bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of evidence on reported non-genetic risk factors of congenital heart defects: the updated umbrella review
Authors: Nie Xiaolu , Liu Xiaohang , Wang Chen , Wu Zehao , Sun Zimo , Su Jian , Yan Ruohua , Peng Yaguang , Yang Yuxuan , Wang Chengrong , Cai Siyu , Liu Yali , Yu Huanling , Wu Qingqing , Peng Xiaoxia , Yin Chenghong
Published: April 2022

Background

Congenital heart defect (CHD) is the leading cause of birth defects globally, which results in a great disease burden. It is still imperative to detect the risk factors of CHD. This umbrella review aimed to comprehensively summarize the evidence and grade the evidence of the associations between non-genetic risk factors and CHD.

Methods

Databases including Medline, Embase, Web of Science, Cochrane Library, and four Chinese databases were searched from inception to 18 Jan 2022. The reference lists of systematic reviews (SR) and meta-analyses (MA) were screened, which aimed to explore the non-genetic risk factors of CHD. Subsequently, titles and abstracts of identified records and full texts of selected SR/MA were screened by two independent reviewers based on predefined eligibility criteria. A priori developed extraction form was used to abstract relative data following the PRISMA 2020 and MOOSE guidelines. The risk of bias was assessed with the AMSTAR2 instrument. Data were synthesized using fixed-effects and random-effects meta-analyses, respectively. Finally, the evidence on the association of non-genetic risk factors and CHD was graded using Ioannidis’s five-class evidence grade.

Results

A total of 56 SRs, encompassing 369 MAs, were identified. The risk factors included relative factors on air pollution, reproductive-related factors, parental age and BMI, parental life habits, working and dwelling environment, maternal drug exposure, and maternal disease. Based on AMSTAR2 criteria, only 16% (9/56) of SRs were classified as “Moderate”. One hundred and two traceable positive association MAs involving 949 component individual studies were included in further analysis and grading of evidence. Family genetic history, number of abortions, maternal obesity, especially moderate or severe obesity, decoration materials, harmful chemicals, noise during pregnancy, folic acid supplementation, SSRIs, SNRIs, any antidepressants in the first trimester, maternal DM (including both PGDM and GDM), and gestational hypertension were convincing and highly suggestive factors for CHD. After sensitivity analyses based on cohort studies, some grades of evidence changed.

Conclusion

The present umbrella review will provide evidence-based information for women of childbearing age before or during pregnancy to prevent CHD. In addition, sensitivity analysis based on cohort studies showed the changed evidence levels. Therefore, future SR/MA should concern the sensitivity analysis based on prospective birth cohort studies and case-control studies.
Routes to cancer diagnosis for patients with pre-existing psychiatric disorders: a nationwide register-based cohort study
Authors: Virgilsen Line Flytkjær , Vedsted Peter , Falborg Alina Zalounina , Pedersen Anette Fischer , Prior Anders , Jensen Henry
Published: April 2022

Background

Poor cancer prognosis has been observed in patients with pre-existing psychiatric disorders. Therefore, we need better knowledge about the diagnosis of cancer in this patient group. The aim of the study was to describe the routes to cancer diagnosis in patients with pre-existing psychiatric disorders and to analyse how cancer type modified the routes.

Methods

A register-based cohort study was conducted by including patients diagnosed with incident cancer in 2014–2018 (n = 155,851). Information on pre-existing psychiatric disorders was obtained from register data on hospital contacts and prescription medication. Multinomial regression models with marginal means expressed as probabilities were used to assess the association between pre-existing psychiatric disorders and routes to diagnosis.

Results

Compared to patients with no psychiatric disorders, the population with a psychiatric disorder had an 8.0% lower probability of being diagnosed through cancer patient pathways initiated in primary care and a 7.6% higher probability of being diagnosed through unplanned admissions. Patients with pre-existing psychiatric disorders diagnosed with rectal, colon, pancreatic, liver or lung cancer and patients with schizophrenia and organic disorders were less often diagnosed through cancer patient pathways initiated in primary care.

Conclusion

Patients with pre-existing psychiatric disorders were less likely to be diagnosed through Cancer Patient Pathways from primary care. To some extent, this was more pronounced among patients with cancer types that often present with vague or unspecific symptoms and among patients with severe psychiatric disorders. Targeting the routes by which patients with psychiatric disorders are diagnosed, may be one way to improve the prognosis among this group of patients.
Thyroid function in children with Prader-Willi syndrome in Southern China: a single-center retrospective case series
Authors: Huang Xinjiang , Yin Xi , Wu Dongyan , Cai Yanna , Li Xiuzhen , Zhang Wen , Zeng Chunhua , Mao Xiaojian , Liu Li
Published: April 2022

Background

To investigate hypothalamic-pituitary-thyroid function in children of different ages, nutritional phases, and genotypes that were diagnosed with Prader-Willi syndrome (PWS), as well as the effects of recombinant human growth hormone (rhGH) treatment on thyroid hormones in PWS patients.

Methods

One hundred and thirty PWS patients (87 boys and 43 girls) aged from newborn to 15 years (y) (median 1.25 y, mean, SD: 2.95 ± 3.45 y), were surveyed in this study. Serum thyroid hormone levels were examined at least once per3-6 months during the 2 years follow-up study. Central hypothyroidism (C-HT) was identified as low/normal thyroid-stimulating hormone (TSH) and low free thyroxine 4 (FT4).

