bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-scarring effects of conbercept on human Tenon’s fibroblasts: comparisons with bevacizumab
Authors: Zuo Lei , Zhu Shaopin , Gu Shengjie , Xu Xun
Published: April 2023

Background

Safely inhibiting the formation of scar in the glaucoma filtration surgery (GFS) has always been an issue for clinical glaucoma doctors. Anti-vascular endothelial growth factor (VEGF) agents can reduce angiogenesis, and anti-placental growth factor (PIGF) agents can affect reactive gliosis. However, the effect of conbercept, which can bind to both VEGF and PIGF, on human Tenon’s fibroblasts (HTFs) is unknown.

Methods

HTFs were cultured in vitro and treated with conbercept or bevacizumab (BVZ). No drug was added to the control group. The effects of drugs on cell proliferation were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the collagen type I alpha1(Col1A1) mRNA expression level was measured using quantitative polymerase chain reaction (qPCR). HTF cell migration after drug interventions was evaluated using the scratch wound assay along with the measurement of the expression levels of VEGF and PIGF in human umbilical vein endothelial cells (HUVECs) using enzyme-linked immunosorbent assay, as well as the detection of the VEGF(R) mRNA expression level in HTFs using qPCR.

Results

After the addition of conbercept (0.01, 0.1, and 1 mg/mL) to the cultured HTFs or HUVECs, no significant cytotoxicity was observed compared with the control group, while the cytotoxicity of 2.5 mg/mL BVZ on HTFs was obvious. Conbercept significantly inhibited HTF cell migration and Col1A1 mRNA expression level in HTFs. It was superior to BVZ in inhibiting HTF migration. After the intervention with conbercept, the expression level of PIGF and VEGF in HUVECs significantly decreased; and the inhibitory effect of conbercept on the expression level of VEGF in HUVECs was weaker than that of BVZ. Conbercept was more advantageous than BVZ in inhibiting the expression level of VEGFR-1 mRNA in HTFs. However, its effect in terms of inhibiting the expression level of VEGFR-2 mRNA in HTFs was weaker than that of BVZ.

Conclusion

The results suggested the low cytotoxicity and significant anti-scarring effect of conbercept in HTF with significant anti-PIGF and inferior anti-VEGF effects compared with BVZ, thus providing a better understanding of the role of conbercept in the GFS wound healing process.
A case of choroidal melanocytosis observed by multimodal imaging with laser speckle flowgraphy
Authors: Mitamura Mizuho , Kase Satoru , Hirooka Kiriko , Ishida Susumu
Published: April 2023

Background

Choroidal melanocytosis is characterized by congenital diffuse melanin pigmentation with extensive parenchymal infiltration of spindle cells in the choroid; however, little is known about the choroidal circulation and morphological changes. We herein report a case of choroidal melanocytosis observed by multimodal imaging with laser speckle flowgraphy (LSFG).

Case Presentation

A 56-year-old woman was referred to our hospital because of serous retinal detachment (SRD) in her left eye. At the initial examination, her best-corrected visual acuity (BCVA) was 1.5 oculus dexter (OD) and 0.8 oculus sinister (OS). An irregular, flat, brownish lesion was noted around the macula OS. Optical coherence tomography showed a choroidal structure with marked hyporeflectivity and SRD where the retinal thickness was preserved. Indocyanine green angiography demonstrated fluorescence blockade throughout. Fundus autofluorescence revealed enlarged macular hypofluorescence, suggesting chronic retinal pigment epithelium damage associated with prolonged SRD. B-mode echography showed no choroidal elevation. Based on the clinical findings, the left eye was diagnosed with choroidal melanocytosis. Four years and 10 months after the initial visit, her BCVA was 0.5 and SRD remained. During the entire period of observation, the mean blur rate (MBR) (mean ± standard deviation) of choroidal blood flow velocity on LSFG was 10.15 ± 0.72 arbitrary units (AU) OD and 1.31 ± 0.06 AU OS.

Conclusion

Choroidal melanocytosis presented with chronic minor circulatory disturbances due to melanocyte proliferation in the choroid, but the markedly low MBR values by LSFG were dissociated from her retinal thickness and visual function. The proliferation of melanocytes may be a cause of overestimating the cold-color signal of LSFG due to their pigmentation.
Declining life expectancy in the Great Lakes region: contributors to Black and white longevity change across educational attainment
Authors: Roberts Max Tyler , Lim Sojung , Reither Eric N.
Published: April 2023

Background

The East North Central Census division (aka the Great Lakes region) experienced a decrease in life expectancy of 0.3 years from 2014 to 2016 – one of the largest declines across the nine Census divisions. Disadvantaged groups that typically have below-average life expectancy, including Black individuals and those without a college education, may have been disproportionately affected by this longevity shift. This investigation examines life expectancy changes among different sex, race, and education groups in the Great Lakes region, and how specific causes of death contributed to within-group longevity changes over time and across age.

