bluuebunny/crossref_metadata_2025 huggingface dataset:
Antizyme inhibitor family: biological and translational research implications
Authors: Feng Qiaohui , Wang Huijie , Shao Youcheng , Xu Xiaoyan
Published: January 2024

Metabolism of polyamines is of critical importance to physiological processes. Ornithine decarboxylase (ODC) antizyme inhibitors (AZINs) are capable of interacting with antizymes (AZs), thereby releasing ODC from ODC-AZs complex, and promote polyamine biosynthesis. AZINs regulate reproduction, embryonic development, fibrogenesis and tumorigenesis through polyamine and other signaling pathways. Dysregulation of AZINs has involved in multiple human diseases, especially malignant tumors. Adenosine-to-inosine (A-to-I) RNA editing is the most common type of post-transcriptional nucleotide modification in humans. Additionally, the high frequencies of RNA-edited AZIN1 in human cancers correlates with increase of cancer cell proliferation, enhancement of cancer cell stemness, and promotion of tumor angiogenesis. In this review, we summarize the current knowledge on the various contribution of AZINs related with potential cancer promotion, cancer stemness, microenvironment and RNA modification, especially underlying molecular mechanisms, and furthermore explored its promising implication for cancer diagnosis and treatment.
TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis
Authors: Hao Xiang-lin , Lv Yang-fan , Li De-feng , Bai Fu-hai , Gong Ji , Pan Guang-qiang , Su Lin-xi , Wang Ya-li , Fu Wan-lei , Liu Bo , Huang Lu , Yan Dong , Tan Qiu-lin , Liu Jin-yi , Guo Qiao-nan
Published: January 2024

Background

Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood.

Methods

Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays.

Results

Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level.

Conclusions

Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.
Impact of NQO1 dysregulation in CNS disorders
Authors: Yuhan Li , Khaleghi Ghadiri Maryam , Gorji Ali
Published: January 2024

NAD(P)H Quinone Dehydrogenase 1 (NQO1) plays a pivotal role in the regulation of neuronal function and synaptic plasticity, cellular adaptation to oxidative stress, neuroinflammatory and degenerative processes, and tumorigenesis in the central nervous system (CNS). Impairment of the NQO1 activity in the CNS can result in abnormal neurotransmitter release and clearance, increased oxidative stress, and aggravated cellular injury/death. Furthermore, it can cause disturbances in neural circuit function and synaptic neurotransmission. The abnormalities of NQO1 enzyme activity have been linked to the pathophysiological mechanisms of multiple neurological disorders, including Parkinson's disease, Alzheimer's disease, epilepsy, multiple sclerosis, cerebrovascular disease, traumatic brain injury, and brain malignancy. NQO1 contributes to various dimensions of tumorigenesis and treatment response in various brain tumors. The precise mechanisms through which abnormalities in NQO1 function contribute to these neurological disorders continue to be a subject of ongoing research. Building upon the existing knowledge, the present study reviews current investigations describing the role of NQO1 dysregulations in various neurological disorders. This study emphasizes the potential of NQO1 as a biomarker in diagnostic and prognostic approaches, as well as its suitability as a target for drug development strategies in neurological disorders.
Local injection of infliximab into calcinosis lesions in patients with juvenile dermatomyositis (JDM): a clinical trial
Authors: Shiari Reza , Khalili Mitra , Zeinali Vahide , Shashaani Niloufar , Samami Mohammad , Moghaddamemami Foroughossadat Hosseini
Published: January 2024

Background

Juvenile Dermatomyositis (JDM) is a rare autoimmune disorder that primarily affects muscles and skin. One of the severe complications associated with JDM is calcinosis, and treating this condition presents significant challenges. This study aimed to evaluate the efficacy and safety of local injection of infliximab into calcinosis lesions in patients with JDM.

Methods

In this clinical trial, five patients diagnosed with JDM and calcinosis lesions were enrolled. The primary treatment consisted of weekly infliximab injections for 16 weeks, targeting all four sides of each lesion. Lesion dimensions, including length and width, were documented and monitored weekly. Before the intervention, patients underwent radiographic imaging. After the final injection in week 16, a follow-up radiographic assessment was performed. Data were analyzed using the Generalized Estimating Equation (GEE) method.

Results

The lesions’ size significantly decreased in both length and width during each visit. On average, the lesion length reduced by 2.66%, and the width shrank by 3.32% per visit. Based on radiographic findings, the average length and width of lesions at the initial visit were 12.09 ± 5.05 mm (range: 6.00-25.50 mm) and 6.35 ± 3.00 mm (range: 2.00–16.00 mm), respectively. The average length and width at the last visit were 5.59 ± 7.05 mm (range: 0–23.00 mm) and 3.41 ± 4.05 mm (range: 0–13.00 mm), respectively. No specific side effects related to the treatment were reported.