Results

All study participants had normal neonatal TSH screening test results. The prevalence of C-HT is 36.2% (47/130). No C-HT cases were diagnosed in PWS either below 1 month (m) or above 12 y. The prevalence of C-TH would be increased with age before 3 y until reaching the peak, followed by a gradual decline over the years. The prevalence of C-HT varies significantly at different ages (Pearson's χ2 = 19.915;p < 0.01). However, there is no correlation between the C-HT prevalence and nutritional phases (Pearson's χ2 = 4.992;p = 0.288), genotypes (Pearson's χ2 = 0.292;p = 0.864), or rhGH therapy (Pearson's χ2 = 1.799;p = 0.180).

Conclusions

This study suggests the prevalence of C-TH was increased with the age before 3 y, and reached the peak in the 1 to 3 y group, then gradually declined over the years. There is no correlation between C-HT prevalence and nutritional phases, genotypes, or rhGH treatment.
A novel TCN2 mutation with unusual clinical manifestations of hemolytic crisis and unexplained metabolic acidosis: expanding the genotype and phenotype of transcobalamin II deficiency
Authors: Pongphitcha Pongpak , Sirachainan Nongnuch , Khongkraparn Arthaporn , Tim-Aroon Thipwimol , Songdej Duantida , Wattanasirichaigoon Duangrurdee
Published: April 2022

Background

Transcobalamin deficiency is a rare inborn metabolic disorder, characterized by pancytopenia, megaloblastic anemia, failure to thrive, diarrhea, and psychomotor retardation.

Case presentation

We describe a patient who first presented at 3 months of age, with pancytopenia, hepatosplenomegaly, recurrent infection, metabolic acidosis, and acute hemolytic crisis. Extensive hematologic and immunologic investigations did not identify inherited bone marrow failure syndrome, acute leukemia or its related disorders. Whole exome sequencing identified a novel homozygous TCN2 mutation, c.428-2A > G and mRNA study confirmed an aberrant transcription of exon 4 skipping. The mutant protein is predicted to have an in-fame 51 amino acids deletion (NP_000346:p.Gly143_Val193del). The patient exhibited marked clinical improvement following hydroxocobalamin treatment.

Conclusions

Transcobalamin deficiency should be investigated in infants with unexplained pancytopenia and acute hemolytic crisis with or without typical evidence of vitamin B12 deficiency.
Self-rated health changes of individuals in same-sex compared to different-sex relationships: a longitudinal study
Authors: Wang Yiwen
Published: April 2022

Background

Prior scholarship on same-sex relationships and health has primarily relied on cross-sectional data, leaving a number of unanswered questions about health changes of same-sex couples over time. This study examined the self-rated health statuses and changes of individuals in same- and different-sex cohabitations and marriages over time (2014–2017).

Methods

Data were drawn from the 2014 panel of the Survey of Income and Program Participation (SIPP), a nationally representative and longitudinal study (N = 23,297) in the United States. Mixed- and fixed-effects regression models were performed to investigate the self-rated health changes of individuals in same-sex compared to different-sex relationships.

Results

Results show that same-sex married individuals report a faster decline in self-rated health compared to different-sex married counterparts despite similar initial health statuses. Similarly, same-sex cohabitors also exhibit a more rapid health decline as compared to different-sex cohabitors.

Conclusions

The results point to health change disadvantages experienced by same-sex married and cohabiting individuals during the study period. The findings from this study advance scholarly knowledge on the health changes of individuals in marginalized intimate relationships and highlight the importance of studying sexual minorities’ health using longitudinal data.
Pedicled frontal periosteal rescue flap via eyebrow incision for skull base reconstruction (SevEN-002)
Authors: Jang Chang Ki , Park Soo Jeong , Kim Eui Hyun , Cho Jin Mo , Moon Ju Hyung , Sung Kyoung Su , Hong Je Beom , Lim Jaejoon Joon , Na Minkyun , Hong Chang-Ki , Roh Tae Hoon , Oh Jiwoong
Published: April 2022

Purpose

Cerebrospinal fluid (CSF) leakage is one of the major complications after endoscopic endonasal surgery. The reconstructive nasoseptal flap is widely used to repair CSF leakage. However, it could not be utilized in all cases; thus, there was a need for an alternative. We developed a pericranial rescue flap that could cover both sellar and anterior skull base defects via the endonasal approach. A modified surgical technique that did not violate the frontal sinus and cause cosmetic problems was designed using the pericranial rescue flap.

Methods

We performed 12 cadaveric dissections to investigate the applicability of the lateral pericranial rescue flap. An incision was made, extending from the middle to the lateral part of the eyebrow. The pericranium layer was dissected away from the galea layer, from the supraorbital region towards the frontoparietal region. With endoscopic assistance, the periosteal flap was raised, the flap base was the pericranium layer at the eyebrow incision. After a burr-hole was made in the supraorbital bone, the pericranial flap was inserted via the intradural or extradural pathway.

Results

The mean size of the pericranial flap was 11.5 cm × 3.2 cm. It was large enough to cross the midline and cover the dural defects of the anterior skull base, including the sellar region.

