it was not associated with a squamous lesion, and in addition, the pagetoid spread was unusual and has only occasionally been described. As such, MCCIS should be added to list of in situ epidermal lesions with pagetoid spread.
Primary Dermal Melanoma: A Case Report
Authors: Weiss Amy , Christensen Rachel E. , Maghari Amin , Wassef Cindy
Published: November 2021

Primary dermal melanoma (PDM) is defined as a primary melanoma tumor confined to the dermis, subcutis, or both, without epidermal involvement. The significant overlap of histopathological features in PDM and cutaneous metastatic melanoma makes diagnostic accuracy of PDM challenging. We present a case of a 48-year-old man with a nontender 1.5 × 1.5 cm subcutaneous nodule on the left leg, which had been present for years. Biopsy revealed a dermal tumor with melanocytic differentiation noted to be positive for SOX-10. Additional pathology findings included a high Ki-67 proliferation index and a loss of p16 expression. Pathology reports were consistent with primary tumor stage 4a, and the patient was referred to surgical oncology where examination and workup demonstrated no evidence of the residual lesion representing a metastasis from a primary site. As PDM is histologically indistinguishable from melanoma metastasis to the skin, clues including a history of an evolving subepidermal nodule and exclusion of previous or concurrent melanomas can assist in its accurate diagnosis. Currently, a consensus on the criteria, staging, and management of PDM does not exist. Poorly defined diagnostic criteria and general lack of awareness of PDM result in high rates of incorrect and late-stage diagnoses. This case report highlights the importance of physician familiarity with PDM to ensure accurate recognition, evidence-based management, and improved patient outcomes.
Poorly Differentiated Scrotal Carcinoma With Apocrine Immunophenotype
Authors: Kamanda Sonia , Epstein Jonathan I. , Osunkoya Adeboye O. , Cimino-Mathews Ashley , Argani Pedram , Sangüeza Martin , Plaza Jose Antonio , Matoso Andres
Published: November 2021

Cutaneous carcinoma of the scrotum is rare with the most common type being squamous cell carcinoma. Here, we report 6 cases of poorly differentiated carcinoma with apocrine immunophenotype. Mean age at presentation was 68 years (range: 31–91 years). Clinical presentation included eczematous rash over mass, scrotal cyst, ulcerated mass, and mass. Tumor size ranged from 1.2 to 5.5 cm (average 2.5 cm). The tumors were solid with involvement of the dermis/hypodermis and composed of cords and nests of eosinophilic cells displaying nuclei with prominent nucleoli and surrounded by desmoplastic stroma. Focal squamous differentiation was evident in one case (17%). An intraductal component was seen in one case (17%). Pagetoid spread in the epidermis was seen in 3 cases. There was no morphologic evidence of apocrine differentiation. By immunohistochemistry, the tumor cells were positive for GCDFP-15 (n = 6/6), GATA3 (n = 6/6), CK7 (n = 5/5), AR (n = 4/4), and mammaglobin (n = 3/5). Five (83%) patients had metastases at diagnosis. Treatment included wide local excisions and inguinal lymph node dissection, followed by chemotherapy (gemcitabine, carboplatin; n = 3), trastuzumab/Lupron (n = 1), tamoxifen/Arimidex (n = 1), and radiotherapy (n = 1). Two patients (40%) were dead of disease, less than 2 years from diagnosis. Four patients developed metastases to lymph nodes, liver, bones, and lungs. Molecular analysis (n = 2) detected a HER-2 mutation in one and microsatellite instability in another. Although the presence of an intraepidermal pagetoid component could hint toward the diagnosis of invasive extramammary Paget disease, tumors without an intraepidermal component could be diagnostically challenging given the lack of morphologic evidence of apocrine differentiation.
The challenging screen detection of ovarian cancer in BRCA mutation carriers adhering to a 6-month follow-up program: results from a 6-years surveillance
Authors: Grandi Giovanni , Fiocchi Federica , Cortesi Laura , Toss Angela , Boselli Fausto , Sammarini Margaret , Sighinolfi Giovanna , Facchinetti Fabio
Published: November 2021

Objective:

Approximately 25% of ovarian cancer (OC) cases are related to an inherited predisposition. Genetic mutations for the oncosuppressor genes BRCA1 and 2 have the best-known linkage to a higher incidence of OC and breast cancer, in approximately 70% to 80% of hereditary OC cases. To provide the first comprehensive clinical description of screen-detected (SD) OCs during a 6-years surveillance of a cohort of young BRCA carriers and carriers who refuse risk-reducing salpingo-oophorectomy.

