bluuebunny/crossref_metadata_2025 huggingface dataset:
Metformin counteracts stimulatory effects induced by insulin in primary breast cancer cells
Authors: Scordamaglia Domenica , Cirillo Francesca , Talia Marianna , Santolla Maria Francesca , Rigiracciolo Damiano Cosimo , Muglia Lucia , Zicarelli Azzurra , De Rosis Salvatore , Giordano Francesca , Miglietta Anna Maria , De Francesco Ernestina Marianna , Vella Veronica , Belfiore Antonino , Lappano Rosamaria , Maggiolini Marcello
Published: June 2022

Background

Metabolic disorders are associated with increased incidence, aggressive phenotype and poor outcome of breast cancer (BC) patients. For instance, hyperinsulinemia is an independent risk factor for BC and the insulin/insulin receptor (IR) axis is involved in BC growth and metastasis. Of note, the anti-diabetic metformin may be considered in comprehensive therapeutic approaches in BC on the basis of its antiproliferative effects obtained in diverse pre-clinical and clinical studies.

Methods

Bioinformatics analysis were performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project. The naturally immortalized BC cell line, named BCAHC-1, as well as cancer-associated fibroblasts (CAFs) derived from BC patients were used as model systems. In order to identify further mechanisms that characterize the anticancer action of metformin in BC, we performed gene expression and promoter studies as well as western blotting experiments. Moreover, cell cycle analysis, colony and spheroid formation, actin cytoskeleton reorganization, cell migration and matrigel drops evasion assays were carried out to provide novel insights on the anticancer properties of metformin.

Results

We first assessed that elevated expression and activation of IR correlate with a worse prognostic outcome in estrogen receptor (ER)-positive BC. Thereafter, we established that metformin inhibits the insulin/IR-mediated activation of transduction pathways, gene changes and proliferative responses in BCAHC-1 cells. Then, we found that metformin interferes with the insulin-induced expression of the metastatic gene CXC chemokine receptor 4 (CXCR4), which we found to be associated with poor disease-free survival in BC patients exhibiting high levels of IR. Next, we ascertained that metformin prevents a motile phenotype of BCAHC-1 cells triggered by the paracrine liaison between tumor cells and CAFs upon insulin activated CXCL12/CXCR4 axis.

Conclusions

Our findings provide novel mechanistic insights regarding the anti-proliferative and anti-migratory effects of metformin in both BC cells and important components of the tumor microenvironment like CAFs. Further investigations are warranted to corroborate the anticancer action of metformin on the tumor mass toward the assessment of more comprehensive strategies halting BC progression, in particular in patients exhibiting metabolic disorders and altered insulin/IR functions.
Comparison of dynamic susceptibility contrast enhanced MR and FDG-PET brain studies in patients with Alzheimer’s disease and amnestic mild cognitive impairment
Authors: Wabik Aleksandra , Trypka Elżbieta , Bladowska Joanna , Statkiewicz Mikołaj , Sąsiadek Marek , Zimny Anna
Published: June 2022

Background

The aim of this study was to compare Dynamic Susceptibility Contrast Enhanced MRI (DSC-MRI) and PET with [18F]flurodeoxyglucose (FDG-PET) in the diagnosis of Alzheimer’s Disease (AD) and amnestic Mild Cognitive Impairment (aMCI).

Methods

Twenty-seven age-and sex-matched patients with AD, 39 with aMCI and 16 controls underwent brain DSC-MRI followed by FDG-PET. Values of relative Cerebral Blood Volume (rCBV) and rCBV z-scores from frontal, temporal, parietal and PCG cortices were correlated with the rate of glucose metabolism from PET. Sensitivity, specificity and accuracy of DSC-MRI and FDG-PET in the diagnosis of AD and aMCI were assessed and compared.

Results

In AD, hypoperfusion was found within all the examined locations, while in aMCI in both parietal and temporal cortices and left PCG. FDG-PET showed the greatest hypometabolism in parietal, temporal and left PCG regions in both AD and aMCI. FDG-PET was more accurate in distinguishing aMCI from the controls than DSC-MRI. In the AD and combined group (AD + aMCI) there were numerous correlations between DSC-MRI and FDG-PET results.

Conclusions

In AD the patterns of hypoperfusion and glucose hypometabolism are similar, thus DSC-MRI may be a competitive method to FDG-PET. FDG-PET is a more accurate method in the diagnosis of aMCI.
A randomized comparison of health-related quality of life outcomes of dolutegravir versus efavirenz-based antiretroviral treatment initiated in the third trimester of pregnancy
Authors: Ochanda Perez Nicholas , Lamorde Mohammed , Kintu Kenneth , Wang Duolao , Chen Tao , Malaba Thokozile , Myer Landon , Waitt Catriona , Reynolds Helen , Khoo Saye
Published: June 2022

Introduction

Evidence on health-related quality of life (HRQoL) outcomes is limited for new antiretroviral therapies (ART). Dolutegravir-based treatment is being rolled out as the preferred first-line treatment for HIV in many low- and middle-income countries. We compared HRQoL between treatment-naïve pregnant women randomized to dolutegravir- or efavirenz-based ART in a clinical trial in Uganda and South Africa.