Conclusion

We demonstrated a modified endoscopic technique to repair the anterior skull base defects. This minimally invasive pericranial flap may resolve neurosurgical complications, such as CSF leakage.
Preoperative risk factors of lymph node metastasis in clinical N0 lung adenocarcinoma of 3 cm or less in diameter
Authors: Fang Cheng , Xiang Yangwei , Han Weili
Published: April 2022

Background

Lung adenocarcinoma is the most common subtype of non-small cell lung cancer. The surgical strategy of lymph node dissection is controversial because many more patients are diagnosed at an early stage in clinical practice.

Methods

We retrospectively reviewed 622 clinical N0 lung adenocarcinoma patients with 3 cm or less in tumor size who underwent lobectomy or segmentectomy combined with lymph node dissection in our hospital from January 2017 to December 2019. We performed univariate and multivariate analyses to identify preoperative risk factors of lymph node metastasis.

Results

Lymph node metastasis was found in 60 out of 622 patients. On univariate analysis, lymph node metastasis was linked to smoking history, preoperative CEA level, tumor size, tumor location (peripheral or central), consolidation/tumor ratio, pleural invasion, and pathologic type. However, only the preoperative CEA level, tumor size, and consolidation/tumor ratio were independent risk factors in multivariate analysis. The ROC curve showed that the cutoff value of tumor size was 1.7 cm. There was no lymph node metastasis in patients without risk factors.

Conclusions

The preoperative CEA level, tumor size, and consolidation/tumor ratio were independent risk factors of lymph node metastasis in clinical N0 lung adenocarcinoma with tumor size ≤ 3 cm. The lymph node metastasis rate was extremely low in clinical N0 lung adenocarcinoma patients without risk factors and lymph node dissection should be avoided in these patients to reduce surgical trauma.
Machine learning approaches to predict the 1-year-after-initial-AMI survival of elderly patients
Authors: Lee Jisoo , Lee Sulyun , Street W. Nick , Polgreen Linnea A.
Published: April 2022

Background

While multiple randomized controlled trials (RCTs) are available, their results may not be generalizable to older, unhealthier or less-adherent patients. Observational data can be used to predict outcomes and evaluate treatments; however, exactly which strategy should be used to analyze the outcomes of treatment using observational data is currently unclear. This study aimed to determine the most accurate machine learning technique to predict 1-year-after-initial-acute-myocardial-infarction (AMI) survival of elderly patients and to identify the association of angiotensin-converting- enzyme inhibitors and angiotensin-receptor blockers (ACEi/ARBs) with survival.

Methods

We built a cohort of 124,031 Medicare beneficiaries who experienced an AMI in 2007 or 2008. For analytical purposes, all variables were categorized into nine different groups: ACEi/ARB use, demographics, cardiac events, comorbidities, complications, procedures, medications, insurance, and healthcare utilization. Our outcome of interest was 1-year-post-AMI survival. To solve this classification task, we used lasso logistic regression (LLR) and random forest (RF), and compared their performance depending on category selection, sampling methods, and hyper-parameter selection. Nested 10-fold cross-validation was implemented to obtain an unbiased estimate of performance evaluation. We used the area under the receiver operating curve (AUC) as our primary measure for evaluating the performance of predictive algorithms.

Results

LLR consistently showed best AUC results throughout the experiments, closely followed by RF. The best prediction was yielded with LLR based on the combination of demographics, comorbidities, procedures, and utilization. The coefficients from the final LLR model showed that AMI patients with many comorbidities, older ages, or living in a low-income area have a higher risk of mortality 1-year after an AMI. In addition, treating the AMI patients with ACEi/ARBs increases the 1-year-after-initial-AMI survival rate of the patients.

Conclusions

Given the many features we examined, ACEi/ARBs were associated with increased 1-year survival among elderly patients after an AMI. We found LLR to be the best-performing model over RF to predict 1-year survival after an AMI. LLR greatly improved the generalization of the model by feature selection, which implicitly indicates the association between AMI-related variables and survival can be defined by a relatively simple model with a small number of features. Some comorbidities were associated with a greater risk of mortality, such as heart failure and chronic kidney disease, but others were associated with survival such as hypertension, hyperlipidemia, and diabetes. In addition, patients who live in urban areas and areas with large numbers of immigrants have a higher probability of survival. Machine learning methods are helpful to determine outcomes when RCT results are not available.
Integrated delivery of family planning and childhood immunisation services: a mixed methods assessment of service responsiveness
Authors: Hamon Jessie K. , Kambanje Misozi , Pryor Shannon , Kaponda Alice S. , Mwale Erick , Burchett Helen E. D. , Mayhew Susannah H. , Webster Jayne
Published: April 2022

Background

Postpartum women represent a considerable share of the global unmet need for modern contraceptives. Evidence suggests that the integration of family planning (FP) with childhood immunisation services could help reduce this unmet need by providing repeat opportunities for timely contact with FP services. However, little is known about the clients’ experiences of FP services that are integrated with childhood immunisations, despite being crucial to contraceptive uptake and repeat service utilisation.

Methods

The responsiveness of FP services that were integrated with childhood immunisations in Malawi was assessed using cross-sectional convergent mixed methods. Exit interviews with clients (n=146) and audits (n=15) were conducted in routine outreach clinics. Responsiveness scores across eight domains were determined according to the proportion of clients who rated each domain positively. Text summary analyses of qualitative data from cognitive interviewing probes were also conducted to explain responsiveness scores. Additionally, Spearman rank correlation and Pearson’s chi-squared test were used to identify correlations between domain ratings and to examine associations between domain ratings and client, service and clinic characteristics.