Methods:

A prospective cohort study in a university hospital describing 191 women with BRCA1 and 2 mutations adhering continuously to our surveillance between 2015 and 2020, including a 6-monthly evaluation of cancer antigen 125 (CA 125) with concomitant transvaginal ultrasound (TVUS) performed by a dedicated specialist. Main outcomes were tumor's laterality, CA 125 at diagnosis, TVUS and computed tomography (CT) findings.

Results:

Risk-reducing salpingo-oophorectomy was performed in 58/191 (30.4%) of mutation carriers during the study period (one OC case identified). Nine SD-OCs and no interval OCs were found in the remaining 133 women. OCs (FIGO stage I or II: 88.9%) occur mainly in BRCA 1 (77.8%), being bilateral in 85.7% BRCA 1 and unilateral in 100% BRCA 2. No lesions involved only the tubes: left ovaries/tubes were more frequently involved. We have described three new possible scenarios regarding imaging: 1) Evident cases (33.3%, TVUS and CT obvious for OC, CA 125 sensitivity: 100%), 2) Possible cases (55.6%, TVUS and CT are in general accordance, documenting new TVUS signs: increased solid pattern of the ovary with peripheral cortical small cysts, hypoechoic circular mass near the ovary, intraparenchymal small hyperechoic foci), and 3) Hidden cases (11.1%, the smallest lesion but the highest stage (IIIA2), with CA 125 44.2 U/mL and concomitant endometrial hyperplasia).

Conclusions:

Different diagnostic tools must integrate to ensure early diagnosis of OC in BRCA mutation carriers adhering to a follow-up program.
Factors Affecting Lower-pole Stretch after Breast Augmentation
Authors: Weniger Frederick G. , Barrero Carlos E. , Weidman Allan A. , Amarillo Sarah M.
Published: November 2021

Background:

Breast augmentation surgical planning based on soft-tissue characteristics including the type of lower-pole pocket direction has been described. Objective outcome measures of the effects of some of these choices on postoperative lower-pole settling, including dual-plane dissection type, have been lacking.

Objective:

The aim of this study was to determine whether the type/extent of dual-plane dissection, patient age, or variables in breast implant characteristics affected implant–soft tissue dynamics of the lower pole of the breast enough to cause difference in implant settling during the postoperative period.

Methods:

Measurements of nipple-to-inframammary fold distance in primary breast augmentation patients were collected prospectively for 227 female primary breast augmentation patients during postoperative visits over an 8-year period. Changes in this distance during the postoperative period were evaluated for correlation with dual-plane dissection type, patient age, implant fill material, implant size, and implant profile.

Results:

Increasing dual-plane dissection type did demonstrate a trend toward greater postoperative lower-pole stretch. Only implant profile affected lower-pole stretch, with statistical significance shown in the ultrahigh-profile group. Age, implant fill material, and size of implant did not show any notable effect.

Conclusions:

Ultrahigh-profile implants cause significantly more lower-pole stretch postoperatively, whereas increasing dual-plane dissection type appears to have some effect as well. Age, implant material, and size of implant are of less importance over a 6-month period.
An Unoperated Crouzon Family Treated with Monobloc Distraction: Challenges and Lessons
Authors: Hart Justin , Lu Stephen , Gasteratos Konstantinos , Chaiyasate Kongkrit
Published: November 2021

Background:

Crouzon syndrome (CS) is a rare form of craniosynostosis characterized by bicoronal craniosynostosis and facial features including severe midface hypoplasia, exophthalmos, and hypertelorism. Most patients are diagnosed and treated in early childhood; however, there are a few reports of Crouzon patients treated as adults with monobloc facial advancement. To our knowledge, this is the first report of a family affected by CS treated sequentially with monobloc facial advancement using combined internal and external distraction osteogenesis (rigid external distraction).