Conclusions

The results suggest that the direct administration of infliximab into the calcinosis lesions of patients with JDM could be a safe and effective treatment approach.

Trial registration

Name of the registry: The effect of infliximab injection into calcinosis lesions on patients with juvenile dermatomyositis (JDM), Trial registration number: IRCT20210808052107N1, Registration date: 2022-07-22, URL of trial registry record: https://en.irct.ir/trial/58329.
Optimizing exoskeleton assistance to improve walking speed and energy economy for older adults
Authors: Lakmazaheri Ava , Song Seungmoon , Vuong Brian B. , Biskner Blake , Kado Deborah M. , Collins Steven H.
Published: January 2024

Background

Walking speed and energy economy tend to decline with age. Lower-limb exoskeletons have demonstrated potential to improve either measure, but primarily in studies conducted on healthy younger adults. Promising techniques like optimization of exoskeleton assistance have yet to be tested with older populations, while speed and energy consumption have yet to be simultaneously optimized for any population.

Methods

We investigated the effectiveness of human-in-the-loop optimization of ankle exoskeletons with older adults. Ten healthy adults > 65 years of age (5 females; mean age: 72 ± 3 yrs) participated in approximately 240 min of training and optimization with tethered ankle exoskeletons on a self-paced treadmill. Multi-objective human-in-the-loop optimization was used to identify assistive ankle plantarflexion torque patterns that simultaneously improved self-selected walking speed and metabolic rate. The effects of optimized exoskeleton assistance were evaluated in separate trials.

Results

Optimized exoskeleton assistance improved walking performance for older adults. Both objectives were simultaneously improved; self-selected walking speed increased by 8% (0.10 m/s; p = 0.001) and metabolic rate decreased by 19% (p = 0.007), resulting in a 25% decrease in energetic cost of transport (p = 8e-4) compared to walking with exoskeletons applying zero torque. Compared to younger participants in studies optimizing a single objective, our participants required lower exoskeleton torques, experienced smaller improvements in energy use, and required more time for motor adaptation.

Conclusions

Our results confirm that exoskeleton assistance can improve walking performance for older adults and show that multiple objectives can be simultaneously addressed through human-in-the-loop optimization.
Is the commercial determinants conversation confined to the health sciences? Potentially, and that’s a problem
Authors: Hagenaars Luc Louis , Maani Nason , Schmidt Laura Anne
Published: January 2024

The commercial determinants of health (CDoH) are attracting increased interest and are of great importance when discussing how trade affects health. Through a citation analysis of recent foundational CDoH documents (a Lancet paper series and an Oxford University textbook), we find that fully 71% of all citations reference the health sciences. The health sciences may be well suited to documenting the specific pathways of how commercial (by)products and practices harm human health. However, to operationalize upstream solutions for mitigating these harms, our citation analysis suggests that the field can engage political scientists, economists, sociologists, the trade law and business, as well as advocates in civil society and journalism, more so than it currently does. With CDoH explicitly referring to the interaction between commerce and health, CDoH researchers might be uniquely positioned to get health on the agenda of others, which requires that CDoH methods, datasets, evidence reviews, and proposed interventions are drawn from the widest possible range of sources.
A comparative analysis of unhealthy food and beverage television advertising to children in Thailand, between 2014 and 2022
Authors: Jindarattanaporn Nongnuch , Kelly Bridget , Phulkerd Sirinya
Published: January 2024

Background

Food marketing is a key factor that influences children’s dietary behaviors. This study assessed the nature and extent of food and beverage advertising on television (TV) in 2014 and 2022 in Thailand.

Methods

TV was recorded for one week in March 2014 and in May 2022 from 7-9am and 3-7 pm on weekends, and 3-7 pm on weekdays across two channels (64 h recorded each year). The nutrient profile model from Bureau of Nutrition, Ministry of Public Health Thailand was used to classify food and non-alcoholic beverages as: Group A (‘healthy’), Group B (‘less unhealthy’) or Group C (‘unhealthy’).

Results

In 2014, 475 food advertisements were identified, with on average of 6.3 unhealthy food advertisements per hour. In 2022, 659 food advertisements were identified, with an average of 9.2 unhealthy food advertisement per hour. In both time periods, the most frequently advertised food products were non-alcoholic beverages. The rate of unhealthy food advertising per hour of broadcast was significantly higher than for other moderately unhealthy and healthy foods, and was also significantly higher in 2022 than in 2014.

