bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic prediction of degrons and E3 ubiquitin ligase binding via deep learning
Authors: Hou Chao , Li Yuxuan , Wang Mengyao , Wu Hong , Li Tingting
Published: July 2022

Background

Degrons are short linear motifs, bound by E3 ubiquitin ligase to target protein substrates to be degraded by the ubiquitin-proteasome system. Mutations leading to deregulation of degron functionality disrupt control of protein abundance due to mistargeting of proteins destined for degradation and often result in pathologies. Targeting degrons by small molecules also emerges as an exciting drug design strategy to upregulate the expression of specific proteins. Despite their essential function and disease targetability, reliable identification of degrons remains a conundrum. Here, we developed a deep learning-based model named Degpred that predicts general degrons directly from protein sequences.

Results

We showed that the BERT-based model performed well in predicting degrons singly from protein sequences. Then, we used the deep learning model Degpred to predict degrons proteome-widely. Degpred successfully captured typical degron-related sequence properties and predicted degrons beyond those from motif-based methods which use a handful of E3 motifs to match possible degrons. Furthermore, we calculated E3 motifs using predicted degrons on the substrates in our collected E3-substrate interaction dataset and constructed a regulatory network of protein degradation by assigning predicted degrons to specific E3s with calculated motifs. Critically, we experimentally verified that a predicted SPOP binding degron on CBX6 prompts CBX6 degradation and mediates the interaction with SPOP. We also showed that the protein degradation regulatory system is important in tumorigenesis by surveying degron-related mutations in TCGA.

Conclusions

Degpred provides an efficient tool to proteome-wide prediction of degrons and binding E3s singly from protein sequences. Degpred successfully captures typical degron-related sequence properties and predicts degrons beyond those from previously used motif-based methods, thus greatly expanding the degron landscape, which should advance the understanding of protein degradation, and allow exploration of uncharacterized alterations of proteins in diseases. To make it easier for readers to access collected and predicted datasets, we integrated these data into the website http://degron.phasep.pro/.
Modest effect of statins on fasting glucose in a longitudinal electronic health record based cohort
Authors: Haldar Tanushree , Oni-Orisan Akinyemi , Hoffmann Thomas J. , Schaefer Catherine , Iribarren Carlos , Krauss Ronald M. , Medina Marisa W. , Risch Neil
Published: July 2022

Background

Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels.

Methods

Using electronic health record (EHR) data from a large and diverse longitudinal cohort, we defined long-term statin exposure in two ways: the cumulative years of statin use (cumulative supply) and the years’ supply-weighted sum of doses (cumulative dose). Simvastatin, lovastatin, atorvastatin and pravastatin were included in the analysis. The relationship between statin exposure and FG was examined using linear regression with mixed effects modeling, comparing statin users before and after initiating statins and statin never-users.

Results

We examined 593,130 FG measurements from 87,151 individuals over a median follow up of 20 years. Of these, 42,678 were never-users and 44,473 were statin users with a total of 730,031 statin prescriptions. FG was positively associated with cumulative supply of statin but not comulative dose when both measures were in the same model. While statistically significant, the annual increase in FG attributable to statin exposure was modest at only 0.14 mg/dl, with only slight and non-significant differences among statin types.

Conclusions

Elevation in FG level is associated with statin exposure, but the effect is modest. The results suggest that the risk of a clinically significant increase in FG attributable to long-term statin use is small for most individuals.
Relationship between ATOH1 and tumor microenvironment in colon adenocarcinoma patients with different microsatellite instability status
Authors: Mou Weiming , Zhu Lingxuan , Yang Tao , Lin Anqi , Lyu Qiong , Guo Linlang , Liu Zaoqu , Cheng Quan , Zhang Jian , Luo Peng
Published: July 2022

Background

Colon adenocarcinoma (COAD) is one of the major varieties of malignant tumors threatening human health today. Immune checkpoint inhibitors (ICIs) have recently begun to emerge as an effective option for the treatment of COAD patients, but not all patients can benefit from ICI treatment. Previous studies have suggested that ICIs boast significant clinical effects on patients with microsatellite instability-high (MSI-H), while conversely patients with microsatellite-stable/microsatellite instability-low (MSS/MSI-L) have shown limited response.

Methods

We used ATAC-seq, RNA-seq, and mutation data from The Cancer Genome Atlas Colon adenocarcinoma (TCGA-COAD) cohort to perform multi-omics differential analysis on COAD samples with different MSI statuses, then further screened genes by additionally combining these results with survival analysis. We analyzed the effects of the screened genes on the tumor microenvironment and immunogenicity of COAD patients, and subsequently determined their influence on the efficacy of ICIs in COAD patients using a series of predictive indexes.

Results

Twelve genes were screened in the TCGA-COAD cohort, and after the combined survival analysis, we identified ATOH1 as having significant effects. ATOH1 is characterized by high chromatin accessibility, high expression, and high mutation in COAD patients in the MSI-H group. COAD patients with high ATOH1 expression are associated with a better prognosis, unique immune microenvironment, and higher efficacy in ICI treatment. Enrichment analysis showed that COAD patients with high ATOH1 expression displayed significant upregulation in their humoral immunity and other related pathways.

