bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD
Authors: Zhang Ziqi , Ji Guang , Li Meng
Published: August 2023

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (GCKR), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the GCKR gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the GCKR gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the GCKR gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.
Unlocking the post-transplant microenvironment for successful islet function and survival
Authors: Doherty Daniel T. , Khambalia Hussein A. , van Dellen David , Jennings Rachel E. , Piper Hanley Karen
Published: August 2023

Islet transplantation (IT) offers the potential to restore euglycemia for patients with type 1 diabetes mellitus (T1DM). Despite improvements in islet isolation techniques and immunosuppressive regimes, outcomes remain suboptimal with UK five-year graft survivals (5YGS) of 55% and most patients still requiring exogenous insulin after multiple islet infusions. Native islets have a significant non-endocrine component with dense extra-cellular matrix (ECM), important for islet development, cell survival and function. Collagenase isolation necessarily disrupts this complex islet microenvironment, leaving islets devoid of a supporting framework and increasing vulnerability of transplanted islets. Following portal venous transplantation, a liver injury response is potentially induced, which typically results in inflammation and ECM deposition from liver specific myofibroblasts. The impact of this response may have important impact on islet survival and function. A fibroblast response and ECM deposition at the kidney capsule and eye chamber alongside other implantation sites have been shown to be beneficial for survival and function. Investigating the implantation site microenvironment and the interactions of transplanted islets with ECM proteins may reveal therapeutic interventions to improve IT and stem-cell derived beta-cell therapy.
Trends in birth attendants in Sudan using three consecutive household surveys (from 2006 to 2014)
Authors: Altijani Noon , Khogali Mustafa , Hinton Lisa , Opondo Charles , Eljack Eman , Knight Marian , Nair Manisha
Published: August 2023

Introduction

Improving maternal health and survival remains a public health priority for Sudan. Significant investments were made to expand access to maternal health services, such as through the training and deployment of providers with varying skills and competencies to work across the country. This study investigates trends in the coverage of different birth attendants and their relationship with the maternal mortality ratio (MMR).

Methods

Trend analyses were conducted using data from the 2006, 2010, and 2014 Sudan Household surveys. Three categories of birth attendants were identified: (1) skilled birth attendants (SBA) such as doctors, nurse-midwives, and health visitors, (2) locally certified midwives, and (3) traditional birth attendants (TBA). Multivariable logistic regression models were used to examine trends in SBAs (vs. locally certified midwives and TBAs), locally certified midwives (vs SBAs and TBAs), and SBAs and locally certified midwives by place of birth (health facility and home). The analyses were adjusted for potential confounders. An ecological analysis was conducted to assess the relationship between birth attendants by place of birth and MMR at the state level.

Results

Births by 15,848 women were analysed. Locally certified midwives attended most births in each survey year, with their contribution increasing from 36.3% in 2006 to 55.5% in 2014. The contributions of SBAs and TBAs decreased over the same period. In 2014 compared with 2006, births were more likely to be attended by a locally certified midwife (aOR: 2.19; 95%CI: 1.82–2.63) but less likely to be attended by a SBA (aOR: 0.46; 95%CI: 0.37–0.56). The decrease in SBA was more substantial for births taking place at home (aOR: 0.17; 95%CI: 0.12–0.23) than for health facility births (aOR: 0.45; 95%CI: 0.31–0.65). In the ecological analysis 2014–2016, the proportion of births attended by SBA in health facilities correlated negatively with MMR at state level (rho −0.55; p: 0.02).

Conclusion

This analysis suggests that although an improved coverage of maternal health with locally certified midwives has been observed, it has not provided the skill level reached by SBA. SBAs working in facility settings were a key correlating factor to reduced maternal mortality. Urgent action is needed to improve access to SBAs in health facilities, thereby accelerating progress in reducing maternal mortality.
Heparins are potent inhibitors of ectonucleotide pyrophosphatase/phospho-diesterase-1 (NPP1) – a promising target for the immunotherapy of cancer
Authors: Lopez Vittoria , Schuh H. J. Maximilian , Mirza Salahuddin , Vaaßen Victoria J. , Schmidt Michael S. , Sylvester Katharina , Idris Riham M. , Renn Christian , Schäkel Laura , Pelletier Julie , Sévigny Jean , Naggi Annamaria , Scheffler Björn , Lee Sang-Yong , Bendas Gerd , Müller Christa E.
Published: August 2023

Introduction

Heparins, naturally occurring glycosaminoglycans, are widely used for thrombosis prevention. Upon application as anticoagulants in cancer patients, heparins were found to possess additional antitumor activities. Ectonucleotidases have recently been proposed as novel targets for cancer immunotherapy.

Methods and results

In the present study, we discovered that heparin and its derivatives act as potent, selective, allosteric inhibitors of the poorly investigated ectonucleotidase NPP1 (nucleotide pyrophosphatase/phosphodiesterase-1, CD203a). Structure-activity relationships indicated that NPP1 inhibition could be separated from the compounds’ antithrombotic effect. Moreover, unfractionated heparin (UFH) and different low molecular weight heparins (LMWHs) inhibited extracellular adenosine production by the NPP1-expressing glioma cell line U87 at therapeutically relevant concentrations. As a consequence, heparins inhibited the ability of U87 cell supernatants to induce CD4+ T cell differentiation into immunosuppressive Treg cells.