Results

Responsiveness scores varied across domains: dignity (97.9%); service continuity (90.9%); communication (88.7%); ease of access (77.2%); counselling (66.4%); confidentiality (62.0%); environment (53.9%) and choice of provider (28.4%). Despite some low performing domains, 98.6% of clients said they would recommend the clinic to a friend or family member interested in FP. The choice of provider, communication, confidentiality and counselling ratings were positively associated with clients’ exclusive use of one clinic for FP services. Also, the organisation of services in the clinics and the providers’ individual behaviours were found to be critical to service responsiveness.

Conclusions

This study establishes that in routine outreach clinics, FP services can be responsive when integrated with childhood immunisations, particularly in terms of the dignity and service continuity afforded to clients, though less so in terms of the choice of provider, environment, and confidentiality experienced. Additionally, it demonstrates the value of combining cognitive interviewing techniques with Likert questions to assess service responsiveness.
Factors associated with willingness to receive a novel community care service for older people in Foshan, China: a cross-sectional study
Authors: Xie Fengjiao , Deng Aiwen , Chen Jianhao , Xiong Ribo
Published: April 2022

Background

In China, the majority of community care for older people is planned and offered in a few large cities. The provision of community care to the rural population is a new concept. This study aimed to assess the prevalence of willingness to receive a novel community care service that incorporates community rehabilitation among older people, and identify the possible factors influencing utilization willingness in Foshan, China.

Methods

A cross-sectional study was conducted involving 413 older people in Lishui county, China from January to March 2021. Trained staff interviewed older people using structured questionnaires. Multivariate logistic regression analysis was used to determine factors that were significantly associated with the willingness to receive this novel community care.

Results

The prevalence of willingness to receive community care for older people was 61.9% (n = 245) in Foshan, China. Older people who were living alone or living with spouses were about two times significantly more likely to receive community care compared to those living with children/others (OR = 2.19, 95%CI:2.44 ~ 3.19, OR = 2.015, 95%CI: 1.39 ~ 2.23, respectively). Older people who lived closer to the community care center were about two times significantly more likely to receive community care compared to those who lived far away (OR = 2.10, 95%CI: 1.61 ~ 2.41). Older people with activity of daily living disability were about three times significantly more likely to receive community care compared to those without a disability (OR = 3.13, 95%CI: 2.38 ~ 3.29).

Conclusions

A majority of rural older people were willing to receive this novel community care service that includes community rehabilitation. The findings suggest the need for policies and programs to not only improve the provision of this novel community care service but also promote its uptake among older people in the study setting.
Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6
Authors: Husain Mansoor , Consoli Agostino , De Remigis Alessandra , Pettersson Meyer Anna Sina , Rasmussen Søren , Bain Stephen
Published: April 2022

Background

Cardiovascular outcome trials (CVOTs) are conducted on a background of standard of care including metformin. These analyses sought to determine whether the cardiovascular (CV) effects of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RAs) vary according to baseline metformin use.

Methods

A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline. Additionally, a trial-level meta-analysis was conducted using data from seven CVOTs with GLP-1RAs–SUSTAIN 6, PIONEER 6, HARMONY OUTCOMES, LEADER, REWIND, EXSCEL and AMPLITUDE-O–including adults with type 2 diabetes at high CV risk, and a primary endpoint of time to first major adverse CV event (MACE).

Results

In the post hoc analysis, the no-metformin subgroup was older, with a higher body mass index, lower estimated glomerular filtration rate and higher CV risk at baseline vs the metformin subgroup. Hazard ratios (95% confidence intervals) for the reduction in risk of MACE with semaglutide vs placebo in the metformin and no-metformin subgroups were 0.70 (0.55;0.89) and 0.86 (0.60;1.22), respectively. No significant interaction between the treatment effect on MACE and metformin subgroup was observed. Findings for other CV endpoints were similar. In the meta-analysis, treatment effect (GLP-1RA vs placebo) on CV outcomes was no different with vs without baseline metformin (overall ratio between the hazard ratios for metformin vs no-metformin 1.09 [0.96;1.22]).

Conclusion

These findings indicate that the CV outcomes for semaglutide were similar regardless of baseline metformin use, which may also apply to all GLP-1RAs.

Trial registration SUSTAIN 6 (NCT01720446), PIONEER 6 (NCT02692716).
FGFR1 is a potential therapeutic target in neuroblastoma
Authors: Cimmino Flora , Montella Annalaura , Tirelli Matilde , Avitabile Marianna , Lasorsa Vito Alessandro , Visconte Feliciano , Cantalupo Sueva , Maiorino Teresa , De Angelis Biagio , Morini Martina , Castellano Aurora , Locatelli Franco , Capasso Mario , Iolascon Achille
Published: April 2022

Background

FGFR1regulates cell–cell adhesion and extracellular matrix architecture and acts as oncogene in several cancers. Potential cancer driver mutations ofFGFR1occur in neuroblastoma (NB), a neural crest-derived pediatric tumor arising in sympathetic nervous system, but so far they have not been studied experimentally. We investigated the driver-oncogene role ofFGFR1and the implication of N546K mutation in therapy-resistance in NB cells.