Methods

We used 2008 to 2017 death counts from the National Center for Health Statistics and American Community Survey population estimates to measure within-group change in life expectancy at age 25 among non-Hispanic Black and white males and females by educational attainment. We decomposed life expectancy change over time for each subgroup by 24 causes of death and measured their contribution to longevity change across 13 age groups.

Results

Among persons with ≤ 12 years of education, white males and females experienced 1.3- and 1.7-year longevity declines respectively, compared to a 0.6-year decline among Black males and a 0.3-year decline among Black females. Life expectancy declined among all groups with 13–15 years of education, but especially Black females, who experienced a 2.2-year loss. With the exception of Black males, all groups with 16 + years of education experienced longevity gains. Homicide contributed 0.34 years to longevity decline among Black males with ≤ 12 years of education. Drug poisoning made large contributions to longevity losses among Black females with ≤ 12 years of education (0.31 years), white males and females with 13–15 years of education (0.35 and 0.21 years, respectively), and white males and females with ≤ 12 years of education (0.92 and 0.65 years, respectively).

Conclusions

Public health efforts to reduce the risks of homicide among Black males without a college education and drug poisoning among all groups could improve life expectancy and reduce racial and educational longevity disparities in the Great Lakes region.
Awake prone position in COVID-19-related acute respiratory failure: a meta-analysis of randomized controlled trials
Authors: Qin Sun , Chang Wei , Peng Fei , Hu Zihan , Yang Yi
Published: April 2023

Background

We aimed to investigate the effects of awake prone positioning (APP) in nonintubated adult patients with acute hypoxemic respiratory failure due to COVID-19.

Methods

The PubMed, Embase, Web of Science and Cochrane Central Register databases were searched up to June 1, 2022. All randomized trials investigating the effects of APP were included in the present meta-analysis. The primary outcome was intubation rate, and the secondary outcomes included the length of intensive care unit (ICU) stay, hospital stay, and mortality. Prescribed subgroup analysis was also conducted.

Results

A total of 10 randomized trials enrolling 2324 patients were ultimately included in the present study. The results indicated that APP was associated with a significant reduction in the intubation rate (OR 0.77, 95% CI 0.63 to 0.93, P = 0.007). However, no differences could be observed in the length of ICU stay or hospitalization or mortality. Subgroup analysis suggested that patients in the ICU settings (OR 0.74, 95% CI 0.60 to 0.91, P = 0.004), patients whose median APP time was more than 4 h (OR 0.77, 95% CI 0.63 to 0.93, P = 0.008), and patients with an average baseline SpO2 to FiO2 ratio less than 200 (OR 0.75, 95% CI 0.61 to 0.92) were more likely to benefit from APP, indicated a significantly reduced intubation rate.

Conclusion

Based on the current evidence, nonintubated adult patients with hypoxemic respiratory failure due to COVID-19 infection who underwent APP were shown to have a significantly reduced intubation rate. However, no differences in ICU or hospital length of stay or mortality could be observed between APP and usual care.

Registration number

CRD42022337846
Giving and receiving thanks: a mixed methods pilot study of a gratitude intervention for palliative patients and their carers
Authors: Bernard Mathieu , Poncin Emmanuelle , Bovet Emilie , Tamches Emmanuel , Cantin Boris , Pralong Josiane , Borasio Gian Domenico
Published: April 2023

Background

Psychological research examining the nature and workings of gratitude has burgeoned over the past two decades. However, few studies have considered gratitude in the palliative care context. Based on an exploratory study which found that gratitude was correlated with better quality of life and less psychological distress in palliative patients, we designed and piloted a gratitude intervention where palliative patients and a carer of their choice wrote and shared a gratitude letter with each other. The aims of this study are to establish the feasibility and acceptability of our gratitude intervention and provide a preliminary assessment of its effects.

Methods

This pilot intervention study adopted a mixed-methods, concurrent nested, pre-post evaluation design. To assess the intervention’s effects, we employed quantitative questionnaires on quality of life, quality of relationship, psychological distress, and subjective burden, as well as semi-structured interviews. To assess feasibility, we considered patients and carers’ eligibility, participation and attrition rates, reasons for refusal to participate, appropriateness of intervention timeframe, modalities of participation, and barriers and facilitators. Acceptability was assessed through post-intervention satisfaction questionnaires.

Results

Thirty-nine participants completed the intervention and twenty-nine participated in interviews. We did not find any statistically significant pre/post intervention changes for patients, but found significant decrease in psychological distress for carers in terms of depression (median = 3 at T0, 1.5 at T1, p = .034) and total score (median = 13 at T0, 7.5 at T1, p = .041). Thematic analysis of interviews indicates that overall, the intervention had: (1) multiple positive outcomes for over a third of interviewees, in the form of positive emotional, cognitive, and relational effects; (2) single positive outcomes for nearly half of interviewees, who experienced emotional or cognitive effects; (3) no effect on two patients; and (4) negative emotional effects on two patients. Feasibility and acceptability indicators suggest that the intervention was well received by participants, and that it should adopt flexible modalities (e.g. writing or dictating a gratitude message) to ensure that it is feasible and adapted to individual needs and preferences.