Methods:

We present a family from Jamaica (mother 47 years old, older daughter 17, and younger daughter 9) who were brought to our craniofacial clinic with stigmata of CS and no previous surgical intervention. Patients had bicoronal craniosynostosis and exorbitism, with varying severity, sequelae, and comorbidities. Here, we delineate our technique of monobloc distraction osteogenesis with advancement osteotomies using dual “push–pull” method, elevation of a split anteriorly based tunneled pericranial flap to seal off nasal cavity, and internal and external distraction.

Results:

Our patients had favorable outcomes after reconstruction to reduce ocular symptoms and improve midface hypoplasia and aesthetic appearance. No intracranial injury, hardware/soft-tissue infection, hardware failure, or (new) loss of vision were encountered in 10 months follow-up.

Conclusions:

Dual “push–pull” monobloc distraction is safe and effective for a range of ages in CS; it allows good vector control, accommodates patient compliance, and allows early rigid external distraction device removal with sufficient time for consolidation. This surgery can be performed with highly satisfactory results.
Upper Lip Reconstruction Using Fujimori Gate Flap in an Electrical Burn Patient
Authors: Poncio Mar Aristeo G. , Nable-Aguilera Ma. Adela
Published: November 2021

The Fujimori gate flap has been known and used for reconstruction of defects resulting from oncologic surgery. In this case report, we describe how this flap was utilized in reconstructing the upper lip of a patient who experienced an electrical burn injury resulting in 70% tissue loss of the upper lip with exposed alveolar bone. A 22-year-old man presented to our institution with near total full-thickness burn over the upper lip, deep partial thickness burns over left upper lid, and superficial partial thickness burns over both malar areas, anterior chest, and both legs. He underwent full-thickness skin grafting of the left upper lid and upper cutaneous lip. After 3 weeks, a unilateral gate flap was performed. The flap was elevated with care to preserve the right angular artery and the Stensen’s duct. The flap was rotated 90 degrees medially and was sutured to the contralateral orbicularis oris, gingivobuccal mucosa, and to the rest of the upper cutaneous lip. The patient was followed up at 6 months and 1 year postoperatively. The flap was able to restore oral competence and enabled the patient to speak and chew with no difficulty. Patients suffering from high-voltage electrical burns, especially involving the mouth, present a challenging case for surgeons for reconstruction. Here, the goals of the reconstruction are to restore oral competence and ability to articulate, and still provide good appearance. A feasible and aesthetically acceptable flap providing good functional outcome is provided by the use of the unilateral Fujimori gate flap among patients suffering from high-voltage electrical burns of the oral cavity.
Accessible, Open-source Hardware and Process Designs for 3D Bioprinting and Culturing Channels Lined with iPSC-derived Vascular Endothelial Cells
Authors: Gross Andrew R , Santos Roberta S. , Sareen Dhruv
Published: November 2021

Indirect bioprinting for cell culture requires the use of several technologies and techniques which currently prevent many researchers not specialized in electrical engineering or materials science from accessing these new tools. In this paper, a printer and all necessary associated hardware was developed and tested for the purpose of seeding human induced Pluripotent Stem Cell (iPSC)-derived endothelial cells (iECs) onto all surfaces of a fibringelatin channel. Immature iECs were seeded onto all channel surfaces and completed differentiation along channel walls. All required tools and methods, including engineering drawing, printable files, code, and hand-tool templates, have been provided with sufficient clarity to enable full, open-source replication of all technique employed.
Inhibition of SAR S-CoV-2 infection and replication by lactoferrin, MUC1 and α-lactalbumin identified in human breastmilk
Authors: Lai Xinyuan , Yu Yanying , Xian Wei , Ye Fei , Ju Xiaohui , Luo Yuqian , Dong Huijun , Zhou Yihua , Tan Wenjie , Zhuang Hui , Li Tong , Liu Xiaoyun , Ding Qiang , Xiang Kuanhui
Published: November 2021

