bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss aversion and high stakes
Authors: Easton Stephen , Pinder Sean
Published: May 2021

Following Kahneman and Tversky, studies such as those by Haigh and List, Ert and Erev and Mukherjee et al. find that loss aversion increases as stake increases. This study extends the 2011 work of Berger and Pope by analysing over 68,000 US professional basketball games played from the initial National Basketball Association (NBA) season in 1946/1947 to the 2018/2019 season, and over 69,000 National Collegiate Athletic Association (NCAA) games played from the 2007/2008 season to the 2018/2019 season. We posit that, a priori, stakes, and therefore loss aversion, will be greater for NBA teams than for NCAA teams, and higher for home teams than for away teams. Further, loss aversion is expected to be greater for favourites, that is, teams that are expected to win. We model outcomes using a digital call option. This model allows for necessary non‐linearity in the relation between halftime score and winning percentage. It also provides an analysis for which the result for home (favourite) teams is not simply the converse of that for away (underdog) teams. We find evidence of better‐than‐expected performance for NBA home teams that are behind by up to four points, and for favourites that are behind by between two and seven points. We find no evidence of this effect with respect to NBA away teams, NBA underdogs, nor for NCAA teams – whether home or away. Our results suggest that loss aversion is apparent when stakes are high.
Assessment of land use and land cover changes in Kenya’s Mt. Elgon forest ecosystem
Authors: Masayi Nelly Nambande , Omondi Paul , Tsingalia Mugatsia
Published: May 2021

Current land‐use trends in Kenya's montane forest ecosystems show that land uses are changing fast due to natural and anthropogenic factors and these changes could have devastating effects on the environment. One such montane forest is the transboundary Mt. Elgon forest located in western Kenya. This study analysed trends in land use–land cover changes in Mt. Elgon forest ecosystem over the last 45 years. Landsat imageries downloaded from the United States Geological Survey archives were used to assess land use–land cover changes between 1973 and 2019 by applying supervised classification using Arc GIS 10.5. The IDRISI Selva 17.0 was used to calculate area under different land uses and generate change maps. The major Land Use–Land Cover (LULC) classified were mixed farming, natural forests, planted forests, bamboo forest, fallow land, tea plantation. The landsat images had an average overall classification accuracy of 87.12% and kappa coefficient (K) of 0.84. The kappa coefficient was rated as substantial and the classified images qualified for further analysis. Results established that there was an 18% decline in the natural forest cover between 1977 and 2019. There was a similar decline of 15.19% in bamboo forest cover. Plantation forests established in the 1990's also showed a 15.6% decline between 1999 and 2019. There was, however, a 29% increase in mixed farming, a 10% increase in fallow land and a 0.13% increase in tea plantations. These changes in land uses and land cover call for an urgent need to develop sustainable management plans to protect and conserve the Mt. Elgon forest ecosystem. Sustainable land management strategies to be used in the future may include education on the significance of the forest ecosystem, community participation in sustainable utilisation of forest eco‐services and the introduction of sustainable alternative sources of livelihoods, such as bee farming.
Effect of male age on pregnancy and neonatal outcomes in the first frozen‐thawed embryo transfer cycles of IVF/ICSI treatment
Authors: Kong Pengcheng , Liu Yanan , Zhu Qianqian , Yin Mingru , Teng Xiaoming
Published: May 2021

Background

The effect of male age on pregnancy outcomes after assisted reproductive technology (ART) treatment shown in the previous literature is controversial. In addition, the influence of male age on neonatal outcomes following ART treatment has less been investigated.

Objectives

The aim of this study was to evaluate the effect of male age on reproductive and neonatal outcomes in couples following ART treatment.

Materials and methods

A retrospective cohort study was performed in two centers for assisted reproduction from June 2010 to February 2019. A total of 5512 frozen‐thawed embryo transfer (FET) cycles were included according to the criteria. The primary outcome measures were pregnancy and neonatal outcomes. Patients were categorized into five groups according to male age (younger than 30, 31–35, 36–40, 41–45, and older than 45), and the group younger than 30 years old was treated as the reference group.

Results

The logistic regression analysis showed that clinical pregnancy and live birth were all no statistic difference among the male age‐groups compared with the reference group (p values, 0.743, 0.979, 0.948, 0.28; p values, 0.823, 0.342, 0.817, 0.381, respectively). Furthermore, no significant differences were found in the preterm birth rate, child sex, neonatal malformation, birth weight, and gestational age (p > 0.05). The advanced male age was not associated with a higher risk of adverse neonatal outcomes.

Discussion and Conclusion

This study showed that there were no effects of male age on pregnancy or neonatal outcomes in infertile couples following their first FET cycles when females were younger than 36 years old.
When to ask for an MRI of the scrotum
Authors: Tsili Athina C. , Argyropoulou Maria I. , Dolciami Miriam , Ercolani Giada , Catalano Carlo , Manganaro Lucia
Published: May 2021

Background

Multiparametric MRI (mpMRI) of the scrotum has been established as a useful second‐line diagnostic tool for the investigation of scrotal diseases. Recently, recommendations on clinical indications for scrotal MRI were issued by the Scrotal and Penile Imaging Working Group of the European Society of Urogenital Radiology.

