bluuebunny/crossref_metadata_2025 huggingface dataset:
Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2+breast cancer by ceramide-loaded nanoparticles
Authors: Kumar Sandeep , Das Subhasis , Sun Jingjing , Huang Yixian , Singh Sunil Kumar , Srivastava Piush , Sondarva Gautam , Nair Rakesh Sathish , Viswakarma Navin , Ganesh Balaji B. , Duan Lei , Maki Carl G. , Hoskins Kent , Danciu Oana , Rana Basabi , Li Song , Rana Ajay
Published: September 2022

Trastuzumab is the first-line therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but often patients develop acquired resistance. Although other agents are in clinical use to treat trastuzumab-resistant (TR) breast cancer; still, the patients develop recurrent metastatic disease. One of the primary mechanisms of acquired resistance is the shedding/loss of the HER2 extracellular domain, where trastuzumab binds. We envisioned any new agent acting downstream of the HER2 should overcome trastuzumab resistance. The mixed lineage kinase 3 (MLK3) activation by trastuzumab is necessary for promoting cell death in HER2+breast cancer. We designed nanoparticles loaded with MLK3 agonist ceramide (PPP-CNP) and tested their efficacy in sensitizing TR cell lines, patient-derived organoids, and patient-derived xenograft (PDX). The PPP-CNP activated MLK3, its downstream JNK kinase activity, and down-regulated AKT pathway signaling in TR cell lines and PDX. The activation of MLK3 and down-regulation of AKT signaling by PPP-CNP induced cell death and inhibited cellular proliferation in TR cells and PDX. The apoptosis in TR cells was dependent on increased CD70 protein expression and caspase-9 and caspase-3 activities by PPP-CNP. The PPP-CNP treatment alike increased the expression of CD70, CD27, cleaved caspase-9, and caspase-3 with a concurrent tumor burden reduction of TR PDX. Moreover, the expressions of CD70 and ceramide levels were lower in TR than sensitive HER2+human breast tumors. Our in vitro and preclinical animal models suggest that activating the MLK3–CD70 axis by the PPP-CNP could sensitize/overcome trastuzumab resistance in HER2+breast cancer.
Electric fields control water-gated proton transfer in cytochrome
c
oxidase
Authors: Saura Patricia , Riepl Daniel , Frey Daniel M. , Wikström Mårten , Kaila Ville R. I.
Published: September 2022

Aerobic life is powered by membrane-bound enzymes that catalyze the transfer of electrons to oxygen and protons across a biological membrane. Cytochrome
c
oxidase (C
c
O) functions as a terminal electron acceptor in mitochondrial and bacterial respiratory chains, driving cellular respiration and transducing the free energy from O
2
reduction into proton pumping. Here we show that C
c
O creates orientated electric fields around a nonpolar cavity next to the active site, establishing a molecular switch that directs the protons along distinct pathways. By combining large-scale quantum chemical density functional theory (DFT) calculations with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations and atomistic molecular dynamics (MD) explorations, we find that reduction of the electron donor, heme
a
, leads to dissociation of an arginine (Arg438)–heme
a
3
D-propionate ion-pair. This ion-pair dissociation creates a strong electric field of up to 1 V Å
−1
along a water-mediated proton array leading to a transient proton loading site (PLS) near the active site. Protonation of the PLS triggers the reduction of the active site, which in turn aligns the electric field vectors along a second, “chemical,” proton pathway. We find a linear energy relationship of the proton transfer barrier with the electric field strength that explains the effectivity of the gating process. Our mechanism shows distinct similarities to principles also found in other energy-converting enzymes, suggesting that orientated electric fields generally control enzyme catalysis.
A common vesicle proteome drives fungal biofilm development
Authors: Zarnowski Robert , Sanchez Hiram , Jaromin Anna , Zarnowska Urszula J. , Nett Jeniel E. , Mitchell Aaron P. , Andes David
Published: September 2022

Extracellular vesicles mediate community interactions among cells ranging from unicellular microbes to complex vertebrates. Extracellular vesicles of the fungal pathogen
Candida albicans
are vital for biofilm communities to produce matrix, which confers environmental protection and modulates community dispersion. Infections are increasingly due to diverse
Candida
species, such as the emerging pathogen
Candida auris
, as well as mixed
Candida
communities. Here, we define the composition and function of biofilm-associated vesicles among five species across the
Candida
genus. We find similarities in vesicle size and release over the biofilm lifespan. Whereas overall cargo proteomes differ dramatically among species, a group of 36 common proteins is enriched for orthologs of
C. albicans
biofilm mediators. To understand the function of this set of proteins, we asked whether mutants in select components were important for key biofilm processes, including drug tolerance and dispersion. We found that the majority of these cargo components impact one or both biofilm processes across all five species. Exogenous delivery of wild-type vesicle cargo returned mutant phenotypes toward wild type. To assess the impact of vesicle cargo on interspecies interactions, we performed cross-species vesicle addition and observed functional complementation for both biofilm phenotypes. We explored the biologic relevance of this cross-species biofilm interaction in mixed species and mutant studies examining the drug-resistance phenotype. We found a majority of biofilm interactions among species restored the community’s wild-type behavior. Our studies indicate that vesicles influence the development of protective monomicrobial and mixed microbial biofilm communities.
Exchange Structure: Refinements to the model through a study of multiparty discourse of 4 to 5 year-old children
Authors: Berry Margaret , Mukherjee Sarah Jane
Published: September 2022