Methods

Public datasets were used to predict the correlation ofFGFR1expression with NB clinical outcomes. Whole genome sequencing data of 19 paired diagnostic and relapse NB samples were used to find somatic mutations. In NB cell lines, silencing by short hairpin RNA and transient overexpression ofFGFR1were performed to evaluate the effect of the identified mutation by cell growth, invasion and cologenicity assays. HEK293, SHSY5Y and SKNBE2 were selected to investigate subcellular wild-type and mutated protein localization. FGFR1 inhibitor (AZD4547), alone or in combination with PI3K inhibitor (GDC0941), was used to rescue malignant phenotypes induced by overexpression of FGFR1 wild-type and mutated protein.

Results

HighFGFR1expression correlated with low relapse-free survival in two independent NB gene expression datasets. In addition, we found the somatic mutation N546K, the most recurrent point mutation ofFGFR1in all cancers and already reported in NB, in one out of 19 matched primary and recurrent tumors. Loss ofFGFR1function attenuated invasion and cologenicity in NB cells, whereasFGFR1overexpression enhanced oncogenicity. The overexpression of FGFR1N546Kprotein showed a higher nuclear localization compared to wild-type protein and increased cellular invasion and cologenicity. Moreover, N546K mutation caused the failure in response to treatment with FGFR1 inhibitor by activation of ERK, STAT3 and AKT pathways. The combination of FGFR1 and PI3K pathway inhibitors was effective in reducing the invasive and colonigenic ability of cells overexpressing FGFR1 mutated protein.

Conclusions

FGFR1is an actionable driver oncogene in NB and a promising therapy may consist in targetingFGFR1mutations in patients with therapy-resistant NB.
Integrated regulation of chondrogenic differentiation in mesenchymal stem cells and differentiation of cancer cells
Authors: Yang Xiaohui , Tian Shifeng , Fan Linlin , Niu Rui , Yan Man , Chen Shuo , Zheng Minying , Zhang Shiwu
Published: April 2022

Chondrogenesis is the formation of chondrocytes and cartilage tissues and starts with mesenchymal stem cell (MSC) recruitment and migration, condensation of progenitors, chondrocyte differentiation, and maturation. The chondrogenic differentiation of MSCs depends on co-regulation of many exogenous and endogenous factors including specific microenvironmental signals, non-coding RNAs, physical factors existed in culture condition, etc. Cancer stem cells (CSCs) exhibit self-renewal capacity, pluripotency and cellular plasticity, which have the potential to differentiate into post-mitotic and benign cells. Accumulating evidence has shown that CSCs can be induced to differentiate into various benign cells including adipocytes, fibrocytes, osteoblast, and so on. Retinoic acid has been widely used in the treatment of acute promyelocytic leukemia. Previous study confirmed that polyploid giant cancer cells, a type of cancer stem-like cells, could differentiate into adipocytes, osteocytes, and chondrocytes. In this review, we will summarize signaling pathways and cytokines in chondrogenic differentiation of MSCs. Understanding the molecular mechanism of chondrogenic differentiation of CSCs and cancer cells may provide new strategies for cancer treatment.
Cancer-associated fibroblasts and resistance to anticancer therapies: status, mechanisms, and countermeasures
Authors: Feng Bing , Wu Jianzhong , Shen Bo , Jiang Feng , Feng Jifeng
Published: April 2022

Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment (TME) with diverse functions such as extracellular matrix (ECM) remodeling, modulation of metabolism and angiogenesis, and crosstalk with both cancer cells and infiltrating immune cells by production of growth factors, cytokines, and chemokines. Within the TME milieu, CAFs exhibit morphological and functional transitions with relatively specific markers and hold tremendous potential to facilitate tumorigenesis, development, and resistance towards multiple therapeutic strategies including chemotherapy, radiotherapy, targeted therapy, anti-angiogenesis therapy, immunotherapy, and endocrine therapy. Accordingly, CAFs themselves and the downstream effectors and/or signaling pathways are potential targets for optimizing the sensitivity of anti-cancer therapies. This review aims to provide a detailed landscape of the role that CAFs play in conferring therapeutic resistance in different cancers and the underlying mechanisms. The translational and therapeutic perspectives of CAFs in the individualized treatment of malignant tumors are also discussed.
Potential impacts of synthetic food dyes on activity and attention in children: a review of the human and animal evidence
Authors: Miller Mark D. , Steinmaus Craig , Golub Mari S. , Castorina Rosemary , Thilakartne Ruwan , Bradman Asa , Marty Melanie A.
Published: April 2022

Concern that synthetic food dyes may impact behavior in children prompted a review by the California Office of Environmental Health Hazard Assessment (OEHHA). OEHHA conducted a systematic review of the epidemiologic research on synthetic food dyes and neurobehavioral outcomes in children with or without identified behavioral disorders (particularly attention and activity). We also conducted a search of the animal toxicology literature to identify studies of neurobehavioral effects in laboratory animals exposed to synthetic food dyes. Finally, we conducted a hazard characterization of the potential neurobehavioral impacts of food dye consumption. We identified 27 clinical trials of children exposed to synthetic food dyes in this review, of which 25 were challenge studies. All studies used a cross-over design and most were double blinded and the cross-over design was randomized. Sixteen (64%) out of 25 challenge studies identified some evidence of a positive association, and in 13 (52%) the association was statistically significant. These studies support a relationship between food dye exposure and adverse behavioral outcomes in children. Animal toxicology literature provides additional support for effects on behavior. Together, the human clinical trials and animal toxicology literature support an association between synthetic food dyes and behavioral impacts in children. The current Food and Drug Administration (FDA) acceptable daily intakes are based on older studies that were not designed to assess the types of behavioral effects observed in children. For four dyes where adequate dose-response data from animal and human studies were available, comparisons of the effective doses in studies that measured behavioral or brain effects following exposure to synthetic food dyes indicate that the basis of the ADIs may not be adequate to protect neurobehavior in susceptible children. There is a need to re-evaluate exposure in children and for additional research to provide a more complete database for establishing ADIs protective of neurobehavioral effects.
Analysis of different domains of physical activity with health-related quality of life in adults: 2-year cohort
Authors: Scarabottolo Catarina Covolo , Tebar William Rodrigues , Gobbo Luis Alberto , Ohara David , Ferreira Aline Duarte , da Silva Canhin Daniel , Christofaro Diego Giulliano Destro
Published: April 2022