Objective

To update current research on when to ask for an MRI of the scrotum.

Methods

PubMed database was searched for original articles and reviews published during 2010–2021.

Results

Eighty‐three articles fulfilled the search criteria. Scrotal MRI is mainly recommended after inconclusive US findings or inconsistent with the clinical examination and should be asked in the following cases: differentiation between intratesticular and paratesticular lesions (in rare cases of uncertain US findings), characterization of paratesticular and intratesticular lesions (when US findings are indeterminate), discrimination between germ cell and sex cord‐stromal testicular tumors, local staging of testicular malignancies (in patients planned for testis‐sparing surgery), differentiation between seminomas and non‐seminomatous tumors (when immediate chemotherapy is planned and orchiectomy is delayed), assessment of acute scrotum and scrotal trauma (rarely needed, in cases of non‐diagnostic US findings) and detection and localization of undescended testes (in cases of inconlusive US findings). Although preliminary data show promising results in the evaluation of male infertility, no established role for mpMRI still exists.

Conclusion

Multiparametric MRI of the scrotum, by assessing morphologic and functional data represents a valuable problem‐solving tool, helping to improve our understanding on the nature of scrotal pathology and the process of spermatogenesis. The technique may improve patient care and reduce the number of unnecessary surgical procedures.
Impact of P‐wave indices in prediction of atrial fibrillation—Insight from loop recorder analysis
Authors: Kreimer Fabienne , Aweimer Assem , Pflaumbaum Andreas , Mügge Andreas , Gotzmann Michael
Published: May 2021

Background

Several P‐wave indices are associated with the development of atrial fibrillation (AF). However, previous studies have been limited in their ability to reliably diagnose episodes of AF. Implantable loop recorders allow long‐term, continuous, and therefore more reliable detection of AF.

Hypothesis

The aim of this study is to identify and evaluate ECG parameters for predicting AF by analyzing patients with loop recorders.

Methods

This study included 366 patients (mean age 62 ± 16 years, mean LVEF 61 ± 6%, 175 women) without AF who underwent loop recorder implantation between 2010–2020. Patients were followed up on a 3 monthly outpatient interval.

Results

During a follow‐up of 627 ± 409 days, 75 patients (20%) reached the primary study end point (first detection of AF). Independent predictors of AF were as follows: age ≥68 years (hazard risk [HR], 2.66; 95% confidence interval [CI], 1.668–4.235; p < .001), P‐wave amplitude in II <0.1 mV (HR, 2.11; 95% CI, 1.298–3.441; p = .003), P‐wave terminal force in V1 ≤ −4000 µV × ms (HR, 5.3; 95% CI, 3.249–8.636; p < .001, and advanced interatrial block (HR, 5.01; 95% CI, 2.638–9.528; p < .001). Our risk stratification model based on these independent predictors separated patients into 4 groups with high (70%), intermediate high (41%), intermediate low (18%), and low (4%) rates of AF.

Conclusions

Our study indicated that P‐wave indices are suitable for predicting AF episodes. Furthermore, it is possible to stratify patients into risk groups for AF using simple ECG parameters, which is particularly important for patients with cryptogenic stroke.
A few statistical principles for data science
Authors: Cressie Noel
Published: May 2021

In any other circumstance, it might make sense to define the extent of the terrain (Data Science) first, and then locate and describe the landmarks (Principles). But this data revolution we are experiencing defies a cadastral survey. Areas are continually being annexed into Data Science. For example, biometrics was traditionally statistics for agriculture in all its forms but now, in Data Science, it means the study of characteristics that can be used to identify an individual. Examples of non‐intrusive measurements include height, weight, fingerprints, retina scan, voice, photograph/video (facial landmarks and facial expressions) and gait. A multivariate analysis of such data would be a complex project for a statistician, but a software engineer might appear to have no trouble with it at all. In any applied‐statistics project, the statistician worries about uncertainty and quantifies it by modelling data as realisations generated from a probability space. Another approach to uncertainty quantification is to find similar data sets, and then use the variability of results between these data sets to capture the uncertainty. Both approaches allow ‘error bars’ to be put on estimates obtained from the original data set, although the interpretations are different. A third approach, that concentrates on giving a single answer and gives up on uncertainty quantification, could be considered as Data Engineering, although it has staked a claim in the Data Science terrain. This article presents a few (actually nine) statistical principles for data scientists that have helped me, and continue to help me, when I work on complex interdisciplinary projects.
Development of angle closure and associated risk factors: The Handan eye study
Authors: Zhang Ye , Zhang Qing , Thomas Ravi , Li Si Zhen , Wang Ning Li
Published: May 2021

Purpose

To investigate the development of angle closure from baseline open angle and associated risk factors in a rural Chinese population through a longitudinal study over a 5‐year period.