Methods

We gathered HRQoL data from 203 pregnant women of mean age 28 years, randomized to either dolutegravir- or efavirenz-based ART. We used the medical outcomes study-HIV health survey at baseline, 24 and 48 weeks between years 2018 and 2019. Physical health summary (PHS) and mental health summary (MHS) scores were the primary study outcomes, while the 11 MOS-HIV subscales were secondary outcomes. We applied mixed model analysis to estimate differences within and between-treatment groups. Multivariate regression analysis was included to identify associations between primary outcomes and selected variables.

Results

At 24 weeks postpartum, HRQoL scores increased from baseline in both treatment arms: PHS (10.40, 95% CI 9.24, 11.55) and MHS (9.23, 95% CI 7.35, 11.10) for dolutegravir-based ART; PHS (10.24, 95% CI 9.10, 11.38) and MHS (7.54, 95% CI 5.66, 9.42) for efavirenz-based ART. Increased scores for all secondary outcomes were significant at p < 0.0001. At 48 weeks, improvements remained significant for primary outcomes within group comparison. Estimated difference in PHS were higher in the dolutegravir-based arm, while increases in MHS were more for women in the efavirenz-based armat 24 and 48 weeks. No significant differences were noted for corresponding PHS scores at these time points compared between groups. Differences between arms were observed in two secondary outcomes: role function (1.11, 95% CI 0.08, 2.13), p = 0.034 and physical function outcomes (2.97, 95% CI 1.20, 4.73), p = 0.001. In the multivariate analysis, internet access was associated with higher PHS scores while owning a bank account, using the internet and longer treatment duration were associated with an increase in MHS scores.

Conclusion

We found no important differences in HRQoL outcomes among HIV-positive women started on dolutegravir relative to efavirenz in late pregnancy. Increases in HRQoL in the first year after delivery provide additional support for the initiation of ART in HIV-positive women presenting late in pregnancy.

Trial Registration Clinical Trial Number: NCT03249181
Floating EMG sensors and stimulators wirelessly powered and operated by volume conduction for networked neuroprosthetics
Authors: Becerra-Fajardo Laura , Krob Marc Oliver , Minguillon Jesus , Rodrigues Camila , Welsch Christine , Tudela-Pi Marc , Comerma Albert , Oliveira Barroso Filipe , Schneider Andreas , Ivorra Antoni
Published: June 2022

Background

Implantable neuroprostheses consisting of a central electronic unit wired to electrodes benefit thousands of patients worldwide. However, they present limitations that restrict their use. Those limitations, which are more adverse in motor neuroprostheses, mostly arise from their bulkiness and the need to perform complex surgical implantation procedures. Alternatively, it has been proposed the development of distributed networks of intramuscular wireless microsensors and microstimulators that communicate with external systems for analyzing neuromuscular activity and performing stimulation or controlling external devices. This paradigm requires the development of miniaturized implants that can be wirelessly powered and operated by an external system. To accomplish this, we propose a wireless power transfer (WPT) and communications approach based on volume conduction of innocuous high frequency (HF) current bursts. The currents are applied through external textile electrodes and are collected by the wireless devices through two electrodes for powering and bidirectional digital communications. As these devices do not require bulky components for obtaining power, they may have a flexible threadlike conformation, facilitating deep implantation by injection.

Methods

We report the design and evaluation of advanced prototypes based on the above approach. The system consists of an external unit, floating semi-implantable devices for sensing and stimulation, and a bidirectional communications protocol. The devices are intended for their future use in acute human trials to demonstrate the distributed paradigm. The technology is assayed in vitro using an agar phantom, and in vivo in hindlimbs of anesthetized rabbits.

Results

The semi-implantable devices were able to power and bidirectionally communicate with the external unit. Using 13 commands modulated in innocuous 3 MHz HF current bursts, the external unit configured the sensing and stimulation parameters, and controlled their execution. Raw EMG was successfully acquired by the wireless devices at 1 ksps.

Conclusions

The demonstrated approach overcomes key limitations of existing neuroprostheses, paving the way to the development of distributed flexible threadlike sensors and stimulators. To the best of our knowledge, these devices are the first based on WPT by volume conduction that can work as EMG sensors and as electrical stimulators in a network of wireless devices.
Molecular cytogenetic analysis of partial monosomy 10p and trisomy 10q resulting from familial pericentric inversion (10): a first case report in Chinese population
Authors: Zhuang Jianlong , Chen Chunnuan , Huang Rongfu , Luo Qi , Jiang Yuying , Zeng Shuhong , Wang Yuanbai , Xie Yingjun
Published: June 2022

Background

Chromosome aberrations of 10p monosomy and 10q trisomy resulting from parental pericentric inversion 10 are extremely rare, and to date, very few reports have been published on the matter.