Conclusions

Larger scale deployment and evaluation of the gratitude intervention, including a control group, is warranted in order to have a more reliable evaluation of its effectiveness in palliative care.
Improving measurement-based care implementation in adult ambulatory psychiatry: a virtual focus group interview with multidisciplinary healthcare professionals
Authors: Ko Hayoung , Gatto Alyssa J. , Jones Sydney B. , O’Brien Virginia C. , McNamara Robert S. , Tenzer Martha M. , Sharp Hunter D. , Kablinger Anita S. , Cooper Lee D.
Published: April 2023

Background

Measurement-Based Care (MBC) is an evidence-based practice shown to enhance patient care. Despite being efficacious, MBC is not commonly used in practice. While barriers and facilitators of MBC implementation have been described in the literature, the type of clinicians and populations studied vary widely, even within the same practice setting. The current study aims to improve MBC implementation in adult ambulatory psychiatry by conducting focus group interviews while utilizing a novel virtual brainwriting premortem method.

Methods

Semi-structured focus group interviews were conducted with clinicians (n = 18) and staff (n = 7) to identify their current attitudes, facilitators, and barriers of MBC implementation in their healthcare setting. Virtual video-conferencing software was used to conduct focus groups, and based on transcribed verbatin, emergent barriers/facilitators and four themes were identified. Mixed methods approach was utilized for this study. Specifically, qualitative data was aggregated and re-coded separately by three doctoral-level coders. Quantitative analyses were conducted from a follow-up questionnaire surveying clinician attitudes and satisfaction with MBC.

Results

The clinician and staff focus groups resulted in 291 and 91 unique codes, respectively. While clinicians identified a similar number of barriers (40.9%) and facilitators (44.3%), staff identified more barriers (67%) than facilitators (24.7%) for MBC. Four themes emerged from the analysis; (1) a description of current status/neutral opinion on MBC; (2) positive themes that include benefits of MBC, facilitators, enablers, or reasons on why they conduct MBC in their practice, (3) negative themes that include barriers or issues that hinder them from incorporating MBC into their practice, and (4) requests and suggestions for future MBC implementation. Both participant groups raised more negative themes highlighting critical challenges to MBC implementation than positive themes. The follow-up questionnaire regarding MBC attitudes showed the areas that clinicians emphasized the most and the least in their clinical practice.

Conclusion

The virtual brainwriting premortem focus groups provided critical information on the shortcomings and strengths of MBC in adult ambulatory psychiatry. Our findings underscore implementation challenges in healthcare settings and provide insight for both research and clinical practice in mental health fields. The barriers and facilitators identified in this study can inform future training to increase sustainability and better integrate MBC with positive downstream outcomes in patient care.
Empowered patients and informal care-givers as partners?—a survey study of healthcare professionals’ perceptions
Authors: Scott Duncan Therese , Riggare Sara , Bylund Ami , Hägglund Maria , Stenfors Terese , Sharp Lena , Koch Sabine
Published: April 2023

Background

More knowledge is needed regarding the perceptions of healthcare professionals when encountering empowered patients and informal caregivers in clinical settings. This study aimed to investigate healthcare professionals’ attitudes towards and experiences of working with empowered patients and informal caregivers, and perception of workplace support in these situations.

Methods

A multi-centre web survey was conducted using a non-probability sampling of both primary and specialized healthcare professionals across Sweden. A total of 279 healthcare professionals completed the survey. Data was analysed using descriptive statistics and Thematic analysis.

Results

Most respondents perceived empowered patients and informal caregivers as positive and had to some extent experience of learning new knowledge and skills from them. However, few respondents stated that these experiences were regularly followed-up at their workplace. Potentially negative consequences such as increased inequality and additional workload were, however, mentioned. Patients’ engagement in the development of clinical workplaces was seen as positive by the respondents, but few had own experience of such engagement and considered it difficult to be achieved .

Conclusion

Overall positive attitudes of healthcare professionals are a fundamental prerequisite to the transition of the healthcare system recognizing empowered patients and informal caregivers as partners.
Sperm-borne microRNA-34c regulates maternal mRNA degradation and preimplantation embryonic development in mice
Authors: Cui Long , Fang Li , Zhuang Lili , Shi Biwei , Lin Chao-Po , Ye Yinghui
Published: April 2023

Background

Studies have shown that sperm-borne microRNAs (miRNAs) are involved in mammalian preimplantation embryonic development. In humans, spermatozoan miR-34c levels are correlated with in vitro fertilization outcomes, such as embryo quality and the clinical pregnancy and live birth rates. In rabbits and cows, miR-34c improves the developmental competence of embryos generated by somatic cell nuclear transfer. However, the mechanisms underlying the regulation of embryonic development by miR-34c remain unknown.