Conclusions

Food and beverage advertising on Thai television is predominantly promotes unhealthy foods and, in particular, sugar-sweetened beverages. Therefore, Thai Government should enact new legislation to protect children from food TV ads in order to control both the frequency and nature of unhealthy TV food marketing to protect the health of Thai children.
Ovarian non-gestational placental site trophoblastic tumor with lung metastasis: further evidence for a distinct category of trophoblastic neoplasm
Authors: Shahi Maryam , Katsakhyan Levon , Hopkins Mark , Allen-Rhoades Wendy , Cepress Marissa K. , Langstraat Carrie , Ishitani Michael B. , Vang Russell , Ronnett Brigitte M. , Xing Deyin
Published: January 2024

We previously described a series of cases which characterize a distinct group of primary ovarian placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) as a non-gestational set consistent with germ cell type/origin. Here we report a new case of ovarian non-gestational PSTT. The patient was a 13 year-old young female admitted for a spontaneous pneumothorax of the left lung. The pathology of lung wedge excision specimen demonstrated metastatic PSTT and ovarian biopsy showed atypical intermediate trophoblastic proliferation which was found to be PSTT in the subsequent salpingo-oophorectomy specimen. In the ovary, the tumor was composed of singly dispersed or small clusters of predominantly mononuclear cells and rare multinucleated cells extensively infiltrating the ovarian parenchyma, tubal mucosa, and paraovarian/paratubal soft tissue. A minor component of mature cystic teratoma (less than 5% of total tumor volume) was present. Immunohistochemically, the neoplastic cells of main tumor were diffusely immunoreactive for hPL, Gata3 and AE1/AE3, and had only rare hCG-positive or p63-positive cells. The morphology and immunohistochemical results support a PSTT. Molecular genotyping revealed an identical genotype pattern between the normal lung tissue and the metastatic PSTT, indicating its non-gestational nature of germ cell type/origin. This case represents the first case of such tumor with distant (lung) metastasis. This case also provides further evidence to support our recommendation that primary ovarian non-gestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, should be formally recognized in classification systems.
Association of initial lactate levels and red blood cell transfusion strategy with outcomes after severe trauma: a post hoc analysis of the RESTRIC trial
Authors: Kosaki Yoshinori , Hongo Takashi , Hayakawa Mineji , Kudo Daisuke , Kushimoto Shigeki , Tagami Takashi , Naito Hiromichi , Nakao Atsunori , Yumoto Tetsuya
Published: January 2024

Background

The appropriateness of a restrictive transfusion strategy for those with active bleeding after traumatic injury remains uncertain. Given the association between tissue hypoxia and lactate levels, we hypothesized that the optimal transfusion strategy may differ based on lactate levels. This post hoc analysis of the RESTRIC trial sought to investigate the association between transfusion strategies and patient outcomes based on initial lactate levels.

Methods

We performed a post hoc analysis of the RESTRIC trial, a cluster-randomized, crossover, non-inferiority multicenter trials, comparing a restrictive and liberal red blood cell transfusion strategy for adult trauma patients at risk of major bleeding. This was conducted during the initial phase of trauma resuscitation; from emergency department arrival up to 7 days after hospital admission or intensive care unit (ICU) discharge. Patients were grouped by lactate levels at emergency department arrival: low (< 2.5 mmol/L), middle (≥ 2.5 and < 4.0 mmol/L), and high (≥ 4.0 mmol/L). We compared 28 days mortality and ICU-free and ventilator-free days using multiple linear regression among groups.

Results

Of the 422 RESTRIC trial participants, 396 were analyzed, with low (n = 131), middle (n = 113), and high (n = 152) lactate. Across all lactate groups, 28 days mortality was similar between strategies. However, in the low lactate group, the restrictive approach correlated with more ICU-free (β coefficient 3.16; 95% CI 0.45 to 5.86) and ventilator-free days (β coefficient 2.72; 95% CI 0.18 to 5.26) compared to the liberal strategy. These findings persisted even after excluding patients with severe traumatic brain injury.

Conclusions

Our results suggest that restrictive transfusion strategy might not have a significant impact on 28-day survival rates, regardless of lactate levels. However, the liberal transfusion strategy may lead to shorter ICU- and ventilator-free days for patients with low initial blood lactate levels.
Implementation status of pharmacological studies in the development of orphan drugs
Authors: Yokoshiki Saki , Arato Teruyo
Published: January 2024

Background

The nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of animal models. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan.