Case Presentation

A 30-year-old pregnant woman with recurrent pregnancy loss is enrolled in this research. In this pregnancy, spontaneous abortion occurred in the first trimester of her pregnancy. Chromosomal microarray analysis of the abortion tissue showed a partial 10p monosomy (arr[GRCh37] 10p15.3p11.21(100,047_34,848,853) × 1) and a duplication of 10q (arr[GRCh37] 10q26.13q26.3(126,093,990_135,426,386) × 3). Further parental karyotype analysis indicated that the chromosomal abnormalities in the fetus was resulted from paternal pericenric inversion inv(10)(p11.21q26.13). This study presents the first case of a large deletion of 10p combined with 10q trisomy, resulting in pregnancy loss. Of these two manifestations, the large deletion of chromosome 10p may be the primary reason for spontaneous abortion in this subject.

Conclusions

This study presents the first case of partial 10p monosomy associated with 10q trisomy in Chinese population. It provides more information on the chromosome aberration of 10p monosomy and 10q trisomy and further strengthens the application value of microarray in the molecular etiological diagnosis of recurrent spontaneous abortion.
Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial
Authors: Boyle Andrew James , Ferris Peter , Bradbury Ian , Conlon John , Shankar-Hari Manu , Rogers Angela J. , O’Kane Cecilia M. , McAuley Daniel F.
Published: June 2022

Background

Interleukin (IL)-18 is a marker of inflammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin was associated with benefit in patients with ARDS and high plasma IL-18.

Methods

In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the effect on secreted IL-18 and IL-1β compared.

Results

511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥ 800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30–2.73]; p = 0.001). Allocation to simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p = 0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated macrophage secretion of IL-18 and IL-1β.

Conclusion

In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.
Early intubation and patient-centered outcomes in septic shock: a secondary analysis of a prospective multicenter study
Authors: Mellado-Artigas Ricard , Ferrando Carlos , Martino Frédéric , Delbove Agathe , Ferreyro Bruno L. , Darreau Cedric , Jacquier Sophie , Brochard Laurent , Lerolle Nicolas
Published: June 2022

Purpose

Despite the benefits of mechanical ventilation, its use in critically ill patients is associated with complications and had led to the growth of noninvasive techniques. We assessed the effect of early intubation (first 8 h after vasopressor start) in septic shock patients, as compared to non-early intubated subjects (unexposed), regarding in-hospital mortality, intensive care and hospital length of stay.

Methods

This study involves secondary analysis of a multicenter prospective study. To adjust for baseline differences in potential confounders, propensity score matching was carried out. In-hospital mortality was analyzed in a time-to-event fashion, while length of stay was assessed as a median difference using bootstrapping.

Results

A total of 735 patients (137 intubated in the first 8 h) were evaluated. Propensity score matching identified 78 pairs with similar severity and characteristics on admission. Intubation was used in all patients in the early intubation group and in 27 (35%) subjects beyond 8 h in the unexposed group. Mortality occurred in 35 (45%) and in 26 (33%) subjects in the early intubation and unexposed groups (hazard ratio 1.44 95% CI 0.86–2.39, p = 0.16). ICU and hospital length of stay were not different among groups [9 vs. 5 (95% CI 1 to 7) and 14 vs. 16 (95% CI − 7 to 8) days]. All sensitivity analyses confirmed the robustness of our findings.

Conclusions

An early approach to invasive mechanical ventilation did not improve outcomes in this matched cohort of patients. The limited number of patients included in these analyses out the total number included in the study may limit generalizability of these findings.

Trial registration NCT02780466. Registered on May 19, 2016.
Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets
Authors: Guo Michael H. , Sama Prashanth , LaBarre Brenna A. , Lokhande Hrishikesh , Balibalos John , Chu Ci , Du Xiaomi , Kheradpour Pouya , Kim Charles C. , Oniskey Taylor , Snyder Thomas , Soghoian Damien Z. , Weiner Howard L. , Chitnis Tanuja , Patsopoulos Nikolaos A.
Published: June 2022

Background

Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear.

Results

We utilize chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We find that CD4 T and B cells are independently enriched for MS genetics and further refine the driver subsets to Th17 and memory B cells, respectively. We replicate our findings in data from untreated and treated MS patients and find that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominate numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes.

Conclusions

Overall, our study finds that open chromatin regions in CD4 T cells and B cells independently drive MS genetic signals. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease.
INSPIRA: study protocol for a randomized-controlled trial about the effect of spirometry-assisted preoperative inspiratory muscle training on postoperative complications in abdominal surgery
Authors: Birrer D. L. , Kuemmerli C. , Obwegeser A. , Liebi M. , von Felten S. , Pettersson K. , Horisberger K.
Published: June 2022

Background

Rehabilitation strategies after abdominal surgery enhance recovery and improve outcome. A cornerstone of rehabilitation is respiratory physiotherapy with inspiratory muscle training to enhance pulmonary function.

Pre-habilitation is the process of enhancing functional capacity before surgery in order to compensate for the stress of surgery and postoperative recovery. There is growing interest in deploying pre-habilitation interventions prior to surgery.

The aim of this study is to assess the impact of preoperative inspiratory muscle training on postoperative overall morbidity. The question is, whether inspiratory muscle training prior to elective abdominal surgery reduces the number of postoperative complications and their severity grade.