Background

It is estimated that, worldwide, 9% of deaths occur as a result of insufficient physical activity (PA) practice. Practicing PA can prevent and/or reduce the deleterious effects of different types of diseases and can improve general health aspects related to health-related quality of life (HRQoL).

Purpose

To analyze the relationship of different PA domains with different HRQoL domains over a two-year period.

Methods

This is an observational study with a two-year longitudinal design. The sample, composed of adults, was selected from a randomization of the streets of the different regions (north, south, east, west and center) covering individuals from all areas of the city. To assess the practice of PA, the Baecke questionnaire was used. The instrument Medical Outcomes Study SF-36-Item Short Form Health Survey was used to assess the HRQoL domains. Linear regression models were used to analyzed the association of different PA domains with changes in HRQoL. Multivariate statistical models were adjusted for gender, age, socioeconomic status, marital status, the respective PA score at baseline, smoking, body mass index, and morbidity.

Results

331 adults were evaluated. There was a decrease in the practice of PA in the occupational domain and an increase in the leisure/locomotion domain. Regarding HRQoL, there was an increase in the scores of body pain and mental health, and a decrease in scores of general health, vitality, social aspects and emotional aspects. The PA practice in the occupational domain was inversely related to functional capacity (β = − 7.2 [CI 95% − 13.0; − 1.4]). The practice of PA through sports in leisure time was positively associated with vitality (β = 5.5 [CI 95% 0.2; 10.7]) and mental health (β = 15.2 [CI 95% 6.8; 23.7]). PA practice during leisure and locomotion was inversely associated with functional capacity (β = − 5.68 [CI 95% − 10.7; − 0.6]) and positively associated with vitality β = 4.8 [CI 95% 0.8; 8.7]) and mental health (β = 8.4 [CI 95% 2.0; 14.9]). The total PA practice was inversely associated with functional capacity (β = − 3.8 [CI 95% − 6.5; − 1.2]) and positively associated with pain in the body (β = 4.9 [CI 95% 0.3; 9.4]), vitality (β = 2.9 [CI 95% 0.7; 5.0]) and mental health (β = 5.7 [CI 95% 2.2; 9.2]).

Conclusions

It is suggested that practicing PA continuously within a period of two years can positively affect some physical aspects and some mental aspects related to HRQoL, but not all of them. A strategy for public policy actions is to explore these variables by domain and thus detect the real needs and improvements that can be made for the population.
Macrophage-based delivery of interleukin-13 improves functional and histopathological outcomes following spinal cord injury
Authors: Van Broeckhoven Jana , Erens Céline , Sommer Daniela , Scheijen Elle , Sanchez Selien , Vidal Pia M. , Dooley Dearbhaile , Van Breedam Elise , Quarta Alessandra , Ponsaerts Peter , Hendrix Sven , Lemmens Stefanie
Published: April 2022

Background

Spinal cord injury (SCI) elicits a robust neuroinflammatory reaction which, in turn, exacerbates the initial mechanical damage. Pivotal players orchestrating this response are macrophages (Mφs) and microglia. After SCI, the inflammatory environment is dominated by pro-inflammatory Mφs/microglia, which contribute to secondary cell death and prevent regeneration. Therefore, reprogramming Mφ/microglia towards a more anti-inflammatory and potentially neuroprotective phenotype has gained substantial therapeutic interest in recent years. Interleukin-13 (IL-13) is a potent inducer of such an anti-inflammatory phenotype. In this study, we used genetically modified Mφs as carriers to continuously secrete IL-13 (IL-13 Mφs) at the lesion site.

Methods

Mφs were genetically modified to secrete IL-13 (IL-13 Mφs) and were phenotypically characterized using qPCR, western blot, and ELISA. To analyze the therapeutic potential, the IL-13 Mφs were intraspinally injected at the perilesional area after hemisection SCI in female mice. Functional recovery and histopathological improvements were evaluated using the Basso Mouse Scale score and immunohistochemistry. Neuroprotective effects of IL-13 were investigated using different cell viability assays in murine and human neuroblastoma cell lines, human neurospheroids, as well as murine organotypic brain slice cultures.

Results

In contrast to Mφs prestimulated with recombinant IL-13, perilesional transplantation of IL-13 Mφs promoted functional recovery following SCI in mice. This improvement was accompanied by reduced lesion size and demyelinated area. The local anti-inflammatory shift induced by IL-13 Mφs resulted in reduced neuronal death and fewer contacts between dystrophic axons and Mφs/microglia, suggesting suppression of axonal dieback. Using IL-4Rα-deficient mice, we show that IL-13 signaling is required for these beneficial effects. Whereas direct neuroprotective effects of IL-13 on murine and human neuroblastoma cell lines or human neurospheroid cultures were absent, IL-13 rescued murine organotypic brain slices from cell death, probably by indirectly modulating the Mφ/microglia responses.

