bluuebunny/crossref_metadata_2025 huggingface dataset:
OLMALINC/OCT4/BMP2 axis enhances osteogenic-like phenotype of renal interstitial fibroblasts to participate in Randall’s plaque formation
Authors: Zhu Zewu , Huang Fang , Jiang Yingcheng , Ruan Shuhao , Liu Minghui , Zhang Youjie , Li Yongchao , Chen Jinbo , Cui Yu , Chen Zhiyong , Chen Hequn , Zeng Feng
Published: December 2022

Background

Randall’s plaques (RP) are identified as anchored sites for kidney calcium oxalate stones, but the mechanism remains unclear. Given the importance of osteogenic-like cells in RP formation and OCT4 in reprogramming differentiated cells to osteoblasts, the current study explored the potential role of OCT4 in RP formation.

Methods

OCT4 and biomineralization were evaluated in RP, and immunofluorescence co-staining was performed to identify these cells with alteration of OCT4 and osteogenic markers. Based on the analysis of tissue, we further investigated the mechanism of OCT4 in regulating osteogenic-like differentiation of primary human renal interstitial fibroblasts (hRIFs) in vitro and vivo.

Results

We identified the upregulated OCT4 in RP, with a positive correlation to osteogenic markers. Interestingly, fibroblast marker Vimentin was partially co-localized with upregulated OCT4 and osteogenic markers in RP. Further investigations revealed that OCT4 significantly enhanced the osteogenic-like phenotype of hRIFs in vitro and in vivo. Mechanically, OCT4 directly bound to BMP2 promoter and facilitated its CpG island demethylation to transcriptionally promote BMP2 expression. Furthermore, combination of RIP and RNA profiling uncovered that lncRNA OLMALINC physically interacted with OCT4 to promote its stabilization via disrupting the ubiquitination. Additionally, OLMALINC was upregulated in fibroblasts in RP visualized by FISH, and a positive correlation was revealed between OLMALINC and OCT4 in RP.

Conclusions

The upregulation of OCT4 in hRIFs was a pathological feature of RP formation, and OLMALINC/OCT4/BMP2 axis facilitated hRIFs to acquire osteogenic-like phenotype under osteogenic conditions, through which the pathway might participate in RP formation. Our findings opened up a new avenue to better understand RP formation in which osteogenic-like process was partially triggered by lncRNAs and pluripotency maintenance related genes.
Molecular machineries of ciliogenesis, cell survival, and vasculogenesis are differentially expressed during regeneration in explants of the demosponge Halichondria panicea
Authors: Riesgo Ana , Santodomingo Nadia , Koutsouveli Vasiliki , Kumala Lars , Leger Michelle M. , Leys Sally P. , Funch Peter
Published: December 2022

Sponges are interesting animal models for regeneration studies, since even from dissociated cells, they are able to regenerate completely. In particular, explants are model systems that can be applied to many sponge species, since small fragments of sponges can regenerate all elements of the adult, including the oscula and the ability to pump water. The morphological aspects of regeneration in sponges are relatively well known, but the molecular machinery is only now starting to be elucidated for some sponge species. Here, we have used an explant system of the demosponge Halichondria panicea to understand the molecular machinery deployed during regeneration of the aquiferous system. We sequenced the transcriptomes of four replicates of the 5–day explant without an osculum (NOE), four replicates of the 17–18–day explant with a single osculum and pumping activity (PE) and also four replicates of field–collected individuals with regular pumping activity (PA), and performed differential gene expression analysis. We also described the morphology of NOE and PE samples using light and electron microscopy. Our results showed a highly disorganised mesohyl and disarranged aquiferous system in NOE that is coupled with upregulated pathways of ciliogenesis, organisation of the ECM, and cell proliferation and survival. Once the osculum is formed, genes involved in “response to stimulus in other organisms” were upregulated. Interestingly, the main molecular machinery of vasculogenesis described in vertebrates was activated during the regeneration of the aquiferous system. Notably, vasculogenesis markers were upregulated when the tissue was disorganised and about to start forming canals (NOE) and angiogenic stimulators and ECM remodelling machineries were differentially expressed once the aquiferous system was in place (PE and PA). Our results are fundamental to better understanding the molecular mechanisms involved in the formation of the aquiferous system in sponges, and its similarities with the early onset of blood-vessel formation in animal evolution.
A young patient with heart failure was diagnosed with extra-adrenal paraganglioma: a case report
Authors: Zhang Jing , Cao Lihua , Yan Lina , Jin Cong , Zhang Dan
Published: December 2022

Background

We present a case of pelvic paraganglioma that presented with heart failure as the primary symptom.

Case presentation

A 35-year-old man was admitted to hospital due to heart failure. Contrast-enhanced pelvic CT showed mass shadows in the posterior wall of the bladder and multiple enlarged lymph nodes in the retroperitoneal area. Ultrasound-guided puncture was performed, and the pathologic diagnosis was extra-adrenal paraganglioma. The patient refused any chemotherapy and died within six months of diagnosis.

