bluuebunny/crossref_metadata_2025 huggingface dataset:
Brazil's Amazon Fund: A “Green Fix” between Offset Pressures and Deforestation Crisis
Authors: Horn Claudia
Published: March 2023

Emissions trading and nature‐based solutions, particularly REDD+, have lent themselves to the critical literature on the “socioecological fix” in neoliberal capital accumulation and state regulation. Prone to reversals, land conflict, and leakage, these mechanisms displace the burden of carbon emissions reductions to global South countries, promote new green commodities, and thus increase rather than curb the chance of capital accumulations by big polluters. Studies of existing REDD+ projects register the privatisation of forest management on the one hand and “aidification” on the other, suggesting impediments to fully commodifying forest carbon ranging from social movement resistance to technical issues. This case study of Brazil's national Amazon Fund points to global South protagonism in constructing and negotiating REDD+, challenging Northern and market hegemonies. Progressive Southern actors use the political space of the fix to defend rural communities' territorial rights and demand resources in line with historic responsibilities and climate justice.
Severe COVID‐19 during pregnancy in Sweden, Norway, and Denmark
Authors: Örtqvist Anne K. , Magnus Maria C. , Aabakke Anna J. M. , Urhoj Stine Kjaer , Vinkel Hansen Anne , Nybo Andersen Anne‐Marie , Krebs Lone , Pettersson Karin , Håberg Siri E. , Stephansson Olof
Published: March 2023

Introduction

Pregnancy is a risk factor for severe coronavirus disease 2019 (COVID‐19) and adverse pregnancy outcomes. We aimed to explore maternal characteristics, pregnancy outcomes, vaccination status, and virus variants among pregnant women admitted to intensive care units (ICU) with severe COVID‐19.

Material and methods

We identified pregnant women admitted to ICU in Sweden (n = 96), Norway (n = 31), and Denmark (n = 16) because of severe COVID‐19, from national registers and clinical databases between March 2020 and February 2022 (Denmark), August 2022 (Sweden), or December 2022 (Norway). Their background characteristics, pregnancy outcome, and vaccination status were compared with all birthing women and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) test‐positive pregnant women during the same time period. We calculated the number admitted to ICU per 10 000 birthing and per 1000 SARS‐CoV‐2 test‐positive women during the Index, Alpha, Delta, and Omicron periods.

Results

Women admitted to ICU had a higher mean body mass index, were more often of non‐Scandinavian origin, had on average lower education and income levels, had a higher proportion of chronic and pregnancy‐related conditions, delivered preterm, had neonates with low Apgar scores, and had more infants admitted to neonatal care, compared with all birthing and test‐positive pregnant women. Of those admitted to ICU, only 7% had been vaccinated before admission. Overall, the highest proportion of women admitted to ICU per birthing was during the Delta period (4.1 per 10 000 birthing women). In Norway, the highest proportion admitted to ICU per test‐positive pregnant women was during the Delta period (17.8 per 1000 test‐positive), whereas the highest proportion of admitted per test‐positive in Sweden and Denmark was seen during the Index period (15.4 and 8.9 per 1000 test‐positive, respectively).

Conclusions

Admission to ICU because of COVID‐19 in pregnancy was a rare event in the Scandinavian countries, but women who were unvaccinated, of non‐Scandinavian origin, and with lower socio‐economic status were at higher risk of admission to ICU. In addition, women admitted to ICU for COVID‐19 had higher risk of adverse pregnancy outcomes.
Does income inequality increase status anxiety? Not directly, the role of perceived upward and downward mobility
Authors: Melita Davide , Rodríguez‐Bailón Rosa , Willis Guillermo B.
Published: March 2023

Status anxiety theory posits that higher income inequality leads people to attribute more importance to their socioeconomic status and to worry about the position they occupy on the social ladder. We investigated through two experimental studies (N = 1117) the causal effect of economic inequality on status anxiety and whether expected upward and downward mobility mediates this effect. In Study 1, perceived economic inequality indirectly increased status anxiety through lesser expected upward mobility. In Study 2, perceived economic inequality decreased both expected upward and downward mobility, with opposite indirect effects on status anxiety. This suggests that the relationship between inequality and status anxiety is not straightforward, and could implicate the presence of multiple processes working at the same time—whereas lower expected downward mobility could suppress the effect of inequality, lower expected upward mobility could exacerbate it.
The COVID‐19 pandemic has not changed stage at presentation nor treatment patterns of head and neck cancer: A retrospective cohort study
Authors: Clements Kelten , Cowell Anna , White Gillian , Flynn William , Conway David I. , Douglas Catriona M. , Paterson Claire
Published: March 2023

Objectives

To evaluate the impact of the COVID‐19 lockdown measures on HNC, by comparing the stage at presentation and treatment of HNC before and after the most severe COVID‐19 restrictions.

Design

A retrospective cohort study.

Setting

A regional cancer network serving a patient population of 2.4 million.

Participants

Newly diagnosed patients with HNC between June and October 2019 (pre‐pandemic) and June and October 2021 (post‐pandemic).

Main outcome measures

Symptom duration before diagnosis, stage at diagnosis, patient performance status (PS) and intent of treatment delivered (palliative vs. curative).

Results

Five hundred forty‐five patients were evaluated—250 in the 2019 and 295 in the 2021 cohort. There were no significant differences in symptom duration between the cohorts (p = .359) or patient PS (p = .821). There were no increased odds of presenting with a late (Stage III or IV) AJCC cancer stage in 2021 compared with 2019 (odds ratio [OR] = 0.90; 95% confidence interval [CI]: 0.76–1.08); nor increased odds of receiving palliative rather than curative treatment in 2021 compared with 2019 (OR = 0.68; 95% CI: 0.45–1.03).