Conclusions

Collectively, our data suggest that the IL-13-induced anti-inflammatory Mφ/microglia phenotype can preserve neuronal tissue and ameliorate axonal dieback, thereby promoting recovery after SCI.
Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies
Authors: Lu Yuting , Yuan Xiangliang , Wang Miao , He Zhihao , Li Hongzhong , Wang Ji , Li Qin
Published: April 2022

The gut microbiota have long been recognized to play a key role in human health and disease. Currently, several lines of evidence from preclinical to clinical research have gradually established that the gut microbiota can modulate antitumor immunity and affect the efficacy of cancer immunotherapies, especially immune checkpoint inhibitors (ICIs). Deciphering the underlying mechanisms reveals that the gut microbiota reprogram the immunity of the tumor microenvironment (TME) by engaging innate and/or adaptive immune cells. Notably, one of the primary modes by which the gut microbiota modulate antitumor immunity is by means of metabolites, which are small molecules that could spread from their initial location of the gut and impact local and systemic antitumor immune response to promote ICI efficiency. Mechanistic exploration provides novel insights for developing rational microbiota-based therapeutic strategies by manipulating gut microbiota, such as fecal microbiota transplantation (FMT), probiotics, engineered microbiomes, and specific microbial metabolites, to augment the efficacy of ICI and advance the age utilization of microbiota precision medicine.
Autologous hematopoietic stem cell transplantation promotes connective tissue remodeling in systemic sclerosis patients
Authors: Zanin-Silva Djúlio C. , Santana-Gonçalves Maynara , Kawashima-Vasconcelos Marianna Y. , Lima-Júnior João R. , Dias Juliana B. E. , Moraes Daniela A. , Covas Dimas T. , Malmegrim Kelen C. R. , Ramalho Leandra , Oliveira Maria Carolina
Published: April 2022

Background

Autologous hematopoietic stem cell transplantation (AHSCT) treats patients with severe and progressive systemic sclerosis (SSc). However, basic mechanisms associated with the therapeutic efficacy of the procedure are not entirely understood. We aimed to evaluate how AHSCT affects skin fibrosis in SSc patients.

Methods

Clinical data, serum, and skin samples from 39 SSc patients who underwent AHSCT were retrospectively evaluated. Skin biopsies were analyzed by immunohistochemistry with anti-MMP-1, -MMP-2, -MMP-3, -MMP-9, -TIMP-1, -α-SMA, -TGF-β, and -NF-κB p65 antibodies, and stained with hematoxylin and eosin and picrosirius red to assess skin thickness and collagen density, respectively. Serum samples were evaluated by Multiplex Assay for COL1A1, COL4A1, FGF-1, MMP-1, MMP-3, MMP-12, MMP-13, PDGF-AA, PDGF-BB, S100A9, and TIMP-1 levels and compared to healthy controls.

Results

After AHSCT, SSc patients showed clinical improvement in skin involvement, assessed by modified Rodnan’s skin score (mRSS). Histologically, collagen density and skin thickness decreased after AHSCT. Immunohistochemical analyses showed increased expression of MMP-2, MMP-3, MMP-9, and TIMP-1 after AHSCT, whereas expression of NF-κB p65 decreased. At baseline, serum levels of COL4A1 and S100A9 were higher than in healthy controls. Serum levels of S100A9 normalized after AHCST in SSc patients compared to controls. Serum levels of PDGF-AA, PDGF-BB, TIMP-1, and MMP-1 decreased, while COL1A1 increased after AHSCT in SSc patients. No changes were detected in MMP-3, MMP-12, MMP-13, and FGF-1 serum levels after AHSCT.

Conclusions

Our results suggest that the therapeutic effects of AHSCT on skin fibrosis are related to changes in molecules associated with connective tissue maintenance and inflammation in SSc.
Hyperspectral time series datasets of maize during the grain filling period
Authors: Craig Valerie , Earl Hugh , Sulik John , Lee Elizabeth A.
Published: April 2022

Objectives

Remotely sensed hyperspectral data are increasingly being used to assess crop development and growth throughout the growing season. Large datasets capturing key growth stages can be useful to researchers studying many physiological plant responses. A time series analysis of hyperspectral reflectance measurements taken during the grain filling period and published within a publicly accessible database are described herein. These datasets document the spectral reflectance pattern of the canopy within the visible and near-infrared portion of the electromagnetic spectrum during the late stages of the grain filling period as plants approach and reach physiological maturity.

Data description

Included within the data repository are canopy-level hyperspectral datasets collected in 2017 and 2018. Data is included in its raw form, as well as with several manipulations to smooth and standardize the raw data. Data are released as comma separated value spreadsheets as well as Microsoft Excel open XLSX spreadsheets. These are accompanied by README text files which further describe the data and supplemental files that record hybrids used and plant phenology for each year of data collection.
Batch-effect detection, correction and characterisation in Illumina HumanMethylation450 and MethylationEPIC BeadChip array data
Authors: Ross Jason P. , van Dijk Susan , Phang Melinda , Skilton Michael R. , Molloy Peter L. , Oytam Yalchin
Published: April 2022

Background

Genomic technologies can be subject to significant batch-effects which are known to reduce experimental power and to potentially create false positive results. The Illumina Infinium Methylation BeadChip is a popular technology choice for epigenome-wide association studies (EWAS), but presently, little is known about the nature of batch-effects on these designs. Given the subtlety of biological phenotypes in many EWAS, control for batch-effects should be a consideration.