Conclusion

The possibility of neuroendocrine-related tumors, for example paragangliomas, should be considered in young patients with heart failure, especially those with concomitant hypertension and diabetes.
Acremonium (Sarocladium) periprosthetic joint infection: case report, literature review, and proposed antifungal regimen
Authors: Tabliago Nikko Rowe A. , Maish David , Martinez Raquel M. , Shelly Mark A. , Yablonski Bridget , Kwon Taesung
Published: December 2022

Background

Fungal periprosthetic joint infections are rare. Acremonium osteoarticular infections are scarcely reported. Variable susceptibility to antifungal agents have been reported and optimal pharmacotherapy has yet to be established. Here we illustrate an Acremonium osteoarticular infection involving a prosthetic joint and present an antifungal regimen that had led to treatment success.

Case presentation

A 60-year-old female with a body mass index (BMI) of 40 had left total knee arthroplasty done in 2012 with a cementless implant for knee osteoarthritis. In 2019, the patient had asymptomatic, progressive osteolysis with fracture and migration of the femoral component warranting replacement. Eleven months later, the patient developed significant pain, redness, and swelling in the left leg and knee concerning for periprosthetic joint infection that failed outpatient antibiotic treatment. Further investigation revealed infection by Acremonium species. A revision of the joint was successfully completed, and the patient was placed on voriconazole for one year. Subsequent cultures did not yield any fungal growth.

Conclusion

While an optimal antifungal regimen for periprosthetic joint infections has not been well established, voriconazole is a relatively safe and effective agent that can be used as a long-term therapy. With variable susceptibility testing in reported isolates, individualized antifungal susceptibility should be used to guide therapy for Acremonium infections.
Bacteremia and adrenal gland abscess due to Nocardia cyriacigeorgica: a case report and review
Authors: Saunier Florian , Grange Sylvain , Rigaill Josselin , Lutz Marie-France , Gagneux-Brunon Amandine , Botelho-Nevers Elisabeth
Published: December 2022

Background

Nocardia cyriacigeorgica is one of the most common Nocardia species found in human infections, recently reclassified. Even though Nocardia may affect all organs by hematogenous dissemination, bacteremia are uncommon. Among all possible dissemination sites, the involvement of the adrenal glands is particularly rare.

Case presentation

We report here a rare case of Nocardia disseminated infection with notably bacteremia and adrenal gland abscess, in a 77-years-old immunocompetent man. Adrenal gland abscess diagnosis was made by imaging (computerized tomography, magnetic resonance and positron emission tomography scan). A complete regression of all lesions including the left adrenal gland was obtained after 6 months of antibiotics. A review of literature was also performed.

Conclusion

Nocardia bacteremia is a rare event but blood cultures may help to improve detection of Nocardia spp. in a non-invasive way. Adrenal abscess due to Nocardia spp. is very rare with only fourteen cases reported in the literature, but it is a true cause of adrenal masses. Our report suggests that clinician should be aware of this rare location and prioritize a non-invasive diagnosis strategy.
The influence of day 3 embryo cell number on the clinical pregnancy and live birth rates of day 5 single blastocyst transfer from frozen embryo transfer cycles
Authors: Wang Jie , Diao Zhenyu , Fang Junshun , Zhu Lihua , Xu Zhipeng , Lin Fei , Zhang Ningyuan , Chen Linjun
Published: December 2022

Background

To evaluate the influence of day 3 embryo cell number on the clinical pregnancy and live birth rates of day 5 single blastocyst transfer in frozen embryo transfer (FET) cycles.

Methods

Our retrospective study included 3761 day 5 single blastocyst FET cycles between January 2015 and December 2019. These FET cycles were divided into three groups according to the day 3 embryo cell number: 939 cycles in the < 8-cell group, 1224 cycles in the 8-cell group and 1598 cycles in the > 8-cell group. The clinical pregnancy and live birth rates were compared among the three groups.

Results

The clinical pregnancy rate of day 5 single blastocyst transfer in FET cycles increased significantly as the day 3 embryo cell number increased (52.2%, 61.4% and 66.8%, P < 0.001). Similarly, the live birth rate increased significantly as the day 3 embryo cell number increased (42.7%, 49.8% and 54.9%, P < 0.001). The results of the subgroup analysis showed that the clinical pregnancy and live birth rates were not significantly different among the three groups when good-quality blastocysts were transferred. The clinical pregnancy and live birth rates increased significantly as the day 3 embryo cell number increased when fair- and poor-quality blastocysts were transferred.

Conclusion

The day 3 embryo cell number needs to be considered when day 5 single blastocyst transfer is performed in FET cycles, especially when fair- and poor-quality blastocysts are used for transfer. The transfer of a day 5 single blastocyst derived from an embryo with faster development on day 3 may shorten the time to achieving a live birth.
Effects of intraocular lens anterior edge design on anterior capsule morphology changes following femtosecond laser-assisted capsulotomy
Authors: Liu Qian , Zhang Suhua , Wang Xiaogang , Liu Jianting , Zhou Guohong , Yuan Xiaoyong
Published: December 2022

Purpose

To compare morphological changes in the anterior capsule of two intraocular lenses (IOLs) with different anterior edge designs 6 months after femtosecond laser-assisted capsulotomy surgery (FLACs).