Results

A total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease animal models and normal animals were used for evaluation, since animal models did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials.

Conclusions

It was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus lead to approval.
Neurexin-1-dependent circuit activity is required for the maintenance of photoreceptor subtype identity in Drosophila
Authors: Lim-Kian-Siang Gabrielle , Izawa-Ishiguro Arianna R. , Rao Yong
Published: January 2024

In the human and Drosophila color vision system, each photoreceptor neuron (cone cell in humans and R7/R8 photoreceptor cell in Drosophila) makes a stochastic decision to express a single photopigment of the same family with the exclusion of the others. While recent studies have begun to reveal the mechanisms that specify the generation of cone subtypes during development in mammals, nothing is known about how the mosaic of mutually exclusive cone subtypes is maintained in the mammalian retina. In Drosophila, recent work has led to the identification of several intrinsic factors that maintain the identity of R8 photoreceptor subtypes in adults. Whether and how extrinsic mechanisms are involved, however, remain unknown. In this study, we present evidence that supports that the Drosophila transsynaptic adhesion molecule Neurexin 1 (Dnrx-1) is required non-cell autonomously in R8p subtypes for the maintenance of R8y subtype identity. Silencing the activity of R8p subtypes caused a phenotype identical to that in dnrx-1 mutants. These results support a novel role for Nrx-1-dependent circuit activity in mediating the communication between R8 photoreceptor subtypes for maintaining the subtype identity in the retina.
RPTOR blockade suppresses brain metastases of NSCLC by interfering the ceramide metabolism via hijacking YY1 binding
Authors: Lin Ying , Wu Yun , Zhang Qiangzu , Tu Xunwei , Chen Sufang , Pan Junfan , Xu Nengluan , Lin Ming , She Peiwei , Niu Gang , Chen Yusheng , Li Hongru
Published: January 2024

Background

Ceramide metabolism is crucial in the progress of brain metastasis (BM). However, it remains unexplored whether targeting ceramide metabolism may arrest BM.

Methods

RNA sequencing was applied to screen different genes in primary and metastatic foci and whole-exome sequencing (WES) to seek crucial abnormal pathway in BM + and BM-patients. Cellular arrays were applied to analyze the permeability of blood–brain barrier (BBB) and the activation or inhibition of pathway. Database and Co-Immunoprecipitation (Co-IP) assay were adopted to verify the protein–protein interaction. Xenograft and zebrafish model were further employed to verify the cellular results.

Results

RNA sequencing and WES reported the involvement of RPTOR and ceramide metabolism in BM progress. RPTOR was significantly upregulated in BM foci and increased the permeability of BBB, while RPTOR deficiency attenuated the cell invasiveness and protected extracellular matrix. Exogenous RPTOR boosted the SPHK2/S1P/STAT3 cascades by binding YY1, in which YY1 bound to the regions of SPHK2 promoter (at -353 ~ -365 nt), further promoting the expression of SPHK2. The latter was rescued by YY1 RNAi. Xenograft and zebrafish model showed that RPTOR blockade suppressed BM of non-small cell lung cancer (NSCLC) and impaired the SPHK2/S1P/STAT3 pathway.

Conclusion

RPTOR is a key driver gene in the brain metastasis of lung cancer, which signifies that RPTOR blockade may serve as a promising therapeutic candidate for clinical application.
A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/β-catenin and modulates the immune cells
Authors: Feng Chunyan , Yu Albert , Wang Zhongfu , Wang Kun , Chen Jiawei , Wu Yaojiong , Deng Ting , Chen Huaqing , Hou Yibo , Ma Shaohua , Dai Xiaoyong , Huang Laiqiang
Published: January 2024

Background

Podoplanin (PDPN) is a highly conserved, mucin-type protein specific to the lymphatic system. Overexpression of PDPN is associated with the progression of various solid tumors, and plays an important roles in the tumor microenvironment by regulating the immune system. However, the role of PDPN-mediated signal activation in the progression of melanoma is still unknown.

Methods

PDPN expression was first analyzed in 112 human melanoma tissue microarrays and melanoma cell lines. Functional experiments including proliferation, clone formation, migration, and metastasis were utilized to identify the suppressive effects of PDPN. The Ph.D.TM-12 Phage Display Peptide Library was used to obtain a PDPN antagonist peptide, named CY12-RP2. The immunofluorescence, SPR assay, and flow cytometry were used to identify the binding specificity of CY12-RP2 with PDPN in melanoma cells. Functional and mechanistic assays in vivo and in vitro were performed for discriminating the antitumor and immune activation effects of CY12-RP2.