Conclusion

The predicted stage shift to more advanced disease at the time of diagnosis of HNC due to the COVID‐19 pandemic has not been realised in the longer term. In keeping with this, there was no difference in symptom duration, patient PS, or treatment patterns between the 2019 and 2021 cohorts.
Recent advances in the role of endogenous hydrogen sulphide in cancer cells
Authors: Chen Hao‐Jie , Li Ke , Qin Yang‐Zhe , Zhou Jing‐Jing , Li Tao , Qian Lei , Yang Chang‐Yong , Ji Xin‐Ying , Wu Dong‐Dong
Published: March 2023

Hydrogen sulphide (H2S) is a gaseous neurotransmitter that can be self‐synthesized by living organisms. With the deepening of research, the pathophysiological mechanisms of endogenous H2S in cancer have been increasingly elucidated: (1) promote angiogenesis, (2) stimulate cell bioenergetics, (3) promote migration and proliferation thereby invasion, (4) inhibit apoptosis and (5) activate abnormal cell cycle. However, the increasing H2S levels via exogenous sources show the opposite trend. This phenomenon can be explained by the bell‐shaped pharmacological model of H2S, that is, the production of endogenous (low concentration) H2S promotes tumour growth while the exogenous (high concentration) H2S inhibits tumour growth. Here, we review the impact of endogenous H2S synthesis and metabolism on tumour progression, summarize the mechanism of action of H2S in tumour growth, and discuss the possibility of H2S as a potential target for tumour treatment.
Identification and comparison of Chlamydia psittaci, Legionella and Mycoplasma pneumonia infection
Authors: Zhu Ning , Zhou Daibing , Yuan Ruyu , Ruzetuoheti Yiminniyaze , Li Jing , Zhang Xiujuan , Li Shengqing
Published: March 2023

Introduction

Conventional etiological detection and pathogenic antibody methods make it challenging to identify the atypical pathogens among the community‐acquired pneumonia (CAP). Metagenomic next‐generation sequencing (mNGS) could rapidly detect all potentially infectious diseases and identifies novel or potential pathogens.

Methods

Eighteen patients diagnosed with atypical CAP were enrolled in this retrospective study, including nine Chlamydia psittaci pneumonia (C. p), four Legionella pneumonia (L. p) and five Mycoplasma pneumonia (M. p). We simultaneously tested bronchoalveolar lavage fluid (BALF) samples for conventional microbiological methods and mNGS, and blood specimens were analysed. We also collected and compared baseline and clinical characteristics and treatment responses.

Results

Patients with C. p and L. p had similar symptoms, including fever, cough, headache, dyspnoea, asthenia, shivering and headache, compared with M. p, whose symptoms were slight. C. p and L. p usually showed multiple lobar distributions with pleural effusion. Serologic testing indicated that L. p had higher levels of white blood cells (WBCs), neutrophils, C‐reactive protein (CRP), procalcitonin (PCT), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and creatinine compared with M. p and L. p (p < 0.05). However, patients with C. p had lower levels of albumin (p < 0.05), and M. p had a minimum risk of cardiac volume loads (p < 0.05). CD4/CD8 ratio, lymphocytes, aspartate aminotransferase (AST), creatine kinase (CK), cell counting of BALF and coagulation had no difference (p < 0.05). Pathogenic IgM assay showed that 4/5 cases were positive for M. p and no positive detection for C. p and L. p infection. We timely adjusted the antibiotics according to the final mNGS results. Eventually, 16/18 patients recovered fully. Conditions of L. p patients were worse than those of C. p patients, and those of M. p patients were the least.

Conclusion

Early application of mNGS detection increased the atypical pathogenic identification, improved the prognosis and made up for the deficiency of conventional detection methods.
Down‐expression of Foxj1 on airway epithelium with impaired cilia architecture in non‐cystic fibrosis bronchiectasis implies disease severity
Authors: Zou Xiao‐Ling , Yang Hai‐Ling , Ding Wen‐Wen , Li Hai‐Ke , Zhou Yu‐Qi , Zhang Tian‐Tuo
Published: March 2023

Introduction

The pathogenesis of non‐cystic fibrosis bronchiectasis has not been clearly clarified. This study aimed to investigate the expression of ciliary regulating protein forkhead box protein j1 (Foxj1) on airway epithelium in non‐cystic fibrosis bronchiectasis and its association with airway cilia structure disorder and disease severity.

Methods

Lung tissue sections excised from 47 patients with non‐cystic fibrosis bronchiectasis were included between January 2018 and June 2021. Specimens from 26 subjects who underwent a lobectomy due to lung nodule were chosen as controls. Clinical information was collected, and pathologic analysis was performed to assess the epithelial structure and expression of ciliary regulating Foxj1.

Results

Of the 47 patients with non‐cystic fibrosis bronchiectasis, 25 were considered as mild, 12 were moderate whereas the remaining 10 cases were severe according to the bronchiectasis severity index score evaluation. Epithelial hyperplasia, hyperplasia of goblet cells and inflammatory cell infiltration were observed in non‐cystic fibrosis bronchiectasis, compared with control subjects. Cilia length in non‐cystic fibrosis bronchiectasis patients were shorter than that in the control group, (5.34 ± 0.89) μm versus (7.34 ± 0.71) μm, respectively (P = 0.002). The expression of Foxj1 was (2.69 ± 1.09) × 106 in non‐cystic fibrosis bronchiectasis, compared with (6.67 ± 1.15) × 106 in the control group (P = 0.001). Moreover, patients with lower expression of Foxj1 showed shorter airway cilia and worse in disease severity.