Methods

This study included 168 eyes from168 patients undergoing FLACs. Group A included 74 eyes from 74 patients who had an Acrysof IQ Restor SN6AD3 IOL implantation with a flat anterior edge and Group B included 94 eyes of 94 patients with a TECNIS Multifocal ZMB00 IOL implantation and a "peak-like" anterior edge. All patients were followed up for 6 months. We assessed anterior capsule morphological changes including variation of anterior opening diameters and lens epithelial cell (LEC) proliferation in four directions, variation of anterior opening area, and the level of anterior capsule opacification (ACO).

Results

Variation of anterior opening diameters in 4 directions were significantly lower in Group B (P < 0.05). Obvious shrinkage ratio of anterior opening diameters and contraction of anterior opening area (P < 0.05) appeared in Group A. LEC proliferation was along the "peak" in Group B, while it spread to the edge of anterior capsule in Group A. ACO grades 6 months after operation in Groups A and B were as follows: grade I in 28.38% and 82.98% of eyes, grade II in 51.35% and 17.02% of eyes, and grade III in 20.27% and 0% of eyes, respectively.

Conclusions

These findings suggest that a "peak-like" IOL anterior edge design played an important role in maintaining the morphology of anterior capsule in the early postoperative stage.
Somatic symptoms mediate the association between subclinical anxiety and depressive symptoms and its neuroimaging mechanisms
Authors: Kong Zhifei , Zhu Ximei , Chang Suhua , Bao Yanping , Ma Yundong , Yu Wenwen , Zhu Ran , Sun Qiqing , Sun Wei , Deng Jiahui , Sun Hongqiang
Published: December 2022

Background

Subclinical anxiety, depressive and somatic symptoms appear closely related. However, it remains unclear whether somatic symptoms mediate the association between subclinical anxiety and depressive symptoms and what the underlying neuroimaging mechanisms are for the mediating effect.

Methods

Data of healthy participants (n = 466) and participants in remission of major depressive disorder (n = 53) were obtained from the Human Connectome Project. The Achenbach Adult Self-Report was adopted to assess anxiety, depressive and somatic symptoms. All participants completed four runs of resting-state functional magnetic resonance imaging. Mediation analyses were utilized to explore the interactions among these symptoms and their neuroimaging mechanisms.

Results

Somatic symptoms partially mediated the association between subclinical anxiety and depressive symptoms in healthy participants (anxiety→somatic→depression: effect: 0.2785, Boot 95% CI: 0.0958–0.3729; depression→somatic→anxiety: effect: 0.0753, Boot 95% CI: 0.0232–0.1314) and participants in remission of MDD (anxiety→somatic→depression: effect: 0.2948, Boot 95% CI: 0.0357–0.7382; depression→somatic→anxiety: effect: 0.0984, Boot 95% CI: 0.0007–0.2438). Resting-state functional connectivity (FC) between the right medial superior frontal gyrus and the left thalamus and somatic symptoms as chain mediators partially mediated the effect of subclinical depressive symptoms on subclinical anxiety symptoms in healthy participants (effect: 0.0020, Boot 95% CI: 0.0003–0.0043). The mean strength of common FCs of subclinical depressive and somatic symptoms, somatic symptoms, and the mean strength of common FCs of subclinical anxiety and somatic symptoms as chain mediators partially mediated the effect of subclinical depressive symptoms on subclinical anxiety symptoms in remission of MDD (effect: 0.0437, Boot 95% CI: 0.0024–0.1190). These common FCs mainly involved the insula, precentral gyri, postcentral gyri and cingulate gyri. Furthermore, FC between the triangular part of the left inferior frontal gyrus and the left postcentral gyrus was positively associated with subclinical anxiety, depressive and somatic symptoms in remission of MDD (FDR-corrected p < 0.01).

Conclusions

Somatic symptoms partially mediate the interaction between subclinical anxiety and depressive symptoms. FCs involving the right medial superior frontal gyrus, left thalamus, triangular part of left inferior frontal gyrus, bilateral insula, precentral gyri, postcentral gyri and cingulate gyri maybe underlie the mediating effect of somatic symptoms.
Evaluation of a public COVID-19 dashboard in the Western Cape, South Africa: a tool for communication, trust, and transparency
Authors: Ismail Muzzammil , Morden Erna , Hussey Hannah , Paleker Masudah , Jacobs Theuns , Laenen Inneke , Hunter Mehreen , Moodley Melvin , Smith Mariette , Mutemaringa Themba , Bam Jamy-Lee , Dane Pierre , Heekes Alexa , Boulle Andrew , Davies Mary-Ann
Published: December 2022

Background

Public health dashboards have been used in the past to communicate and guide local responses to outbreaks, epidemics, and a host of various health conditions. During the first year of the COVID-19 pandemic, dashboards proliferated but the availability and quality differed across the world. This study aimed to evaluate the quality, access, and end-user experience of one such dashboard in the Western Cape province, South Africa.

Methods

We analysed retrospective aggregate data on viewership over time for the first year since launch of the dashboard (30 April 2020 – 29 April 2021) and conducted a cross-sectional survey targeting adult users of the dashboard at one year post the initial launch. The self-administered, anonymous questionnaire with a total of 13 questions was made available via an online digital survey tool for a 2-week period (6 May 2021 – 21 May 2021).