Methods

Subjects aged ≥30 years and older with bilateral open angles at baseline of the Handan Eye Study who participated in the follow‐up and had undergone both baseline and follow‐up gonioscopic examinations were included. Subjects with any form of angle closure, glaucoma, incisional ocular surgery or other conditions that could influence the results were excluded. The development of angle closure was defined as the presence of primary angle closure suspect (PACS) or primary angle closure (PAC)/primary angle closure glaucoma (PACG) during the follow‐up in normal subjects with baseline bilateral open angles. Logistic regression was performed to identify the baseline risk factors for the development of angle closure.

Results

A total of 457 subjects with bilateral open angles at baseline aged 53.0 (45.5, 58.0) years were enrolled. 94.7% of the included cases developed PACS, 5.3% developed PAC and no one developed PACG after 5 years. In logistic regression, significant risk factors for the development of angle closure were shallower central anterior chamber depth (ACD) (p = 0.002) and narrower mean angle width (p < 0.001).

Conclusions

This study reports the development from baseline open angle to angle closure after a 5‐year follow‐up. We confirm that the mean angle width and central ACD were independent predictive risk factors for the development of any form of angle closure.
Thrombosis is not a marker of bridging vein rupture in infants with alleged abusive head trauma
Authors: Zahl Sverre Morten , Mack Julie A. , Rossant Cyrille , Squier Waney , Wester Knut
Published: May 2021

Aim

Thrombosis of bridging veins has been suggested to be a marker of bridging vein rupture, and thus AHT, in infants with subdural haematoma.

Methods

This is a non‐systematic review based on Pubmed search, secondary reference tracking and authors’ own article collections.

Results

Radiological studies asserting that imaging signs of cortical vein thrombosis were indicative of traumatic bridging vein rupture were unreliable as they lacked pathological verification of either thrombosis or rupture, and paid little regard to medical conditions other than trauma. Autopsy attempts at confirmation of ruptured bridging veins as the origin of SDH were fraught with difficulty. Moreover, microscopic anatomy demonstrated alternative non‐traumatic sources of a clot in or around bridging veins. Objective pathological observations did not support the hypothesis that a radiological finding of bridging vein thrombosis was the result of traumatic rupture by AHT. No biomechanical models have produced reliable and reproducible data to demonstrate that shaking alone can be a cause of bridging vein rupture.

Conclusion

There is no conclusive evidence supporting the hypothesis that diagnostic imaging showing thrombosed bridging veins in infants correlates with bridging vein rupture. Hence, there is no literature support for the use of thrombosis as a marker for AHT.
Daily bidirectional associations between adolescent negative peer interactions and sleep in rural China: The moderating effect of parental migration
Authors: Zhang Youchuan , Wang Yijie
Published: May 2021

Left‐behind adolescents’ biobehavioral adjustment, such as sleep, is poorly understood by research. Using daily data over one week from 90 middle school students (Mage = 13.69) in rural China, this study investigated daily bidirectional associations between negative peer interactions and sleep disturbances, and how these associations varied by parental migration. On days when adolescents reported higher levels of negative peer interactions, they also reported greater daytime dysfunction the following day. Conversely, when adolescents had more nighttime disturbances the previous night, they also reported higher levels of negative peer interactions. The effects of other sleep disturbance indicators (poor sleep quality the previous night and daytime dysfunction on the same day) on negative peer interactions were significant for adolescents with at least one parent migrating and for those with both parents migrating. Findings highlight the importance of considering dynamic interrelations between interpersonal and biobehavioral factors for the healthy development of left‐behind adolescents.
Population pharmacokinetics of free flucloxacillin in patients treated with oral flucloxacillin plus probenecid
Authors: Drennan Philip G. , Green Jared K. , Gardiner Sharon J. , Metcalf Sarah C. L. , Kirkpatrick Carl M. J. , Everts Richard J. , Zhang Mei , Chambers Stephen T.
Published: May 2021

Aims

Oral flucloxacillin may be coadministered with probenecid to reduce flucloxacillin clearance and increase attainment of pharmacokinetic–pharmacodynamic (PK/PD) targets. The aims of this study were to develop a population PK model of free flucloxacillin when administered orally with probenecid, and to identify optimal dosing regimens for this combination.

Methods

We performed a prospective observational study of adults (45 participants) treated with oral flucloxacillin 1000 mg and probenecid 500 mg 8‐hourly for proven or probable staphylococcal infections. Steady‐state mid‐dose‐interval flucloxacillin measurements (45 concentrations) were combined with existing data from a crossover study of healthy participants receiving flucloxacillin with and without probenecid (11 participants, 363 concentrations). We developed a population pharmacokinetic model of free flucloxacillin concentrations within Monolix, and used Monte Carlo simulation to explore optimal dosing regimens to attain PK/PD targets proposed in the literature (free drug time above minimum inhibitory concentration).