Results

PDPN was overexpressed in melanoma tissue and cells, and inhibited melanoma cells proliferation, migration, and metastasis by blocking the EMT and Wnt/β-catenin pathway. PDPN antagonistic peptide, CY12-RP2, could specifically bind with PDPN, suppressing melanoma various functions inducing apoptosis in both melanoma cells and 3D spheroids. CY12-RP2 also enhanced the anti-tumor capacity of PBMC, and inhibited melanoma cells growth both in xenografts and allogeneic mice model. Moreover, CY12-RP2 could inhibit melanoma lung metastasis, and abrogated the immunosuppressive effects of PDPN by increasing the proportion of CD3 + CD4 + T cells, CD3 + CD8 + T cells, CD49b + Granzyme B + NK cells, and CD11b + CD86 + M1-like macrophages and the levels of IL-1β, TNF-α, and IFN-γ.

Conclusions

This study has demonstrated the important role of PDPN in the progression of melanoma and formation of immunosuppressive environment, and provided a potential approach of treating melanoma using the novel CY12-RP2 peptide.

Graphical Abstract

In melanoma, PDPN is overexpressed in the cancer cells, and promotes melanoma cells growth and metastasis through activating the Wnt/β-catenin pathway. Treatment with the PDPN antagonistic peptide CY12-RP2 could not only inhibit the melanoma growth and metastasis both in vitro and in vivo through Wnt/β-catenin pathway blockade, but also abrogate the immunosuppressive effects of PDPN through modulating immune cells.
Loratidine is associated with improved prognosis and exerts antineoplastic effects via apoptotic and pyroptotic crosstalk in lung cancer
Authors: Liu Xiwen , Zhong Ran , Huang Jiaxing , Chen Zisheng , Xu Haoxiang , Lin Lixuan , Cai Qi , He Miao , Lao Shen , Deng Hongsheng , Li Caichen , Li Jianfu , Zheng Yongmei , Liu Xiaoyan , Zeng Riqi , He Jianxing , Liang Wenhua
Published: January 2024

Background

Tumor-associated inflammation suggests that anti-inflammatory medication could be beneficial in cancer therapy. Loratadine, an antihistamine, has demonstrated improved survival in certain cancers. However, the anticancer mechanisms of loratadine in lung cancer remain unclear.

Objective

This study investigates the anticancer mechanisms of loratadine in lung cancer.

Methods

A retrospective cohort of 4,522 lung cancer patients from 2006 to 2018 was analyzed to identify noncancer drug exposures associated with prognosis. Cellular experiments, animal models, and RNA-seq data analysis were employed to validate the findings and explore the antitumor effects of loratadine.

Results

This retrospective study revealed a positive association between loratadine administration and ameliorated survival outcomes in lung cancer patients, exhibiting dose dependency. Rigorous in vitro and in vivo assays demonstrated that apoptosis induction and epithelial-mesenchymal transition (EMT) reduction were stimulated by moderate loratadine concentrations, whereas pyroptosis was triggered by elevated dosages. Intriguingly, loratadine was found to augment PPARγ levels, which acted as a gasdermin D transcription promoter and caspase-8 activation enhancer. Consequently, loratadine might incite a sophisticated interplay between apoptosis and pyroptosis, facilitated by the pivotal role of caspase-8.

Conclusion

Loratadine use is linked to enhanced survival in lung cancer patients, potentially due to its role in modulating the interplay between apoptosis and pyroptosis via caspase-8.
Analysis and applications of respiratory surface EMG: report of a round table meeting
Authors: Jonkman A. H. , Warnaar R. S. P. , Baccinelli W. , Carbon N. M. , D’Cruz R. F. , Doorduin J. , van Doorn J. L. M. , Elshof J. , Estrada-Petrocelli L. , Graßhoff J. , Heunks L. M. A. , Koopman A. A. , Langer D. , Moore C. M. , Nunez Silveira J. M. , Petersen E. , Poddighe D. , Ramsay M. , Rodrigues A. , Roesthuis L. H. , Rossel A. , Torres A. , Duiverman M. L. , Oppersma E.
Published: January 2024