Methods

Female C57BL/6 mice (6–8 weeks old) were superovulated, and pronucleated zygotes were collected and microinjected with an miR-34c inhibitor or a negative-control RNA. The embryonic development of the microinjected zygotes was evaluated, and the messenger RNA (mRNA) expression profiles of the embryos at the two-cell, four-cell and blastocyst stages (five embryos per group) were determined by RNA sequencing analysis. Gene expression levels were verified by reverse transcription–quantitative polymerase chain reaction. Cluster analysis and heat map visualization were performed to detect differentially expressed mRNAs. Pathway and process enrichment analyses were performed using ontology resources. Differentially expressed mRNAs were systematically analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins database to determine their biological functions.

Results

Embryonic developmental potential was significantly reduced in zygotes microinjected with the miR-34c inhibitor compared with those microinjected with a negative-control RNA. Two-cell stage embryos microinjected with an miR-34c inhibitor presented altered transcriptomic profiles, with upregulated expression of maternal miR-34c target mRNAs and classical maternal mRNAs. Differentially expressed transcripts were mainly of genes associated with lipid metabolism and cellular membrane function at the two-cell stage, with cell-cycle phase transition and energy metabolism at the four-cell stage; and with vesicle organization, lipid biosynthetic process and endomembrane system organization at the blastocyst stage. We also showed that genes related to preimplantation embryonic development, including Alkbh4, Sp1, Mapk14, Sin3a, Sdc1 and Laptm4b, were significantly downregulated after microinjection of an miR-34c inhibitor.

Conclusions

Sperm-borne miR-34c may regulate preimplantation embryonic development by affecting multiple biological processes, such as maternal mRNA degradation, cellular metabolism, cell proliferation and blastocyst implantation. Our data demonstrate the importance of sperm-derived miRNAs in the development of preimplantation embryos.
A qualitative longitudinal study of motivation in the REtirement in ACTion (REACT) physical activity intervention for older adults with mobility limitations
Authors: Cross Rosina , Greaves Colin , Withall Janet , Kritz Marlene , Stathi Afroditi
Published: April 2023

Background

Physical activity (PA) is beneficial for older adults’ health, however they remain the least active age group in the UK. This qualitative longitudinal study aims to understand motivations in older adults receiving the REACT physical activity intervention, through the lens of self-determination theory.

Methods

Participants were older adults randomised to the intervention arm of the Retirement in ACTion (REACT) Study, a group-based physical activity and behaviour maintenance intervention to prevent decline of physical functioning in older adults (≥ 65 years). Stratified purposive sampling by physical functioning (Short Physical Performance Battery scores) and 3-month attendance was employed. Fifty-one semi-structured interviews were conducted at 6, 12 and 24-months with twenty-nine older adults (Mean age (baseline) = 77.9 years, SD 6.86, 69% female) and at 24-months with twelve session leaders and two service managers. Interviews were audio recorded, transcribed verbatim and analysed using Framework Analysis.

Results

Perceptions of autonomy, competence and relatedness were associated with adherence to the REACT programme and maintenance of an active lifestyle. Motivational processes and participants’ support needs, changed during the 12-month REACT intervention and across the 12-months post-intervention. Group interactions were an important source of motivation during the first six months but increased competence and mobility drove motivation at the later stages (12 months) and post-intervention (24 months).

Conclusions

Motivational support needs vary in different stages of a 12-month group-based programme (adoption and adherence) and post-intervention (long-term maintenance). Strategies to accommodate those needs include, (a) making exercise social and enjoyable, (b) understanding participants’ capabilities and tailoring the programme accordingly, (c) capitalising on group support to motivate participants to try other activities and prepare sustainable active living plans.

Trial registration

The REACT study was a pragmatic multi-centre, two-arm, single-blind, parallel-group, RCT (ISRCTN registration number 45627165).
Extending inherited metabolic disorder diagnostics with biomarker interaction visualizations
Authors: Slenter Denise N. , Hemel Irene M. G. M. , Evelo Chris T. , Bierau Jörgen , Willighagen Egon L. , Steinbusch Laura K. M.
Published: April 2023

Background

Inherited Metabolic Disorders (IMDs) are rare diseases where one impaired protein leads to a cascade of changes in the adjacent chemical conversions. IMDs often present with non-specific symptoms, a lack of a clear genotype–phenotype correlation, and de novo mutations, complicating diagnosis. Furthermore, products of one metabolic conversion can be the substrate of another pathway obscuring biomarker identification and causing overlapping biomarkers for different disorders. Visualization of the connections between metabolic biomarkers and the enzymes involved might aid in the diagnostic process. The goal of this study was to provide a proof-of-concept framework for integrating knowledge of metabolic interactions with real-life patient data before scaling up this approach. This framework was tested on two groups of well-studied and related metabolic pathways (the urea cycle and pyrimidine de-novo synthesis). The lessons learned from our approach will help to scale up the framework and support the diagnosis of other less-understood IMDs.

Methods

Our framework integrates literature and expert knowledge into machine-readable pathway models, including relevant urine biomarkers and their interactions. The clinical data of 16 previously diagnosed patients with various pyrimidine and urea cycle disorders were visualized on the top 3 relevant pathways. Two expert laboratory scientists evaluated the resulting visualizations to derive a diagnosis.