Results

Flucloxacillin disposition was best described by a 1‐compartment model with a lag time and first‐order absorption. Free flucloxacillin clearance depended on probenecid, allometrically‐scaled fat free mass (FFM) and estimated glomerular filtration rate (eGFR). Predicted PK/PD target attainment was suboptimal with standard dosing regimens with flucloxacillin alone, but substantially improved in the presence of probenecid.

Conclusion

The simulation results reported can be used to identify dose regimens that optimise flucloxacillin exposure according to eGFR and FFM. Patients with higher FFM and eGFR may require the addition of probenecid and 6‐hourly dosing to achieve PK/PD targets. The regimen was well‐tolerated, suggesting a potential for further evaluation in controlled clinical trials to establish efficacy.
A randomised evaluation of low‐dose cytosine arabinoside (ara‐C) plus tosedostat versus low‐dose ara‐C in older patients with acute myeloid leukaemia: results of the LI‐1 trial
Authors: Dennis Mike , Burnett Alan , Hills Robert , Thomas Ian , Ariti Cono , Severinsen Marianne T. , Hemmaway Claire , Greaves Paul , Clark Richard E. , Copland Mhairi , Russell Nigel ,   the National Cancer Research Institute (NCRI) acute myeloid leukaemia (AML) Working Group
Published: May 2021

Older patients with acute myeloid leukaemia (AML) account for nearly half of those with the disease. Because they are perceived to be unfit for, unwilling to receive, or unlikely to benefit from conventional chemotherapy they represent an important unmet need. Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy. We report the only randomised study of low‐dose cytosine arabinoside (LDAC) combined with tosedostat (LDAC‐T) versus LDAC in untreated older patients not suitable for intensive treatment. A total of 243 patients were randomised 1:1 as part of the ‘Pick‐a‐Winner’ LI‐1 trial. There was a statistically non‐significant increase in the complete remission (CR) rate with the addition of tosedostat, LDAC‐T 19% versus LDAC 12% [odds ratio (OR) 0·61, 95% confidence interval (CI) 0·30–1·23; P = 0·17]. For overall response (CR+CR with incomplete recovery of counts), there was little evidence of a benefit to the addition of tosedostat (25% vs. 18%; OR 0·68, 95% CI 0·37–1·27; P = 0·22). However, overall survival (OS) showed no difference (2‐year OS 16% vs. 12%, hazard ratio 0·97, 95% CI 0·73–1·28; P = 0·8). Exploratory analyses failed to identify any subgroup benefitting from tosedostat. Despite promising pre‐clinical, early non‐randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML.

International Standard Randomised Controlled Trial Number: ISRCTN40571019
When cultures clash: Links between perceived cultural distance in values and attitudes towards migrants
Authors: Albada Katja , Hansen Nina , Otten Sabine
Published: May 2021

Migration elicits mixed reactions from the host‐society. Negative responses towards migrants seem to emerge when migrants are perceived as culturally different. We investigated when and why perceived cultural distance (PCD) is associated with negative migrant attitudes by focussing on differences in cultural values. We expected that PCD in social values (focus on relationships and society) should be more strongly associated with attitudes towards migrants than personal values (individual needs and gains) and should be mediated by symbolic threat. In two quasi‐experimental studies (N = 200, N = 668) with Dutch participants (host‐society), we simultaneously tested effects of respondents’ perception of Dutch values, their perceptions of migrant values (of Moroccan, Syrian, Polish ethnic origin), and PCD between Dutch‐migrant value on attitudes. For all migrant groups, PCD in social values was associated with more negative attitudes, less tolerance, and less policy support regarding migrants; this was mediated by symbolic threat. These links were weaker for personal values.
Impact of the first surge of the COVID‐19 pandemic on a tertiary referral centre for kidney cancer
Authors: Kuusk Teele , Cullen David , Neves Joana Briosa , Campain Nicholas , Barod Ravi , Boleti Ekaterini , El‐Sheihk Soha , Grant Lee , Kelly John , Marchetti Marta , Mumtaz Faiz , Patki Prasad , Ramachandran Navin , Silva Pedro , Tran‐Dang My‐Anh , Walkden Miles , Tran Maxine G.B. , Powles Thomas , Bex Axel
Published: May 2021

Objective

To analyse the impact of the COVID‐19 pandemic on a centralized specialist kidney cancer care pathway.

Materials and Methods

We conducted a retrospective analysis of patient and pathway characteristics including prioritization strategies at the Specialist Centre for Kidney Cancer located at the Royal Free London NHS Foundation Trust (RFH) before and during the surge of COVID‐19.

Results

On 18 March 2020 all elective surgery was halted at RFH to redeploy resources and staff for the COVID‐19 surge. Prioritizing of patients according to European Association of Urology guidance was introduced. Clinics and the specialist multidisciplinary team (SMDT) meetings were maintained with physical distancing, kidney surgery was moved to a COVID‐protected site, and infection prevention measurements were enforced. During the 7 weeks of lockdown (23 March to 10 May 2020), 234 cases were discussed at the SMDT meetings, 53% compared to the 446 cases discussed in the 7 weeks pre‐lockdown. The reduction in referrals was more pronounced for small and asymptomatic renal masses. Of 62 low‐priority cancer patients, 27 (43.5%) were deferred. Only one (4%) COVID‐19 infection occurred postoperatively, and the patient made a full recovery. No increase in clinical or pathological upstaging could be detected in patients who underwent deferred surgery compared to pre‐COVID practice.