Conclusion

Foxj1 declined in the airway epithelium of patients with non‐cystic fibrosis bronchiectasis, positively correlated to cilia length and might imply worse disease severity.
Center expansion of liver transplants using donation after circulatory death organs is associated with reduced overall waitlist mortality
Authors: Kathawate Ranganath G. , Abt Peter L. , Bittermann Therese
Published: March 2023

Introduction

Waitlist outcomes in liver transplantation (LT) for individual recipients are improved by use of allografts procured through donation after circulatory death (DCD). However, the impact of increased DCD acceptance on overall center outcomes is unknown.

Methods

Using the United Network for Organ Sharing database, 88 centers performing an average of ≥10 LTs/year between 1/2004 and 12/2019 were compared by percent DCD use quartile and categorized into four phenotypes according to temporal usage trends. Overall center median Model for End‐stage Liver Disease at LT (MMaT), waitlist mortality, and waiting time were evaluated.

Results

The overall DCD rate was 6.1% (N = 4906/80,709), ranging from 0% to 25.5%. Centers in the top DCD use quartile had lower MMaT (24 vs. 26; p < .001) and shorter overall waiting times (median 66 days vs. 90 days; p < .001) compared to bottom quartile centers. MMaT increased less over time at centers with increasing DCD use and was lower than at centers with declining DCD use (27 vs. 32; p = .017). Overall waitlist mortality between 2016 and 2019 was lower at increasing DCD use centers (17.8% vs. 22.5%, p = .034), yet did not affect 1‐year mortality (p = .747).

Conclusions

The improved waitlist outcomes at centers with expanded DCD use extend beyond DCD recipients alone without negative consequences to overall post‐LT center metrics.
Successful clinical and virological outcomes of liver transplantation for HDV/HBV‐related disease after long‐term discontinuation of hepatitis B immunoglobulins
Authors: Lenci Ilaria , Tariciotti Laura , Angelico Roberta , Milana Martina , Signorello Alessandro , Manzia Tommaso Maria , Toti Luca , Tisone Giuseppe , Angelico Mario , Baiocchi Leonardo
Published: March 2023

Background

Indefinite, long‐term administration of hepatitis B immunoglobulins (HBIg), together with a third generation nucleos(t)ide analog (NA), is the currently recommended prophylactic strategy to prevent viral recurrence after liver transplantation (LT) for Hepatitis Delta virus (HDV)/Hepatitis B virus (HBV)‐related disease.

Methods

We retrospectively analyzed the safety and long‐term clinical and virological outcomes of a consecutive cohort of 16 patients (10 males, median age 64.5, range 41–75) transplanted for HDV/HBV‐related cirrhosis at our Institution, who discontinued HBIg after a median of 24.5 months (range 15–116) after transplant. All patients continued prophylaxis with same NA used before LT. Recurrence of HDV/HBV infection was defined as reappearance of serum HDV‐RNA with detectable serum HBsAg and/or HBV‐DNA.

Results

The median follow‐up after LT was 138 months (range 73–316) and 110 months (range 52–200) after HBIg withdrawal. All patients were HBsAg‐positive, HBV‐DNA negative, and anti‐HDV positive at the time of LT and without coinfections with HCV or HIV. Patients were followed with biochemical and virological tests every 3–6 months after HBIg withdrawal. No recurrences of HDV/HBV infection or disease were observed during monoprophylaxis with NA. In addition, eight patients (50%) spontaneously developed anti‐HBs titers above 10 IU/L at a median of 74 months (range 58–140) following HBIG discontinuation.

Conclusions

HBIg withdrawal after LT is a safe and efficacious strategy in patients transplanted for HDV/HBV disease and is frequently associated with the spontaneous development of serological immunity against HBV. These data call for a revision of current prophylactic recommendations in this setting.
Prognostic value of severe acute respiratory syndrome coronavirus‐2 viral load and antibodies in patients hospitalized with COVID‐19
Authors: Bauer Rebecca N. , Teterina Anastasia , Shivram Haridha , McBride Jacqueline , Rosenberger Carrie M. , Cai Fang , Bao Min , Tsai Larry , Gordon Oliver , Lee Ivan T. , Wallin Jeffrey J. , Porter Danielle , Juneja Kavita , Camus Gregory , Rosas Ivan O. , Wildum Steffen
Published: March 2023

Observational studies have identified the potential prognostic value for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) viral load and anti‐SARS‐CoV‐2 antibodies in coronavirus disease 2019 (COVID‐19). However, viral load in nasopharyngeal (NP) swabs produced inconsistent results in prognostic analyses, and the prognostic value of viral load or antibodies has not been confirmed in large clinical trials. COVACTA and REMDACTA were double‐blind, randomized, controlled trials with a combined enrollment of 1078 patients hospitalized with COVID‐19 treated with tocilizumab or placebo in COVACTA or tocilizumab plus remdesivir or placebo plus remdesivir in REMDACTA. We assessed the potential prognostic value of NP and serum SARS‐CoV‐2 viral load and serum anti‐SARS‐CoV‐2 antibodies at baseline as biomarkers for clinical outcomes in patients enrolled in these trials. In adjusted Cox proportional hazard models, serum viral load was a more reliable predictor of clinical outcomes than NP viral load; high serum viral load was associated with higher risk for death and mechanical ventilation/death and lower likelihood of hospital discharge (high vs. negative viral load hazard ratios [95% confidence interval {CI}] were 2.87 [1.57–5.25], 3.86 [2.23–6.68], and 0.23 [0.14–0.36], respectively, in COVACTA and 8.11 [2.95–22.26], 10.29 [4.5–23.55], and 0.21 [0.15–0.29], respectively, in REMDACTA) and high serum viral load correlated with levels of inflammatory cytokines and lung damage biomarkers. High anti‐SARS‐CoV‐2 spike protein antibody (ACOV2S) levels were associated with higher likelihood of hospital discharge (high vs. below the limit of quantification hazard ratios [95% CI] were 2.55 [1.59–4.08] for COVACTA and 1.54 [1.13–2.09] for REMDACTA). These results support the role of baseline SARS‐CoV‐2 serum viral load and ACOV2S antibody titers in predicting clinical outcomes for patients hospitalized with COVID‐19.
Colchicin – Renaissance eines „uralten“ Arzneimittels
Authors: Huber Stephanie Marie , Navarini Alexander , Brandt Oliver , Müller Simon
Published: March 2023