Discussion

NPP1 inhibition likely contributes to the anti-cancer effects of heparins, and their specific optimization may lead to improved therapeutics for the immunotherapy of cancer.
The impact of the COVID-19 pandemic on the global tuberculosis epidemic
Authors: Falzon Dennis , Zignol Matteo , Bastard Mathieu , Floyd Katherine , Kasaeva Tereza
Published: August 2023

Tuberculosis (TB) is a major cause of ill health worldwide. Until the coronavirus (COVID-19) pandemic, TB was the leading cause of death from a single infectious agent. COVID-19 has caused enormous health, social and economic upheavals since 2020, impairing access to essential TB services. In marked contrast to the steady global increase in TB detection between 2017 and 2019, TB notifications dropped substantially in 2020 compared with 2019 (-18%), with only a partial recovery in 2021. TB epidemiology worsened during the pandemic: the estimated 10.6 million people who fell ill with TB worldwide in 2021 is an increase of 4.5% from the previous year, reversing many years of slow decline. The annual number of TB deaths worldwide fell steadily between 2005 and 2019, reaching 1.4 million in 2019, but this trend was reversed in 2020 (1.5 million), and by 2021 global TB deaths were back to the level of 2017 (1.6 million). Intensified efforts backed by increased funding are urgently required to reverse the negative impacts of COVID-19 on TB worldwide, made more pressing by ongoing conflicts, a global energy crisis and uncertainties in food security that are likely to worsen the broader determinants of TB.
Targeting neoantigens to APC-surface molecules improves the immunogenicity and anti-tumor efficacy of a DNA cancer vaccine
Authors: Barrio-Calvo Marina , Kofoed Søren Vester , Holste Sofie Cens , Sørensen Anders Bundgård , Viborg Nadia , Kringelum Jens Vindahl , Kleine-Kohlbrecher Daniela , Steenmans Christian Skjødt , Thygesen Christian Bahne , Rønø Birgitte , Friis Stine
Published: August 2023

Introduction

Tumor-specific mutations generate neoepitopes unique to the cancer that can be recognized by the immune system, making them appealing targets for therapeutic cancer vaccines. Since the vast majority of tumor mutations are patient-specific, it is crucial for cancer vaccine designs to be compatible with individualized treatment strategies. Plasmid DNA vaccines have substantiated the immunogenicity and tumor eradication capacity of cancer neoepitopes in preclinical models. Moreover, early clinical trials evaluating personalized neoepitope vaccines have indicated favorable safety profiles and demonstrated their ability to elicit specific immune responses toward the vaccine neoepitopes.

Methods

By fusing in silico predicted neoepitopes to molecules with affinity for receptors on the surface of APCs, such as chemokine (C-C motif) ligand 19 (CCL19), we designed an APC-targeting cancer vaccine and evaluated their ability to induce T-cell responses and anti-tumor efficacy in the BALB/c syngeneic preclinical tumor model.

Results

In this study, we demonstrate how the addition of an antigen-presenting cell (APC) binding molecule to DNA-encoded cancer neoepitopes improves neoepitope-specific T-cell responses and the anti-tumor efficacy of plasmid DNA vaccines. Dose-response evaluation and longitudinal analysis of neoepitope-specific T-cell responses indicate that combining APC-binding molecules with the delivery of personalized tumor antigens holds the potential to improve the clinical efficacy of therapeutic DNA cancer vaccines.

Discussion

Our findings indicate the potential of the APC-targeting strategy to enhance personalized DNA cancer vaccines while acknowledging the need for further research to investigate its molecular mechanism of action and to translate the preclinical results into effective treatments for cancer patients.
Advances of mesenchymal stem cells and their derived extracellular vesicles as a promising therapy for acute respiratory distress syndrome: from bench to clinic
Authors: Zhuang Xiaoli , Jiang Yu , Yang Xiaofang , Fu Lin , Luo Lan , Dong Ziyuan , Zhao Ju , Hei Feilong
Published: August 2023

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury characterized by diffuse alveolar damage. The period prevalence of ARDS was 10.4% of ICU admissions in 50 countries. Although great progress has been made in supportive care, the hospital mortality rate of severe ARDS is still up to 46.1%. Moreover, up to now, there is no effective pharmacotherapy for ARDS and most clinical trials focusing on consistently effective drugs have met disappointing results. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have spawned intense interest of a wide range of researchers and clinicians due to their robust anti-inflammatory, anti-apoptotic and tissue regeneration properties. A growing body of evidence from preclinical studies confirmed the promising therapeutic potential of MSCs and their EVs in the treatment of ARDS. Based on the inspiring experimental results, clinical trials have been designed to evaluate safety and efficacy of MSCs and their EVs in ARDS patients. Moreover, trials exploring their optimal time window and regimen of drug administration are ongoing. Therefore, this review aims to present an overview of the characteristics of mesenchymal stem cells and their derived EVs, therapeutic mechanisms for ARDS and research progress that has been made over the past 5 years.
Novel T cell/organoid culture system allows ex vivo modeling of intestinal graft-versus-host disease
Authors: Matthe Diana M. , Dinkel Martin , Schmid Benjamin , Vogler Tina , Neurath Markus F. , Poeck Hendrik , Neufert Clemens , Büttner-Herold Maike , Hildner Kai
Published: August 2023