Methods

We describe a prospective randomized-controlled single-centre trial in a tertiary referral centre. The primary outcome is the Comprehensive Complication Index (CCI) at 90 days after surgery. The CCI expresses morbidity on a continuous numeric scale from 0 (no complication) to 100 (death) by weighing all postoperative complications according to the Clavien-Dindo classification for their respective severity.

In the intervention group, patients will be instructed by physiotherapists to perform inspiratory muscle training containing of 30 breaths twice a day for at least 2 weeks before surgery using Power®Breathe KHP2. Depending on the surgical schedule, training can be extended up to 6 weeks. In the control group, no preoperative inspiratory muscle training will be performed. After the operation, both groups receive the same physiotherapeutic support.

Discussion

Existing data about preoperative inspiratory muscle training on postoperative complications are ambiguous and study protocols are often lacking a clear design and a clearly defined endpoint. Most studies consist of multi-stage concepts, comprehensively supervised and long-term interventions, whose implementation in clinical practice is hardly possible. There is a clear need for randomized-controlled studies with a simple protocol that can be easily transferred into clinical practice. This study examines the effortless adjustment of the common respiratory physiotherapy from currently postoperative to preoperative. The external measurement by the device eliminates the diary listing of patients’ performances and allows the exercise adherence and thus the effect to be objectively recorded.

Trial registration

ClinicalTrials.govNCT04558151. Registered on September 15, 2020.
E-HEalth treatment in Long-term Dialysis (E-HELD): study protocol for a multicenter randomized controlled trial evaluating personalized Internet-based cognitive-behavioral therapy in dialysis patients
Authors: Tommel Judith , Evers Andrea W. M. , van Hamersvelt Henk W. , van Dijk Sandra , Chavannes Niels H. , Wirken Lieke , Hilbrands Luuk B. , van Middendorp Henriët
Published: June 2022

Background

Kidney failure and dialysis treatment have a large impact on a patient’s life. Patients experience numerous, complex symptoms and usually have multiple comorbid conditions. Despite the multitude of problems, patients often have priorities for improvement of specific aspects of their functioning, which would be helpful for clinicians to become informed of. This highlights a clear need for patient-centered care in this particular patient group, with routine screening as a vital element to timely recognize symptoms and tailored treatment to match individual patients’ needs and priorities. By also providing feedback on patient’s screening results to the patient itself, the patient is empowered to actively take control in one’s mostly uncontrollable disease process. The current paper describes the study design of a multicenter randomized controlled trial evaluating the effectiveness of the “E-HEealth treatment in Long-term Dialysis” (E-HELD) intervention. This therapist-guided Internet-based cognitive-behavioral therapy (ICBT) intervention is focused on and personalized to the myriad of problems that dialysis patients experience and prioritize.

Methods

After a screening procedure on adjustment problems, 130 eligible dialysis patients will be randomized to care as usual or the E-HELD intervention. Patients will complete questionnaires on distress (primary outcome measure), several domains of functioning (e.g., physical, psychological, social), potential predictors and mediators of treatment success, and the cost-effectiveness of the intervention, at baseline, 6-month follow-up, and 12-month follow-up. In addition, to take account of the personalized character of the intervention, the Personalized Priority and Progress Questionnaire (PPPQ) will be administered which is a personalized instrument to identify, prioritize, and monitor individual problems over time.

Discussion

The present study design will provide insight in the effectiveness of tailored ICBT in patients with kidney failure who are treated with dialysis. When proven effective, the screening procedure and the subsequent ICBT intervention could be implemented in routine care to detect, support, and treat patients struggling with adjustment problems.

Trial registration

NL63422.058.17 [Registry ID: METC-LDD]

NL7160 [Netherlands Trial Register; registered on 16 July 2018]
Keeping up with the guidelines: design changes to the STREAM stage 2 randomised controlled non-inferiority trial for rifampicin-resistant tuberculosis
Authors: Goodall Ruth L. , Sanders Karen , Bronson Gay , Gurumurthy Meera , Torrea Gabriela , Meredith Sarah , Nunn Andrew , Rusen I. D. ,   on behalf of the STREAM Trial Team, Bronson Gay , Gurumurthy Meera , Komrska Jan , Patel Leena , Qawiy Ishmael , Rusen I. D. , Ali Sonia , Bellenger Katharine , Bennet Deborah , Bennet Rachel , Dodds Wendy , Goodall Ruth , Meredith Sarah , Murphy Brendan , Nunn Andrew , Roach Carol , Sanders Karen , Whitney Johanna , Van Deun Armand , Torrea Gabriela , Chiang Chen-Yuan , Rosu Laura , Squire Bertie , Madan Jason
Published: June 2022

Results from the STREAM stage 1 trial showed that a 9-month regimen for patients with rifampicin-resistant tuberculosis was non-inferior to the 20-month regimen recommended by the 2011 WHO treatment guidelines. Similar levels of severe adverse events were reported on both regimens suggesting the need for further research to optimise treatment. Stage 2 of STREAM evaluates two additional short-course regimens, both of which include bedaquiline. Throughout stage 2 of STREAM, new drug choices and a rapidly changing treatment landscape have necessitated changes to the trial’s design to ensure it remains ethical and relevant. This paper describes changes to the trial design to ensure that stage 2 continues to answer important questions. These changes include the early closure to recruitment of two trial arms and an adjustment to the definition of the primary endpoint. If the STREAM experimental regimens are shown to be non-inferior or superior to the stage 1 study regimen, this would represent an important contribution to evidence about potentially more tolerable and more efficacious MDR-TB regimens, and a welcome advance for patients with rifampicin-resistant tuberculosis and tuberculosis control programmes globally.