This paper proposes a number of refinements to the original theory of Exchange Structure as first conceived. It first offers a summary of the early ideas and considers challenges made by others. The study responds to these challenges through new analysis of multiparty discourse. The paper discusses revisions to the model based on these challenges drawing on the iterative analysis conducted and considers other points relevant to multiparty discourse. The data is drawn from transcribed video recordings of small groups of 4 to 5 year-old children’s peer-led dialogic interactions as they engage in role-play. In addition to the development of Exchange Structure theory, this new analysis sheds light on the nature of negotiation within multiparty discourse and the dynamics of negotiation by young children in this playful context.
The origin and the development of 焉 yān in Old Chinese
Authors: Chang Jung-Im
Published: September 2022

The Old Chinese function word 焉 yān is frequently interpreted as a fusion of [於 (‘at/on/in’) + 此 (near demonstrative pronoun)] in terms of its meaning. Ever since Kennedy (1940a, b; 1953) argued that 焉 is a fusion of [於 + *an (third-person pronoun)], it has been controversial as to exactly which third-person pronoun/demonstrative pronoun *an corresponds to in Old Chinese. There is no third-person pronoun/demonstrative pronoun that is appropriate for this reconstruction.

This paper illustrates how 焉 *Ɂan is a fusion of 於 *Ɂa and *niɁ; *nih or *nɔɁ; *nɔh, which means ‘this’ in Proto-Austroasiatic (PAA). The demonstrative is borrowed into Chinese through language contact in the Early Archaic Chinese period (10th to 6th c. BC). This fusion is plausible in historical and phonological terms, while the grammaticalization path of 焉 also accords with that of [於 + demonstrative].

The grammaticalization path of 焉 is examined by analyzing all occurrences of it in the Bronze Inscriptions (BI), The book of odes (Shījīng 詩經), The book of documents (Shàngshū 尚書), and Zuo’s commentary (Zuǒzhuàn 左傳). Also, the usages of its etymological doublet 爰, which is considered to be a fusion of [于 *wa (‘at/on/in’) + near demonstrative pronoun], are analyzed in order to strengthen the argument.
On the “one+verbal classifier” sequence as a delimitative aspect marker in Taiwanese Southern Min
Authors: Hsieh Miao-Ling , Hsiao Su-Ying
Published: September 2022

This paper studies the “one+verbal classifier” sequencetsi̍t-ēthat appears after an indefinite object complement in Taiwanese Southern Min. We call it the post-complement (PC)tsi̍t-ē. While thetsi̍t-ēsequence can be a durative phrase when it is immediately preceded by a verb, the PCtsi̍t-ēcannot be replaced by the durative phrasetsi̍t-ē-á‘a while’ (tsi̍t-ēplus the diminutive suffixá) or other durative phrases. We show that the PCtsi̍t-ēis a sentence-final particle, not a durative phrase serving as a predicate or complement. Moreover, it marks delimitativity, which means ‘termination in a short time.’ It is the same kind of delimitativity that verb reduplication in Mandarin Chinese expresses despite the fact that the latter targets on the verb and is more selective in terms of the verb types that it can occur with. Moreover, the PCtsi̍t-ēcarries the ‘down-play’ meaning. Syntactically, we suggest that it heads an AspP, which occurs above avP.
Formation and constraints of scalar structure in Taiwanese Southern Min
Authors: Lien Chinfa
Published: September 2022

The paper explores the formation and constraint of an aspect of scalar structure in Taiwanese Southern Min (TSM). The scale structure as we understand it is realized as a relation between the degree adverb and the gradable predicates it selects. The gradable predicate that the degree adverb selects must bear the feature of degree. There are two approaches to compose the degree adverb and the gradable predicates it modifies: (1) the top-down construal and (2) the bottom-up construal. The first approach is simple and straightforward and applicable in most cases. However, there will be difficulties when the immediate modified element is an ambivalent element. A way out of the dilemma is the second approach. We give a unitary account ofu7-headed VP constructions in terms of the bottom-up approach, and if viable, it attains a measure of economy. This study also touches on the parametric variations in TSM vis-à-vis Mandarin in the patterns of degree expressions. Such variations in the degree expressions have some implications in the studies of Sinitic languages as well as language universals.
Lifetime extension of gears and main bearings in wind turbines, scientific calculations and practical implementation
Authors: Bill S , Bill V
Published: September 2022

REWITEC, as a part of Cargill Bioindustrial, is a developer and manufacturer of an innovative particle-based surface treatment phyllosilicate-technology for increasing the reliability and the lifetime of wind turbine gears and bearings. The active particles are compatible to all common oils and greases and use lubricants as a carrier to build through their adsorption a protective and repairing phyllosilicate-based coating on the surface. The modified surface has a significantly lower surface roughness, which ensures a better load distribution, lower local pressure and lower tribological stress. Additionally, due to the special layered material structure the particles can be sheared in the tribological contact, which leads to a reduction in friction. All in all, when applying the products systems can run better with reduced friction, wear, surface roughness and temperature. These effects lead to higher reliability and a longer lifetime and thus to cost savings for operators. We would like to show our new scientific study about the lifetime calculation of a grease-lubricated wind turbine main bearing (1.5 MW) with and without the use of technology. The project is a cooperation between REWITEC and Sentient Science who performs lifetime calculations using digital clone method based on real friction coefficient and surface roughness data. The project includes data generation using MTM test bench, in a wind turbine bearing and subsequent simulation based on this data and bearing geometry. The simulation shows that with REWITEC the probability for a bearing failure significantly decreases which leads to a lifetime extension of up to 17.3 years.
Study of blockage and wakes for an on-shore Wind Farm using SCADA data and CFD simulations
Authors: Castellani F. , Khedr A. , Astolfi D. , Celesti L. , Natili F. , Vedovelli M.
Published: September 2022