Acute graft-versus-host disease (GvHD) remains the biggest clinical challenge and prognosis-determining complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor T cells are acceptedly key mediators of alloreactivity against host tissues and here especially the gut. In support of previous studies, we found that the intestinal intra-epithelial lymphocyte (IEL) compartment was dynamically regulated in the course of MHC class I full mismatch allo-HSCT. However, while intestinal epithelial cell (IEC) damage endangers the integrity of the intestinal barrier and is a core signature of intestinal GvHD, the question whether and to what degree IELs are contributing to IEC dysregulation is poorly understood. To study lymphoepithelial interaction, we employed a novel ex vivo T cell/organoid co-culture model system. Here, allogeneic intra-epithelial T cells were superior in inducing IEC death compared to syngeneic IEL and allogeneic non-IEL T cells. The ability to induce IEC death was predominately confined to TCRβ+ T cells and was executed in a largely IFNγ-dependent manner. Alloreactivity required a diverse T cell receptor (TCR) repertoire since IELs genetically modified to express a TCR restricted to a single, non-endogenous antigen failed to mediate IEC pathology. Interestingly, minor histocompatibility antigen (miHA) mismatch was sufficient to elicit IEL-driven IEC damage. Finally, advanced live cell imaging analyses uncovered that alloreactive IELs patrolled smaller areas within intestinal organoids compared to syngeneic controls, indicating their unique migratory properties within allogeneic IECs. Together, we provide here experimental evidence for the utility of a co-culture system to model the cellular and molecular characteristics of the crosstalk between IELs and IEC in an allogeneic setting ex vivo. In the light of the emerging concept of dysregulated immune-epithelial homeostasis as a core aspect of intestinal GvHD, this approach represents a novel experimental system to e.g. screen therapeutic strategies for their potential to normalize T cell/IEC- interaction. Hence, analyses in pre-clinical in vivo allo-HSCT model systems may be restricted to hereby positively selected, promising approaches.
Shipping noise assessment in the Black Sea: insights from large-scale ASI CeNoBS survey data
Authors: Frassà Veronica , Prospathopoulos Aristides M. , Maglio Alessio , Ortega Noelia , Paiu Romulus-Marian , Azzellino Arianna
Published: August 2023

Sighting data deriving from the ACCOBAMS1 Survey Initiative (ASI), conducted through the CeNoBS2 project, enabled the investigation of the habitat preferences for three different cetacean subspecies occurring in the Black Sea waters: the bottlenose dolphins (Tursiops truncatus), the common dolphins (Delphinus delphis) and the harbour porpoise (Phocoena phocoena). ASI aerial surveys, aiming at assessing the distribution and abundance of cetacean populations, were conducted during summer of 2019 in waters in front of Romania, Georgia, Bulgaria, Turkey and Ukraine. The surveys allowed recording of 1716 sightings: 117 bottlenose dolphins, 715 common dolphins and 884 harbour porpoises. The aim of this study was twofold: (i) to develop habitat models, using physical characteristics, such as depth and slope, as covariates, in order to estimate the presence probability of the three cetacean species in the Black Sea; (ii) to demonstrate the usefulness of the habitat models in support of environmental status assessments on marine mammals where the stressor is the shipping noise. The results of this study show the reliability of physical covariates as predictors of the probability of occurrence for the three species of interest in the Black Sea, providing additional knowledge, complementary to abundance estimates, which may support the assessment of the vulnerability of marine areas to different pressures, including noise.
Inhaled therapies targeting prostacyclin pathway in pulmonary hypertension due to COPD: systematic review
Authors: Alqarni Abdullah A. , Aldhahir Abdulelah M. , Bintalib Heba M. , Alqahtani Jaber S. , Siraj Rayan A. , Majrshi Mansour , AlGarni Abdulkareem A. , Naser Abdallah Y. , Alghamdi Sara A. , Alwafi Hassan
Published: August 2023

Background

Pulmonary hypertension due to chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is classified as group 3 pulmonary hypertension. Inhaled treprostinil, a prostaglandin I2 analogue also known as prostacyclin, has recently been approved as a first drug for patients with pulmonary hypertension secondary to ILD. However, due to a lack of evidence, no therapies are currently approved for those with COPD-associated pulmonary hypertension. Thus, this systematic review aims to summarise the current evidence to assess the impact of inhaled prostaglandin I2 analogue use on the pulmonary hemodynamics, exercise function, lung function, and gas exchange in patients with pulmonary hypertension due to COPD.

Methods

We systematically searched the electronic databases of Medline, Embase, Scopus and Cochrane from inception to 1 February 2023. Studies of adult patients with a confirmed diagnosis of COPD-associated pulmonary hypertension who received inhaled drugs targeting the prostacyclin pathway were included in the systematic review. Case reports, systematic reviews, conference abstracts with no full text, non-full-text articles, non-English manuscripts and book chapters were excluded from this systematic review. A risk-of-bias assessment was carried out for the studies included in this review, using two different Cochrane risk-of-bias tools for randomised and non-randomised clinical trials.