Results

The proof-of-concept platform resulted in varying numbers of relevant biomarkers (five to 48), pathways, and pathway interactions for each patient. The two experts reached the same conclusions for all samples with our proposed framework as with the current metabolic diagnostic pipeline. For nine patient samples, the diagnosis was made without knowledge about clinical symptoms or sex. For the remaining seven cases, four interpretations pointed in the direction of a subset of disorders, while three cases were found to be undiagnosable with the available data. Diagnosing these patients would require additional testing besides biochemical analysis.

Conclusion

The presented framework shows how metabolic interaction knowledge can be integrated with clinical data in one visualization, which can be relevant for future analysis of difficult patient cases and untargeted metabolomics data. Several challenges were identified during the development of this framework, which should be resolved before this approach can be scaled up and implemented to support the diagnosis of other (less understood) IMDs. The framework could be extended with other OMICS data (e.g. genomics, transcriptomics), and phenotypic data, as well as linked to other knowledge captured as Linked Open Data.
The spectrum of imaging manifestations of Gorham–Stout disease: a novel dynamic contrast-enhanced MR lymphangiography
Authors: Lee Yuna , Lee Seunghyun , Hur Saebeom , Jeong Yun Soo , Suh Dong In , Moon Jangsup , Kim Man Jin , Choi Young Hun , Cheon Jung-Eun
Published: April 2023

Background

To describe the radiological features of Gorham–Stout disease (GSD) as evaluated using plain radiography and dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) imaging techniques.

Methods

Clinical and conventional imaging data were retrospectively reviewed for 15 patients with GSD between January 2001 and December 2020. After December 2018, DCMRL examinations were performed for lymphatic vessel evaluation in patients with GSD and reviewed in four patients.

Results

The median age at diagnosis was 9 years (range: 2 months–53 years). The clinical manifestations were dyspnea in seven patients (46.7%), sepsis in 12 (80.0%), orthopedic problems in seven (46.7%), and bloody chylothorax in seven (46.7%). The common sites of osseous involvement were the spine (73.3%) and pelvic bone (60.0%). Among the non-osseous involvements, peri-osseous infiltrative soft-tissue abnormalities adjacent to the area of bone involvement were the most common (86.7%), followed by splenic cysts (26.7%) and interstitial thickening (26.7%). DCMRL demonstrated weak central conducting lymphatic flow in two patients with abnormal giant tortuous thoracic ducts and no flow in one patient. All patients who underwent DCMRL in this study presented with altered anatomical lymphatics and functional flow with collateralization.

Conclusion

DCMRL imaging and plain radiography are very useful for determining the extent of GSD. DCMRL is a novel imaging tool for the visualization of abnormal lymphatics in patients with GSD, which helps in further treatment. Therefore, in patients with GSD, it might be necessary to obtain not only plain radiographs but also MR and DCMRL images.
Microendoscopy in vivo for the pathological diagnosis of cervical precancerous lesions and early cervical cancer
Authors: Liu Min , Lu Jianqiao , Zhi Yong , Ruan Yetian , Cao Guangxu , Xu Xinxin , An Xin , Gao Jinli , Li Fang
Published: April 2023

Background

Cervical cancer is an important public health problem. Conventional colposcopy is inefficient in the diagnosis of cervical lesions and massive biopsies result in trauma. There is an urgent need for a new clinical strategy to triage women with abnormal cervical screening results immediately and effectively. In this study, the high-resolution microendoscopy combined with methylene blue cell staining technology was used to perform real-time in vivo imaging of the cervix for the first time.

Methods

A total of 41 patients were enrolled in the study. All patients underwent routine colposcopy and cervical biopsy, and high-resolution images of methylene blue-stained cervical lesions were obtained in vivo using microendoscopy. The cell morphological features of benign and neoplastic cervical lesions stained with methylene blue under microendoscopy were analyzed and summarized. The microendoscopy and histopathology findings of the high-grade squamous intraepithelial lesion (HSIL) and more severe lesions were compared.

Results

The overall consistency of microendoscopy diagnosis with pathological diagnosis was 95.12% (39/41). Diagnostic cell morphological features of cervicitis, low-grade squamous intraepithelial lesion (LSIL), HSIL, adenocarcinoma in situ, and invasive cancer were clearly demonstrated in methylene blue stained microendoscopic images. In HSIL and more severe lesions, microendoscopic methylene blue cell staining technology can show the microscopic diagnostic features consistent with histopathology.

Conclusions

This study was an initial exercise in the application of the microendoscopy imaging system combined with methylene blue cell staining technology to cervical precancerous lesions and cervical cancer screening. The results provided the basis for a novel clinical strategy for triage of women with abnormal cervical screening results using in vivo non-invasive optical diagnosis technology.
MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat
Authors: Chen Jasmine , Guanizo Aleks C. , Jakasekara W. Samantha N. , Inampudi Chaitanya , Luong Quinton , Garama Daniel J. , Alamgeer Muhammad , Thakur Nishant , DeVeer Michael , Ganju Vinod , Watkins D. Neil , Cain Jason E. , Gough Daniel J.
Published: April 2023

Background

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance.