Das bereits von den alten Ägyptern angewendete Colchicin erfuhr jüngst – dank seines breiten therapeutischen Wirkspektrums – eine Renaissance in verschiedenen medizinischen Disziplinen inklusive der Dermatologie. Aufgrund seines potenziell erheblichen Nebenwirkungsprofiles bei systemischer Anwendung setzen viele Kliniker Colchicin aber nur zurückhaltend ein. Diese Arbeit gibt einen praxisnahen Überblick über die Datenlage zum etablierten und neuen Einsatz von systemischem und topischem Colchicin bei dermatologischen Krankheiten.
Effect of slope borders in reducing splash erosion during sediment transport by rain‐induced overland flow
Authors: Liu Lin , Zhang Yi , Li Zhongwu , Xu Fei , Zhang Qinghui
Published: March 2023

Splash erosion plays a vital role in the loss of eroded materials. Unlike those in slope central areas, laterally ejected splashed materials in slope border areas cannot be replenished easily because slope edges prevent splash erosion particles from entering the slope. Thus, splashed materials in slope border areas are less than those in slope central areas because of the lack of source areas for splash‐eroded materials. However, this phenomenon, called the slope border effect, has received minimal attention by researchers. The partially missing splash erosion induced by the slope border effect on sediment transport was investigated to understand the slope erosion mechanism further in this paper. A modified soil pan divided into four areas, namely, central erosion test area (length = 100 cm, width = 35 cm, depth = 45 cm), border erosion test area (length = 100 cm, width = 35 cm, depth = 45 cm), splash compensate border area (length = 110 cm, width = 30 cm, depth = 45 cm) and splash collection area (length = 100 cm, width = 2.5 cm, depth = 45 cm) was used to monitor diffusion and splash erosion under simulated rainfall. Results showed that the splash detachment rate increased with the increase in slope but initially decreased and then increased with the increase in rainfall intensity. The runoff rate and diffuse erosion rates for complete splash erosion (SE) treatments were higher than those without partial splash erosion (SEL). Under low rainfall erosive power and runoff transport capacity (e.g., 5° slope and 60 mm h−1), the transported clay in SE treatments was approximately 2% more than that in SEL treatments. This amount changed to more than 2% sand under high rainfall and runoff erosive power. However, the mass fraction accounted for by silt particles in the sediments of the SEL treatments was more than that in the SE treatments. Thus, the partially missing splash erosion can weaken the selective transport ability of runoff for sediments. The effect of missing partial splash erosion on diffuse erosion was enhanced with an increase in erosive power. The results of our paper will provide insights into the effect of the boundary effect zone of slope on soil erosion and its related mechanisms.
Mutualistic interactions shape global spatial congruence and climatic niche evolution in Neotropical mimetic butterflies
Authors: Doré Maël , Willmott Keith , Lavergne Sebastien , Chazot Nicolas , Freitas André V. L. , Fontaine Colin , Elias Marianne
Published: March 2023

Understanding the mechanisms underlying species distributions and coexistence is both a priority and a challenge for biodiversity hotspots such as the Neotropics. Here, we highlight that Müllerian mimicry, where defended prey species display similar warning signals, is key to the maintenance of biodiversity in the c. 400 species of the Neotropical butterfly tribe Ithomiini (Nymphalidae: Danainae). We show that mimicry drives large‐scale spatial association among phenotypically similar species, providing new empirical evidence for the validity of Müller's model at a macroecological scale. Additionally, we show that mimetic interactions drive the evolutionary convergence of species climatic niche, thereby strengthening the co‐occurrence of co‐mimetic species. This study provides new insights into the importance of mutualistic interactions in shaping both niche evolution and species assemblages at large spatial scales. Critically, in the context of climate change, our results highlight the vulnerability to extinction cascades of such adaptively assembled communities tied by positive interactions.
Interparental conflict and adolescent emotional security across family structures
Authors: O'Hara Karey L. , Cummings E. Mark , Davies Patrick T.
Published: March 2023

This study investigated whether interparental conflict was differentially related to forms of emotional security (i.e., family, interparental, parent–child) and whether forms of emotional security were differentially associated with mental health problems for adolescents in married versus divorced/separated families. Participants were 1032 adolescents (ages 10–15; 51% male, 49% female; 82% non‐Hispanic White, 9% Black/African American, 5% Hispanic, 2% Asian or Pacific Islander, 2% Native American) recruited from a public school in a middle‐class suburb of a United States metropolitan area. We used multiple group multivariate path analysis to assess (1) associations between interparental conflict and multiple measures of emotional insecurity (i.e., family, interparental, and parent–child), (2) associations between measures of emotional insecurity and internalizing and externalizing problems, and (3) moderation effects of parent–child relationships. The patterns of association were similar across family structures. A high‐quality parent–child relationship did not mitigate the harmful effects of interparental conflict on emotional insecurity or mental health problems. Findings suggest that regardless of family structure, emotional security across multiple family systems may be a critical target for intervention to prevent youth mental health problems, in addition to interventions that reduce conflict and improve parent–child relationships.
Recreating the extracellular matrix: novel 3D cell culture platforms in cancer research
Authors: Kyriakopoulou Konstantina , Koutsakis Christos , Piperigkou Zoi , Karamanos Nikos K.
Published: March 2023