Results

A total of four studies met our inclusion criteria and were included in this systematic review. The results of one prospective clinical trial showed an improvement in the pulmonary hemodynamics (e.g., cardiac index, cardiac output and mean pulmonary artery pressure) in response to inhaled prostacyclin use in patients with pulmonary hypertension secondary to COPD. However, the severity of dyspnoea, lung function, exercise capacity and gas exchange were not affected when inhaled prostacyclin was used for patients with COPD-related pulmonary hypertension.

Conclusion

This systematic review demonstrated that although inhaled prostacyclin does not seem to improve COPD-related outcomes (e.g., lung function and exercise capacity), short-term use of inhaled prostacyclin has the potential to reduce mean pulmonary artery pressure and pulmonary vascular resistance without impairing ventilation-perfusion mismatch. Further studies with larger sample sizes are warranted.

Systematic review registration

CRD42022372803, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=372803.
Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1G93A mice
Authors: Tomiyama Ana Laura M. R. , Cartarozzi Luciana Politti , de Oliveira Coser Lilian , Chiarotto Gabriela Bortolança , Oliveira Alexandre L. R.
Published: August 2023

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively affects motoneurons, causing muscle atrophy and evolving to death. Astrocytes inhibit the expression of MHC-I by neurons, contributing to a degenerative outcome. The present study verified the influence of interferon β (IFN β) treatment, a proinflammatory cytokine that upregulates MHC-I expression, in SOD1G93A transgenic mice. For that, 17 days old presymptomatic female mice were subjected to subcutaneous application of IFN β (250, 1,000, and 10,000 IU) every other day for 20 days. Rotarod motor test, clinical score, and body weight assessment were conducted every third day throughout the treatment period. No significant intergroup variations were observed in such parameters during the pre-symptomatic phase. All mice were then euthanized, and the spinal cords collected for comparative analysis of motoneuron survival, reactive gliosis, synapse coverage, microglia morphology classification, cytokine analysis by flow cytometry, and RT–qPCR quantification of gene transcripts. Additionally, mice underwent Rotarod motor assessment, weight monitoring, and neurological scoring. The results show that IFN β treatment led to an increase in the expression of MHC-I, which, even at the lowest dose (250 IU), resulted in a significant increase in neuronal survival in the ALS presymptomatic period which lasted until the onset of the disease. The treatment also influenced synaptic preservation by decreasing excitatory inputs and upregulating the expression of AMPA receptors by astrocytes. Microglial reactivity quantified by the integrated density of pixels did not decrease with treatment but showed a less activated morphology, coupled with polarization to an M1 profile. Disease progression upregulated gene transcripts for pro- and anti-inflammatory cytokines, and IFN β treatment significantly decreased mRNA expression for IL4. Overall, the present results demonstrate that a low dosage of IFN β shows therapeutic potential by increasing MHC-I expression, resulting in neuroprotection and immunomodulation.
Electrophysiological evidence for increased auditory crossmodal activity in adult ADHD
Authors: Schramm Mia , Goregliad Fjaellingsdal Tatiana , Aslan Behrem , Jung Paul , Lux Silke , Schulze Marcel , Philipsen Alexandra
Published: August 2023

Background

Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by core symptoms of inattention, and/or impulsivity and hyperactivity. In order to understand the basis for this multifaceted disorder, the investigation of sensory processing aberrancies recently reaches more interest. For example, during the processing of auditory stimuli comparable low sensory thresholds account for symptoms like higher distractibility and auditory hypersensitivity in patients with ADHD. It has further been shown that deficiencies not only exist on an intramodal, but also on a multimodal level. There is evidence that the visual cortex shows more activation during a focused auditory task in adults with ADHD than in healthy controls. This crossmodal activation is interpreted as the reallocation of more attentional resources to the visual domain as well as deficient sensory inhibition. In this study, we used, for the first time, electroencephalography to identify a potential abnormal regulated crossmodal activation in adult ADHD.

Methods

15 adult subjects with clinically diagnosed ADHD and 14 healthy controls comparable in age and gender were included. ERP components P50, P100, N100, P200 and N200 were measured during the performance of a unimodal auditory and visual discrimination task in a block design. Sensory profiles and ADHD symptoms were assessed with inattention as well as childhood ADHD scores. For evaluating intramodal and crossmodal activations, we chose four EEG channels for statistical analysis and group-wise comparison.

Results

At the occipital channel O2 that reflects possible crossmodal activations, a significantly enhanced P200 amplitude was measured in the patient group. At the intramodal channels, a significantly enhanced N200 amplitude was observed in the control group. Statistical analysis of behavioral data showed poorer performance of subjects with ADHD as well as higher discrimination thresholds. Further, the correlation of the assessed sensory profiles with the EEG parameters revealed a negative correlation between the P200 component and sensation seeking behavior.

Conclusion

Our findings show increased auditory crossmodal activity that might reflect an altered stimulus processing resource allocation in ADHD. This might induce consequences for later, higher order attentional deployment. Further, the enhanced P200 amplitude might reflect more sensory registration and therefore deficient inhibition mechanisms in adults with ADHD.
Pan-cancer analysis of kinesin family members with potential implications in prognosis and immunological role in human cancer
Authors: Zhong Ming , Gong Lian , Li Na , Guan Hui , Gong Kai , Zhong Yong , Zhu Enyi , Wang Xiaohua , Jiang Shan , Li Jinhong , Lei Yan , Liu Yu , Chen Jiasi , Zheng Zhihua
Published: August 2023

Background

Kinesin is a molecular motor for transporting “goods” within cells and plays a key role in many types of tumors. The multi-angle study of kinesin at the pan-cancer level is conducive to understanding its role in tumorigenesis and development and clinical treatment potential.