Methods

Elevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC.

Results

MYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival.

Conclusions

MYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.
A comprehensive map of human glucokinase variant activity
Authors: Gersing Sarah , Cagiada Matteo , Gebbia Marinella , Gjesing Anette P. , Coté Atina G. , Seesankar Gireesh , Li Roujia , Tabet Daniel , Weile Jochen , Stein Amelie , Gloyn Anna L. , Hansen Torben , Roth Frederick P. , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus
Published: April 2023

Background

Glucokinase (GCK) regulates insulin secretion to maintain appropriate blood glucose levels. Sequence variants can alter GCK activity to cause hyperinsulinemic hypoglycemia or hyperglycemia associated with GCK-maturity-onset diabetes of the young (GCK-MODY), collectively affecting up to 10 million people worldwide. Patients with GCK-MODY are frequently misdiagnosed and treated unnecessarily. Genetic testing can prevent this but is hampered by the challenge of interpreting novel missense variants.

Result

Here, we exploit a multiplexed yeast complementation assay to measure both hyper- and hypoactive GCK variation, capturing 97% of all possible missense and nonsense variants. Activity scores correlate with in vitro catalytic efficiency, fasting glucose levels in carriers of GCK variants and with evolutionary conservation. Hypoactive variants are concentrated at buried positions, near the active site, and at a region of known importance for GCK conformational dynamics. Some hyperactive variants shift the conformational equilibrium towards the active state through a relative destabilization of the inactive conformation.

Conclusion

Our comprehensive assessment of GCK variant activity promises to facilitate variant interpretation and diagnosis, expand our mechanistic understanding of hyperactive variants, and inform development of therapeutics targeting GCK.
A metabolic perspective of selection for fruit quality related to apple domestication and improvement
Authors: Lin Qiong , Chen Jing , Liu Xuan , Wang Bin , Zhao Yaoyao , Liao Liao , Allan Andrew C. , Sun Chongde , Duan Yuquan , Li Xuan , Grierson Donald , Verdonk Julian C. , Chen Kunsong , Han Yuepeng , Bi Jinfeng
Published: April 2023

Background

Apple is an economically important fruit crop. Changes in metabolism accompanying human-guided evolution can be revealed using a multiomics approach. We perform genome-wide metabolic analysis of apple fruits collected from 292 wild and cultivated accessions representing various consumption types.

Results

We find decreased amounts of certain metabolites, including tannins, organic acids, phenolic acids, and flavonoids as the wild accessions transition to cultivated apples, while lysolipids increase in the “Golden Delicious” to “Ralls Janet” pedigree, suggesting better storage. We identify a total of 222,877 significant single-nucleotide polymorphisms that are associated with 2205 apple metabolites. Investigation of a region from 2.84 to 5.01 Mb on chromosome 16 containing co-mapping regions for tannins, organic acids, phenolic acids, and flavonoids indicates the importance of these metabolites for fruit quality and nutrition during breeding. The tannin and acidity-related genesMyb9-likeandPH4are mapped closely to fruit weight locusfw1from 3.41 to 3.76 Mb on chromosome 15, a region under selection during domestication. Lysophosphatidylethanolamine (LPE) 18:1, which is suppressed byfatty acid desaturase-2(FAD2), is positively correlated to fruit firmness. We find the fruit weight is negatively correlated with salicylic acid and abscisic acid levels. Further functional assays demonstrate regulation of these hormone levels byNAC-like activated by Apetala3/Pistillata(NAP) andATP binding cassette G25(ABCG25), respectively.

Conclusions

This study provides a metabolic perspective for selection on fruit quality during domestication and improvement, which is a valuable resource for investigating mechanisms controlling apple metabolite content and quality.
Immunomodulatory effects of modified Liu-Wei-Di-Huang-Wan Traditional Chinese medicine on allergic asthmatic mice
Authors: Tsai Jaw-Ji , Yen Chung-Yang , Hsu Chun-Hsien , Yu Sheng-Jie , Chen Chao-Hsien , Liao En-Chih
Published: April 2023

Background

Allergic asthma occurs worldwide and is particularly prevalent in westernized countries characterized by chronic airway inflammation resulting in airway hyperresponsiveness. The house dust mites (HDM) including Dermatophagoides pteronyssinus are major sources of sensitization and triggering allergic symptoms in asthmatic patients. The Der p 2 is a major allergen and the predominant source of causative respiratory disorders which induce airway inflammation and bronchial constriction in mite-allergic patients. Few studies evaluate the ameliorating effects of modified Liu-Wei-Di-Huang-Wan (modified LWDHW) on allergic asthma.