Trial registration: ISRCTN ISRCTN18148631. Registered 10 February 2016
Behavioural intervention to promote the uptake of planned care in urgent dental care attenders: study protocol for the RETURN randomised controlled trial
Authors: Harris R. , Lowers V. , Hulme C. , Burnside G. , Best A. , Clarkson J. E. , Cooke R. , Van Der Zande M. , Maitland R.
Published: June 2022

Background

People with disadvantaged backgrounds are less likely to visit the dentist for planned care, even though they have disproportionately poorer oral health. They are correspondingly more likely to experience dental problems and use urgent dental care, general practices and Accident and Emergency departments, which not only makes meeting their needs expensive, but, since these services often rely on prescriptions rather than addressing the clinical cause, can contribute to antimicrobial resistance.

Methods

The RETURN intervention has been developed with substantial community co-production, to be delivered opportunistically in urgent dental care settings. This brief intervention is delivered by dental nurses and involves material relevant to the ‘in-group’ targeted. The material includes booklets relating to barriers to planned dental visiting with corresponding short video clips featuring local people and including a modelling element. Dental nurses are trained to have supportive and non-judgemental conversations, assisting patients to set personal goals and action plans, which are reinforced in a follow-up text within a few weeks. A randomised controlled trial will be undertaken in 3 types of sites: dental practices delivering urgent care (a) within working hours, (b) out of hours, and (c) in a Dental Hospital. The trial will recruit 1180 adult urgent dental care users over 12 months, who have not visited a dentist for a planned care appointment for 2 years or more and do not have a dentist who they visit for routine care. It aims to investigate the effectiveness and cost-effectiveness of the intervention and to explore whether the intervention has different effects across the socio-economic gradient. Participants will be followed up at 6, 12 and 18 months after randomisation. Co-primary outcomes are attendance at a dental practice for planned care within 12 months and self-reported oral health-related quality of life at 12 months.

Discussion

This is a pragmatic trial, evaluating the effectiveness of the intervention under the usual condition in which it might be applied. Since dental practices work as independent contractors to the NHS, this brings implementation and fidelity challenges which will be explored and described in embedded qualitative work.

Trial registration

ISRCTN registry identifier ISRCTN84666712. Registered 12/04/2021.
Large granular lymphocytic leukemia cured by allogeneic stem cell transplant: a case report
Authors: Carey Edward , Ward Nicholas , Abdul-Hay Maher
Published: June 2022

Background

Large granular lymphocytic leukemia is a rare lymphocytic neoplasm that can pose a treatment challenge in patients with severe neutropenia in whom conventional therapies fail. We report one of the first cases in which allogeneic stem cell therapy was used as treatment for large granular lymphocytic leukemia.

We report and discuss the case of a 42-year-old white Caucasian female who, despite multiple therapies including methotrexate, cyclophosphamide, prednisone, cyclosporine, and pentostatin, continued to show severe neutropenia and recurrent infections. The patient was treated successfully and cured by allogeneic stem cell transplant without any major complications.

Conclusions

The significant importance of this case report is the introduction of a new treatment algorithm for challenging cases of T-cell large granular lymphocytic leukemia in which standard care fails. We hope that this case report will raise awareness of the potential benefits of allogeneic stem cell transplant in the treatment of aggressive forms of T-cell large granular lymphocytic leukemia.
Psoralen alleviates radiation-induced bone injury by rescuing skeletal stem cell stemness through AKT-mediated upregulation of GSK-3β and NRF2
Authors: Yin Bo-Feng , Li Zhi-Ling , Yan Zi-Qiao , Guo Zheng , Liang Jia-Wu , Wang Qian , Zhao Zhi-Dong , Li Pei-Lin , Hao Rui-Cong , Han Meng-Yue , Li Xiao-Tong , Mao Ning , Ding Li , Chen Da-Fu , Gao Yue , Zhu Heng
Published: June 2022

Background

Repairing radiation-induced bone injuries remains a significant challenge in the clinic, and few effective medicines are currently available. Psoralen is a principal bioactive component of Cullen corylifolium (L.) Medik and has been reported to have antitumor, anti-inflammatory, and pro-osteogenesis activities. However, less information is available regarding the role of psoralen in the treatment of radiation-induced bone injury. In this study, we explored the modulatory effects of psoralen on skeletal stem cells and their protective effects on radiation-induced bone injuries.