Results

After significant communication by senior provincial political leaders, adequate media coverage and two waves of COVID-19 the Western Cape public COVID-19 dashboard attracted a total of 2,248,456 views during its first year. The majority of these views came from Africa/South Africa with higher median daily views during COVID-19 wave periods. A total of 794 participants responded to the survey questionnaire. Reported devices used to access the dashboard differed statistically between occupational status groups with students tending toward using mobile devices whilst employed and retired participants tending toward using desktop computers/laptops. Frequency of use increases with increasing age with 65.1% of those > 70 years old viewing it daily. Overall, 76.4% of respondents reported that the dashboard influenced their personal planning and behaviour. High Likert score ratings were given for clarity, ease of use and overall end-user experience, with no differences seen across the various age groups surveyed.

Conclusion

The study demonstrated that both the availability of data and an understanding of end-user need is critical when developing and delivering public health tools that may ultimately garner public trust and influence individual behaviour.
The Localization, development and validation of a survey instrument to assess attitudes toward professionalism based on the opinions of clinical teachers
Authors: Hosseinizadeh Adeleh , Shakour Mahsa , Afshar Leila
Published: December 2022

Background

This study examined the validation of a survey instrument to assess attitudes toward professionalism based on the opinions of clinical teachers in Iran and localized it.

Methods

The research is applied-descriptive, that is conducted in two stages: qualitative and quantitative. Fifteen expert professors in the field of professionalism from Iranian universities of medical sciences participated in qualitative stage by Delphi. sampling method was purposive. In the quantitative stage, using simple and quota sampling method, 82 samples were collected from all clinical professors of first ranked universities of medical sciences. We used “The Penn State College of Medicine Professionalism Questionnaire”( PSCOM) as a basic questionnaire. Its validity assessed by Delphi and survey. Some items changed, deleted and added. Then it confirmed by confirmatory factor analysis.

Data analysis was performed using one-sample t-test and SmartPLS software.

Results

Seven dimensions and 48 final indicators were approved and all 7 dimensions were in good condition. Among the approved dimensions, “the enrichment” with a factor load of 0.238, was the biggest factor in measuring the variable of professionalism. The dimensions of “respect”, “responsibility”, “altruism”, “duty”, “honor, honesty and justice”, “respectively” with factor loads of 0.215, 0.212, 0.163, 0.146, 0.106 and 0.047 are ranked in order.

Conclusion

the most dimensions in PSCOM are accepted by experts and teachers, but there are many differences in details. If we want to have an accurate tool for measuring attitudes toward professionalism, then, it is necessary to study localization and validation of instrument to assess attitudes toward professionalism in every new community. Delphi and factor analysis could be useful for assessing tool in new community.
Relationship between high fructose corn syrup sweetened drinks, diet soft drinks, and serum sodium: NHANES 2003–2006
Authors: Li Mingxi , Gong Weijun , Wang Shidong , Li Zhe
Published: December 2022

Background

Consumption of high fructose corn syrup sweetened drinks and diet soft drinks has increased in the United States. However, the relationship between the intake of high fructose corn syrup sweetened drinks and diet soft drinks, and serum sodium has been scarcely studied. Our objective is to evaluate the relation between intake of high fructose corn syrup sweetened drinks and diet soft drinks, and serum sodium, and explore the possible effect modifiers in a nationally representative sample of adults from the United States.

Methods

We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey 2003–2006. The study participants included 6989 adults aged ≥18 years. Using survey-weighted generalized linear regression analyses, we investigated the relationship between high fructose corn syrup sweetened drink, diet soft drink consumption, and serum sodium. Consumption of high fructose corn syrup sweetened drinks and diet soft drinks was evaluated through a food-frequency questionnaire.

Results

Serum sodium levels increased as high fructose corn syrup sweetened drink intake increased. Serum sodium levels were higher in participants in the highest high fructose corn syrup sweetened drink consumption quantile, compared with those in the lowest high fructose corn syrup sweetened drink intake quantile (p = 0.020). The multivariate betas for serum sodium, according to the corresponding high fructose corn syrup sweetened drink intake quantiles, were 0.16, 0.19, and 0.21, respectively (P for trend = 0.051). We found no relationship between diet soft drink consumption and serum sodium after adjustment of confounding. (multivariate P > 0.05).

Conclusion

There was a a step-wise increase in serum sodium concentration with increasing consumption of HFCS sweetened beverages. Even moderate HFCS sweetened soft drink intake was associated with an elevated serum sodium level - a risk factor for hypertension.
Catastrophic pharmaceutical expenditure in patients with type 2 diabetes in Iran
Authors: Zarei Leila , Moradi Najmeh , Peiravian Farzad , Hatami-Mazinani Nazafarin , Mahi-Birjand Motahareh , Arabloo Jalal , Babar Zaheer-Ud-Din
Published: December 2022

Objectives

This study aimed to assess the financial burden of out-of-pocket (OOP) payments to purchase antidiabetic medicines for type 2 patients in Iran.