Cancer initiation and progression heavily rely on microenvironmental cues derived from various components of the niche including the extracellular matrix (ECM). ECM is a complex macromolecular network that governs cell functionality. Although the two‐dimensional (2D) cell culture systems provide useful information at the molecular level and preclinical testing, they could not accurately represent the in vivo matrix microenvironmental architecture. Hence, it is no surprise that researchers in the last decade have focussed their efforts on establishing novel advanced in vitro culture models that mimic tumour and tissue‐specific niches and interactions. These numerous three‐dimensional (3D) culture systems that are now widely available, as well as those still under development, grant researchers with new, improved tools to study cancer progression and to explore innovative therapeutic options. Herein, we report on the emerging methods and cutting‐edge technologies in 3D cell culture platforms and discuss their potential use in unveiling tumour microenvironmental cues, drug screening and personalized treatment.
A study on XFEM simulation of tensile, fracture toughness, and fatigue crack growth behavior of Al 2024 alloy through fatigue crack growth rate models using genetic algorithm
Authors: Gairola Saurabh , Rengaswamy Jayaganthan , Verma Raviraj
Published: March 2023

This study aims to numerically validate and simulate the fatigue crack growth rate (FCGR), tensile, and fracture toughness properties of T3 and T351 tempered aerospace grade Al 2024 alloy. The extended finite element method (XFEM) coupled with a genetic algorithm (GA) was used to predict FCGR behavior in the framework of an in‐house developed MATLAB code. The numerical simulation was performed using three different FCGR models, i.e., Paris, Forman, and Nasgro. The FCGR prediction ability of simulation models was improved and compared further using GA. The Nasgro model with genetically optimized parameters shows the highest FCGR prediction accuracy compared to other FCGR models. The critical stress intensity factor and von Mises stress distribution under static loading were also predicted for C(T) specimen. A similar XFEM approach was used for analyzing the tensile behavior using a center cracked specimen at the gage section of a dog bone‐shaped specimen.
Phase I study of a novel therapeutic vaccine as perioperative treatment for patients with surgically resectable hepatocellular carcinoma: The YCP02 trial
Authors: Nakajima Masao , Hazama Shoichi , Tokumitsu Yukio , Shindo Yoshitaro , Matsui Hiroto , Matsukuma Satoshi , Nakagami Yuki , Tamada Koji , Udaka Keiko , Sakamoto Michiie , Saito Akira , Kouki Yasunari , Uematsu Toshinari , Xu Ming , Iida Michihisa , Tsunedomi Ryouichi , Suzuki Nobuaki , Takeda Shigeru , Ioka Tatsuya , Doi Shun , Nagano Hiroaki
Published: March 2023

Aim

Developing effective adjuvant therapies is essential for improving the surgical outcomes in patients with hepatocellular carcinoma (HCC). Immunotherapy against HCC has become a promising strategy; however, only approximately 30% of all HCC patients respond to immunotherapy. Previously, we generated the novel therapeutic vaccine comprising multi‐human leukocyte antigen‐binding heat shock protein 70/glypican‐3 peptides with a novel adjuvant combination of hLAG‐3Ig and poly‐ICLC. We also confirmed the safety of this vaccination therapy, as well as its capacity for the effective induction of immune responses in a previous clinical trial.

Methods

In this phase I study, we administered this vaccine intradermally six times before surgery, and 10 times after surgery to patients with untreated, surgically resectable HCC (stage II to IVa). The primary end‐points of this study were the safety and feasibility of this treatment. We also analyzed the resected tumor specimens pathologically using hematoxylin–eosin staining and immunohistochemistry for heat shock protein 70, glypican 3, CD8 and programmed death‐1.

Results

A total of 20 human leukocyte antigen‐matched patients received this vaccination therapy with an acceptable side‐effect profile. All patients underwent planned surgery without vaccination‐related delay. Immunohistochemical analyses revealed that potent infiltration of CD8+ T cells into tumors with target antigen expression was observed in 12 of 20 (60%) patients.

Conclusions

This novel therapeutic vaccine was safe as perioperative immunotherapy for patients with HCC, and has the potential to strongly induce CD8+ T cells infiltration into tumors.
Whole‐body MRI for cancer surveillance in ataxia–telangiectasia: A qualitative study of the perspectives of people affected by A‐T and their families
Authors: Neves Renata , Perez Blanca de Dios , Tindall Tierney , Fernandez Natasha Schneider , Panek Rafal , Wilne Sophie , Suri Mohnish , Whitehouse William , Jagani Sumit , Dandapani Madhumita , Dineen Robert A. , Glazebrook Cris
Published: March 2023

Background/Objectives

Ataxia–telangiectasia (A‐T) is a complex inherited disease associated with an increased risk of malignancy. Surveillance guidelines have demonstrated significant health benefits in other cancer predisposition syndromes. However, evidence‐based guidelines for cancer screening are not currently used in the United Kingdom for people affected by A‐T. This study aims to understand how people with A‐T and their parents feel about cancer surveillance using whole‐body magnetic resonance imaging (MRI) to inform the future development of cancer surveillance guidelines.