Methods

The protective effects of psoralen on radiation-induced osteoporosis and irradiated bone defects were evaluated by microCT and pathological analysis. In addition, the cell proliferation, osteogenesis, and self-renewal of SSCs were explored. Further, the underlying mechanisms of the protective of psoralen were investigated by using RNA sequencing and functional gain and loss experiments in vitro and in vivo. Statistical significance was analyzed using Student's t test. The one-way ANOVA was used in multiple group data analysis.

Results

Here, we demonstrated that psoralen, a natural herbal extract, mitigated radiation-induced bone injury (irradiation-induced osteoporosis and irradiated bone defects) in mice partially by rescuing the stemness of irradiated skeletal stem cells. Mechanistically, psoralen restored the stemness of skeletal stem cells by alleviating the radiation-induced suppression of AKT/GSK-3β and elevating NRF2 expression in skeletal stem cells. Furthermore, the expression of KEAP1 in skeletal stem cells did not significantly change in the presence of psoralen. Moreover, blockade of NRF2 in vivo partially abolished the promising effects of psoralen in a murine model of irradiation-induced osteoporosis and irradiated bone regeneration.

Conclusions

In summary, our findings identified psoralen as a potential medicine to mitigate bone radiation injury. In addition, skeletal stem cells and AKT-GSK-3β and NRF2 may thus represent therapeutic targets for treating radiation-induced bone injury.

Graphical Abstract
Changes in best-corrected visual acuity in patients with dry age-related macular degeneration after stem cell transplantation: systematic review and meta-analysis
Authors: Li Licheng , Yu Yang , Lin Shu , Hu Jianmin
Published: June 2022

Background

Stem cell transplantation may improve visual acuity in patients with dry age-related macular degeneration. Herein, we aimed to summarise the evidence on the risks and benefits of stem cell transplantation for improving visual acuity, including the risk of adverse events.

Methods

Data were obtained from the PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases, and each database was interrogated from the date of inception until 19 March 2022. The rates of visual acuity outcomes and adverse events associated with stem cell transplantation were examined. All statistical analyses were conducted using Review Manager 5.4. The study was registered with PROSPERO (CRD 42022322902).

Results

The analysis examined 10 studies (102 patients), including one and three, randomised and non-randomised clinical trials, and one and five, multicentre prospective and prospective clinical trials, respectively. Meta-analysis showed changes in best-corrected visual acuity in the study eyes after stem cell transplantation (6 months: risk ratio [RR] = 17.00, 95% confidence interval [CI] 6.08–47.56, P < 0.00001; 12 months: RR = 11.00, 95% CI 2.36–51.36, P = 0.002). Subgroup analysis showed that different stem cell types achieved better best-corrected visual acuity at post-operative 6 months, compared to that observed at baseline. Four cases of related ocular adverse events and no related systemic adverse events were reported.

Conclusion

This meta-analysis suggests that stem cell transplantation may improve best-corrected visual acuity in dry age-related macular degeneration, based on small sample sizes and fewer randomised controlled trials.
PIKAChU: a Python-based informatics kit for analysing chemical units
Authors: Terlouw Barbara R. , Vromans Sophie P. J. M. , Medema Marnix H.
Published: June 2022

As efforts to computationally describe and simulate the biochemical world become more commonplace, computer programs that are capable of in silico chemistry play an increasingly important role in biochemical research. While such programs exist, they are often dependency-heavy, difficult to navigate, or not written in Python, the programming language of choice for bioinformaticians. Here, we introduce PIKAChU (Python-based Informatics Kit for Analysing CHemical Units): a cheminformatics toolbox with few dependencies implemented in Python. PIKAChU builds comprehensive molecular graphs from SMILES strings, which allow for easy downstream analysis and visualisation of molecules. While the molecular graphs PIKAChU generates are extensive, storing and inferring information on aromaticity, chirality, charge, hybridisation and electron orbitals, PIKAChU limits itself to applications that will be sufficient for most casual users and downstream Python-based tools and databases, such as Morgan fingerprinting, similarity scoring, substructure matching and customisable visualisation. In addition, it comes with a set of functions that assists in the easy implementation of reaction mechanisms. Its minimalistic design makes PIKAChU straightforward to use and install, in stark contrast to many existing toolkits, which are more difficult to navigate and come with a plethora of dependencies that may cause compatibility issues with downstream tools. As such, PIKAChU provides an alternative for researchers for whom basic cheminformatic processing suffices, and can be easily integrated into downstream bioinformatics and cheminformatics tools. PIKAChU is available at https://github.com/BTheDragonMaster/pikachu.