Conclusions

We speculate that ATOH1 may influence the efficacy of ICIs therapy in patients with COAD by affecting the immune microenvironment and immunogenicity of the tumor.
Anti-mosquito properties of Pelargonium roseum (Geraniaceae) and Juniperus virginiana (Cupressaceae) essential oils against dominant malaria vectors in Africa
Authors: Yohana Revocatus , Chisulumi Paulo S. , Kidima Winifrida , Tahghighi Azar , Maleki-Ravasan Naseh , Kweka Eliningaya J.
Published: July 2022

Background

More than 90% of malaria cases occur in Africa where the disease is transmitted by Anopheles gambiae and Anopheles arabiensis. This study evaluated the anti-mosquito properties of Juniperus virginiana (JVO) and Pelargonium roseum (PRO) essential oils (EOs) against larvae and adults of An. gambiae sensu lato (s.l.) from East Africa in laboratory and semi-field conditions.

Methods

EOs was extracted from the aerial green parts of Asian herbs by hydrodistillation. Their constituents were characterized by gas chromatography-mass spectrometry (GC-MS). Larvicidal activities of JVO, PRO, and PRO components [citronellol (CO), linalool (LO), and geraniol (GO)] were investigated against An. gambiae sensu stricto (s.s.). The percentage of knockdown effects and mortality rates of all oils were also evaluated in the adults of susceptible An. gambiae s.s. and permethrin-resistant An. arabiensis.

Results

GC-MS analyses identified major constituents of JVO (sabinene, dl-limonene, β-myrcene, bornyl acetate, and terpinen-4-ol) and PRO (citronellol, citronellyl formate, L-menthone, linalool, and geraniol). Oils showed higher larvicidal activity in the laboratory than semi-field trials. The LC50 values for JVO/PRO were computed as 10.82–2.89/7.13–0.9 ppm and 10.75–9.06/13.63–8.98 ppm in laboratory and semi-field environments, respectively at exposure time of 24–72 h. The percentage of knockdown effects of the oils were also greater in An. gambiae s.s. than in An. arabiensis. Filter papers impregnated with JVO (100 ppm) and PRO (25 ppm) displayed 100% mortality rates for An. gambiae s.s. and 3.75% and 90% mortality rates, for An. arabiensis populations, respectively. Each component of CO, LO, and GO exhibited 98.13%, 97.81%, and 87.5%, respectively, and a mixture of the PRO components indicated 94.69% adult mortality to permethrin-resistant An. arabiensis.

Conclusions

The findings of this study show that PRO and its main constituents, compared to JVO, have higher anti-mosquito properties in terms of larvicidal, knockdown, and mortality when applied against susceptible laboratory and resistant wild populations of An. gambiae s.l. Consequently, these oils have the potential for the development of new, efficient, safe, and affordable agents for mosquito control.
Feasibility of community at-home dried blood spot collection combined with pooled reverse transcription PCR as a viable and convenient method for malaria epidemiology studies
Authors: Hergott Dianna E. B. , Owalla Tonny J. , Balkus Jennifer E. , Apio Bernadette , Lema Jimmy , Cemeri Barbara , Akileng Andrew , Seilie Annette M. , Chavtur Chris , Staubus Weston , Chang Ming , Egwang Thomas G. , Murphy Sean C.
Published: July 2022

Background

Many Plasmodium infections in endemic regions exist at densities below the limit of detection of standard diagnostic tools. These infections threaten control efforts and may impact vaccine and therapeutic drug studies. Simple, cost-effective methods are needed to study the natural history of asymptomatic submicroscopic parasitaemia. Self-collected dried blood spots (DBS) analysed using pooled and individual quantitative reverse transcription polymerase chain reaction (qRT-PCR) provide such a solution. Here, the feasibility and acceptability of daily at-home DBS collections for qRT-PCR was studied to better understand low-density infections.

Methods

Rapid diagnostic test (RDT)-negative individuals in Katakwi District, northeastern Uganda, were recruited between April and May 2021. Venous blood samples and clinic-collected DBS were taken at enrollment and at four weekly clinic visits. Participants were trained in DBS collection and asked to collect six DBS weekly between clinic visits. Opinions about the collection process were solicited using daily Diary Cards and a Likert scale survey at the final study visit. Venous blood and DBS were analysed by Plasmodium 18S rRNA qRT-PCR. The number of participants completing the study, total DBS collected, and opinions of the process were analysed to determine compliance and acceptability. The human internal control mRNA and Plasmodium 18S rRNA were evaluated for at-home vs. clinic-collected DBS and venous blood to assess quality and accuracy of at-home collected samples.

Results

One-hundred two adults and 29 children were enrolled, and 95 and 26 completed the study, respectively. Three individuals withdrew due to pain or inconvenience of procedures. Overall, 96% of participants collected ≥ 16 of 24 at-home DBS, and 87% of DBS contained ≥ 40 µL of blood. The procedure was well tolerated and viewed favourably by participants. At-home collected DBS were acceptable for qRT-PCR and showed less than a one qRT-PCR cycle threshold shift in the human control mRNA compared to clinic-collected DBS. Correlation between Plasmodium falciparum 18S rRNA from paired whole blood and DBS was high (R = 0.93).