Method

The “budget share” and “capacity to pay” approaches were employed to assess the catastrophic pharmaceutical expenditures of antidiabetic medication therapies. The catastrophic thresholds were adjusted for pharmaceutical sectors. The data was 2019 monthly household expenditures in rural and urban areas, insurance coverages of antidiabetic medicines and patients' out-of-pocket (OOP) payments in 30-day treatment schedules.

Results

The results show that expenditure on diabetes medication therapies in the form of mono-dual therapy and some cases triple oral therapies were not catastrophic even for rural households. Insulin puts patients at risk of catastrophic pharmaceutical expenditures when added to the treatment schedules, and lack of financial protection intensifies it. In general, the poorer households and those resistant to first-line treatments were at increased risk of catastrophic pharmaceutical expenditures. The number of treatments that put patients at risk of catastrophic pharmaceutical expenditure in "budget share" was higher than the "capacity to pay" approach.

Conclusions

Assessing medication treatment affordability instead of a single medicine assessment is needed. Assessment could be done by utilizing a macro-level data approach and applying adjusted pharmaceutical sector threshold values. Considering the variation between treatment schedules that put patients at risk of catastrophic pharmaceutical expenditures, targeted pharmaceutical policies and reimbursement decisions are recommended to promote Universal Health Coverage (UHC) and to protect vulnerable populations from hardship.
Prenatal exposure to heavy metal mixtures and anthropometric birth outcomes: a cross-sectional study
Authors: Michael Tal , Kohn Elkana , Daniel Sharon , Hazan Ariela , Berkovitch Matitiahu , Brik Anna , Hochwald Ori , Borenstein-Levin Liron , Betser Moshe , Moskovich Miki , Livne Ayelet , Keidar Rimona , Rorman Efrat , Groisman Luda , Weiner Zeev , Rabin Adi Malkoff , Solt Ido , Levy Amalia
Published: December 2022

Background

Numerous studies have suggested significant associations between prenatal exposure to heavy metals and newborn anthropometric measures. However, little is known about the effect of various heavy metal mixtures at relatively low concentrations. Hence, this study aimed to investigate associations between prenatal exposures to a wide range of individual heavy metals and heavy metal mixtures with anthropometric measures of newborns.

Methods

We recruited 975 mother–term infant pairs from two major hospitals in Israel. Associations between eight heavy metals (arsenic, cadmium, chromium, mercury, nickel, lead, selenium, and thallium) detected in maternal urine samples on the day of delivery with weight, length, and head circumference at birth were estimated using linear and Bayesian kernel machine regression (BKMR) models.

Results

Most heavy metals examined in our study were observed in lower concentrations than in other studies, except for selenium. In the linear as well as the BKMR models, birth weight and length were negatively associated with levels of chromium. Birth weight was found to be negatively associated with thallium and positively associated with nickel.

Conclusion

By using a large sample size and advanced statistical models, we could examine the association between prenatal exposure to metals in relatively low concentrations and anthropometric measures of newborns. Chromium was suggested to be the most influential metal in the mixture, and its associations with birth weight and length were found negative. Head circumference was neither associated with any of the metals, yet the levels of metals detected in our sample were relatively low. The suggested associations should be further investigated and could shed light on complex biochemical processes involved in intrauterine fetal development.
Responses of the tree peony (Paeonia suffruticosa, Paeoniaceae) cultivar ‘Yu Hong’ to heat stress revealed by iTRAQ-based quantitative proteomics
Authors: Ma Jin , Wang Qun , Wei Ling-Ling , Zhao Yu , Zhang Guo-Zhe , Wang Jie , Gu Cui-Hua
Published: December 2022

Horticulture productivity has been increasingly restricted by heat stress from growing global warming, making it far below the optimum production capacity. As a popular ornamental cultivar of tree peony, Paeonia suffruticosa ‘Yu Hong’ has also been suffering from heat stress not suitable for its optimal growth. To better understand the response mechanisms against heat stress of tree peony, investigations of phenotypic changes, physiological responses, and quantitative proteomics were conducted. Phenotypic and physiological changes indicated that 24 h of exposure to heat stress (40 °C) was the critical duration of heat stress in tree peony. The proteomic analyses revealed a total of 100 heat-responsive proteins (HRPs). According to bioinformatic analysis of HRPs, the heat tolerance of tree peony might be related to signal transduction, synthesis/degradation, heat kinetic proteins, antioxidants, photosynthesis, energy conversion, and metabolism. Our research will provide some new insights into the molecular mechanism under the response against the heat stress of tree peony, which will benefit the future breeding of heat-resistant ornamental plants.
Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials
Authors: Bellerba Federica , Chatziioannou Anastasia Chrysovalantou , Jasbi Paniz , Robinot Nivonirina , Keski-Rahkonen Pekka , Trolat Amarine , Vozar Béatrice , Hartman Sheri J. , Scalbert Augustin , Bonanni Bernardo , Johansson Harriet , Sears Dorothy D. , Gandini Sara
Published: December 2022

Background

Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment.

Methods

Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC–QTOF-MS metabolomics, targeted LC–MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment.

Results

Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism.

Conclusions

Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies.