Design/Methods

We conducted semistructured interviews with people affected by A‐T. Data were analysed inductively using thematic analysis.

Results

Nine parents of children with A‐T and four adults with A‐T were interviewed. Five main themes emerged from the data, including (1) cancer screening was considered invaluable with the perceived value of early detection highlighted; (2) the cancer fear can increase anxiety; (3) the perceived limitations around current practice, with the responsibility for monitoring falling too strongly on parents and patients; (4) the need for effective preparation for cancer screening, including clear communication and (5) the challenges associated with MRI screening, where specific recommendations were made for improving the child's experience.

Conclusion

This study suggests that stakeholders are positive about the perceived advantages of a cancer screening programme. Ongoing support and preparation techniques should be adopted to maximise adherence and minimise adverse psychosocial outcomes.

Patient or Public Contribution

People with A‐T and parents of people with A‐T were actively involved in this study by giving their consent to be interviewed. An independent parent representative contributed to the study, supporting the research team in interpreting and commenting on the appropriateness of the language used in this report.
Large cell calcifying Sertoli cell tumour: molecular and immunohistochemical assessment of a series comprising non‐metastasising and metastasising neoplasms
Authors: Yu Sanhong , Sholl Lynette M , Siegmund Stephanie , Ulbright Thomas M , Collins Katrina , Colecchia Maurizio , del Pilar Gonzalez‐Peramato Maria , Michalová Květoslava , Gordetsky Jennifer B , Cornejo Kristine M , Kao Chia‐Sui , Wobker Sara E , Vargas Sara O , Maclean Fiona , Idrees Muhammad T , Anderson William J , Fletcher Christopher D M , Acosta Andres M
Published: March 2023

Aims

Large cell calcifying Sertoli cell tumour (LCCSCT) is a type of testicular sex cord‐stromal tumour that may occur sporadically or in the context of Carney complex and other genetic syndromes. A subset is clinically malignant, and the molecular mechanisms that drive such aggressive behaviour remain unknown.

Methods and results

We analysed 21 samples from 20 patients with LCCSCT (12 non‐metastasising and eight metastasising) using PRKAR1A immunohistochemistry (IHC) and next‐generation sequencing. All tumours except two (cases 17 and 20, both metastasising) demonstrated loss of PRKAR1A expression. Among 11 cases with interpretable sequencing results, all harboured pathogenic single nucleotide variants of PRKAR1A. Evidence of loss of heterozygosity (LOH) of PRKAR1A was present in all tumours with interpretable zygosity data, but the mechanisms of LOH were different for non‐metastasising and metastasising tumours. Non‐metastasising tumours demonstrated only copy‐neutral LOH, while metastasising tumours demonstrated a spectrum of mechanisms of LOH, including copy‐loss LOH, two concurrent mutations or copy‐neutral LOH. Relevant molecular findings in non‐metastasising LCCSCT were limited to PRKAR1A variants. In contrast, all metastasising LCCSCTs with interpretable data harboured additional pathogenic variants, including (but not restricted to) BRCA2 mutations with evidence of LOH and bi‐allelic CDKN2A/B deletions. Three patients harboured PRKAR1A variants of inferred germline origin, including one with Carney complex and two without known syndromic features.

Conclusions

This study further confirms that PRKAR1A IHC is a useful diagnostic tool for both non‐metastasising and metastasising tumours and suggests that molecular analyses can be helpful to identify non‐metastasising tumours with malignant potential in selected patients. Importantly, these results highlight that germline assessment could be beneficial for all patients presenting with LCCSCT.
What are the predictors of change in multimorbidity among people with HIV? A longitudinal observational cohort study
Authors: Casten Michael , Herbert Simone , Smith David J. , Petoumenos Kathy , Coorey Craig , Edmiston Natalie
Published: March 2023

Introduction

Multimorbidity is common among people living with HIV (PLWH), with numerous cross‐sectional studies demonstrating associations with older age and past immunosuppression. Little is known about the progression of multimorbidity, particularly in the setting of long‐term access to antiretrovirals. This study aims to determine factors predictive of change in multimorbidity in PLWH.

Methods

People living with HIV who attended a regional HIV service were recruited to a consented observational cohort between September 2016 and March 2020. Demographic data, laboratory results and a Cumulative Illness Rating Scale (CIRS) were collected at enrolment and first clinical review of every subsequent year. Change in CIRS score was calculated from enrolment to February 2021. Associations with change were determined through univariate and multivariate linear regression.

Results

Of 253 people, median age was 58.9 [interquartile range (IQR): 51.9–64.4] years, 91.3% were male, and HIV was diagnosed a median of 22.16 years (IQR: 12.1–30.9) beforehand. Length of time in the study was a median of 134 weeks (IQR: 89.0–179.0), in which a mean CIRS score change of 1.21 (SD 2.60) was observed. Being older (p < 0.001) and having a higher body mass index (p = 0.008) and diabetes (p = 0.014) were associated with an increased likelihood of worsening multimorbidity. PLWH with a higher level of multimorbidity at baseline were less likely to worsen over time (p < 0.001).