Conclusions

At-home DBS collection is a feasible, acceptable, and robust method to obtain blood to evaluate the natural history of low-density Plasmodium infections by qRT-PCR.
Highly sensitive Curcumin-conjugated nanotheranostic platform for detecting amyloid-beta plaques by magnetic resonance imaging and reversing cognitive deficits of Alzheimer's disease via NLRP3-inhibition
Authors: Ruan Yuting , Xiong Ying , Fang Wenli , Yu Qun , Mai Yingren , Cao Zhiyu , Wang Kexi , Lei Ming , Xu Jiaxin , Liu Yan , Zhang Xingcai , Liao Wang , Liu Jun
Published: July 2022

Background

Alzheimer's disease (AD) is the most common neurodegenerative disorder without effective therapy and lack diagnosis strategy for preclinical AD patients. There is an urgent need for development of both early diagnosis and therapeutic intervention of AD.

Results

Herein, we developed a nanotheranostics platform consisting of Curcumin (Cur), an anti-inflammatory molecule, and superparamagnetic iron oxide (SPIO) nanoparticles encapsulated by diblock 1,2-dio-leoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylene glycol)] (DSPE-PEG) that are modified with CRT and QSH peptides on its surface. Furthermore, we demonstrated that this multifunctional nanomaterial efficiently reduced β-amyloid plaque burden specifically in APP/PS1 transgenic mice, with the process noninvasively detected by magnetic resonance imaging (MRI) and the two-dimensional MRI images were computed into three-dimension (3D) plot. Our data demonstrated highly sensitive in vivo detection of β-amyloid plaques which more closely revealed real deposition of Aβ than previously reported and we quantified the volumes of plaques for the first time based on 3D plot. In addition, memory deficits of the mice were significantly rescued, probably related to inhibition of NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasomes.

Conclusions

Gathered data demonstrated that this theranostic platform may have both early diagnostic and therapeutic potential in AD.

Graphical Abstract
A new polysaccharide platform constructs self-adjuvant nanovaccines to enhance immune responses
Authors: Chen Sisi , Yang Liu , Ou Xia , Li Jin-Yu , Zi Cheng-Ting , Wang Hao , Hu Jiang-Miao , Liu Ye
Published: July 2022

Background

Nanovaccines have shown the promising potential in controlling and eradicating the threat of infectious diseases worldwide. There has been a great need in developing a versatile strategy to conveniently construct diverse types of nanovaccines and induce potent immune responses. To that end, it is critical for obtaining a potent self-adjuvant platform to assemble with different types of antigens into nanovaccines.

Results

In this study, we identified a new natural polysaccharide from the rhizomes of Bletilla striata (PRBS), and used this polysaccharide as a platform to construct diverse types of nanovaccines with potent self-adjuvant property. In the construction process of SARS-CoV-2 nanovaccine, PRBS molecules and RBD protein antigens were assembled into ~ 300 nm nanoparticles by hydrogen bond. For HIV nanovaccine, hydrophobic effect dominantly drove the co-assembly between PRBS molecules and Env expression plasmid into ~ 350 nm nanospheres. Importantly, PRBS can potently activate the behaviors and functions of multiple immune cells such as macrophages, B cells and dendritic cells. Depending on PRBS-mediated immune activation, these self-adjuvant nanovaccines can elicit significantly stronger antigen-specific antibody and cellular responses in vivo, in comparison with their corresponding traditional vaccine forms. Moreover, we also revealed the construction models of PRBS-based nanovaccines by analyzing multiple assembly parameters such as bond energy, bond length and interaction sites.

Conclusions

PRBS, a newly-identified natural polysaccharide which can co-assemble with different types of antigens and activate multiple critical immune cells, has presented a great potential as a versatile platform to develop potent self-adjuvant nanovaccines.
Immune-regulating strategy against rheumatoid arthritis by inducing tolerogenic dendritic cells with modified zinc peroxide nanoparticles
Authors: Qiao Han , Mei Jingtian , Yuan Kai , Zhang Kai , Zhou Feng , Tang Tingting , Zhao Jie
Published: July 2022

In hypoxic dendritic cells (DCs), a low level of Zn2+ can induce the activation of immunogenic DCs (igDCs), thereby triggering an active T-cell response to propel the immune progression of rheumatoid arthritis (RA). This finding indicates the crucial roles of zinc and oxygen homeostasis in DCs during the pathogenesis of RA. However, very few studies have focused on the modulation of zinc and oxygen homeostasis in DCs during RA treatment. Proposed herein is a DC-targeting immune-regulating strategy to induce igDCs into tolerogenic DCs (tDCs) and inhibit subsequent T-cell activation, referred to as ZnO2/Catalase@liposome-Mannose nanoparticles (ZnCM NPs). ZnCM NPs displayed targeted intracellular delivery of Zn2+ and O2 towards igDCs in a pH-responsive manner. After inactivating OTUB1 deubiquitination, the ZnCM NPs promoted CCL5 degradation via NF-κB signalling, thereby inducing the igDC-tDC transition to further inhibit CD4+ T-cell homeostasis. In collagen-induced arthritis (CIA) mice, this nanoimmunoplatform showed significant accumulation in the spleen, where immature DCs (imDCs) differentiated into igDCs. Splenic tDCs were induced to alleviate ankle swelling, improve walking posture and safely inhibit ankle/spleen inflammation. Our work pioneers the combination of DC-targeting nanoplatforms with RA treatments and highlights the significance of zinc and oxygen homeostasis for the immunoregulation of RA by inducing tDCs with modified ZnO2 NPs, which provides novel insight into ion homeostasis regulation for the treatment of immune diseases with a larger variety of distinct metal or nonmetal ions.