The global pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection confers great threat to the public health. Human breastmilk is an extremely complex with nutritional composition to nourish infants and protect them from different kinds of infection diseases and also SARS-CoV-2 infection. Previous studies have found that breastmilk exhibited potent antiviral activity against SARS-CoV-2 infection. However, it is still unknown which component(s) in the breastmilk is responsible for its antiviral activity. Here, we identified Lactoferrin (LF), MUC1 and α-Lactalbumin (α-LA) from human breastmilk by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and in vitro confirmation that inhibited SARS-CoV-2 infection and analyzed their antiviral activity using the SARS-CoV-2 pseudovirus system and transcription and replication-competent SARS-CoV-2 virus-like-particles (trVLP) in the Huh7.5, Vero E6 and Caco-2-N cell lines. Additionally, we found that LF and MUC1 could inhibit viral attachment, entry and post-entry replication, while α-LA just inhibit viral attachment and entry. Importantly, LF, MUC1 and α-LA possess potent antiviral activities towards not only wild-type but also variants such as B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma) and B.1.617.1 (kappa). Moreover, LF from other species (e.g., bovine and goat) is still capable of blocking viral attachment to cellular heparan sulfate. Taken together, our study provided the first line of evidence that human breastmilk components (LF, MUC1 and α-LA) are promising therapeutic candidates warranting further development or treatingVID-19 given their exceedingly safety levels.
WY14643 Increases Herpesvirus Replication Independently of PPARα Expression and Inhibits IFNβ Production
Authors: Tao Lili , Dryden Phillip , Lowe Alexandria , Wang Guoxun , Dozmorov Igor , Chang Tyron , Reese Tiffany A.
Published: November 2021

Peroxisome proliferator activated receptor (PPAR) agonists are commonly used to treat metabolic disorders in humans because they regulate fatty acid oxidation and cholesterol metabolism. In addition to their roles in controlling metabolism, PPAR agonists also regulate inflammation and are immunosuppressive in models of autoimmunity. We aimed to test whether activation of PPARα with clinically relevant ligands could impact herpesvirus infection using the model strain murine gammaherpesvirus-68. We found that PPARα agonists WY14643 and fenofibrate increased herpesvirus replication in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARα. Investigating the mechanism of action for WY14643, we found that it suppresses production of type I interferon by inhibiting stimulator of interferon (STING), which lies downstream of the cytoplasmic DNA sensor cGAS. Thus, WY14643 regulates interferon downstream of cytoplasmic DNA recognition and increases herpesvirus replication in a PPARα-independent manner. Taken together, our data indicate that caution should be employed when using PPARα agonists in immuno-metabolic studies, as they can have off-target effects on viral replication.

Importance

PPAR agonists are used clinically to treat both metabolic and inflammatory disorders. Because viruses are known to rewire host metabolism to their own benefit, the intersection of immunity, metabolism, and virology is an important research area. Our article is an important contribution to this field because for two reasons. First, it shows a role for PPARα agonists in altering virus detection by cells. Second, it shows that PPARα agonists can affect virus replication in a manner unrelated to their expected genetic function. This knowledge is valuable for anyone seeking to use PPARα agonists as a research tool.
Nuclear activation in dual-durotaxing cells on a matrix with cell-scale stiffness-heterogeneity
Authors: Kidoaki Satoru , Ebata Hiroyuki , Moriyama Kosuke , Kuboki Thasaneeya , Tsuji Yukie , Sawada Rumi , Sasaki Saori , Okuda Tatsuya , Hamano Kosuke , Kawano Takahito , Yamamoto Aki , Kono Ken , Tanaka Kazusa
Published: November 2021

Living organisms are typically composed of various tissues with microscopic cell-scale stiffness-heterogeneity, in which some cells receive dynamically fluctuating mechanical stimuli from the heterogeneous extracellular milieu during long-term movement. Although intracellular stress dynamics (ISD), which are closely related to the regulation of cell functions such as proliferation and differentiation, can be characteristically modulated in cells migrating on a matrix with stiffness-heterogeneity, it has been unclear how the mode of fluctuation of ISD affects cell functions. In the present study, we demonstrate that mesenchymal stem cells (MSCs) dual-durotaxing (i.e., both forward and reverse durotaxis) on microelastically-patterned gels with stiff triangular domains markedly amplify the fluctuation of ISD, nuclear shape, and the spatial distribution of chromatins, which makes the cells remain far from tensional equilibrium. We provide evidence that amplified chromatin fluctuation in the dual-durotaxing MSCs can cause activation of cellular vigor and maintenance of the stemness.