Conclusion

The first surge of the COVID‐19 pandemic severely impacted diagnosis, referral and treatment of kidney cancer at a tertiary referral centre. With a policy of prioritization and COVID‐protected pathways, capacity for time‐sensitive oncological interventions was maintained and no immediate clinical harm was observed.
Identification of patients at risk for biochemical recurrence after radical prostatectomy with intra‐operative frozen section
Authors: Tully Karl H. , Schulmeyer Max , Hanske Julian , Reike Moritz J. , Brock Marko , Moritz Rudolf , Jütte Hendrik , Tannapfel Andrea , von Bodman Christian , Noldus Joachim , Palisaar Rein‐Jüri , Roghmann Florian
Published: May 2021

Objective

To identify patients at risk for biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) with intra‐operative whole‐mount frozen section (FS) of the prostate.

Material and Methods

We examined differences in BCR between patients with initial negative surgical margins at FS, patients with final negative surgical margins with initial positive margins at FS without residual PCa after secondary tumour resection, and patients with final negative surgical margins with initially positive margins at FS with residual PCa in the secondary tumour resection specimen. Institutional data of 883 consecutive patients undergoing RP were collected. Intra‐operative whole‐mount FS was routinely used to check for margin status and, if necessary, to resect more periprostatic tissue in order to achieve negative margins. Patients with lymph node‐positive disease or final positive surgical margins were excluded from the analysis. Kaplan−Meier curves and multivariable Cox proportional hazards regression analyses adjusting for clinical covariates were employed to examine differences in biochemical recurrence‐free survival (BRFS) according to the resection status mentioned above.

Results

The median follow‐up was 22.4 months. The 1‐ and 2‐year BRFS rates in patients with (81.0% and 72.9%, respectively; P = 0.001) and without residual PCa (90.3% and 82.3%, respectively; P = 0.033) after secondary tumour resection were significantly lower compared to patients with initial R0 status (93.4% and 90.9%, respectively). On multivariable Cox regression only residual PCa in the secondary tumour resection was associated with a higher risk of BCR compared to initial R0 status (hazard ratio 1.99, 95% confidence interval 1.01–3.92; P = 0.046).

Conclusion

Despite being classified as having a negative surgical margin, patients with residual PCa in the secondary tumour resection specimen face a high risk of BCR. These findings warrant closer post‐RP surveillance of this particular subgroup. Further research of this high‐risk subset of patients should focus on examining whether these patients benefit from early salvage therapy and how resection status impacts oncological outcomes in the changing landscape of PCa treatment.
The effects of cocaine exposure in adolescence: Behavioural effects and neuroplastic mechanisms in experimental models
Authors: Caffino Lucia , Mottarlini Francesca , Zita Gianmaria , Gawliński Dawid , Gawlińska Kinga , Wydra Karolina , Przegaliński Edmund , Fumagalli Fabio
Published: May 2021

Drug addiction is a devastating disorder with a huge economic and social burden for modern society. Although an individual may slip into drug abuse throughout his/her life, adolescents are at higher risk, but, so far, only a few studies have attempted to elucidate the underlying cellular and molecular bases of such vulnerability. Indeed, preclinical evidence indicates that psychostimulants and adolescence interact and contribute to promoting a dysfunctional brain. In this review, we have focused our attention primarily on changes in neuroplasticity brought about by cocaine, taking into account that there is much less evidence from exposure to cocaine in adolescence, compared with that from adults. This review clearly shows that exposure to cocaine during adolescence, acute or chronic, as well as contingent or non‐contingent, confers a vulnerable endophenotype, primarily, by causing changes in neuroplasticity. Given the close relationship between drug abuse and psychiatric disorders, we also discuss the translational implications providing an interpretative framework for clinical studies involving addictive as well as affective or psychotic behaviours.

LINKED ARTICLES

This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc
Establishment and characterization of a novel treatment‐related neuroendocrine prostate cancer cell line KUCaP13
Authors: Okasho Kosuke , Mizuno Kei , Fukui Tomohiro , Lin Yen‐Yi , Kamiyama Yuki , Sunada Takuro , Li Xin , Kimura Hiroko , Sumiyoshi Takayuki , Goto Takayuki , Kobayashi Takashi , Lin Dong , Wang Yuzhuo , Collins Colin C. , Inoue Takahiro , Ogawa Osamu , Akamatsu Shusuke
Published: May 2021

The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC‐associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient‐derived, treatment‐related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.
Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma
Authors: Inoue Jun , Kishikawa Masahiro , Tsuda Hitoshi , Nakajima Yasuaki , Asakage Takahiro , Inazawa Johji
Published: May 2021