Graphical Abstract
Health-related quality of life and influencing factors in drug addicts based on the scale QLICD-DA: a cross-sectional study
Authors: Ma Zilin , Liu Yuxi , Wan Chonghua , Jiang Jianming , Li Xiaomei , Zhang Ying
Published: July 2022

Background

Drug abuse has many negative effects not only on individuals but also on society. Nowadays, researchers pay a lot of attention to quality of life of drug addicts. However, there are few scales available to measure quality of life of drug addicts. The scale QLICD-DA (quality of life instrument for chronic diseases-drug addition) developed by modular approach could be used to measure quality of life of drug addicts with good validity, reliability and sensitivity.

Objective

This study is aimed to understand the quality of life status and influencing factors in drug addicts by suitable sensitively scale, with the hypothesis of the quality of life in drug addicts being different from that of other peoples and possibly being influenced by many factors.

Methods

By cluster random sampling method, 192 drug addicts at Kunming compulsory drug rehabilitation center were recruited to take part in the investigation. All participants completed the general information questionnaire and the scale QLICD-DA. We used a t-test to compare the scores of the quality of life of the participants with the norm (QOL scores from 1953 patients of 10 chronic diseases). A stepwise regression method was applied to explore the influencing factors of the quality of life in drug addicts.

Results

192 participants ranged in age from 19 to 59 with an average age of 34.86. Most of them were male (70.3%), high school education level (67.7%) and of Han nationality (82.8%). The quality of life of drug addicts was lower than the norm in the physical domain, psychological domain, social domain, and general module, and the differences were statistically significant (p < 0.001). Sex and mode of drug abuse were the influencing factors in total score (p = 0.006) and specific module (p = 0.019). Past family atmosphere and the mode of drug abuse were the influencing factors in the general module (p = 0.027, p = 0.037).

Conclusion

The quality of life of drug addicts was worse than that of patients with other chronic diseases, and the influencing factors of the quality of life of drug abusers were sex, mode of drug abuse, and past family atmosphere.
Costing the outpatient rehabilitation services: time-driven activity-based costing approach
Authors: Mohammadpour Farzaneh , Basakha Mehdi , Kamal Seyed Hossein Mohaqeqi , Azari Nadia
Published: July 2022

Background

Considering the importance of healthcare services costing in resource allocation, the aim of this study is to calculate the cost of rehabilitation services in an outpatient rehabilitation clinic in Tehran, Iran.

Methods

The data for this study were categorised as financial data and information about the process of rehabilitation services. The first category was extracted from the financial documents and the second was obtained by observation of patient flow and interviews with the clinic staff in 2016. The cost of rehabilitation services has been estimated using the time-driven activity-based costing approach.

Results

The findings show that the cost of physical occupational therapy in the Asma rehabilitation center was $18.79 per unit of service. This amount for speech therapy services was $17.23 to $19.40, taking into account the difference in the quality of the service delivered. The cost of mental health occupational therapy service was between $19.46 and $23.57. Comparing the cost of these services with the government’s tariffs makes it clear that there is a huge gap.

Conclusion

The limited number of patients referred to the center makes the cost of one unit of rehabilitation services much higher than the official tariffs. This is true for almost all similar institutions and makes the profitability of small rehabilitation institutions extremely unstable. Therefore, proper marketing for rehabilitation services by promoting patient referral links with larger healthcare centers and reallocation of resources to the formation of integrated rehabilitation complexes can play a significant role in their profitability.
SENP1 regulates the transformation of lung resident mesenchymal stem cells and is associated with idiopathic pulmonary fibrosis progression
Authors: Sun Wei , Liu Xiaoshu , Yang Xiaoyu , Jing Xiaoyan , Duan Chunyan , Yang Ganghao , Wu Chi , Huang Hui , Luo Qun , Xia Shu , Zhang Qian , Yang Yang , Xu Zuojun
Published: July 2022

Background

Lung resident mesenchymal stem cells (LR-MSCs) play an important role in idiopathic pulmonary fibrosis (IPF) by transforming into myofibroblasts, thereby losing their repair ability. Evidence suggests that key proteins of multiple signaling pathways are involved in myofibroblast differentiation of LR-MSCs, such as β-Catenin and GLI family zinc finger 1 (GLI1). These proteins are regulated by SUMO (small ubiquitin-like modifier) modification, which is a post-translational modification that promotes protein degradation, while Sumo specific protein 1 (SENP1)-mediated deSUMOylation produces the opposite biological effects. Therefore, we speculated that SENP1 might be a potential target for treating pulmonary fibrosis by preventing the myofibroblast differentiation of LR-MSCs.