Graphical Abstract
Targeting tumor-associated macrophages for cancer treatment
Authors: Li Mengjun , He Linye , Zhu Jing , Zhang Peng , Liang Shufang
Published: June 2022

Tumor-associated macrophages (TAMs) are abundant, nearly accounting for 30–50% of stromal cells in the tumor microenvironment. TAMs exhibit an immunosuppressive M2-like phenotype in advanced cancer, which plays a crucial role in tumor growth, invasion and migration, angiogenesis and immunosuppression. Consequently, the TAM-targeting therapies are particularly of significance in anti-cancer strategies. The application of TAMs as anti-cancer targets is expected to break through traditional tumor-associated therapies and achieves favorable clinical effect. However, the heterogeneity of TAMs makes the strategy of targeting TAMs variable and uncertain. Discovering the subset specificity of TAMs might be a future option for targeting TAMs therapy. Herein, the review focuses on highlighting the different modalities to modulate TAM’s functions, including promoting the phagocytosis of TAMs, TAMs depletion, blocking TAMs recruitment, TAMs reprogramming and suppressing immunosuppressive tumor microenvironment. We also discuss about several ways to improve the efficacy of TAM-targeting therapy from the perspective of combination therapy and specificity of TAMs subgroups.
Shotgun proteomics of extracellular matrix in late senescent human dermal fibroblasts reveals a down-regulated fibronectin-centered network
Authors: Cho Kun , Yang Kyeong Eun , Nam Soo-Bin , Lee Song-I. , Yeo Eui-Ju , Choi Jong-Soon
Published: June 2022

Extracellular matrix (ECM) proteins play a pivotal role in cell growth and differentiation. To characterize aged ECM proteins, we compared the proteomes by shotgun method of young (passage #15) and late senescent (passage #40) human dermal fibroblasts (HDFs) using SDS-PAGE coupled with LC–MS/MS. The relative abundance of identified proteins was determined using mol% of individual proteins as a semi-quantitative index. Fifteen ECM proteins including apolipoprotein B (APOB) and high-temperature requirement factor 1 (HTRA1) were up-regulated, whereas 50 proteins including fibronectin 1 (FN1) and vitronectin (VTN) were down-regulated in late senescent HDFs. The identified ECM proteins combined with plasma membrane were queried to construct the protein–protein interaction network using Ingenuity Pathways Analysis, resulting in a distinct FN1-centered network. Of differentially abundant ECM proteins in shotgun proteomics, the protein levels of FN1, VTN, APOB, and HTRA1 were verified by immunoblot analysis. The results suggest that the aging process in HDFs might be finally involved in the impaired FN1 regulatory ECM network combined with altered interaction of neighboring proteins. Shotgun proteomics of highly aged HDFs provides insight for further studies of late senescence-related alterations in ECM proteins.
Comparison of the tidal signatures in sporadic E and vertical ion convergence rate, using FORMOSAT-3/COSMIC radio occultation observations and GAIA model
Authors: Sobhkhiz-Miandehi Sahar , Yamazaki Yosuke , Arras Christina , Miyoshi Yasunobu , Shinagawa Hiroyuki
Published: June 2022

Sporadic E or Es is a transient phenomenon where thin layers of enhanced electron density appear in the ionospheric E region (90–120 km altitude). The neutral wind shear caused by atmospheric tides can lead ions to converge vertically at E-region heights and form the Es layer. This research aims to determine the role of atmospheric solar and lunar tides in Es occurrence. For this purpose, radio occultation data of FORMOSAT-3/COSMIC have been used, which provide complete global coverage of Es events. Moreover, GAIA model simulations have been employed to evaluate the vertical ion convergence induced by solar tides. The results show both migrating and non-migrating solar tidal signatures and the semidiurnal migrating lunar tidal signature mainly in low and mid-latitude Es occurrence. The seasonal variation of the migrating solar tidal components of Es is in good agreement with those in the vertical ion convergence derived from GAIA at higher altitudes. Furthermore, some non-migrating components of solar tides, including semidiurnal westward wavenumbers 1 and 3 and diurnal eastward wavenumbers 2 and 3, also significantly affect the Es occurrence rate.

Graphical Abstract
The ghrelin-GHSR-1a pathway inhibits high glucose-induced retinal angiogenesis in vitro by alleviating endoplasmic reticulum stress
Authors: Li Rong , Yao Guomin , Zhou Lingxiao , Zhang Min , Yan Jin
Published: June 2022

Background

To investigate the effect of ghrelin, a brain-gut peptide hormone, on high glucose-induced retinal angiogenesis in vitro and explore its association with endoplasmic reticulum (ER) stress.

Methods

Human retinal microvascular endothelial cells (HRMECs) were first divided into control and high-glucose groups, and the mRNA and protein expression levels of the receptor for ghrelin [growth hormone secretin receptor 1a, (GHSR-1a)] in cells were determined. HRMECs were then treated with high glucose alone or in combination with ghrelin or siGHSR-1a, and cell viability, migration, tube formation and the expression of the ER stress-related proteins PERK, ATF4 and CHOP were detected. Finally, to clarify whether the effects of ghrelin are related to ER stress, tunicamycin, an inducer of ER stress, was used to treat HRMECs, and cell viability, cell migration, and tube formation were evaluated.

Results

GHSR-1a expression in HRMECs at both the mRNA and protein levels was inhibited by high-glucose treatment. Under high-glucose conditions, ghrelin promoted cell viability and inhibited migration and tube formation, which were blocked by siGHSR-1a treatment. Ghrelin inhibited the increases in the protein levels of p-PERK, ATF4 and CHOP induced by high-glucose treatment, and combination treatment with siGHSR-1a reversed this effect of ghrelin. When tunicamycin was added, the effects of ghrelin on cell viability, migration and tube formation were all weakened.