Trial registration

ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.
Interleukin-3 is associated with sTREM2 and mediates the correlation between amyloid-β and tau pathology in Alzheimer’s disease
Authors: Wang Zhi-Bo , Ma Ya-Hui , Sun Yan , Tan Lan , Wang Hui-Fu , Yu Jin-Tai ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

Background

Dysfunction of glial cell communication is involved in Alzheimer’s disease (AD) pathogenesis, and the recent study reported that astrocytic secreted interleukin-3 (IL-3) participated in astrocyte–microglia crosstalk and restricted AD pathology in mice, but the effect of IL-3 on the pathological progression of AD in human is still unclear.

Methods

A total of 311 participants with cerebrospinal fluid (CSF) IL-3, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and AD biomarkers were included from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We assessed the associations of IL-3 with sTREM2 and AD biomarkers at baseline, and with cognitive change in longitudinal study. The mediation models were used to explore the potential mechanism of how IL-3 affects AD pathology.

Results

We found that CSF IL-3 was significantly associated with CSF sTREM2 and CSF AD core biomarkers (Aβ42, p-tau, and t-tau) at baseline, and was also markedly related to cognitive decline in longitudinal analysis. Moreover, mediation analysis revealed that CSF IL-3 modulated the level of CSF sTREM2 and contributed to tau pathology (as measured by CSF p-tau/t-tau) and subsequent cognitive decline. In addition, Aβ pathology (as measured by CSF Aβ42) affected the development of tau pathology partly by modifying the levels of CSF IL-3 and CSF sTREM2. Furthermore, the effect of Aβ pathology on cognitive decline was partially mediated by the pathway from CSF IL-3 and CSF sTREM2 to tau pathology.

Conclusions

Our findings provide evidence to suggest that IL-3 is linked to sTREM2 and mediates the correlation between Aβ pathology to tau pathology. It indicates that IL-3 may be a major factor in the spreading from Aβ pathology to tau pathology to cognitive impairment.
Immune checkpoint blockade PD-1 therapy for primary liver cancer: incidence and influencing factors of thyroid dysfunction
Authors: Wu Huili , Xiong Fang , Bao Xuli , Lu Jun
Published: December 2022

Objectives

To investigate the incidence and influencing factors of thyroid dysfunction (TD) in patients with primary liver cancer (PLC) induced by PD-1 monoclonal antibodies.

Methods

Clinical data were collected from 195 PLC patients treated with PD-1. They were divided into TD group and normal thyroid function (NTF) group, and further divided into TD subgroups, the differences between groups and subgroups were analyzed.

Results

A total of 113 of 195 (57.9%) PLC patients developed TD. The positive rate of thyroid antibody (20.6% vs. 0%, P = 0.041) and the median value of TSH (6.20 vs. 2.16 mU/L, P = 0.000) in TD group were higher than those in NTF group. Ten patients (8.8%) had the CTCAE grade of TD above grade 3, of which 2 patients died of liver failure. There were 20 patients (17.7%) in hyperthyroidism group and 93 patients (82.3%) in hypothyroidism group. The decompensated cirrhosis in hyperthyroidism group was lower than that in hypothyroidism group (33.3% vs. 65.6%, P = 0.010), and the proportion of patients who had previously received surgical treatment was higher than that in hypothyroidism group (35.0% vs. 9.7%, P = 0.003); The proportion of clinical hyperthyroidism was higher than that of clinical hypothyroidism (70.0% vs. 31.2%, P = 0.001), the proportion of decompensated liver cirrhosis in clinical hyperthyroidism group was lower than that in clinical hypothyroidism group (23.1% vs. 68.0%, P = 0.022), and the proportion of previous or combined surgical resection was much higher than that in clinical hypothyroidism group (42.9% vs. 7.1%, P = 0.018); The proportion of decompensated cirrhosis in primary TD group was lower than that in secondary TD group (36.5% vs. 83.3%, P = 0.002), and the proportion of patients using antitumor targeted drugs was higher than that in secondary TD group (73.1% vs. 45.0%, P = 0.014).

Conclusion

Patients with PLC had high incidence of TD after receiving PD-1 treatment, primary or subclinical hypothyroidism was the main manifestation type, which was related to the degree of disease and treatment.
Correlation between intracranial pressure monitoring for severe traumatic brain injury with hospital length of stay and discharge disposition: a retrospective observational cohort study
Authors: Foote Christopher W. , Jarvis Stephanie , Doan Xuan-Lan , Guice Jordan , Cruz Bianca , Vanier Cheryl , Betancourt Alejandro , Bar-Or David , Palacio Carlos H.
Published: December 2022

Objectives

Intracranial pressure (ICP) monitoring is recommended for severe traumatic brain injuries (TBI) but some data suggests it may not improve outcomes. The objective was to investigate the effect of ICP monitoring among TBI.

Methods

This retrospective observational cohort study (1/1/2015–6/1/2020) included severe TBI patients. Outcomes [discharge destination, length of stay (LOS)] were compared by ICP monitoring and were stratified by GCS (3 vs. 4–8), α < 0.05.