Methods

LR-MSCs were isolated from mice by using immunomagnetic beads. The extracted LR-MSCs were identified by flow cytometric analysis and multilineage differentiation assays. Lentivirus packaged shRNA silenced the expression of SENP1 in vitro and vivo. The silencing efficacy of SENP1 was verified by real-time quantitative PCR. The effect of down-regulated SENP1 on the myofibroblast differentiation of LR-MSCs was assessed by Immunofluorescence and Western blot. Immunoprecipitation was used to clarify that SENP1 was a key target for regulating the activity of multiple signaling pathways in the direction of LR-MSCs differentiation. LR-MSCs resident in the lung was analyzed with in vivo imaging system. HE and Masson staining was used to evaluate the therapeutic effect of LR-MSCs with SENP1 down-regulation on the lung of BLM mice.

Results

In this study, we found that the myofibroblast differentiation of LR-MSCs in IPF lung tissue was accompanied by enhanced SENP1-mediated deSUMOylation. The expression of SENP1 increased in LR-MSCs transition of bleomycin (BLM)-induced lung fibrosis. Interfering with expression of SENP1 inhibited the transformation of LR-MSCs into myofibroblasts in vitro and in vivo and restored their therapeutic effect in BLM lung fibrosis. In addition, activation of the WNT/β-Catenin and Hedgehog/GLI signaling pathways depends on SENP1-mediated deSUMOylation.

Conclusions

SENP1 might be a potential target to restore the repair function of LR-MSCs and treat pulmonary fibrosis.
Potential inhibitors for blocking the interaction of the coronavirus SARS-CoV-2 spike protein and its host cell receptor ACE2
Authors: Li Changzhi , Zhou Hongjuan , Guo Lingling , Xie Dehuan , He Huiping , Zhang Hong , Liu Yixiu , Peng Lixia , Zheng Lisheng , Lu Wenhua , Mei Yan , Liu Zhijie , Huang Jie , Wang Mingdian , Shu Ditian , Ding Liuyan , Lang Yanhong , Luo Feifei , Wang Jing , Huang Bijun , Huang Peng , Gao Song , Chen Jindong , Qian Chao-Nan
Published: July 2022

Background

The outbreak of SARS-CoV-2 continues to pose a serious threat to human health and social. The ongoing pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious threat to public health and economic stability worldwide. Given the urgency of the situation, researchers are attempting to repurpose existing drugs for treating COVID-19.

Methods

We first established an anti-coronavirus drug screening platform based on the Homogeneous Time Resolved Fluorescence (HTRF) technology and the interaction between the coronavirus spike protein and its host receptor ACE2. Two compound libraries of 2,864 molecules were screened with this platform. Selected candidate compounds were validated by SARS-CoV-2_S pseudotyped lentivirus and ACE2-overexpressing cell system. Molecular docking was used to analyze the interaction between S protein and compounds.

Results

We identified three potential anti-coronavirus compounds: tannic acid (TA), TS-1276 (anthraquinone), and TS-984 (9-Methoxycanthin-6-one). Our in vitro validation experiments indicated that TS-984 strongly inhibits the interaction of the coronavirus S protein and the human cell ACE2 receptor. Additionally, tannic acid showed moderate inhibitory effect on the interaction of S protein and ACE2.

Conclusion

This platform is a rapid, sensitive, specific, and high throughput system, and available for screening large compound libraries. TS-984 is a potent blocker of the interaction between the S-protein and ACE2, which might have the potential to be developed into an effective anti-coronavirus drug.
SLC26A4 correlates with homologous recombination deficiency and patient prognosis in prostate cancer
Authors: Luo Cong , Liu Zhi , Gan Yu , Gao Xiaomei , Zu Xiongbing , Zhang Ye , Ye Wenrui , Cai Yi
Published: July 2022

Background

Homologous recombination deficiency (HRD) is closely associated with patient prognosis and treatment options in prostate cancer (PCa). However, there is a lack of quantitative indicators related to HRD to predict the prognosis of PCa accurately.

Methods

We screened HRD-related genes based on the HRD scores and constructed an HRD cluster system to explore different clinicopathological, genomic, and immunogenomic patterns among the clusters. A risk signature, HRDscore, was established and evaluated by multivariate Cox regression analysis. We noticed that SLC26A4, a model gene, demonstrated unique potential to predict prognosis and HRD in PCa. Multi-omics analysis was conducted to explore its role in PCa, and the results were validated by qRT-PCR and immunohistochemistry.

Results

Three HRD clusters were identified with significant differences in patient prognosis, clinicopathological characteristics, biological pathways, immune infiltration characteristics, and regulation of immunomodulators. Further analyses revealed that the constructed HRDscore system was an independent prognostic factor of PCa patients with good stability. Finally, we identified a single gene, SLC26A4, which significantly correlated with prognosis in three independent cohorts. Importantly, SLC26A4 was confirmed to distinguish PCa (AUC for mRNA 0.845; AUC for immunohistochemistry score 0.769) and HRD (AUC for mRNA 0.911; AUC for immunohistochemistry score 0.689) at both RNA and protein levels in our cohort.