Conclusion

As diabetes and weight predict worsening multimorbidity, routine diabetes screening, body mass index measurement, and multimorbidity status awareness are recommended.
Study on the surface damage of green ZrO2 ceramics in dry cutting based on discrete element method
Authors: Zhu Qi , Liu Yayun , Xu Ziming , Sun Dachao , Wang Chuanyang
Published: March 2023

Discrete element simulation model and cutting tests are conducted to investigate the surface damage during the machining of green ZrO2 ceramics. The discrete element simulation model (DEM) is developed based on the macroscopic physical and mechanical properties of the isostatically pressed green ZrO2 ceramics. The validity of the simulation model is verified by cutting tests on green ZrO2 ceramics. The results show that the physical and mechanical properties of the DEM model established by the PFC2D software are consistent with the macroscopic physical and mechanical properties of the green ZrO2 ceramics. The depth of cut, the cutting speed, and the tool rake angles have a large effect on surface/subsurface cracks. The tool rear angle has large effect on the distribution of the peak residual stresses. When the cutting force increases suddenly, the number of cracks produced increases sharply. Smaller cutting force can reduce the number of cracks and surface damage.
Effect of high hydrostatic pressure and ultrasonic treatment on solubility and structural changes of rice bran protein
Authors: Yi Jia , Liu Kunlun
Published: March 2023

The effect of non‐thermal treatment on the solubility and structural properties of rice bran protein was investigated. It was shown that the non‐thermal treatment significantly improved the solubility of rice bran protein, in which, HHP and US increased it by 76.69% and 136.75%, respectively. The structural analysis showed that the non‐thermal treatment reduced the β‐sheet content and increased the content of free sulfhydryl groups on the surface, indicating that the inter‐chain hydrogen and disulfide bonds of rice bran protein were broken and the protein structure shifted from order to disorder. And the internal chromogenic groups of the protein were exposed and tended to the hydrophilic environment, indicating the exposure of hydrophilic groups. This study provides a theoretical basis for non‐thermal modification of rice bran protein and its processing and utilisation.
AhR activation promotes Treg cell generation by enhancing Lkb1‐mediated fatty acid oxidation via the Skp2/K63‐ubiquitination pathway
Authors: Zhang Qin , Zhu Yanrong , Lv Changjun , Fang Yulai , Liao Minhui , Xia Yufeng , Wei Zhifeng , Dai Yue
Published: March 2023

Several aryl hydrocarbon receptor (AhR) agonists have been reported to promote the generation of regulatory T cells (Treg cells), and the action mechanisms need to be identified. In this study, we addressed the underlying mechanism of AhR activation to induce the generation of Treg cells in the view of cellular metabolism. Naïve CD4+ T cells were purified with mouse CD4+ CD62L+ T Cells Isolation Kits. The proportions of Treg cells were detected by flow cytometry. The value of oxygen consumption rate (OCR) of CD4+ T cells was detected by the Seahorse XFe 96 analyzer. The activation of fatty acid oxidation (FAO)‐related metabolic pathways was detected by Western blotting. Intracellular localization of Lkb1 was detected by immunofluorescence. The Strad‐Mo25‐Lkb1 complex formation and K63 chain ubiquitination modification of Lkb1 were detected by co‐immunoprecipitation. The binding of AhR to the Skp2 promoter was detected by constructing luciferase reporter gene. AhR or carnitine palmitoyltransferases 1 was knockdown in dextran sulphate sodium (DSS)‐induced colitis or collagen‐induced arthritis (CIA) mice by infecting mice with adeno‐associated virus via the tail vein injection. Compared to the control group, exogenous and endogenous AhR agonists 3,3′‐diindolylmethane (DIM) and 2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methyl ester (ITE) were shown to preferentially upregulate the mRNA expression of FAO‐related enzymes and the value of OCR. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of DIM and ITE on the differentiation of Treg cells. DIM and ITE functioned mainly through activating the liver kinase B1 (Lkb1)‐AMPK pathway via promotion of Lkb1‐Strad‐Mo25 complex formation and Lkb1 K63 ubiquitination. DIM and ITE were also shown to upregulate the mRNA expression of Skp2, a ubiquitination‐related enzyme, and facilitate the binding of AhR to the xenobiotic responsive element of Skp2 promoter region by luciferase reporter gene assay. Furthermore, the contribution of Skp2/K63 ubiquitination/Lkb1/FAO axis was verified in (DSS)‐induced colitis or CIA mice. In summary, these findings indicate that AhR activation promotes Treg cell generation by enhancing Lkb1‐mediated FAO via the Skp2/K63‐ubiquitination pathway, and AhR agonists may be used as inducers of Treg cells to prevent and treat autoimmune diseases.
GPR35 and mediators from platelets and mast cells in neutrophil migration and inflammation
Authors: De Giovanni Marco , Chen Hongwen , Li Xiaochun , Cyster Jason G.
Published: March 2023

Neutrophil recruitment from circulation to sites of inflammation is guided by multiple chemoattractant cues emanating from tissue cells, immune cells, and platelets. Here, we focus on the function of one G‐protein coupled receptor, GPR35, in neutrophil recruitment. GPR35 has been challenging to study due the description of multiple ligands and G‐protein couplings. Recently, we found that GPR35‐expressing hematopoietic cells respond to the serotonin metabolite 5‐hydroxyindoleacetic acid (5‐HIAA). We discuss distinct response profiles of GPR35 to 5‐HIAA compared to other ligands. To place the functions of 5‐HIAA in context, we summarize the actions of serotonin in vascular biology and leukocyte recruitment. Important sources of serotonin and 5‐HIAA are platelets and mast cells. We discuss the dynamics of cell migration into inflamed tissues and how multiple platelet and mast cell‐derived mediators, including 5‐HIAA, cooperate to promote neutrophil recruitment. Additional actions of GPR35 in tissue physiology are reviewed. Finally, we discuss how clinically approved drugs that modulate serotonin uptake and metabolism may influence 5‐HIAA‐GPR35 function, and we speculate about broader influences of the GPR35 ligand‐receptor system in immunity and disease.
Binder removal from ceramic stereolithography green bodies: A neutron imaging and thermal analysis study
Authors: McAleer Eoin G. , Alazzawi Mustafa K. , Hwang Chawon , LaManna Jacob M. , Jacobson David L. , Khaykovich Boris , Haber Richard A. , Akdoğan E. Koray
Published: March 2023