Methods

We evaluated the expression of KIF genes, performed differential analysis by using the R package limma, and explored the pan-cancer prognosis of KIF genes by univariate Cox regression analysis. To evaluate the pan-cancer role of KIF genes as a whole, we defined the KIFscore with the help of gene set variation analysis (GSVA) and explored the KIFscores across normal tissues, tumor cell lines, and 33 tumor types in TCGA. Next, we used spearman correlation analysis to extensively study the correlation between the KIFscore and tumor prognosis and be-tween the KIFscore and clinical indicators. We also identified the relationship between the KIFscore and genomic variation and immune molecular signatures by multiplatform analysis. Finally, we identified the key genes in clear cell renal cell carcinoma (ccRCC) through machine learning algorithms and verified the candidate genes by CCK8, wound healing assay, Transwell assay, and flow cytometry.

Results

In most cancers, KIFscores are high and they act as a risk factor for cancer. The KIFscore was significantly associated with copy number variation (CNV), tumor mutation burden (TMB), immune subtypes, DNA repair deficiency, and tumor stemness indexes. Moreover, in almost all cancer species, the KIFscore was positively correlated with T cell CD4+ TH2, the common lymphoid pro-genitor, and the T cell follicular helper. In addition, it was negatively correlated with CXCL16, CCL14, TNFSF13, and TNFRSF14 and positively correlated with ULBP1, MICB, and CD276. Machine learning helped us to identify four hub-genes in ccRCC. The suitable gene, KIF14, is highly expressed in ccRCC and promotes tumor cell proliferation, migration, and invasion.

Conclusion

Our study shows that the KIF genes play an important pan-cancer role and may become a potential new target for a variety of tumor treatments in the future. Furthermore, KIF14, a key molecule in the KIF genes, can provide a new idea for the ccRCC treatment.
Case Report: Dynamic overlap of melanoma, sarcoidosis, and targeted therapy for BRAF-mutant melanoma
Authors: Dar Nakul , Gradecki Sarah E. , Gaughan Elizabeth M.
Published: August 2023

Targeted therapies, including BRAF and MEK inhibitors, are valuable treatment options for patients with unresectable or metastatic BRAF V600-mutant melanoma. With the improvement in survival seen with modern melanoma therapeutics, clinicians are learning the variable patterns associated with extended clinical courses. Sarcoidosis is characterized by non-caseating granulomatous inflammation of unknown etiology, often presenting with cutaneous, lung, or lymph node involvement. There is a known association between sarcoidosis and melanoma, and sarcoidosis is increasingly seen and described in the setting of anti-melanoma therapy. The challenge for clinicians is to differentiate between sarcoid-related and malignancy-related findings, which may follow a variable course over years. We present two cases of BRAF and MEK inhibitor-related sarcoidosis in patients with melanoma and review the literature. The dynamic nature of the clinical and radiographic findings impacted patient management and clinical decisions for years of their treatment course.
Prognostic significance of STING expression in solid tumor: a systematic review and meta-analysis
Authors: Kim Younghoon , Cho Nam-Yun , Jin Lingyan , Jin Hye Yeong , Kang Gyeong Hoon
Published: August 2023

Objective

Stimulator of interferon genes (STING) is a key regulator in initiating innate immune response from sensing cytosolic DNA. Recent studies have revealed that the cGAS-STING signaling pathway has a crucial role in tumor development and progression across cancer types. Herein, we conducted a meta-analysis to explore the relationship between the immunoexpression of STING and the survival outcome of patients in various solid tumors. Studies relevant to the subject were searched from PubMed, Embase, and Web of Science.

Results

Eleven studies including 2,345 patients were eligible for the analysis. STING expression in tumor cells was related to improved disease-free survival/recurrence-free survival (DFS/RFS) (HR = 0.656, 95% CI = 0.455–0.946, p = 0.024) but not with overall survival (OS) (HR = 0.779, 95% CI = 0.534–1.136, p = 0.194). STING expression in stromal cells, however, did not show significant correlation with DFS/RFS and OS (HR = 0.979, 95% CI = 0.565–1.697, p-value = 0.940 and HR = 1.295, 95% CI = 0.845–1.985, p = 0.235, respectively). In a subgroup analysis, STING expression in tumor cells was associated with better DFS (HR = 0.622, 95% CI = 0.428–0.903, p = 0.012). In tumor cells, favorable DFS/RFS were also related to studies from univariate analysis and the gastrointestinal system (HR = 0.667, 95% CI = 0.482–0.923, p = 0.015 and HR = 0.566, 95% CI = 0.330–0.971, p = 0.039).

Conclusions

STING expression in tumor cells is associated with favorable outcome in solid tumors.