Surface electromyography (sEMG) can be used to measure the electrical activity of the respiratory muscles. The possible applications of sEMG span from patients suffering from acute respiratory failure to patients receiving chronic home mechanical ventilation, to evaluate muscle function, titrate ventilatory support and guide treatment. However, sEMG is mainly used as a monitoring tool for research and its use in clinical practice is still limited—in part due to a lack of standardization and transparent reporting. During this round table meeting, recommendations on data acquisition, processing, interpretation, and potential clinical applications of respiratory sEMG were discussed. This paper informs the clinical researcher interested in respiratory muscle monitoring about the current state of the art on sEMG, knowledge gaps and potential future applications for patients with respiratory failure.
Remote ischemic conditioning reduces adverse events in patients with acute ischemic stroke complicating acute myocardial infarction: a randomized controlled trial
Authors: Li Sijie , Xing Xiurong , Wang Lanjing , Xu Jiali , Ren Changhong , Li Yalin , Wang Jing , Liu Zhi , Zhao Heng , Zhao Wenbo , Ji Xunming
Published: January 2024

Background

Acute ischemic stroke (AIS) complicating an acute myocardial infarction (AMI) is not uncommon, but can severely worsen the clinical prognosis. This study aimed to investigate whether remote ischemic conditioning (RIC) could provide clinical benefits to patients with AIS complicating AMI.

Methods

Subjects with AIS complicating AMI were recruited in this double-blind, randomized, controlled trial; assigned to the RIC and sham groups; and respectively underwent twice daily RIC and sham RIC for 2 weeks. All subjects received standard medical therapy. The primary endpoint was the rate of major adverse cardiac and cerebrovascular events (MACCEs) within 3 months after enrollment. MACCEs comprise of death from all causes, unstable anginas, AMI, acute ischemic strokes, and transient ischemic attacks.

Results

Eighty subjects were randomly assigned; 37 patients in the RIC group and 40 patients in the sham-RIC group completed the 3-month follow-up and were included in the final analysis. Both RIC and sham RIC procedures were well tolerated. At 3-month follow-up, 11 subjects (29.7%) in the RIC group experienced MACCEs compared to 21 (52.5%) in the sham group (hazard ratio [HR], 0.396; 95% confidence interval, 0.187–0.838; adjusted p < 0.05). Six subjects (16.2%) in the RIC group had died at the 3-month follow up, significantly lower than the 15 (37.5%) deaths in the sham group (adjusted HR 0.333; 95% CI 0.126–0.881; p = 0.027). Seventeen subjects (45.9%) in the RIC group and 6 subjects (15.0%) in the sham group achieved functional independence (mRS score ≤ 2) at 3-month follow-up (adjusted OR 12.75; 95% CI 2.104–77.21; p = 0.006).

Conclusions

Among patients with acute ischemic stroke complicating acute myocardial infarction, treatment with remote ischemic conditioning decreased the major adverse cardiac and cerebrovascular events and improved functional outcomes at 90 days.

Trial registration: URL: www.clinicaltrials.gov. Unique identifier: NCT03868007. Registered 8 March 2019.
Addition of polygenic risk score to a risk calculator for prediction of breast cancer in US Black women
Authors: Zirpoli Gary R. , Pfeiffer Ruth M. , Bertrand Kimberly A. , Huo Dezheng , Lunetta Kathryn L. , Palmer Julie R.
Published: January 2024

Background

Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC (area under the curve). Following publication of the first PRS to perform well in women of African ancestry (AA-PRS), we conducted an external validation of the AA-PRS and then evaluated the addition of the AA-PRS to a risk calculator for incident breast cancer in Black women based on epidemiologic factors (BWHS model).

Methods

Data from the Black Women’s Health Study, an ongoing prospective cohort study of 59,000 US Black women followed by biennial questionnaire since 1995, were used to calculate AUCs and 95% confidence intervals (CIs) for discriminatory accuracy of the BWHS model, the AA-PRS alone, and a new model that combined them. Analyses were based on data from 922 women with invasive breast cancer and 1844 age-matched controls.

Results

AUCs were 0.577 (95% CI 0.556–0.598) for the BWHS model and 0.584 (95% CI 0.563–0.605) for the AA-PRS. For a model that combined estimates from the questionnaire-based BWHS model with the PRS, the AUC increased to 0.623 (95% CI 0.603–0.644).

Conclusions

This combined model represents a step forward for personalized breast cancer preventive care for US Black women, as its performance metrics are similar to those from models in other populations. Use of this new model may mitigate exacerbation of breast cancer disparities if and when it becomes feasible to include a PRS in routine health care decision-making.
Genetic effects of sequence-conserved enhancer-like elements on human complex traits
Authors: Zhu Xiang , Ma Shining , Wong Wing Hung
Published: January 2024

Background

The vast majority of findings from human genome-wide association studies (GWAS) map to non-coding sequences, complicating their mechanistic interpretations and clinical translations. Non-coding sequences that are evolutionarily conserved and biochemically active could offer clues to the mechanisms underpinning GWAS discoveries. However, genetic effects of such sequences have not been systematically examined across a wide range of human tissues and traits, hampering progress to fully understand regulatory causes of human complex traits.