Stereolithography of ceramics remains one of the most powerful additive manufacturing routes for the creation of intricate ceramic parts. Despite its utility as a forming tool, ceramic stereolithography requires a challenging debinding stage due to the requisite high polymeric loading. Earlier research has identified both the polymeric resin composition and debinding atmosphere to be crucial factors in improving debinding performance. Here, we use a combination of thermogravimetric analysis and neutron imaging to examine samples of different compositions printed using the same processing and exposure parameters. We quantify the influence of both polyethylene glycol addition and the use of different debinding atmospheres (argon and vacuum) on the debinding behavior of ceramic pellets. Specifically, we demonstrate a method for examining the concentration gradients that develop during thermal debinding with the aid of neutron tomography. We find that at a constant heating rate of 1°C/min up to 500°C, vacuum atmosphere appears to result in a greater number of cracks as compared to the use of argon. The vacuum atmosphere led to the development of lower concentration gradients in the samples on average. The greatest improvement resulted with the addition of polyethylene glycol to the samples. This addition led to significantly less cracking and much lower concentration gradients in samples during debinding. These results prompt us to conclude that while keeping printing and exposure parameters constant, composition modification has a more significant effect on the debinding improvement than heating atmosphere.
Climatic stability recorded in speleothems may contribute to higher biodiversity in the Cape Floristic Region
Authors: Braun Kerstin , Cowling Richard M. , Bar‐Matthews Miryam , Matthews Alan , Ayalon Avner , Zilberman Tami , Difford Mark , Edwards R. Lawrence , Li Xianglei , Marean Curtis W.
Published: March 2023

Aim

The geography and genesis of diversity remain an enduring topic in ecology and evolution. Mediterranean Climate Ecosystems (MCEs), with their high plant diversities in winter rainfall climates, pose a challenge to popular hypotheses evoking high water availability and temperature as necessary for the evolution of high diversity. We test the hypothesis of environmental stability as a driver for the evolution of regional‐scale floristic diversity using speleothem oxygen (δ18O) and carbon (δ13C) isotopic values as proxies for past climatic variability in the Cape Floristic Region (CFR) and other MCEs.

Location

south‐western Africa, California, Mediterranean Basin.

Taxon

Plantae.

Methods

We present new speleothem δ18O and δ13C records from a cave near Robertson in the western CFR. Stable isotope samples included in the analyses cover the time intervals between 240 and 670 ka BP with hiatuses at 630–500 ka and 360–310 ka. The dispersion of these stable isotope records is used as a measure for climatic variability. We compare our new analyses to speleothem records that cover full glacial and interglacial conditions in other MCEs (California and the Mediterranean Basin) as well as in eastern regions of the CFR. All sites used in this comparison have lower vascular plant biodiversity than the western CFR.

Results

Analyses of the dispersion of the δ18O and δ13C datasets suggest that the highly diverse western CFR experienced climatic stability across several glacial–interglacial cycles, compared with the less diverse regions within and outside of the CFR.

Main Conclusion

This result provides support for the hypothesis that lower extinction rates associated with Pleistocene biome stability may explain the higher diversity in the CFR relative to other MCEs.
Genome‐wide DNA methylation analysis of aggressive behaviour: a longitudinal population‐based study
Authors: Pishva Ehsan , van den Hove Daniel L. A. , Laroche Valentin , Lvovs Aneth , Roy Arunima , Ortega Gabriela , Burrage Joe , Veidebaum Toomas , Kanarik Margus , Mill Jonathan , Lesch Klaus‐Peter , Harro Jaanus
Published: March 2023

Background

Human aggression is influenced by an interplay between genetic predisposition and experience across the life span. This interaction is thought to occur through epigenetic mechanisms, inducing differential gene expression, thereby moderating neuronal cell and circuit function, and thus shaping aggressive behaviour.

Methods

Genome‐wide DNA methylation (DNAm) levels were measured in peripheral blood obtained from 95 individuals participating in the Estonian Children Personality Behaviours and Health Study (ECPBHS) at 15 and 25 years of age. We examined the association between aggressive behaviour, as measured by Life History of Aggression (LHA) total score and DNAm levels both assessed at age 25. We further examined the pleiotropic effect of genetic variants regulating LHA‐associated differentially methylated positions (DMPs) and multiple traits related to aggressive behaviours. Lastly, we tested whether the DNA methylomic loci identified in association with LHA at age 25 were also present at age 15.

Results

We found one differentially methylated position (DMP) (cg17815886; p = 1.12 × 10−8) and five differentially methylated regions (DMRs) associated with LHA after multiple testing adjustments. The DMP annotated to the PDLIM5 gene, and DMRs resided in the vicinity of four protein‐encoding genes (TRIM10, GTF2H4, SLC45A4, B3GALT4) and a long intergenic non‐coding RNA (LINC02068). We observed evidence for the colocalization of genetic variants associated with top DMPs and general cognitive function, educational attainment and cholesterol levels. Notably, a subset of the DMPs associated with LHA at age 25 also displayed altered DNAm patterns at age 15 with high accuracy in predicting aggression.

Conclusions

Our findings highlight the potential role of DNAm in the development of aggressive behaviours. We observed pleiotropic genetic variants associated with identified DMPs, and various traits previously established to be relevant in shaping aggression in humans. The concordance of DNAm signatures in adolescents and young adults may have predictive value for inappropriate and maladaptive aggression later in life.