Systematic review registration

https://www.crd.york.ac.uk/prospero/, registration number: CRD42023427027
Novel PPFIA1-ALK, ALK-C2orf91(intergenic) double-fusion responded well to alectinib in an advanced lung adenocarcinoma patient: a case report
Authors: Yan Lingxin , Zheng Jiayu , Pan Qingyun , Liang Yuxian , Yu Pengli , Chen Quanfang
Published: August 2023

Non-small cell lung cancers (NSCLCs) with anaplastic lymphoma kinase (ALK)-rearrangement have favorable responses to ALK inhibitors. However, ALK fusion mutations harbored approximately 90 distinct fusion partners. Patients with different ALK fusions might respond distinctly to different-generation ALK inhibitors. In this case report, we identified a novel non-reciprocal ALK fusion, ALK-C2orf91(intergenic) (A19: intergenic) and PPFIA1-ALK (P2:A20), by next-generation DNA sequencing in an advanced lung adenocarcinoma patient. After 2 months of alectinib, the targeted lung lesion regressed significantly, and evaluation of therapeutic efficiency indicated partial response. To date, the patient had achieved 12 months of progression-free survival from alectinib treatment. Our study extended the spectrum of ALK fusion partners in ALK-positive NSCLC, and we reported a new ALK fusion, PPFIA1-ALK and ALK-C2orf91(intergenic), and its sensitivity to alectinib firstly in lung cancer. We believe that this case report has an important clinical reference.
Dual-energy computed tomography to detect early pulmonary vascular changes in children with sickle cell disease: a pilot study
Authors: Joye Raphael , Wacker Julie , Nguyen Duy-Anh , Hachulla Anne-Lise , Maggio Albane B. R. , Cimasoni Laurent , Lador Frederic , Ansari Marc , Beghetti Maurice
Published: August 2023

Introduction

Pulmonary hypertension (PH) is a rare but fatal complication of sickle cell disease (SCD) that is possibly reversible if treated early. Dual-energy computed tomography (DECT) is a valuable tool for diagnosing PH. We attempted to determine if DECT can detect early signs of PH in children with SCD.

Methods

This prospective observational pilot study was conducted at the Geneva University Hospitals and was approved by the local human ethics committee (CCER 2019-01975). A written informed consent was obtained from the patients and/or their legal guardian. Eight children (consisting of five girls and three boys) with homozygous SCD were included in the study. They underwent full cardiological workup using transthoracic echocardiography (TTE) and cardiopulmonary exercise test (CPET), as well as DECT.

Results

The median age of the children was 11 years old (range 8–12). All patients exhibited a normal biventricular systo-diastolic function using the TTE. The median tricuspid regurgitant jet velocity value was 2.24 m/s (range 1.96–2.98). Four children were found to have signs of vasculopathy detected on DECT. Of them, two had abnormal screening test results. They both had an increased VE/VCO2 slope during CPET and an increased TVR of >2.5 m/s on TTE.

Conclusion

DECT is capable of identifying early signs of pulmonary vascular disease in children with SCD. Further studies are needed to understand the correlation between DECT abnormalities and hemodynamic pulmonary circulation better.
Case report: Concomitant EGFR mutation and ALK rearrangement in non-small cell lung cancer
Authors: Hu Haoyue , Tan Songtao , Xie Meng , Guo Peng , Yu Qiang , Xiao Juan , Zhao Kangrui , Liao Qiong , Wang Yi
Published: August 2023

In non-small cell lung cancer (NSCLC), two key genetic alterations, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, are commonly believed to be mutually exclusive. Studies have reported that concurrent EGFR/ALK co-mutation in non-small cell lung cancer patients is rare, with a prevalence ranging from 0.1% to 1.6%. However, the clinical and pathological characteristics of these patients are not well-defined, and the optimal treatment approach for such cases remains controversial. In this report, we present a case of stage IV lung adenocarcinoma with both epidermal growth factor receptor and anaplastic lymphoma kinase mutations, along with high PD-L1 expression. The patient initially received treatment with epidermal growth factor receptor tyrosine kinase inhibitors (TKIs), but the disease progressed. However, following a switch to ALK-TKI therapy and local radiotherapy, the lesion showed regression. Our report also provides a comprehensive summary of the clinical and pathological features, as well as treatment strategies, for non-small cell lung cancer patients with concurrent epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.
Effects of 3-week repeated cold water immersion on leukocyte counts and cardiovascular factors: an exploratory study
Authors: Versteeg Ninja , Clijsen Ron , Hohenauer Erich
Published: August 2023

Aim: This exploratory study aimed to investigate the effects of a 3-week repeated cold water immersion (CWI) intervention on leukocyte counts and cardiovascular factors (mean arterial pressure [MAP], heart rate [HR]) in healthy men.

Methods: A total of n = 12, non-cold-adapted men (age: 25.2 ± 4.0 years; height: 177.8 ± 5.6 cm; weight: 73.8 ± 6.5 kg) were randomly allocated to the CWI or control (CON) group. The CWI group underwent a 3-week repeated CWI intervention (12min at 7°C, 4x/week). The CON group did not receive any cold exposure or therapy. Total leukocyte numbers and proportions (neutrophils, basophils, eosinophils, monocytes, lymphocytes) and cardiovascular factors (MAP, HR) were assessed at baseline and after the 3-week intervention period.