Conclusions

This study experimentally revealed that ghrelin can inhibit high glucose-induced retinal angiogenesis in vitro through GHSR-1a, and alleviation of ER stress may be one of the mechanisms underlying this effect.
Higher-order dynamic effects of uncertainty risk under thick-tailed stochastic volatility
Authors: Gong Xiao-Li , Lu Jin-Yan , Xiong Xiong , Zhang Wei
Published: June 2022

Sudden and uncertain events often cause cross-contagion of risk among various sectors of the macroeconomy. This paper introduces the stochastic volatility shock that follows a thick-tailed Student’st-distribution into a high-order approximate dynamic stochastic general equilibrium (DSGE) model with Epstein–Zin preference to better analyze the dynamic effect of uncertainty risk on macroeconomics. Then, the high-dimensional DSGE model (DSGE-SV-t) is developed to examine the impact of uncertainty risk on the transmission mechanism among macroeconomic sectors. The empirical research found that uncertainty risk generates heterogeneous impacts on macroeconomic dynamics under different inflation levels and economic states. Among them, a technological shock has the strongest impact on employment and consumption channels. The crowding-out effect of a fiscal policy stimulus on consumption and private investments is relatively weakened when considering uncertainty risk but is more pronounced during periods of high inflation. Uncertainty risk can partly explain the decline in investments and the increase in interest rates and employment rates, given the impact of an agent’s risk preferences. Compared with external economic conditions, the inflation factor has a stronger impact on the macro transmission mechanism caused by uncertainty risk.
Signatures of functional bacteriome structure in a tropical direct-developing amphibian species
Authors: Martins Renato A. , Greenspan Sasha E. , Medina Daniel , Buttimer Shannon , Marshall Vanessa M. , Neely Wesley J. , Siomko Samantha , Lyra Mariana L. , Haddad Célio F. B. , São-Pedro Vinícius , Becker C. Guilherme
Published: June 2022

Background

Host microbiomes may differ under the same environmental conditions and these differences may influence susceptibility to infection. Amphibians are ideal for comparing microbiomes in the context of disease defense because hundreds of species face infection with the skin-invading microbe Batrachochytrium dendrobatidis (Bd), and species richness of host communities, including their skin bacteria (bacteriome), may be exceptionally high. We conducted a landscape-scale Bd survey of six co-occurring amphibian species in Brazil’s Atlantic Forest. To test the bacteriome as a driver of differential Bd prevalence, we compared bacteriome composition and co-occurrence network structure among the six focal host species.

Results

Intensive sampling yielded divergent Bd prevalence in two ecologically similar terrestrial-breeding species, a group with historically low Bd resistance. Specifically, we detected the highest Bd prevalence in Ischnocnema henselii but no Bd detections in Haddadus binotatus. Haddadus binotatus carried the highest bacteriome alpha and common core diversity, and a modular network partitioned by negative co-occurrences, characteristics associated with community stability and competitive interactions that could inhibit Bd colonization.

Conclusions

Our findings suggest that community structure of the bacteriome might drive Bd resistance in H. binotatus, which could guide microbiome manipulation as a conservation strategy to protect diverse radiations of direct-developing species from Bd-induced population collapses.
Quantitative shear wave elastography assessment of tibial nerve in diagnosis of diabetic peripheral neuropathy
Authors: Elfattah Hassan Gadalla Amr A. , Nada Hadeer Radwan , Kaddah Randa Osama , Khalil Alshaimaa Sobhi , Saleh Mahmoud Mohamed
Published: June 2022

Background

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus. Diagnosis of DPN is very important in the prognosis of disease and treatment as early treatment of DPN decreases both short-term and long-term morbidities. SWE elastography is a noninvasive and reproducible method for the precise evaluation of nerve stiffness.

Results

Tibial nerve stiffness is notably high at SWE in diabetic patients with DPN (mean shear wave elastography value of RT tibial SWE 75.3 ± 15.1 kPa) compared to patients without DPN (mean shear wave elastography value of RT tibial SWE 37.8 ± 11.6 kPa) and nerve stiffness in healthy control subjects (mean shear wave elastography value of RT tibial SWE 24.9 ± 6.3 kPa). There is a significant increase in the cross-sectional area (CSA) among diabetic patients with DPN (mean cross-sectional area of the right tibial nerve of 17 ± 1.9 mm2) and without DPN (mean cross-sectional area of the right tibial nerve of 14.5 ± 3.8 mm2) in comparison with control subjects (mean cross-sectional area of the right tibial nerve of 13.2 ± 3.1 mm2) in the right side. Borderline significance of the CSA parameters of the tibial nerve study on the left side in different groups. The cutoff point to determine DPN among diabetic patients in the right lower limb is more than 63.8 kPa. With 89% sensitivity and 100% specificity in the detection of DPN on the right side, the SWE has 100% PPV and 95.5% NPV in the detection of DPN on the right side.

Conclusion

SWE is an effective assistant method in the diagnosis of DPN and is useful when a suspected neuropathy is not detectable by electrophysiology.