Results

Of the123 patients who met inclusion criteria, 47% received ICP monitoring. There were baseline differences in the two groups characteristics, ICP monitored patients were younger (p = 0.02), had a subarachnoid hemorrhage less often (p = 0.04), and a subdural hematoma more often (p = 0.04) than those without ICP monitors. ICP monitored patients had a significantly longer median LOS (12 vs. 3, p < 0.01) than patients without monitoring. There was a trend towards more ICP monitored patients discharged home (40% vs. 23%, p = 0.06). Among patients with GCS = 3, ICP monitored patients had a longer LOS (p < 0.01) with no significant differences in discharge destinations. For those with a GCS of 4–8, ICP monitoring was associated with a longer LOS (p = 0.01), but fewer were discharged to a skilled nursing facility or long-term care (p = 0.01).

Conclusions

For TBI patients, ICP monitoring was associated with an increased LOS, with no significant differences in discharge destinations when compared to those without ICP monitoring. However, among only those with a GCS of 4–8, ICP monitoring was associated with a decreased proportion of patients discharged to a skilled nursing facility or long-term acute care .
Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner
Authors: Papadakos Konstantinos S. , Ekström Alexander , Slipek Piotr , Skourti Eleni , Reid Steven , Pietras Kristian , Blom Anna M.
Published: December 2022

Background

Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor.

Methods

In a syngeneic mouse model of breast cancer, tumors expressing SUSD4 had a smaller volume compared with the corresponding mock control tumors. Additionally, data from three different expression databases and online analysis tools confirm that for breast cancer patients, high mRNA expression of SUSD4 in the tumor tissue correlates with a better prognosis. In vitro experiments utilized triple-negative breast cancer cell lines (BT-20 and MDA-MB-468) stably expressing SUSD4. Moreover, we established a cell line based on BT-20 in which the gene for EGFR was knocked out with the CRISPR-Cas9 method.

Results

We discovered that the Epithelial Growth Factor Receptor (EGFR) interacts with SUSD4. Furthermore, triple-negative breast cancer cell lines stably expressing SUSD4 had higher autophagic flux. The initiation of autophagy required the expression of EGFR but not phosphorylation of the receptor. Expression of SUSD4 in the breast cancer cells led to activation of the tumor suppressor LKB1 and consequently to the activation of AMPKα1. Finally, autophagy was initiated after stimulation of the ULK1, Atg14 and Beclin-1 axis in SUSD4 expressing cells.

Conclusions

In this study we provide novel insight into the molecular mechanism of action whereby SUSD4 acts as an EGFR inhibitor without affecting the phosphorylation of the receptor and may potentially influence the recycling of EGFR to the plasma membrane.
Second generation Pichia pastoris strain and bioprocess designs
Authors: Ergün Burcu Gündüz , Laçın Kübra , Çaloğlu Buse , Binay Barış
Published: December 2022

Yeast was the first microorganism used by mankind for biotransformation processes that laid the foundations of industrial biotechnology. In the last decade,Pichia pastorishas become the leading eukaryotic host organism for bioproduct generation. Most of theP. pastorisbioprocess operations has been relying on toxic methanol and glucose feed. In the actual bioeconomy era, for sustainable value-added bioproduct generation, non-conventional yeastP. pastorisbioprocess operations should be extended to low-cost and renewable substrates for large volume bio-based commodity productions. In this review, we evaluated the potential ofP. pastorisfor the establishment of circular bioeconomy due to its potential to generate industrially relevant bioproducts from renewable sources and waste streams in a cost-effective and environmentally friendly manner. Furthermore, we discussed challenges with the second generationP. pastorisplatforms and propose novel insights for future perspectives. In this regard, potential of low cost substrate candidates, i.e., lignocellulosic biomass components, cereal by-products, sugar industry by-products molasses and sugarcane bagasse, high fructose syrup by-products, biodiesel industry by-product crude glycerol, kitchen waste and other agri-food industry by products were evaluated forP. pastoriscell growth promoting effects and recombinant protein production. Further metabolic pathway engineering ofP. pastoristo construct renewable and low cost substrate utilization pathways was discussed. Although, second generationP. pastorisbioprocess operations for valorisation of wastes and by-products still in its infancy, rapidly emerging synthetic biology tools and metabolic engineering ofP. pastoriswill pave the way for more sustainable environment and bioeconomy. From environmental point of view, second generation bioprocess development is also important for waste recycling otherwise disposal of carbon-rich effluents creates environmental concerns.P. pastorishigh tolerance to toxic contaminants found in lignocellulosic biomass hydrolysate and industrial waste effluent crude glycerol provides the yeast with advantages to extend its applications toward second generationP. pastorisstrain design and bioprocess engineering, in the years to come.

Graphical Abstract
Improving the productivity of malic acid by alleviating oxidative stress during Aspergillus niger fermentation
Authors: Wu Na , Xing Mingyan , Chen Yaru , Zhang Chi , Li Yingfeng , Song Ping , Xu Qing , Liu Hao , Huang He
Published: December 2022

Background

As an attractive platform chemical, malic acid has been commonly used in the food, feed and pharmaceutical field. Microbial fermentation of biobased sources to produce malic acid has attracted great attention because it is sustainable and environment-friendly. However, most studies mainly focus on improving yield and ignore shortening fermentation time. A long fermentation period means high cost, and hinders the industrial applications of microbial fermentation. Stresses, especially oxidative stress generated during fermentation, inhibit microbial growth and production, and prolong fermentation period. Previous studies have shown that polypeptides could effectively relieve stresses, but the underlying mechanisms were poorly understood.