The metabolism in tumors is reprogrammed to meet its energetic and substrate demands. However, this metabolic reprogramming creates metabolic vulnerabilities, providing new opportunities for cancer therapy. Metabolic vulnerability as a therapeutic target in esophageal squamous cell carcinoma (ESCC) has not been adequately clarified. Here, we identified pyruvate dehydrogenase (PDH) component X (PDHX) as a metabolically essential gene for the cell growth of ESCC. PDHX expression was required for the maintenance of PDH activity and the production of ATP, and its knockdown inhibited the proliferation of cancer stem cells (CSCs) and in vivo tumor growth. PDHX was concurrently upregulated with the CD44 gene, a marker of CSCs, by co‐amplification at 11p13 in ESCC tumors and these genes coordinately functioned in cancer stemness. Furthermore, CPI‐613, a PDH inhibitor, inhibited the proliferation of CSCs in vitro and the growth of ESCC xenograft tumors in vivo. Thus, our study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex‐associated metabolic vulnerability.
Role of tumor‐associated macrophages at the invasive front in human colorectal cancer progression
Authors: Inagaki Katsuaki , Kunisho Shoma , Takigawa Hidehiko , Yuge Ryo , Oka Shiro , Tanaka Shinji , Shimamoto Fumio , Chayama Kazuaki , Kitadai Yasuhiko
Published: May 2021

Macrophages are an essential component of antitumor activity; however, the role of tumor‐associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM‐CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM‐CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM‐CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan‐, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.
Regulation of vascular permeability in cancer metastasis
Authors: Tomita Takeshi , Kato Masayoshi , Hiratsuka Sachie
Published: May 2021

Enhancement of vascular permeability is indispensable for cancer metastasis. Weakened endothelial barrier function enhances vascular permeability. Circulating tumor cells moving in the microvasculature tend to invade into stromal tissue at the location where vascular permeability is enhanced. Many basic studies have identified permeability factors by using gene‐modified animals and cells. These factors directly/indirectly interact with endothelial cells. Here, we review vascular permeability factors and their molecular mechanisms. Interactions between tumor cells and endothelial cells are also discussed in the process of extravasation, one of the most critical steps in tumor metastasis. In some cases, primary tumors can manipulate permeability in a remote organ by secreting permeability factors. In addition, the importance of glycocalyx, which covers the endothelial cell surface, in controlling vascular permeability and tumor metastasis is also described. Furthermore, analysis of the hyperpermeable region found in a mouse model study is introduced. It clearly showed that tumor‐bearing mouse lungs had a hyperpermeable region due to the influence of a remote primary tumor, and fibrinogen deposition was observed in that region. Given that fibrinogen was reported to be a permeability factor and a key regulator of inflammation, eliminating fibrinogen deposition may prevent future metastasis.
Discovery of novel SecA inhibitors against “Candidatus Liberibacter asiaticus” through virtual screening and biological evaluation
Authors: Zhang Zhengfang , Han Quan , Mao Xiongxing , Liu Jinhua , Wang Wei , Li Dong , Zhou Feng , Ke Yang , Xu Lei , Hu Liu
Published: May 2021

“Candidatus Liberibacter asiaticus” (Ca. L. asiaticus) is the causal agent of Huanglongbing disease of citrus and current study focuses on the discovery of novel small‐molecule inhibitors against SecA protein of Ca. L. asiaticus. In this study, homologous modeling was used to construct the three‐dimensional structure of SecA. Then, molecular docking‐based virtual screening and two rounds of in vitro bacteriostatic experiments were utilized to identify novel small‐molecule inhibitors of SecA. Encouragingly, 93 compounds were obtained and two of them (P684‐2850, P684‐3808) showed strong antimicrobial activities against Liberibacter crescens BT‐1 in bacteriostatic experiments. Finally, molecular dynamics simulations were employed to explore the binding modes of the receptor–ligand complexes. Results in MD simulations showed that compound P684‐3808 was relatively stable during simulation, while compound P684‐2850 left the binding pocket. Compound P684‐3808 might be suitable as a lead compound for further development of antimicrobial compounds against SecA of Ca. L. asiaticus.
Design, synthesis and antifungal evaluation of novel mandelic acid derivatives containing a 1,3,4‐oxadiazothioether moiety
Authors: Hou Shuaitao , Xie Dewen , Yang Jingxin , Niu Xue , Hu Deyu , Wu Zhibing
Published: May 2021