The ever-changing energy scenario call for a central role of wind energy exploitation within the renewable energy portfolio; the wind resource nowadays is a very precious means of clean energy production and year by year its degree of reliability and efficiency is pushed towards the optimum. For these reasons two topics are now very important for the improving further the conversion performances: the study of the blockage, as nowadays a lot of machines are planned to be installed in the neighbors of existing ones, and the analysis of wakes, as they represent still the main source of losses and reliability issues. For this reason in the present study, which is an example of collaboration between academia and industry, a deep analysis of wind farm flow, blockage, and wake effects was developed using numerical simulations and real-world operational data from an on-shore windfarm owned by Lucky Wind. Results demonstrate the fundamental role of CFD numerical simulation in understanding and interpreting the complex physics of wakes and the overall importance of blockage effects.
Urban Renewable Energy Communities and Energy Poverty: a proactive approach to energy transition with Sun4All project
Authors: Cumo F. , Maurelli P. , Pennacchia E. , Rosa F.
Published: September 2022

The transition to an environmentally sustainable, low-carbon economy requires fundamental transformations in various sectors such as industry, technology, and especially in society as a whole. Adopting and encouraging community energy are the key policies to facilitate sustainable energy and ecological and social transition. The Sun4All methodology aims at the design, promotion and building of energy communities based on solidarity, to contrast energy poverty and foresee the engagement of vulnerable households that normally have many difficulties in becoming active members of an energy sharing project realising PV plants. The selection of the beneficiaries’ families in the urban context is a process both technical, including socio-territorial GIS-based analysis, and social, activating the participation of grass-root associations, local schools, and facilitators. The strategic role of the municipality is coherent with the SECAP and results in the offers of several public building roofs with PV plants that are the cores of the Sun4all Energy Communities and will ensure the delivery of economic benefits for the vulnerable households, while through workshops, site visits to the plants, and communication activities will increase the citizens’ knowledge. The purpose of this paper is to explore the benefits that go far beyond energy efficiency, which is only the starting point.
Sunflowers: from soil to oil
Authors: Rao Anup
Published: September 2022

A sunflower is a collection of sets whose pairwise intersections are identical. In this article, we shall go sunflower-picking. We find sunflowers in several seemingly unrelated fields, before turning to discuss recent progress on the famous sunflower conjecture of Erdős and Rado, made by Alweiss, Lovett, Wu, and Zhang, as well as a related resolution of the threshold vs expectation threshold conjecture of Kahn and Kalai discovered by Park and Pham. We give short proofs for both of these results.
Clinical Risk Factors For Kidney Tubule Biomarker Abnormalities Among Hypertensive Adults With Reduced eGFR in the SPRINT Trial
Authors: Ikeme Jesse C , Katz Ronit , Muiru Anthony N , Estrella Michelle M , Scherzer Rebecca , Garimella Pranav S , Hallan Stein I , Peralta Carmen A , Ix Joachim H , Shlipak Michael G
Published: September 2022

BACKGROUND

Urine biomarkers of kidney tubule health may distinguish aspects of kidney damage that cannot be captured by current glomerular measures. Associations of clinical risk factors with specific kidney tubule biomarkers have not been evaluated in detail.

METHODS

We performed a cross-sectional study in the Systolic Blood Pressure Intervention Trial among 2,436 participants with a baseline estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Associations between demographic and clinical characteristics with urine biomarkers of kidney tubule health were evaluated using simultaneous multivariable linear regression of selected variables.

RESULTS

Each standard deviation higher age (9 years) was associated with 13% higher levels of chitinase-3-like protein-1 (YKL-40), indicating higher levels of tubulointerstitial inflammation and repair. Men had 31% higher levels of alpha-1 microglobulin and 16% higher levels of beta-2 microglobulin, reflecting worse tubule resorptive function. Black race was associated with significantly higher levels of neutrophil gelatinase-associated lipocalin (12%) and lower kidney injury molecule-1 (26%) and uromodulin (22%). Each standard deviation (SD) higher systolic blood pressure (SBP) (16 mmHg) was associated with 10% higher beta-2 microglobulin and 10% higher alpha-1 microglobulin, reflecting lower tubule resorptive function.