Conclusion

This study introduces HRDscore to quantify the HRD pattern of individual PCa patients. Meanwhile, SLC26A4 is a novel biomarker and can reasonably predict the prognosis and HRD in PCa.
Application of a virtual reality tracker-based system to measure seated postural stability in stroke patients
Authors: Liang Huey-Wen , Tai Tzu-Ling , Li Yue-Hua , Chen Ying-Chun
Published: July 2022

Background

Postural stability while sitting is an important indicator of balance and an early predictor for future functional improvement in neurorehabilitation, but the evaluation is usually dependent on clinical balance function measures. Meanwhile, instrumental posturography has been used widely to obtain quantitative data and characterize balance abilities and underlying control mechanisms, but not as often for sitting balance. Moreover, traditional kinetic methods using a force platform to test sitting stability often require modification and are costly. We proposed a tracker-based posturography with a commercial virtual reality system, the VIVE Pro system (HTC, Inc. Taiwan), to record the trunk displacement (TD) path with a lumbar tracker for evaluation of sitting stability. The goals were to test the reliability and validity of the TD parameters among stroke patients.

Methods

Twenty-one stroke individuals and 21 healthy adults had their postural sway measured with this system under four sitting conditions, i.e., sitting on a solid surface or a soft surface, with eyes open or closed. The test–retest reliability of the TD parameters was evaluated with intraclass correlation coefficients in 22 participants. We also tested the discriminative validity of these parameters to discriminate between stroke and healthy controls, and among four sitting conditions. Furthermore, the TD parameters were correlated with the three balance function tests: the Berg Balance Scale (BBS), the Postural Assessment Scale for Stroke Patients (PASS) and the Function in Sitting Test (FIST).

Results

The results indicated that the TD parameters obtained by tracker-based posturography had mostly moderate to good reliability across the four conditions, with a few exceptions in the solid surface and eyes open tasks. The TD parameters could discriminate the postural stability between sitting on solid and soft surfaces. The stroke group had more seated postural sway than the control group, especially while sitting on a soft surface. In addition, velocity measures in the sagittal and frontal planes had moderate to high correlations with the PASS and BBS scores.

Conclusions

This tracker-based system is a cost-effective option for the clinical assessment of body stability for stroke patients in a seated position and shows acceptable reliability and validity.
Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation
Authors: Chen Sunnia T. , Azali Leylah , Rosen Lindsay , Zhao Qiuhong , Wiczer Tracy , Palettas Marilly , Gambril John , Kola-Kehinde Onaopepo , Ruz Patrick , Kalathoor Sujay , Rogers Kerry , Kittai Adam , Grever Michael , Awan Farrukh , Byrd John C. , Woyach Jennifer , Bhat Seema A. , Addison Daniel
Published: July 2022

Background

Post-market analyses revealed unanticipated links between first-generation Bruton’s tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown.

Methods

Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed.

Results

Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P < 0.001), yet 34.1% lower than ibrutinib (12.9 observed-to-expected ratio, P < 0.001). In multivariable regression, prior arrhythmias and Black ancestry were associated with new hypertension (HR 1.63, HR 4.35, P < 0.05). The degree of SBP rise within 1 year of treatment initiation predicted MACE risk (42% HR increase for each + 5 mmHg SBP rise, P < 0.001). No single antihypertensive class prevented worsened acalabrutinib-related hypertension.

Conclusions

Collectively, these data suggest that hypertension may be a class effect of BTKi therapies and precedes major cardiotoxic events.
Upregulation of Nox4 induces a pro-survival Nrf2 response in cancer-associated fibroblasts that promotes tumorigenesis and metastasis, in part via Birc5 induction
Authors: Mir Shakeel , Ormsbee Golden Briana D. , Griess Brandon J. , Vengoji Raghupathy , Tom Eric , Kosmacek Elizabeth A. , Oberley-Deegan Rebecca E. , Talmon Geoffrey A. , Band Vimla , Teoh-Fitzgerald Melissa LT.
Published: July 2022

Background

A pro-oxidant enzyme, NADPH oxidase 4 (Nox4) has been reported to be a critical downstream effector of TGFβ-induced myofibroblast transformation during fibrosis. While there are a small number of studies suggesting an oncogenic role of Nox4 derived from activated fibroblasts, direct evidence linking this pro-oxidant to the tumor-supporting CAF phenotype and the mechanisms involved are lacking, particularly in breast cancer.

Methods

We targeted Nox4 in breast patient-derived CAFs via siRNA-mediated knockdown or administration of a pharmaceutical inhibitor (GKT137831). We also determine primary tumor growth and metastasis of implanted tumor cells using a stable Nox4-/- syngeneic mouse model. Autophagic flux of CAFs was assessed using a tandem fluorescent-tagged ptfl-LC3 plasmid via confocal microscopy analysis and determination of the expression level of autophagy markers (beclin-1 and LC3B). Nox4 overexpressing CAFs depend on the Nrf2 (nuclear factor-erythroid factor 2-related factor 2) pathway for survival. We then determined the dependency of Nox4-overexpressing CAFs on the Nrf2-mediated adaptive stress response pathway for survival. Furthermore, we investigated the involvement of Birc5 on CAF phenotype (viability and collagen contraction activity) as well as the expression level of CAF markers, FAP and αSMA.