A series of novel mandelic acid derivatives containing a 1,3,4‐oxadiazothioether moiety were designed and synthesized. Bioassay results showed that some target compounds exhibited certain antifungal activity against six kinds of pathogenic fungi in vitro. Among the compounds, the EC50 values of T41 against Gibberella saubinetii, Verticillium dahlia and Sclerotinia sclerotiorum were 31.0, 27.0 and 32.1 μg/ml, respectively, and the EC50 value of T14 against S. sclerotiorum was 14.7 μg/ml. The antifungal activity against the resistant fungus S. sclerotiorum indicated that this series of target compounds may have the similar action modes or sites as the commercialized succinate dehydrogenase inhibitor carboxin. A morphological study with fluorescence microscope demonstrated that T41 can significantly destroy the membrane integrity of G. saubinetii.
Bone turnover markers are associated with the PTH levels in different subtypes of pseudohypoparathyroidism type 1 patients
Authors: Duan Xiaoye , Yang Yi , Wang Ou , Nie Min , Chu Xueying , Quan Tingting , Guan Wenmin , Jiang Yan , Li Mei , Xia Weibo , Xing Xiaoping
Published: May 2021

Objective

Bone responsiveness to parathyroid hormone (PTH) in different subtypes of pseudohypoparathyroidism type 1 (PHP1) remains controversial. We aimed to investigate this phenomenon using bone turnover markers (BTMs) in a large cohort of PHP1 patients.

Design

Retrospective study.

Patients

Sixty‐three PHP1 patients diagnosed by molecular analysis were used as subjects, and 48 sex‐ and age‐matched patients with nonsurgical hypoparathyroidism (NS‐HP) were used for comparison.

Measurements

Bone turnover markers, alkaline phosphatase (ALP), C‐terminal telopeptide of type I collagen (β‐CTX) and related parameters in PHP1 were compared among different subtypes and with NS‐HP.

Results

Among all the PHP1 patients (15 PHP1A, 14 familial 1B and 34 sporadic 1B), 23.8% had elevated baseline BTM levels. No significant difference was found in the β‐CTX levels among different subtypes. The β‐CTX level was positively correlated with the PTH level for all PHP1, PHP1B and PHP1A patients (B = 0.001, 0.001 and 0.004, respectively; all p < .05). The BTM levels of PHP1 patients were significantly higher than those of NS‐HP patients (β‐CTX: 0.56 ng/ml vs. 0.20 ng/ml, p = .001; ALP: 105 U/L vs. 72 U/L, p = .001). The serum β‐CTX levels in different PHP1 subtypes were all significantly higher than those in NS‐HP patients in adults. Among the 22 followed up patients, changes in BTMs were associated with changes in PTH (β‐CTX: r = .507, p = .023; ALP: r = .475, p = .034).

Conclusions

Bone tissues respond to PTH in different PHP1 subtypes, and it is reasonable to monitor and normalize PTH and BTMs in addition to the serum and urinary calcium levels in the follow‐up of PHP1 patients.
COG1‐congenital disorders of glycosylation: Milder presentation and review
Authors: Salazar Marne , Miyake Noriko , Silva Sebastián , Solar Benjamín , Papazoglu Gabriela M. , Asteggiano Carla G. , Matsumoto Naomichi
Published: May 2021

Congenital disorders of glycosylation (CDG) are a heterogeneous group of genetic defects in glycoprotein and glycolipid glycan synthesis and attachment. A CDG subgroup are defects in the conserved oligomeric Golgi complex encoded by eight genes, COG1–COG8. Pathogenic variants in all genes except the COG3 gene have been reported. COG1‐CDG has been reported in five patients. We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing. Exome sequencing identified a homozygous COG1 variant (NM_018714.3: c.2665dup: p.[Arg889Profs*12]), which has been reported previously in one patient. We review the reported patients.
A homozygous missense mutation in TBPL2 is associated with oocyte maturation arrest and degeneration
Authors: Wang Yu , Xiang Mingfei , Yu Zhaojuan , Hao Yan , Xu Qianhua , Kong Shuai , Wang Fengsong , Shi Xuanming , Song Gaojie , Cao Yunxia , Huang Lingli , Zhu Fuxi
Published: May 2021

The genetic causes in most of patients with oocyte maturation arrest remain largely unknown. In this study, we identified a homozygous missense mutation (c.895T>C; p.C299R) in TBPL2 (TATA box binding protein like 2) in two infertile sisters with oocyte maturation arrest and degeneration from a consanguineous family by whole‐exome sequencing. The TBPL2 mutation is rare and pathogenic, and impaired the transcription initiation function of the protein. Our results showed that TBPL2 mutation might be associated with female infertility due to oocyte maturation arrest and degeneration.
Carbon monoxide alleviates senescence in diabetic nephropathy by improving autophagy
Authors: Chen Li , Mei Guibin , Jiang Chunjie , Cheng Xueer , Li Dan , Zhao Ying , Chen Huimin , Wan Cheng , Yao Ping , Gao Chao , Tang Yuhan
Published: May 2021

Objectives

Senescence, characterized by permanent cycle arrest, plays an important role in diabetic nephropathy (DN). However, the mechanism of renal senescence is still unclear, and the treatment targeting it remains to be further explored.