Results

Using the batch-effect removal approaches in the ComBat and Harman software, we examined two in-house datasets and compared results with three large publicly available datasets, (1214 HumanMethylation450 and 1094 MethylationEPIC BeadChips in total), and find that despite various forms of preprocessing, some batch-effects persist. This residual batch-effect is associated with the day of processing, the individual glass slide and the position of the array on the slide. Consistently across all datasets, 4649 probes required high amounts of correction. To understand the impact of this set to EWAS studies, we explored the literature and found three instances where persistently batch-effect prone probes have been reported in abstracts as key sites of differential methylation. As well as batch-effect susceptible probes, we also discover a set of probes which are erroneously corrected. We provide batch-effect workflows for Infinium Methylation data and provide reference matrices of batch-effect prone and erroneously corrected features across the five datasets spanning regionally diverse populations and three commonly collected biosamples (blood, buccal and saliva).

Conclusions

Batch-effects are ever present, even in high-quality data, and a strategy to deal with them should be part of experimental design, particularly for EWAS. Batch-effect removal tools are useful to reduce technical variance in Infinium Methylation data, but they need to be applied with care and make use of post hoc diagnostic measures.
On the characterization of tidal ocean-dynamo signals in coastal magnetic observatories
Authors: Petereit Johannes , Saynisch-Wagner Jan , Morschhauser Achim , Pick Leonie , Thomas Maik
Published: April 2022

Periodic tidal ocean currents induce electric currents and, therefore, magnetic field signals that are observable using spaceborne and ground-based observation techniques. In theory, the signals can be used to monitor oceanic temperature and salinity variations. Tidal magnetic field amplitudes and phases have been extracted from magnetometer measurements in the past. However, due to uncertainties caused by a plentitude of influencing factors, the shape and temporal variation of these signals are only known to a limited extent. This study uses past extraction methods to characterize seasonal variations and long-term trends in the ten year magnetometer time series of three coastal island observatories. First, we assess data processing procedures used to prepare ground-based magnetometer observations for tidal ocean dynamo signal extraction to demonstrate that existing approaches, i.e., subtraction of core field models or first-order differencing, are unable to reliably remove low-frequency contributions. We hence propose low-frequency filtering using smoothing splines and demonstrate the advantages over the existing approaches. Second, we determine signal and side peak magnitudes of the M2 tide induced magnetic field signal by spectral analysis of the processed data. We find evidence for seasonal magnetic field signal variations of up to $$25\%$$

25
%

from the annual mean. Third, to characterize the long-term behavior of tidal ocean dynamo signal amplitudes and phases, we apply different signal extraction techniques to identify tidal ocean-dynamo signal amplitudes and phases in sub-series of the ten-year time series with incrementally increasing lengths. The analyses support three main findings: (1) trends cause signal amplitude changes of up to $$\approx 1~$$

≈
1

nT and phase changes are in the order of $${\mathcal {O}}(10^{\circ }$$

O
(

10
∘

) within the observation period; (2) at least four years of data are needed to obtain reliable amplitude and phase values with the extraction methods used and (3) signal phases are a less dependent on the chosen extraction method than signal amplitudes.

Graphical Abstract
nNav1.5 expression is associated with glutamate level in breast cancer cells
Authors: Azahar Irfan Irsyad , Sharudin Nur Aishah , Noor Din Ahmad Hafiz Murtadha , Che Has Ahmad Tarmizi , Mohd Nafi Siti Norasikin , Jaafar Hasnan , Mokhtar Noor Fatmawati
Published: April 2022

Background

Glutamate and voltage-gated sodium channels, both have been the target of intense investigation for its involvement in carcinogenesis and progression of malignant disease. Breast cancer with increased level of glutamate often metastasize to other organs (especially bone), whilst re-expression of ‘neonatal’ Nav1.5, nNav1.5 in breast cancer is known to promote cell invasion in vitro, metastasis in vivo and positive lymph node metastasis in patients.

Methods

In this study, the role of nNav1.5 in regulating glutamate level in human breast cancer cells was examined using pharmacological approach (VGSCs specific blocker, TTX, glutamate release inhibitor, riluzole and siRNA-nNav1.5). Effect of these agents were evaluated based on endogenous and exogenous glutamate concentration using glutamate fluorometric assay, mRNA expression of nNav1.5 using qPCR and finally, invasion using 3D culture assay.

Results

Endogenous and exogenous glutamate levels were significantly higher in aggressive human breast cancer cells, MDA-MB-231 cells compared to less aggressive human breast cancer cells, MCF-7 and non-cancerous human breast epithelial cells, MCF-10A. Treatment with TTX to MDA-MB-231 cells resulted in significant reduction of endogenous and exogenous glutamate levels corresponded with significant suppression of cell invasion. Subsequently, downregulation of nNav1.5 gene was observed in TTX-treated cells.

Conclusions

An interesting link between nNav1.5 expression and glutamate level in aggressive breast cancer cells was detected and requires further investigation.