Results

Here we develop a simple yet effective strategy to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 human tissues and cell types. Combined with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, these elements show tissue-specific enrichments of heritability and causal variants for many traits, which are significantly stronger than enrichments based on enhancers without sequence conservation. These elements also help prioritize candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS with large sample sizes.

Conclusions

Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits in diverse tissues and demonstrate a generalizable strategy of integrating evolutionary and biochemical data to elucidate human disease genetics.
DTX2 promotes glioma development via regulation of HLTF
Authors: Li Ren , Chen Yang , Yang Biao , Li Ziao , Li Peize , Chen Yu , Li Jiayu , He Jianhang , Wu Yongqiang , Sun Yanqi , Wang Xiaogang , Guo Xiaolong , Zhang Wenju , Zhao Yuanli , Guo Geng
Published: January 2024

Background

Human Deltex 2 (DTX2) is a ubiquitin E3 ligase that functions as an oncogene and has been shown to participate in many human cancers. However, the role of DTX2 in glioma progression has remained obscure. In this study, we explore the mechanism underlying the function of DTX2 in glioma progression.

Methods

The associations between DTX2 expression and clinical characteristics of glioma were determined by bioinformatic analysis of data from The Cancer Genome Atlas and Human Protein Atlas. The expression of DTX2 in glioma tissues was detected using immunohistochemistry and western blotting. Lentivirus-mediated gene knockdown and overexpression were used to determine the effects of DTX2 and helicase-like transcription element (HLTF) on glioma cell proliferation and migration with CCK-8, cell colony formation, transwell, and wound healing assays; flow cytometry in vitro; and animal models in vivo. The interaction of the DTX2 and HLTF proteins was verified by immunoprecipitation assay and confocal microscopy.

Results

DTX2 was highly expressed in glioma samples, and this was correlated with worse overall survival. Silencing of DTX2 suppressed glioma cell viability, colony formation, and migration and induced cell apoptosis. In vitro ubiquitination assays confirmed that DTX2 could downregulate HLTF protein levels by increasing ubiquitination of the HLTF protein. We also observed that HLTF inhibited proliferation and migration of glioma cells. Subcutaneous xenografts with DTX2-overexpressing U87 cells showed significantly increased tumor volumes and weights.

Conclusions

We have identified DTX2/HLTF as a new axis in the development of glioma that could serve as a prognostic or therapeutic marker.

Graphical abstract
Dreaming during gastrointestinal endoscopy under propofol, ciprofol, or remimazolam anesthesia: study protocol for a parallel-design double-blind, single-center trial
Authors: Xia Le-Qiang , Zhou Rui , Deng Rui , Zhou Dan , Han Jia , Zhao Zhi-Fu , Gao San-Jie , Zhang Xian-Jie , Zhou Yu-Kai , Xiong Li-Ze
Published: January 2024

Background

Dreaming sometimes occurs during sedation. It has been reported that factors such as different anesthetics, depth of anesthesia, age, sex, and preoperative psychological state may affect dreams. Ciprofol and remimazolam are novel choices for painless endoscopy. Herein, we aimed to investigate dreaming during gastrointestinal endoscopy under propofol, ciprofol, and remimazolam anesthesia respectively.

Methods

This is a prospective, parallel-design double-blind, single-center clinical trial. Three hundred and sixty subjects undergoing elective painless gastroscopy, colonoscopy, or gastroenteroscopy will be enrolled. Eligible subjects will undergo propofol-, ciprofol-, or remimazolam-induced anesthesia to finish the examination. Interviews about the modified Brice questionnaire will be conducted in the recovery room. Incidence of dreaming is set as the primary outcome. Secondary outcomes include type of dreams, improvement of sleep quality, evaluation of patients, incidence of insufficient anesthesia, and intraoperative awareness. Safety outcomes are the incidences of hypotension and hypoxia during examination and adverse events during recovery.

Discussion

This study may observe different incidences of dreaming and diverse types of dreams, which might lead to different evaluations to the anesthesia procedure. Based on the coming results, anesthesiologists can make a better medication plan for patients who are going to undergo painless diagnosis and treatment.