Conclusions

We found that deletion of stroma Nox4 and pharmaceutically targeting its activity with GKT137831 significantly inhibited orthotopic tumor growth and metastasis of implanted E0771 and 4T1 murine mammary carcinoma cell lines in mice. More importantly, we found a significant upregulation of Nox4 expression in CAFs isolated from human breast tumors versus normal mammary fibroblasts (RMFs). Our in situ RNA hybridization analysis for Nox4 transcription on a human breast tumor microarray further support a role of this pro-oxidant in the stroma of breast carcinomas. In addition, we found that Nox4 promotes autophagy in CAFs. Moreover, we found that Nox4 promoted survival of CAFs via activation of Nrf2, a master regulator of oxidative stress response. We have further shown Birc5 is involved as a downstream modulator of Nrf2-mediated pro-survival phenotype. Together these studies indicate a role of redox signaling via the Nox4-Nrf2 pathway in tumorigenesis and metastasis of breast cancer cells by promoting autophagy and survival of CAFs.
The center of pressure position in combination with ankle dorsiflexion and trunk flexion is useful in predicting the contribution of the knee extensor moment during double-leg squatting
Authors: Ishida Tomoya , Samukawa Mina , Kasahara Satoshi , Tohyama Harukazu
Published: July 2022

Background

Squatting exercises are commonly used in rehabilitation for knee joint disorders; in these exercises, control of knee extensor moment is important to enhance training effects and to avoid adverse effects. Ankle dorsiflexion and trunk flexion are widely used to reduce knee extensor moments during squatting, but the increased load on the low back is a concern. The purpose of this study was to determine whether the anterior–posterior (AP) center-of-pressure (COP) position and the AP-COP position in combination with ankle dorsiflexion and trunk flexion angles can predict the contribution of the knee extensor moment during double-leg squatting.

Methods

Twenty-eight healthy individuals (14 female and 14 male participants, age 22.8 ± 1.3 years) performed three sets of five consecutive double-leg squats. Kinematics and kinetics were analyzed using a three-dimensional motion analysis system with force plates. Univariate and multivariate regression analyses were performed to predict the contribution of the knee extensor moment (% total support moment) from AP-COP position, ankle dorsiflexion, and trunk flexion.

Results

The AP-COP position was a significant predictor of the knee extensor moment contribution (R2 = 0.168, P = 0.030). Multivariate analysis showed that the ankle dorsiflexion angle (ΔR2 = 0.561, β = 0.842) and AP-COP position (ΔR2 = 0.296, β =  − 0.499) predicted the knee extensor moment contribution (model R2 = 0.857, P < 0.001). Additionally, the combination of trunk flexion (ΔR2 = 0.429, β =  − 0.613) and AP-COP position (ΔR2 = 0.109, β =  − 0.332) predicted the knee extensor moment contribution (model R2 = 0.538, P < 0.001). The limb symmetry index of the knee extensor moment was significantly associated with that of the AP-COP position (R2 = 0.493, P < 0.001) but not with that of the ankle dorsiflexion angle (P = 0.057).

Conclusions

The AP-COP position can predict the contribution of the knee extensor moment and improve the prediction when combined with ankle dorsiflexion and trunk flexion. The present findings suggest that intervention focusing on the AP-COP position in combination with ankle dorsiflexion or trunk flexion would be useful to coordinate the contribution of the knee extensor moment during double-leg squatting.
Utility of support vector machine and decision tree to identify the prognosis of metformin poisoning in the United States: analysis of National Poisoning Data System
Authors: Mehrpour Omid , Saeedi Farhad , Hoyte Christopher , Goss Foster , Shirazi Farshad M.
Published: July 2022

Background

With diabetes incidence growing globally and metformin still being the first-line for its treatment, metformin’s toxicity and overdose have been increasing. Hence, its mortality rate is increasing. For the first time, we aimed to study the efficacy of machine learning algorithms in predicting the outcome of metformin poisoning using two well-known classification methods, including support vector machine (SVM) and decision tree (DT).

Methods

This study is a retrospective cohort study of National Poison Data System (NPDS) data, the largest data repository of poisoning cases in the United States. The SVM and DT algorithms were developed using training and test datasets. We also used precision-recall and ROC curves and Area Under the Curve value (AUC) for model evaluation.

Results

Our model showed that acidosis, hypoglycemia, electrolyte abnormality, hypotension, elevated anion gap, elevated creatinine, tachycardia, and renal failure are the most important determinants in terms of outcome prediction of metformin poisoning. The average negative predictive value for the decision tree and SVM models was 92.30 and 93.30. The AUC of the ROC curve of the decision tree for major, minor, and moderate outcomes was 0.92, 0.92, and 0.89, respectively. While this figure of SVM model for major, minor, and moderate outcomes was 0.98, 0.90, and 0.82, respectively.

Conclusions

In order to predict the prognosis of metformin poisoning, machine learning algorithms might help clinicians in the management and follow-up of metformin poisoning cases.
KiESEL – The Children’s Nutrition Survey to Record Food Consumption for the youngest in Germany
Authors: Nowak Nicole , Diouf Friederike , Golsong Nadine , Höpfner Tobias , Lindtner Oliver
Published: July 2022

Background

With KiESEL, the Children’s Nutrition Survey to Record Food Consumption, the German Federal Institute for Risk Assessment (BfR) collected representative food consumption data for children aged six months up to five years. KiESEL was one of five modules of KiGGS Wave2 (German Health Interview and Examination Survey for Children and Adolescents) conducted by the Robert Koch Institute (RKI). The objective was to update the consumption data for children in Germany and to fill a data gap for the age group of five-year-old children. The study provides an up-to-date and comprehensive database that will be used for exposure assessment, as part of risk assessment of Germany’s youngest consumers.