CONCLUSIONS

Clinical and demographic characteristics, such as race, sex, and elevated SBP, are associated with unique profiles of tubular damage, which could reflect under-recognized patterns of kidney tubule disease among persons with decreased eGFR.
Aortopulmonary communication between the arterial trunks in tetralogy of Fallot with pulmonary atresia
Authors: Zhou Ruofan , Li Xiao , Luo Shuhua
Published: September 2022

We reported a case of a 14-year-old tetralogy of Fallot/pulmonary atresia patient, where a rare tubular aortopulmonary communication between the arterial trunks allowed for well-growth of the pulmonary vasculature. The patient underwent successful one-stage unifocalization, right ventricle-pulmonary artery conduit and ventricular septal defect closure. The tubular communication was considered an aortopulmonary window as opposed to the major aortopulmonary collateral, based on its exclusively intrapericardial course. We highlighted the importance of cross-section imaging in diagnosis and surgical decision-making in such situations.
Sub-inhibitory concentrations of cefotaxime treatment enhances biofilm formation of monophasic Salmonella Typhimurium variant strain SH16SP46
Authors: Zhang Xiuling , Wang Mengran , Bao Xue , Li Pengyun , Cui Ailian , Meng Xianrong , Huang Qi , Li Shaowen
Published: September 2022

Salmonella is one of the most important foodborne and zoonotic pathogens, and monophasic S. Typhimurium is ranked among the top-five Salmonella serovars causing animal and human infections worldwide. Resistance to the third- and higher-generation cephalosporins in Salmonella has attracted great attention. Bacteria are frequently exposed to sub-minimal inhibitory concentrations (sub-MICs) of antimicrobials that can trigger diverse adaptive responses such as biofilm formation. Biofilms can promote bacterial defense to external and internal harsh conditions. This study aimed to investigate the effect of sub-MICs of cefotaxime, one of the third-generation cephalosporins, on biofilm formation by non-clinical S. enterica strains. Crystal violet staining demonstrated that cefotaxime at 1/8 MIC enhanced biofilm formation by two monophasic S. Typhimurium strains. Confocal laser scanning microscopy and enzymatic treatment assay revealed that cellulose was the most dominant extracellular matrix component contributing to Salmonella biofilm formation. Scanning electron microscopy demonstrated that cefotaxime treatment led to bacterial incomplete cell division and filamentous morphology during the whole process of biofilm formation. Our study is the first to report the enhancement effect of cefotaxime on non-clinical, monophasic S. Typhimurium by affecting bacterial morphology. The results will contribute to conducting risk assessments of Salmonella in the pork production chain and guiding the rational use of antimicrobial agents to reduce the risk of biofilm formation.
Association between patient-reported outcomes and impairments in work and activity in patients with rheumatoid arthritis in clinical remission: A retrospective analysis using the IORRA database
Authors: Sakai Ryoko , Tanaka Eiichi , Inoue Eisuke , Sato Minako , Tanaka Masaru , Ikari Katsunori , Yamanaka Hisashi , Harigai Masayoshi
Published: September 2022

Objectives

To explore the patient-reported outcomes (PROs) associated with work productivity and activity impairment (WPAI) in patients with rheumatoid arthritis (RA) in clinical remission.

Methods

We enrolled patients with RA ≥18 years and with a simplified disease activity index ≤3.3 from the Institute of Rheumatology, Rheumatoid Arthritis data set collected in October 2017. The pain-visual analogue scale, patients’ global assessment visual analogue scale (VAS), Japanese version of the Healthcare Assessment Questionnaire (J-HAQ) Disability Index, and duration of morning joint stiffness were selected as the PROs. To evaluate work productivity and activity, the WPAI for RA instrument (WPAI-RA) was used. To assess the contribution of each PRO to the WPAI-RA score, an analysis of variance model was constructed.

Results

The mean age of the 2614 patients was 62.4 years; 85.1% were female. Median values of the WPAI-RA score were 1.1% for absenteeism, 6.5% for presenteeism, 7.4% for work impairment, and 10.2% for activity impairment. Morning joint stiffness contributed the most to absenteeism (18.0%), while pain-VAS contributed the most to presenteeism (57.4%), work productivity loss (51.1%), and daily activity impairment (53.7%). J-HAQ was the second most contributing factor to presenteeism (17.4%), work productivity loss (16.3%), and daily activity impairment (26.0%).

Conclusions

The pain-VAS and J-HAQ highly contributed to WPAI in patients with RA in clinical remission.
Effectiveness and Optimal Duration of Adjunctive Rifampin Treatment in the Management of Staphylococcus aureus Prosthetic Joint Infections After Debridement, Antibiotics, and Implant Retention
Authors: Suzuki Hiroyuki , Goto Michihiko , Nair Rajeshwari , Livorsi Daniel J , Sekar Poorani , Ohl Michael E , Diekema Daniel J , Perencevich Eli N , Alexander Bruce , Jones Michael P , McDaniel Jennifer S , Schweizer Marin L
Published: September 2022

Background

Rifampin is recommended as adjunctive therapy for patients with a Staphylococcus aureus prosthetic joint infection (PJI) managed with debridement, antibiotics, and implant retention (DAIR), with no solid consensus on the optimal duration of therapy. Our study assessed the effectiveness and optimal duration of rifampin for S aureus PJI using Veterans Health Administration (VHA) data.

Methods

We conducted a retrospective cohort study of patients with S aureus PJI managed with DAIR between 2003 and 2019 in VHA hospitals. Patients who died within 14 days after DAIR were excluded. The primary outcome was a time to microbiological recurrence from 15 days up to 2 years after DAIR. Rifampin use was analyzed as a time-varying exposure, and time-dependent hazard ratios (HRs) for recurrence were calculated according to the duration of rifampin treatment.