Results

In this study, polypeptides (especially elastin peptide) addition improves the productivity of malic acid in A. niger, resulting in shortening of fermentation time from 120 to 108 h. Transcriptome and biochemical analyses demonstrated that both antioxidant enzyme-mediated oxidative stress defense system, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), and nonenzymatic antioxidant system, such as glutathione, were enhanced in the presence of elastin peptide, suggesting elastin peptide relieving oxidative stresses is involved in many pathways. In order to further investigate the relationship between oxidative stress defense and malic acid productivity, we overexpressed three enzymes (Sod1, CAT, Tps1) related to oxidation resistance in A. niger, respectively, and these resulting strains display varying degree of improvement in malic acid productivity. Especially, the strain overexpressing the Sod1 gene achieved a malate titer of 91.85 ± 2.58 g/L in 96 h, corresponding to a productivity of 0.96 g/L/h, which performs better than elastin peptide addition.

Conclusions

Our investigation provides an excellent reference for alleviating the stress of the fungal fermentation process and improving fermentation efficiency.
A low-dimensional cognitive-network space in Alzheimer’s disease and frontotemporal dementia
Authors: Pini Lorenzo , de Lange Siemon C , Pizzini Francesca Benedetta , Boscolo Galazzo Ilaria , Manenti Rosa , Cotelli Maria , Galluzzi Samantha , Cotelli Maria Sofia , Corbetta Maurizio , van den Heuvel Martijn P , Pievani Michela
Published: December 2022

Background

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) show network dysfunctions linked with cognitive deficits. Within this framework, network abnormalities between AD and FTD show both convergent and divergent patterns. However, these functional patterns are far from being established and their relevance to cognitive processes remains to be elucidated.

Methods

We investigated the relationship between cognition and functional connectivity of major cognitive networks in these diseases. Twenty-three bvFTD (age: 71±10), 22 AD (age: 72±6), and 20 controls (age: 72±6) underwent cognitive evaluation and resting-state functional MRI. Principal component analysis was used to describe cognitive variance across participants. Brain network connectivity was estimated with connectome analysis. Connectivity matrices were created assessing correlations between parcels within each functional network. The following cognitive networks were considered: default mode (DMN), dorsal attention (DAN), ventral attention (VAN), and frontoparietal (FPN) networks. The relationship between cognition and connectivity was assessed using a bootstrapping correlation and interaction analyses.

Results

Three principal cognitive components explained more than 80% of the cognitive variance: the first component (cogPC1) loaded on memory, the second component (cogPC2) loaded on emotion and language, and the third component (cogPC3) loaded on the visuo-spatial and attentional domains. Compared to HC, AD and bvFTD showed impairment in all cogPCs (p<0.002), and bvFTD scored worse than AD in cogPC2 (p=0.031). At the network level, the DMN showed a significant association in the whole group with cogPC1 and cogPC2 and the VAN with cogPC2. By contrast, DAN and FPN showed a divergent pattern between diagnosis and connectivity for cogPC2. We confirmed these results by means of a multivariate analysis (canonical correlation).

Conclusions

A low-dimensional representation can account for a large variance in cognitive scores in the continuum from normal to pathological aging. Moreover, cognitive components showed both convergent and divergent patterns with connectivity across AD and bvFTD. The convergent pattern was observed across the networks primarily involved in these diseases (i.e., the DMN and VAN), while a divergent FC-cognitive pattern was mainly observed between attention/executive networks and the language/emotion cognitive component, suggesting the co-existence of compensatory and detrimental mechanisms underlying these components.
Investigation of the structure-odor relationship using a Transformer model
Authors: Zheng Xiaofan , Tomiura Yoichi , Hayashi Kenshi
Published: December 2022

The relationships between molecular structures and their properties are subtle and complex, and the properties of odor are no exception. Molecules with similar structures, such as a molecule and its optical isomer, may have completely different odors, whereas molecules with completely distinct structures may have similar odors. Many works have attempted to explain the molecular structure-odor relationship from chemical and data-driven perspectives. The Transformer model is widely used in natural language processing and computer vision, and the attention mechanism included in the Transformer model can identify relationships between inputs and outputs. In this paper, we describe the construction of a Transformer model for predicting molecular properties and interpreting the prediction results. The SMILES data of 100,000 molecules are collected and used to predict the existence of molecular substructures, and our proposed model achieves an F1 value of 0.98. The attention matrix is visualized to investigate the substructure annotation performance of the attention mechanism, and we find that certain atoms in the target substructures are accurately annotated. Finally, we collect 4462 molecules and their odor descriptors and use the proposed model to infer 98 odor descriptors, obtaining an average F1 value of 0.33. For the 19 odor descriptors that achieved F1 values greater than 0.45, we also attempt to summarize the relationship between the molecular substructures and odor quality through the attention matrix.