Methods

This study aimed to investigate the immunological mechanisms of modified LWDHW on the reductions of airway inflammation, signal transduction, inflammatory cytokine production, Th2 cell proliferation, and bronchial obstruction in Der p 2-induced asthmatic mice.

Results

At least ten active ingredients were contained in the formula of modified LWDHW- 1217A and 1217B. Results showed that the immunoglobulin generations (Der p 2 specific- IgE and IgG1), inflammatory cytokine productions (IL-5 and IL-13) in the Sera and BALF could be down-regulated, and the Th1-cytokine productions (IL-12 and IFN-γ) be increased after immunotherapy with modified LWDHW of 1217A or 1217B. The inflammatory cell infiltrations (macrophages, eosinophils, and neutrophils) in the airway and the expressions of TH2-related genes (IL-4, IL-5, and IL-13), TH2-related transcription factor (GATA-3), and neutrophil chemotactic chemokine (IL-8) in the lung tissue of asthmatic mice were significantly decreased after the immunotherapy. The Th1/Th2 polarization had been identified that the IL-4+/CD4+ T cells were downregulated and IFN-γ+/CD4+ T cells were increased. The airway hyperresponsiveness to methacholine inhalation of Penh values was significantly decreased in the treated groups. There were significant improvements in the bronchus histopathology after immunotherapy with 1217A or 1217B which were evaluated by tracheal thickness, inflammatory cell count, and tracheal rupture of mouse lung.

Conclusion

It revealed that 1217A or 1217B could regulate the immune responses and improve pulmonary function. Data suggests that modified LWDHW of 1217A or 1217B have the potential for use as a therapeutic intervention for the treatment of mite allergen Der p 2-induced allergic asthma.
Early expression onset of tissue-specific effector genes during the specification process in sea urchin embryos
Authors: Yamakawa Shumpei , Yamazaki Atsuko , Morino Yoshiaki , Wada Hiroshi
Published: April 2023

Background

In the course of animal developmental processes, various tissues are differentiated through complex interactions within the gene regulatory network. As a general concept, differentiation has been considered to be the endpoint of specification processes. Previous works followed this view and provided a genetic control scheme of differentiation in sea urchin embryos: early specification genes generate distinct regulatory territories in an embryo to express a small set of differentiation driver genes; these genes eventually stimulate the expression of tissue-specific effector genes, which provide biological identity to differentiated cells, in each region. However, some tissue-specific effector genes begin to be expressed in parallel with the expression onset of early specification genes, raising questions about the simplistic regulatory scheme of tissue-specific effector gene expression and the current concept of differentiation itself.

Results

Here, we examined the dynamics of effector gene expression patterns during sea urchin embryogenesis. Our transcriptome-based analysis indicated that many tissue-specific effector genes begin to be expressed and accumulated along with the advancing specification GRN in the distinct cell lineages of embryos. Moreover, we found that the expression of some of the tissue-specific effector genes commences before cell lineage segregation occurs.

Conclusions

Based on this finding, we propose that the expression onset of tissue-specific effector genes is controlled more dynamically than suggested in the previously proposed simplistic regulation scheme. Thus, we suggest that differentiation should be conceptualized as a seamless process of accumulation of effector expression along with the advancing specification GRN. This pattern of effector gene expression may have interesting implications for the evolution of novel cell types.
Gastric villous adenoma: a case report and review of the literature
Authors: Sathirawich Phalat , Pongpaibul Ananya , Parakonthun Thammawat , Kaosombatwattana Uayporn
Published: April 2023

Background

Villous adenoma is the one subtype of adenomatous polyp that is very uncommon in the stomach. Data regarding clinical characteristics, natural history, and prognosis were scarce.

Case presentation

This report presented an 87-year-old Thai woman with a large gastric villous adenoma incidentally revealed in a computed tomography of chest for the evaluation of right pleural effusion. The esophagogastroduodenoscopy demonstrated a huge, glossy, proliferative polypoid mass involving gastric cardia, fundus, and a lesser curve of the upper body. The pathological report confirmed villous adenoma with low grade dysplasia. Although surgical resection was suggested, the patient denied any treatment due to advanced age and multiple comorbidities. She was generally well after 12 months of clinical and radiologic surveillance.

Conclusion

From literature review, only 14 cases of gastric villous adenoma were reported to date. Most of the lesions were large and symptomatic. Malignancy presented in 43% of the cases. Nevertheless, our patient remained asymptomatic without surgical removal following a 12-month period.
In vitro erythrocyte production using human-induced pluripotent stem cells: determining the best hematopoietic stem cell sources
Authors: Cho Youn Keong , Kim Hyun-Kyung , Kwon Soon Sung , Jeon Su-Hee , Cheong June-Won , Nam Ki Taek , Kim Han-Soo , Kim Sinyoung , Kim Hyun Ok
Published: April 2023

Background

Blood transfusion is an essential part of medicine. However, many countries have been facing a national blood crisis. To address this ongoing blood shortage issue, there have been efforts to generate red blood cells (RBCs) in vitro, especially from human-induced pluripotent stem cells (hiPSCs). However, the best source of hiPSCs for this purpose is yet to be determined.