Results

Among 4624 patients, 842 (18.2%) received at least 1 dose of rifampin; 1785 (38.6%) experienced recurrence within 2 years. Rifampin treatment was associated with significantly lower HRs for recurrence during the first 90 days of treatment (HR, 0.60 [95% confidence interval {CI}, .45–.79]) and between days 91 and 180 (HR, 0.16 [95% CI, .04–.66]) but no statistically significant protective effect was observed with longer than 180 days (HR, 0.57 [95% CI, .18–1.81]). The benefit of rifampin was observed for subgroups including knee PJI, methicillin-susceptible or -resistant S aureus infection, and early or late PJI.

Conclusions

This study supports current guidelines that recommend adjunctive rifampin use for up to 6 months among patients with S aureus PJI treated with DAIR.
The Long-Term Effects of Universal Preschool in Boston
Authors: Gray-Lobe Guthrie , Pathak Parag A , Walters Christopher R
Published: September 2022

We use admissions lotteries to estimate the effects of large-scale public preschool in Boston on college-going, college preparation, standardized test scores, and behavioral outcomes. Preschool enrollment boosts college attendance as well as SAT test taking and high school graduation. Preschool also decreases high school disciplinary measures including juvenile incarceration, but has no detectable effect on state achievement test scores. An analysis of subgroups shows that effects on college enrollment, SAT-taking, and disciplinary outcomes are larger for boys than for girls. Our findings illustrate possibilities for large-scale modern, public preschool and highlight the importance of measuring long-term and non–test score outcomes in evaluating the effectiveness of education programs.
Host Specificity of Soilborne Pathogens inHordeumSpecies and Their Relatives
Authors: Jin Yanlong , Chen Shiqiang , Xu Xiao , Jiang Congcong , He Zhentian , Shen Huiquan , Ji Wanquan , Yang Ping
Published: September 2022

Soilborne pathogens destabilize the yields of Triticeae crops, including barley (Hordeum vulgare L.) and wheat (Triticum aestivum L.). Although genetic resistance derived from relatives of these species has been utilized to prevent rust diseases (i.e., in the wheat-rye 1BL-1RS translocation line), research on resistance against soilborne pathogens remains limited. Here, we performed field trials using 76 genotypes representing 28 Hordeum, six Triticum, and two Aegilops species to examine resistance against three soilborne bymoviruses: barley yellow mosaic virus (BaYMV), barley mild mosaic virus (BaMMV), and wheat yellow mosaic virus (WYMV). We also performed greenhouse tests using the soilborne fungal pathogen Fusarium pseudograminearum, which causes Fusarium crown rot (FCR). Using RT-PCR, we detected BaMMV and BaYMV in several Hordeum species, whereas WYMV induced systemic infection in the Triticum and Aegilops species. The identification of FCR susceptibility in all species examined suggests that F. pseudograminearum is a facultative fungal pathogen in Triticeae. Intraspecies variation in FCR disease severity was observed for several species, pointing to the possibility of exploring host resistance mechanisms. Therefore, by unlocking the host specificity of four soilborne pathogens in Hordeum species and their relatives, we obtained insights for the further exploration of wild sources of soilborne pathogen resistance for future wheat and barley improvement programs.
The Use of a Single Dose of Phenobarbital for Inpatient Management of Benzodiazepine Withdrawal: A Case Report
Authors: Messinger John C. , Hakimi Edmond , Vercollone Lisa
Published: September 2022

Introduction

The current standard of care for physiological dependence to benzodiazepines requires prolonged outpatient tapers, which present challenges for patients and providers. Novel protocols for accelerated benzodiazepine tapers are needed. We describe a case of successful management of benzodiazepine withdrawal in the inpatient setting using a single, loading dose of phenobarbital with adjunctive valproate therapy.

Case Report

A 61-year-old woman with benzodiazepine use disorder using 3 to 4 mg of alprazolam daily presented to an inpatient medically supervised withdrawal unit requesting discontinuation of all benzodiazepines and other recreational substances by the time of discharge. Benzodiazepine withdrawal was treated with a single, loading dose of intravenous phenobarbital in line with an approved protocol for the treatment of alcohol withdrawal, as well as adjunctive valproate therapy. The patient experienced resolution of withdrawal symptoms, had no complications, and ongoing abstinence at 60 days of follow-up.

Discussion

A single loading dose of phenobarbital in the inpatient setting is a viable alternative to prolonged outpatient tapers for the management of benzodiazepine withdrawal. Although this strategy requires further optimization, the prospect of a single-dose treatment for benzodiazepine withdrawal creates exciting opportunities for alternative management options and settings.

Conclusions

This case describes the successful management of benzodiazepine withdrawal syndrome using a single loading dose of intravenous phenobarbital derived from an approved protocol for alcohol withdrawal syndrome.
Anti-MDA5 dermatomyositis: an update from bench to bedside
Authors: Fuzzi Enrico , Gatto Mariele , Zen Margherita , Franco Chiara , Zanatta Elisabetta , Ghirardello Anna , Doria Andrea
Published: September 2022

Purpose of review

This review summarizes the recent developments about anti-MDA5 antibody positive dermatomyositis with a focus on its pathogenesis, clinical features and treatment options of rapidly progressive interstitial lung disease, its most ominous complication.