Results: Total leukocyte count decreased in CWI (p = 0.027, 95% CI −2.35 to −0.20 × 103/µL) and CON (p = 0.043, 95% CI −2.75 to −0.50 × 103/µL). CWI showed a decrease in neutrophil number (p = 0.028, 95% CI −1.55 to −0.25 × 103/µL) and proportion (p = 0.046, 95% CI −6.42 to 0.56%). In contrast, CON showed no significant change (p > 0.05). No differences were found for other leukocyte subtypes in CWI or CON (all p > 0.05). MAP (p = 0.028, 95% CI −17 to −8 mmHg) and HR (p = 0.027, 95% CI −7 to −2 bpm) were reduced in CWI, whereas CON showed no change (p > 0.05).

Conclusion: The results suggest no relevant effects of 3-week repeated CWI on leukocyte counts in healthy men. Due to methodological limitations, the effects on the investigated cardiovascular factors remain unclear. Further studies with larger sample sizes are needed to examine the effects on immune function and cardiovascular health.
Effects of whole-body vibration training combined with KAATSU training on lower limb joint muscle strength in older women
Authors: Xiong Weizhi , Liu Xuefeng
Published: August 2023

Objective: This study aimed to investigate the effect of whole-body vibration training (WBVT) combined with KAATSU training (KT) on lower limb joint muscle strength and to provide a reference for improving muscle strength in older women.

Methods: A total of 86 healthy older people was randomly divided into WBVT group (WG, n = 21), KT group (KG, n = 22), combined intervention group (CIG, n = 20) and control group (CG, n = 23). WG and CIG subjects underwent WBVT, and KG and CIG subjects underwent 150 mmHg and lower limb joint and local compression intervention for 16 weeks (three times per week, about 15 min/time). The peak torque (PT) and endurance ratio (ER) of joint flexion or extension were tested for all subjects.

Results: 1) Results at 16 weeks were compared with the baseline data. The knee extension and ankle flexion PT (60°/s) in CIG increased by 14.3% and 15.3%, respectively (p < 0.05). The knee extension PT (180°/s) increased by 16.9, 18.4% and 33.3% in WG, KG and CIG (p < 0.05), respectively, and the ankle extension PT (180°/s) in CIG increased by 31.1% (p < 0.05). The hip, knee extension and ankle flexion ER increased by 10.0, 10.9% and 5.7% in CIG (p < 0.05), respectively. 2) Results were compared among groups at 16 weeks. The relative changes were significantly lower in WG, KG and CG compared to CIG in the knee extension and ankle flexion PT (60°/s) (p < 0.05). The relative changes were significantly greater in WG, KG and CIG compared to CG in the knee extension PT (180°/s) (p < 0.05). The relative changes were significantly lower in WG, KG and CG compared to CIG in the ankle extension PT (180°/s) (p < 0.05). The relative changes were significantly lower in WG, KG and CG compared to CIG in the hip extension ER (p < 0.05). The relative changes were significantly lower in CG compared to CIG in the knee extension ER (p < 0.05).

Conclusion: Sixteen-week WBVT and KT increased the knee extensor strength in older women. Compared with a single intervention, the combined intervention had better improvements in the knee extensor and ankle flexor and extensor strength and hip extension muscle endurance. Appears to be some additional benefit from combined intervention above those derived from single-interventions.
Antitumor effect of plant-produced anti-CTLA-4 monoclonal antibody in a murine model of colon cancer
Authors: Bulaon Christine Joy I. , Khorattanakulchai Narach , Rattanapisit Kaewta , Sun Hongyan , Pisuttinusart Nuttapat , Strasser Richard , Tanaka Shiho , Soon-Shiong Patrick , Phoolcharoen Waranyoo
Published: August 2023

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is an immune checkpoint regulator exclusively expressed on T cells that obstructs the cell’s effector functions. Ipilimumab (Yervoy®), a CTLA-4 blocking antibody, emerged as a notable breakthrough in modern cancer treatment, showing upfront clinical benefits in multiple carcinomas. However, the exhilarating cost of checkpoint blockade therapy is discouraging and even utmost prominent in developing countries. Thereby, affordability of cancer care has become a point of emphasis in drug development pipelines. Plant expression system blossomed as a cutting-edge platform for rapid, facile to scale-up, and economical production of recombinant therapeutics. Here, we describe the production of an anti-CTLA-4 2C8 antibody in Nicotiana benthamiana. ELISA and bio-layer interferometry were used to analyze antigen binding and binding kinetics. Anticancer responses in vivo were evaluated using knocked-in mice implanted with syngeneic colon tumor. At 4 days post-infiltration, the antibody was transiently expressed in plants with yields of up to 39.65 ± 8.42 μg/g fresh weight. Plant-produced 2C8 binds to both human and murine CTLA-4, and the plant-produced IgG1 also binds to human FcγRIIIa (V158). In addition, the plant-produced 2C8 monoclonal antibody is as effective as Yervoy® in inhibiting tumor growth in vivo. In conclusion, our study underlines the applicability of plant platform to produce functional therapeutic antibodies with promising potential in cancer immunotherapy.
Physiological and transcriptomic analysis of salt tolerant Glaux maritima grown under high saline condition
Authors: Gu Rui , Wan Zhi Qiang , Tang Fang , Liu Xue Ting , Yang Yan ting , Shi Feng ling
Published: August 2023