Materials and Methods

The DN mice were induced by HFD and STZ, and 3 types of renal cells were treated with high glucose (HG) to establish in vitro model. Senescence‐related and autophagy‐related markers were detected by qRT‐PCR and Western blot. Further, autophagy inhibitors and co‐immunoprecipitation were used to clarify the mechanism of CO. Additionally, the specific relationship between autophagy and senescence was explored by immunofluorescence triple co‐localization and ELISA.

Results

We unravelled that senescence occurred in vivo and in vitro, which could be reversed by CO. Mechanistically, we demonstrated that CO inhibited the dysfunction of autophagy in DN mice partly through dissociating Beclin‐1‐Bcl‐2 complex. Further results showed that autophagy inhibitors blocked the improvement of CO on senescence. In addition, the data revealed that autophagy regulated the degradation of senescence‐related secretory phenotype (SASP) including Il‐1β, Il‐6, Tgf‐β and Vegf.

Conclusions

These results suggested that CO protects DN mice from renal senescence and function loss via improving autophagy partly mediated by dissociating Beclin‐1‐Bcl‐2 complex, which is possibly ascribed to the degradation of SASP. These findings bring new ideas for the prevention and treatment of DN and the regulation of senescence.
Magnetic resonance imaging‐derived proton density fat fraction (MRI‐PDFF) is a viable alternative to liver biopsy for steatosis quantification in living liver donor transplantation
Authors: Qi Qiaochu , Weinstock Allison K. , Chupetlovska Kalina , Borhani Amir A. , Jorgensen Dana R. , Furlan Alessandro , Behari Jaideep , Molinari Michele , Ganesh Swaytha , Humar Abhinav , Duarte‐Rojo Andres
Published: May 2021

This study aimed to investigate whether magnetic resonance imaging‐derived proton density fat fraction (MRI‐PDFF) can be a viable noninvasive alternative to liver biopsy for the quantification of living liver donor steatosis. Hepatic steatosis for 143 donors was graded by MRI‐PDFF. Study endpoints included liver volume regeneration in donors, recipient outcomes including length of hospital stay, deaths, primary non‐function (PNF), early allograft dysfunction (EAD), and small for size syndrome (SFSS). Correlation between MRI‐PDFF determined donor steatosis and endpoints were analyzed. Donors had lower steatosis grade than non‐donors. Donor remnant liver regenerated to an average of 82% of pre‐donation volume by 101 ± 24 days with no complications. There was no correlation between percent liver regeneration and steatosis severity. Among recipients, 4 underwent redo‐transplantation and 6 died, with no association with degree of steatosis. 52 recipients (36%) fulfilled criteria for EAD (driven by INR), with no difference in hepatic steatosis between groups. MRI‐PDFF reliably predicted donor outcomes. Living donors with no or mild steatosis based on MRI‐PDFF (ie, <20%) and meeting other criteria for donation can expect favorable post‐surgical outcomes, including liver regeneration. Recipients had a low rate of death or retransplantation with no association between mild hepatic steatosis and EAD.
Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis
Authors: Stodtmann Sven , Nader Ahmed , Polepally Akshanth R. , Suleiman Ahmed A. , Winzenborg Insa , Noertersheuser Peter , Ng Juki , Mostafa Nael M. , Shebley Mohamad
Published: May 2021

Elagolix is a novel, oral gonadotropin‐releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose‐dependent suppression of estradiol (E2) in clinical studies. A dose‐response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross‐linked telopeptide of type 1 collagen [CTX]), formation (N‐terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in −0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.
Reimagining the peer‐review system for translational health science journals
Authors: Smith Elise M.
Published: May 2021

Retractions of coronavirus disease 2019 (COVID‐19) papers in high impact journals, such as The Lancet and the New England Journal of Medicine, have been panned as major scientific fraud in public media. The initial reaction to this news was to seek out scapegoats and blame individual authors, peer‐reviewers, editors, and journals for wrong doing. This paper suggests that scapegoating a few individuals for faulty science is a myopic approach to the more profound problem with peer‐review. Peer‐review in its current limited form cannot be expected to adequately address the scope and complexity of large interdisciplinary science research collaboration, which is central in translational research. In addition, empirical studies on the effectiveness of traditional peer‐review reveal its very real potential for bias and groupthink; as such, expectations regarding the capacity and effectiveness of the current peer review process are unrealistic. This paper proposes a new vision of peer‐review in translational science that, on the one hand, would allow for early release of a manuscript to ensure expediency, whereas also creating a forum or a collective of various experts to actively comment, scrutinize, and even build on the research under review. The aim would be to not only generate open discussion and oversight respecting the quality and limitations of the research, but also to assess the extent and the means for that knowledge to translate into social benefit.
A rare cause of parotid swelling in an elderly male
Authors: Kundu Reetu , Handa Uma , Punia Rajpal Singh
Published: May 2021

The case describes the cytological findings of the rare oncocytic carcinoma of the parotid gland. A diagnosis of oncocytoma was rendered on cytology due to lack of malignant features, but the diagnosis of oncocytic carcinoma was made on histology where necrosis and infiltration into the adjacent stromal tissue were evident.