Recent findings

Anti-MDA5+ dermatomyositis has a heterogeneous clinical spectrum with different patient subsets exhibiting widely different outcomes; severe acute interstitial lung disease is the main factor impacting prognosis. The pathogenetic role of anti-MDA5 antibodies is an active area of investigation.

Anti-MDA5+ dermatomyositis has a wider spectrum of manifestations than previously thought. A high index of suspicion is needed not to miss atypical presentations. In the setting of acute interstitial lung involvement, once a confident diagnosis is made, an aggressive approach with early combined immunosuppression affords the best chances of survival.
A cursed goodbye kiss from severe acute respiratory syndrome-coronavirus-2 to its pediatric hosts: multisystem inflammatory syndrome in children
Authors: Haslak Fatih , Gunalp Aybuke , Kasapcopur Ozgur
Published: September 2022

Purpose of review

We aimed to summarize a novel disease called multisystem inflammatory syndrome in children (MIS-C), which develops several weeks after a severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) illness.

Recent findings

Given the rarity of the disease, the question of why a minority of children develop MIS-C is not known. Certain intrinsic susceptibility factors in the host have been described. In addition to hyperinflammation induced by the innate and acquired immune cells, evidence of molecular mimicry was presented for the disease pathogenesis. As there is an increasing number of infected individuals and mass vaccination schedules, concerns regarding the usefulness of the existing diagnostic criteria sets raised.

Although children are likely to have a milder COVID-19 course compared with adults, MIS-C as a postinfectious and life-threatening complication was reported in the pediatric age. After 2 years of the disease definition, optimal treatment regimes, effective preventive measures, and long-term outcomes are still debated.
Evaluation of Free Valproate Concentration in Critically Ill Patients
Authors: Brown Caitlin S. , Liu JiTong , Riker Richard R. , Mara Kristin C. , Rabinstein Alejandro A. , Fraser Gilles L. , May Teresa L. , Seder David , Gagnon David J.
Published: September 2022

OBJECTIVES:

Protein binding of valproate is variable in ICU patients, and the total valproate concentration does not predict the free valproate concentration, even when correcting for albumin. We sought to quantify valproate free concentration among ICU patients, identify risk factors associated with an increasing free valproate concentration, and evaluate the association between free valproate concentration with potential adverse drug effect.

DESIGN:

Retrospective multicenter cohort study.

SETTING:

Two academic medical centers.

PATIENTS:

Patients greater than or equal to 18 years of age with concomitant free and total valproate concentrations collected in the ICU.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Two-hundred fifty-six patients were included in the study, with a median age of 56 years (42–70) and 65% of patients were male. The median total valproate concentration was 53 µg/mL (38–70 µg/mL), the free valproate concentration was 12 µg/mL (7–20 µg/mL), and the free fraction was 23.6% (17.0–33.9%). Therapeutic discordance between the free and total valproate concentration occurred in 70% of patients. On multivariable analysis, increased free valproate concentration was associated with higher total valproate concentration (per 5 µg/mL increase, increase 1.72 µg/mL, 95% CI, 1.48–1.96) and lower serum albumin (per 1 g/dL decrease, increase 4.60 µg/mL, 95% CI, 2.71–6.49). There was no association between free valproate concentration and adverse effects.

CONCLUSIONS:

The valproate total and free concentration was discordant in the majority of patients (70%). Increased valproate free concentration was associated with hypoalbuminemia and total valproate concentration. Clinical decisions based on total valproate concentration may be incorrect for many ICU patients. Prospective, controlled studies are needed to confirm these findings and their clinical relevance.
New perspectives in liquid biopsy for glioma patients
Authors: Pasqualetti Francesco , Rizzo Milena , Franceschi Sara , Lessi Francesca , Paiar Fabiola , Buffa Francesca M.
Published: September 2022

Purpose of review

Gliomas are the most common primary tumors of the central nervous system. They are characterized by a disappointing prognosis and ineffective therapy that has shown no substantial improvements in the past 20 years. The lack of progress in treating gliomas is linked with the inadequacy of suitable tumor samples to plan translational studies and support laboratory developments. To overcome the use of tumor tissue, this commentary review aims to highlight the potential for the clinical application of liquid biopsy (intended as the study of circulating biomarkers in the blood), focusing on circulating tumor cells, circulating DNA and circulating noncoding RNA.

Recent findings

Thanks to the increasing sensitivity of sequencing techniques, it is now possible to analyze circulating nucleic acids and tumor cells (liquid biopsy).

Although studies on the use of liquid biopsy are still at an early stage, the potential clinical applications of liquid biopsy in the study of primary brain cancer are many and have the potential to revolutionize the approach to neuro-oncology, and importantly, they offer the possibility of gathering information on the disease at any time during its history.
Surgical management of skull base meningiomas and vestibular schwannomas
Authors: Gambacciani Carlo , Grimod Gianluca , Sameshima Tetsuro , Santonocito Orazio S.
Published: September 2022

Purpose of review

The aim of this study is to discuss surgical management of meningiomas and schwannomas of skull base.

Recent findings

Meningiomas and schwannomas are typically benign neoplasm with a good prognosis after surgery. Patients should be treated individually related to several features: size and localization of tumor and its proximity with deep critical neurovascular structures, neurological status, age and comorbidity. Also, the widespread use of neuroimaging and the progressive and constant aging of the populations inevitably result in the increase of detection rate of incidental (asymptomatic) neoplasm.