Land salinization considerably limits crop production. Biological improvement of saline and alkaline land is an important way to achieve efficient land use. It is crucial to study the salt tolerance of halophyte resources in order to explore and improve plant resources through biological improvement. Glaux maritima is a mesophyte halophyte with strong salt tolerance. In this study, we conducted research on the salt tolerance mechanism of G. maritima through phenotypic, physiological, and transcriptomic aspects. The results indicate that leaf cross-sections revealed that G. maritima has a salt gland tissue composed of stalk, collecting, and secretory cells, which are trapped in epidermal cells. At the physiological level, the maximum salt tolerance threshold of G. maritima leaves was 600 mM/L. At this concentration, proline content, relative conductivity, and superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) enzyme activities were maximum. At the transcriptional level, transcriptome data of three experimental groups (N0: 0 mM/L, N3: 600 mM/L, and N4: 800 mM/L) were analyzed, and six essential genes related to proline synthesis and five essential genes related to SOD and CAT enzyme activities were identified. Two genes involved in CAT enzyme activity were also found to play an important role in the MAPK signaling pathway. Trend analysis revealed that the MAPK signaling regulation (37 differentially expressed genes (DEGs)), phytohormone regulation (48 DEGs), glutathione metabolism (8 DEGs), flavonoid and flavonoid biosynthesis (2DEGs), and flavonoid biosynthesis (24 DEGs) pathways played important roles in regulating the salt tolerance of G. maritima. These findings provide valuable information for further studies on the functional characteristics of G. maritima in response to abiotic stress and may contribute to salt resistance breeding of fodder crops for cultivation in saline alkali land.
Optimized N application improves N absorption, population dynamics, and ear fruiting traits of wheat
Authors: Zhang Xiangqian , Xu Yunji , Du Shizhou , Qiao Yuqiang , Cao Chengfu , Chen Huan
Published: August 2023

Optimizing the N application amount and topdressing ratio can increase crop yield and decrease N loss, but its internal mechanisms have not been well studied, especially from the aspects of population dynamics and structure, ear fruiting traits. Here, field experiments, with three N rates 120 (N1), 180 (N2), and 240 (N3) kg N ha-1 and three N topdressing ratios T1 (7:3), T2 (6:4), and T3 (5:5) were conducted. At the same N level, results showed that the N accumulation amounts in the leaf, grain, and plant in T2 were higher than in T3 and T1, and increasing 60 kg N ha-1 (N3 compared to N2, N2 compared to N1) significantly enhanced N accumulation amounts. The effect of the N topdressing ratio on partial factor productivity of applied N was consistently T2 > T3 > T1, but T1 was more conducive to improving N utilization efficiency for grain and biomass production. After the jointing stage, compared to T1 and T3, T2 was more conducive to increasing the population growth rate of plant height, leaf area index, leaf area growth rate, dry matter weight, dry matter accumulation rate, light interception rate, and spikelets of population, and the above-mentioned indexes of population could be significantly enhanced by increasing 120 kg N ha-1. T2 increased the fruiting spikelets per ear, grains per ear, grain weight per ear, fruiting rate per ear, grain filling rate per ear, and yield but decreased the sterile spikelets at the top and bottom and imperfect grains per ear. Increasing N from 120 kg ha-1 to 180 kg ha-1 or from 180 kg ha-1 to 240 kg ha-1 significantly enhanced yield. The N accumulation amount in the grain, leaf, plant, leaf area growth rate, dry matter accumulation rate, light interception rate, population spikelets, fruiting spikelets per ear, grain filling rate, and yield were significantly positively correlated with each other. This study demonstrates a suitable N application rate with a N topdressing ratio 6:4 would more effectively improve N efficiency, population dynamics, structure, ear fruiting traits, and yield, but the effect of the N topdressing ratio is not as significant as that of increasing 60 kg N ha-1.
Active permanent greening – a new slope greening technology based on mineral solubilizing microorganisms
Authors: Wang Lingjian , Tang Xinggang , Liu Xin , Zhang Jinchi
Published: August 2023

Introduction

With social and economic development and the associated large-scale exploitation of natural resources, the number of slopes has significantly increased. As slope instability can lead to serious geological disasters, the ecological protection and reconstruction of slopes has become a hot topic of common global concern.

Methods

In order to achieve scientific slope management and overcome the difficulty of maintaining slope greening in the long term, this study explored eight strategies (A, B, C, AB, AC, BC, ABC, CK), involving different patented mineral solubilizing microorganisms (MSMs), and analyzed the field application of active permanent greening (APG) based on MSMs.

Results

The results revealed that MSMs significantly increased the content of effective metal ions and available nutrients in soil and enhanced soil enzyme activity. Among all strategies, strategy A showed significant superiority, with soil effective calcium, magnesium, potassium, nitrogen, phosphorus and organic matter contents increasing by 51.62%, 55.41%, 30.42%, 39.77%, 181.69% and 76.92%, respectively, while urease, sucrase and peroxidase activities increased by 89.59%, 74.68% and 85.30%. MSMs strongly promoted the growth of Amorpha. Strategy A showed the best performance, with plant seedling height, ground diameter, leaf area, root length, and root volume increasing by 95.75%, 47.78%, 124.14%, 108.83%, and 139. 86%, respectively. According to a comprehensive evaluation using the entropy-analysis hierarchy process, strategy A has great potential for application. The field test results verified that APG has significantly better greening performance than the traditional greening method, with high vegetation cover and stable soil layer.

Discussion

The results of this study provide a reliable practical basis and technical reference for the development, promotion, and application of APG.