Methods

In the years 2014 to 2017, 1104 children from all over Germany participated in KiESEL. During home visits, survey staff conducted a questionnaire-based interview including a food propensity questionnaire (FPQ) on seldom eaten foods and questions concerning consumption outside home, dietary habits and diet during first year. The interviewer measured the children’s height and weight. Families and childcare workers filled out a food record, covering three consecutive days and one independent day. Data are based on the FPQ and present consumption frequencies. Depending on the question, socioeconomic status (SES) and migration background were considered.

Results

1104 participants had an interview and filled out the questionnaire on usual food intake, seldom eaten foods and consumption away from home. They were included in sample1. 1008 of these participants additionally reported food consumption of at least three days (sample2). 91.2% of the children follow no special diet and 0.8% are vegetarians. 7% of the older children consuming soya-drink. For some foods differences in consumption across SES or migration status were noted. Children from families with higher SES consume more often soya-based substitute milk as families with lower SES (p < 0.00005).

Conclusions

KiESEL gathered up-to-date consumption data for more than 1000 children living in Germany, aged six month up to including five years. The data will be used for risk assessments of the BfR and provided to national and international partners.
Associations of childhood and adult socioeconomic circumstances with recommended food habits among young and midlife Finnish employees
Authors: Salmela Jatta , Kouvonen Anne , Mauramo Elina , Rahkonen Ossi , Roos Eva , Lallukka Tea
Published: July 2022

Background

Disadvantaged socioeconomic circumstances are associated with certain unhealthy food habits such as inadequate consumption of fruit and vegetables. This study examined whether multiple socioeconomic measures are consistently associated with a variety of food habits.

Methods

We examined associations of 2 childhood and 6 adult socioeconomic measures with 8 recommended food habits among 19–39-year-old employees of the City of Helsinki, Finland. The data were collected in 2017 via online and mailed surveys. Our sample consisted of 4621 employees (80% women). The analyses included adjusted binary logistic regression models.

Results

More advantaged socioeconomic circumstances were positively associated with the recommended consumption of vegetables, fruit or berries, dark bread, skimmed milk products, fish, and cooking oil, but not consistently with red or processed meat and fat spread. All socioeconomic measures were positively associated with having several (6–8) recommended food habits after gender and age adjustments. The strongest associations were found for participant’s education, occupational class, and current financial difficulties. These associations remained after adjustments of childhood and adult socioeconomic measures, although especially participant’s education attenuated the associations for occupational class.

Conclusions

The consistent associations between multiple childhood and adult socioeconomic measures and food habits found among employees highlight the need for improving food habits among people with disadvantaged socioeconomic circumstances in particular. Financial barriers together with social aspects of adhering to healthy diets should be considered in future dietary interventions and policy actions.
Emesis in pregnancy – a qualitative study on trial recruitment failure from the EMPOWER internal pilot
Authors: Lie Mabel Leng Sim , McParlin Catherine , McColl Elaine , Graham Ruth H. , Robson Stephen C.
Published: July 2022

Background

As part of the internal pilot of the EMPOWER trial investigating the second-line antiemetic therapies in severe emesis in pregnancy (https://www.isrctn.com/ISRCTN16924692), a qualitative study of women’s views was carried out, to improve our understanding of why women did, or did not, consent to participation in the trial. Interviews were also conducted with site research staff, to broaden our analysis and explore other factors affecting recruitment.

Methods

The sample comprised women who accepted or declined trial participation (n=21) and site research staff (n=22). A structured topic guide was used, in four email interviews and 17 telephone interviews with women, and semi-structured telephone interviews were carried out with staff. Of the women interviewed, seven had declined trial participation, and of the staff interviewed, 16 were research midwives/research nurses and six were principal investigators. All transcripts were checked for accuracy, anonymised and entered into NVIVO12 for indexing and retrieval. Data was analysed using a reflexive thematic analytic approach. In total, 72 codes were generated from the thematic analysis, and 36 from each sample group.

Results

Three key themes based on all the interviews were (a) the diversity of recruitment pathways and boundaries of care, (b) the impact of trial complexity on recruitment and staff morale and (c) the ethics of caring for a patient with emesis. Ethical issues discussed included the use of double dummy and time to treat, particularly those suffering severely from the effects of nausea and vomiting. To illustrate these themes, staff perspectives are given more prominence.

Conclusions

The main reason the trial was stopped related to the high proportion of women ineligible for recruitment due to prior treatment with study drug(s) because of unanticipated changes in clinical practice. The qualitative results also demonstrate the impact of the trial on women and staff and highlight how the diversity of referral pathways, boundaries of care and the complexity of the trial and protocol resulted in additional barriers to successful trial recruitment. Qualitative work in pilot and feasibility studies of a clinical trial is recommended, to evaluate whether recruitment strategies remain viable in unanticipated contexts.

Trial registration

Trial registration number ISRCTN16924692. Date: 08/01/2018