Methods

In this study, hiPSCs were established from three different hematopoietic stem cell sources—peripheral blood (PB), cord blood (CB) and bone marrow (BM) aspirates (n = 3 for each source)—using episomal reprogramming vectors and differentiated into functional RBCs. Various time-course studies including immunofluorescence assay, quantitative real-time PCR, flow cytometry, karyotyping, morphological analysis, oxygen binding capacity analysis, and RNA sequencing were performed to examine and compare the characteristics of hiPSCs and hiPSC-differentiated erythroid cells.

Results

hiPSC lines were established from each of the three sources and were found to be pluripotent and have comparable characteristics. All hiPSCs differentiated into erythroid cells, but there were discrepancies in differentiation and maturation efficiencies: CB-derived hiPSCs matured into erythroid cells the fastest while PB-derived hiPSCs required a longer time for maturation but showed the highest degree of reproducibility. BM-derived hiPSCs gave rise to diverse types of cells and exhibited poor differentiation efficiency. Nonetheless, erythroid cells differentiated from all hiPSC lines mainly expressed fetal and/or embryonic hemoglobin, indicating that primitive erythropoiesis occurred. Their oxygen equilibrium curves were all left-shifted.

Conclusions

Collectively, both PB- and CB-derived hiPSCs were favorably reliable sources for the clinical production of RBCs in vitro, despite several challenges that need to be overcome. However, owing to the limited availability and the large amount of CB required to produce hiPSCs, and the results of this study, the advantages of using PB-derived hiPSCs for RBC production in vitro may outweigh those of using CB-derived hiPSCs. We believe that our findings will facilitate the selection of optimal hiPSC lines for RBC production in vitro in the near future.
Mesenchymal stem cells transplantation for perianal fistulas: a systematic review and meta-analysis of clinical trials
Authors: Wang H. , Jiang H. Y. , Zhang Y. X. , Jin H. Y. , Fei B. Y. , Jiang J. L.
Published: April 2023

Background

Perianal fistulas, characterised as granulomatous inflammation of fistulas around the anal canal, are associated with significant morbidity resulting in a negative impact on quality of life and a tremendous burden to the healthcare system. Treatment of anal fistulas usually consists of anal surgery; however, results of closure rates are not satisfactory especially with complex perianal fistulas, after which many patients may suffer from anal incontinence. Recently, the administration of mesenchymal stem cells (MSCs) has shown promising efficacy. Herein, we aim to explore whether MSCs are effective for complex perianal fistulas and if they have either short-term, medium-term, long-term or over-long-term efficacy. Additionally, we want to elucidate whether factors such as drug dosage, MSC source, cell type, and disease aetiology influence treatment efficacy.

Main body of the abstract

We searched four online databases and analysed data based on information within the clinical trials registry. The outcomes of eligible trials were analysed with Review Manager 5.4.1. Relative risk and related 95% confidence interval were calculated to compare the effect between the MSCs and control groups. In addition, the Cochrane risk of bias tool was applied to evaluate the bias risk of eligible studies. Meta-analyses showed that therapy with MSCs was superior to conventional treatment for complex perianal fistulas in short-, long- and over-long-term follow-up phases. However, there was no statistical difference in treatment efficacy in the medium term between the two methods. Subgroup meta-analyses showed factors including cell type, cell source and cell dosage were superior compared to the control, but there was no significant difference between different experimental groups of those factors. Besides, local MSCs therapy has shown more promising results for fistulas as a result of Crohn’s Disease (CD). Although we tend to maintain that MSCs therapy is effective for cryptoglandular fistulas equally, more studies are needed to confirm this conclusion in the future.

Short conclusion

MSCs Transplantation could be a new therapeutic method for complex perianal fistulas of both cryptoglandular and CD origin showing high efficacy in the short-term to over-long-term phases, as well as high efficacy in sustained healing. The difference in cell types, cell sources and cell dosages did not influence MSCs’ efficacy.
Effects of hormones on intestinal stem cells
Authors: Liu Li , Zhang Lilong , Li Chunlei , Qiu Zhendong , Kuang Tianrui , Wu Zhongkai , Deng Wenhong
Published: April 2023

The maintenance of intestinal renewal and repair mainly depends on intestinal stem cells (ISCs), which can also contribute to the growth of intestinal tumours. Hormones, which are vital signalling agents in the body, have various effects on the growth and replacement of intestinal stem cells. This review summarises recent progress in the identification of hormones associated with intestinal stem cells. Several hormones, including thyroid hormone, glucagon-like peptide-2, androgens, insulin, leptin, growth hormone, corticotropin-releasing hormone and progastrin, promote the development of intestinal stem cells. However, somatostatin and melatonin are two hormones that prevent the proliferation of intestinal stem cells. Therefore, new therapeutic targets for the diagnosis and treatment of intestinal illnesses can be identified by examining the impact of hormones on intestinal stem cells.