Nowadays, there are still controversies about the correct management strategy.

Surgery represents the gold standard treatment, with the objective of gross total resection; however, it is not always feasible due to localization, encasement of neuro-vascular structure, invasion of cranial nerve and brain parenchyma. Stereotactic radiosurgery and radiation therapy are important to achieve a satisfactory functional outcome and tumor control in case of residue or recurrence. A multidisciplinary approach is pivotal.
Imaging for illuminating actionable pathways in breast cancer
Authors: Gilardi Laura , Airò Farulla Lighea Simona , Ceci Francesco
Published: September 2022

Purpose

Nuclear medicine has the potential to explore and illuminate several pathways in breast cancer (BC) offering different radiopharmaceuticals for positron emission tomography (PET) designed to target specific tumor characteristics. The aim of this critical review is to give an overview about emerging opportunities in PET imaging, underlining the future potential contribution in the management of BC patients.

Recent findings

Beside 2-deoxy-2-[18F]-fluoro-d-glucose (FDG), new generation tracers for PET imaging have been recently proposed to investigate specific characteristics in breast cancer, both targeting tumor cells and the tumor micro-environment (TME).

FDG-PET is a procedure that received extensive clinical validation. However, its role in BC is still suboptimal due to the low-FDG avidity of specific tumor subtypes. Human epidermal growth receptor-2 and integrin targeted PET radiotracers might provide useful information selecting patients more likely to respond to target therapy. FluoroEstradiol (FES) is a FDA-approved PET radiotracer targeting the estrogen receptor (ER), useful to investigate metastatic ER+ patients, to assess in vivo ER heterogeneity and to evaluate hormonal therapy efficacy. Inhibitors of the fibroblast activation protein (FAPi) targeting the cancer-associated fibroblast can explore the TME with PET imaging. FAPi is also proposed a theranostic agent for radio-ligand therapy.
Basal Cell Carcinoma With Perineural Invasion: A Systematic Review and Pooled Survival Analysis
Authors: Abushukur Yasmine , Ibrahim Yousef , Cascardo Camilla , Keeley Jacob , Knackstedt Thomas
Published: September 2022

BACKGROUND

Perineural invasion (PNI) is considered a high-risk histopathologic feature in many skin cancers. Perineural invasion is a well-known poor prognostic factor of squamous cell carcinoma, but is poorly understood in the context of basal cell carcinoma (BCC).

OBJECTIVE

To analyze available demographic, clinical, and treatment data for BCC with PNI and the effect of these variables on recurrence patterns, disease progression, and cancer-specific mortality (CSM).

METHODS

A systematic review and pooled-survival analysis was performed using case reports and series of patients with perineural BCC.

RESULTS

This review included 159 patients from 49 publications. Of these cases, 57 patients reported at least one recurrence. Where reported, median follow-up time was 31 months for patients without recurrence (n = 79) and 21 months for patients with recurrence (n = 32). The cumulative incidence of CSM at 5 years was 8.5% (95% confidence interval [CI] 0.028–0.186) and the overall five-year survival was 90.9% (95% CI 0.796–0.961).

CONCLUSION

Male gender, multifocal nerve involvement, presence of clinical symptoms, and PNI detected on imaging are associated with poor prognosis of BCC with PNI. The high rate of disease recurrence and suboptimal cumulative incidence of CSM highlights the importance of early clinical detection, before the onset of symptomatic PNI and multifocal nerve involvement.
Fenofibrate promotes neuroprotection in a model of rotenone-induced Parkinson’s disease
Authors: Barbiero Janaína K. , Ramos Daniele C. , Boschen Suelen , Bassani Taysa , Da Cunha Cláudio , Vital Maria A. B. F.
Published: September 2022

Parkinson’s disease is a neurodegenerative disease, the etiology of which remains unknown, but some likely causes include oxidative stress, mitochondrial dysfunction and neuroinflammation. Peroxisome-proliferator-activated receptor (PPAR) agonists have been studied in animal models of Parkinson’s disease and have shown neuroprotective effects. In this study, we aimed to (1) confirm the neuroprotective effects of PPAR-alpha agonist fenofibrate. To this end, male rats received fenofibrate (100 mg/kg) orally for 15 days, 5 days before the intraperitoneal injections of rotenone (2.5 mg/kg for 10 days). After finishing the treatment with rotenone and fenofibrate, animals were subjected to the open field, the forced swim test and the two-way active avoidance task. Subsequently, rats were euthanized for measurement of dopamine and metabolites levels in the striatum and quantification of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (SNpc). In addition, we aimed to (2) evaluate the neuroprotective effects of fenofibrate on the accumulation of α-synuclein aggregates. Here, rats were treated for 5 days with fenofibrate continuing for over 28 days with rotenone. Then, animals were perfused for immunohistochemistry analysis of α-synuclein. The results showed that fenofibrate reduced depressive-like behavior and memory impairment induced by rotenone. Moreover, fenofibrate diminished the depletion of striatal dopamine and protected against dopaminergic neuronal death in the SNpc. Likewise, the administration of fenofibrate attenuated the aggregation of α-synuclein in the SNpc and striatum in the rotenone-lesioned rats. Our study confirmed that fenofibrate exerted neuroprotective effects because parkinsonian rats exhibited reduced behavioral, neurochemical and immunohistochemical changes, and importantly, a lower number of α-synuclein aggregates.
Transcatheter tricuspid valve intervention: to repair or to replace?
Authors: Hagemeyer Daniel , Ong Geraldine , Peterson Mark D. , Fam Neil P.
Published: September 2022

Purpose of review

The burden of tricuspid regurgitation (TR) is high in the aging population, almost 4% in the age group over 75 have moderate or more TR. This carries a poor prognosis and an increased incidence of mortality, prolonged hospitalization, and rehospitalization in symptomatic patients with severe TR is observed. Percutaneous tricuspid valve intervention has emerged as a viable therapeutic option, with an increasingly large toolbox of both tricuspid repair and replacement devices. The optimal strategy, timing and patient selection for transcatheter intervention are yet to be determined. This review focuses on the current strengths and limitations of transcatheter tricuspid repair vs. replacement, drawing on lessons learned from surgery.

Recent findings

Early outcome studies have been published in the last 2 years for many of the new percutaneous tricuspid valve devices. We have summarized these results and compared them to surgical tricuspid valve repair and replacement. We found that surgical data shows a tendency to better outcome with tricuspid valve repair compared to replacement. For transcatheter interventions studies comparing repair and replacement are lacking but both interventions show good procedural success rates and are efficient in reducing the grade of tricuspid regurgitation.

Transcatheter tricuspid valve interventions offer a safe and effective alternative to tricuspid surgery or medical therapy. The decision between valve replacement and repair should be based on patient anatomy, operator experience and device availability until head-to-head comparison of different devices are available.
Myocardial infarction with nonobstructive coronary arteries: the need for precision medicine
Authors: Del Buono Marco Giuseppe , La Vecchia Giulia , Rinaldi Riccardo , Sanna Tommaso , Crea Filippo , Montone Rocco Antonio
Published: September 2022

Purpose of review

Myocardial infarction with nonobstructive coronary arteries (MINOCA) represents about 6–8% of all patients with myocardial infarction (MI), and several pathophysiological mechanisms showed to be involved in this heterogeneous clinical condition. Of note, MINOCA proved to be associated with a significant risk of mortality, angina burden and socioeconomic costs.

Recent findings

Results from randomized clinical trials evaluating the clinical effectiveness of a comprehensive diagnostic algorithm, along with the acute and long-term management of patients with MINOCA, are pending.

In this review article, we aim at providing an overview of the clinical features, diagnostic work-up and the therapeutic management of patients presenting with MINOCA, highlighting the recent acquisition along with the remaining important knowledge gaps in this field.
Angiotensin II prompts heart cell apoptosis via AT1 receptor-augmented phosphatase and tensin homolog and miR-320-3p functions to enhance suppression of the IGF1R-PI3K-AKT survival pathway
Authors: Lu Shang-Yeh , Hong Wei-Zhi , Tsai Bruce Chi-Kang , Chang Yu-Chun , Kuo Chia-Hua , Mhone Thomas G. , Chen Ray-Jade , Kuo Wei-Wen , Huang Chih-Yang
Published: September 2022

Background:

Hypertension is a severe public health risk factor worldwide. Elevated angiotensin II (Ang II) produced by the renin–angiotensin–aldosterone system can lead to hypertension and its complications.

Method:

In this study, we addressed the cardiac-injury effects of Ang II and investigated the signaling mechanism induced by Ang II. Both H9c2 cardiomyoblast cells and neonatal rat cardiomyocytes were exposed to Ang II to observe hypertension-related cardiac apoptosis.

Results:

The results of western blotting revealed that Ang II significantly attenuated the IGF1R-PI3K-AKT pathway via the Ang II-AT1 receptor axis and phosphatase and tensin homolog expression. Furthermore, real-time PCR showed that Ang II also activated miR-320-3p transcription to repress the PI3K-Akt pathway. In the heart tissue of spontaneously hypertensive rats, activation of the IGF1R survival pathway was also reduced compared with that in Wistar-Kyoto rats, especially in aged spontaneously hypertensive rats.

Conclusion:

Hence, we speculate that the Ang II-AT1 receptor axis induces both phosphatase and tensin homolog and miR-320-3p expression to downregulate the IGF1R-PI3K-AKT survival pathway and cause cell apoptosis in the heart.
Conjunctival Perivascular Epithelioid Cell Neoplasm With RBM10-TFE3 Fusion Presenting as Recurrent Subconjunctival Hemorrhage
Authors: Park Kathryn S. , Ozzello Daniel J. , Ting Michelle , Fadare Oluwole , Liu Catherine Y. , Kikkawa Don O. , Korn Bobby S.
Published: September 2022

Subconjunctival hemorrhages commonly present to eye care professionals and are frequently regarded as benign self-limited conditions. In selected cases, subconjunctival hemorrhages can be a harbinger of more severe disease. Perivascular epithelioid cell tumors, or PEComas, are rare mesenchymal neoplasms believed to originate from perivascular myoid cells and are rarely present in ocular structures. We present a rare case of a conjunctival perivascular epithelioid cell tumor that initially presented with recurrent subconjunctival hemorrhage. To our knowledge, this is the first description of a PEComa with a RBM10-TFE3 gene fusion, only previously seen with renal cell carcinoma. Physicians should be aware of this rare condition, its location in the fornix and its presentation as a recurrent subconjunctival hemorrhage.