Trial registration

This trial was registered at the Chinese Clinical Trial Registry on May 18, 2023 (registration number ChiCTR2300071565).
ERASURE: early autologous blood pleurodesis for postoperative air leaks—a randomized, controlled trial comparing prophylactic autologous blood pleurodesis versus standard watch and wait treatment for postoperative air leaks following thoracoscopic anatomic lung resections
Authors: Karampinis Ioannis , Ruckes Christian , Doerr Fabian , Bölükbas Servet , Ricciardi Sara , Cardillo Giuseppe , Galvez Carlos , Vidmar Bogdan , Stupnik Tomaz , Fang Vincent , Petersen Rene Horsleben , Roessner Eric Dominic
Published: January 2024

Background

The prolonged air leak is probably the most common complication following lung resections. Around 10–20% of the patients who undergo a lung resection will eventually develop a prolonged air leak. The definition of a prolonged air leak varies between an air leak, which is evident after the fifth, seventh or even tenth postoperative day to every air leak that prolongs the hospital stay. However, the postoperative hospital stay following a thoracoscopic lobectomy can be as short as 2 days, making the above definitions sound outdated. The treatment of these air leaks is also very versatile. One of the broadly accepted treatment options is the autologous blood pleurodesis or “blood patch”. The purpose of this trial is to investigate the impact of a prophylactic autologous blood pleurodesis on reducing the duration of the postoperative air leak and therefore prevent the air leak from becoming prolonged.

Methods

Patients undergoing an elective thoracoscopic anatomic lung resection for primary lung cancer or metastatic disease will be eligible for recruitment. Patients with an air leak of > 100 ml/min within 6 h prior to the morning round on the second postoperative day will be eligible for inclusion in the study and randomization. Patients will be randomized to either blood pleurodesis or watchful waiting. The primary endpoint is the time to drain removal measured in full days. The trial ends on the seventh postoperative day.

Discussion

The early autologous blood pleurodesis could lead to a faster cessation of the air leak and therefore to a faster removal of the drain. A faster removal of the drain would relieve the patient from all the well-known drain-associated complications (longer hospital stay, stronger postoperative pain, risk of drain-associated infection, etc.). From the economical point of view, faster drain removal would reduce the hospital costs as well as the costs associated with the care of a patient with a chest drain in an outpatient setting.

Trial registration

German Clinical Trials Register (DRKS) DRKS00030810. 27 December 2022
Loss of G9a does not phenocopy the requirement for Prdm12 in the development of the nociceptive neuron lineage
Authors: Tsimpos Panagiotis , Desiderio Simon , Cabochette Pauline , Poelvoorde Philippe , Kricha Sadia , Vanhamme Luc , Poulard Coralie , Bellefroid Eric J.
Published: January 2024

Prdm12 is an epigenetic regulator expressed in developing and mature nociceptive neurons, playing a key role in their specification during neurogenesis and modulating pain sensation at adulthood. In vitro studies suggested that Prdm12 recruits the methyltransferase G9a through its zinc finger domains to regulate target gene expression, but how Prdm12 interacts with G9a and whether G9a plays a role in Prdm12’s functional properties in sensory ganglia remain unknown. Here we report that Prdm12-G9a interaction is likely direct and that it involves the SET domain of G9a. We show that both proteins are largely co-expressed in dorsal root ganglia during early murine development, opening the possibility that G9a plays a role in DRG and may act as a mediator of Prdm12’s function in the development of nociceptive sensory neurons. To test this hypothesis, we conditionally inactivated G9a in neural crest using a Wnt1-Cre transgenic mouse line. We found that the specific loss of G9a in the neural crest lineage does not lead to dorsal root ganglia hypoplasia due to the loss of somatic nociceptive neurons nor to the ectopic expression of the visceral determinant Phox2b as observed upon Prdm12 ablation. These findings suggest that Prdm12 function in the initiation of the nociceptive lineage does not critically involves its interaction with G9a.
Discovery of dual rho-associated protein kinase 1 (ROCK1)/apoptosis signal–regulating kinase 1 (ASK1) inhibitors as a novel approach for non-alcoholic steatohepatitis (NASH) treatment
Authors: Zaky Yara A. , Rashad Mai W. , Zaater Marwa A. , El Kerdawy Ahmed M.
Published: January 2024

In the current study we suggest a novel approach to curb non-alcoholic steatohepatitis (NASH) progression, and we suggest privileged scaffolds for the design of novel compounds for this aim. NASH is an advanced form of non-alcoholic fatty liver disease that can further progress into fibrosis, cirrhosis, and hepatocellular carcinoma. It is a widely emerging disease affecting 25% of the global population and has no current approved treatments. Protein kinases are key regulators of cellular pathways, of which, Rho-associated protein kinase 1 (ROCK1) and apoptosis signal–regulating kinase 1 (ASK1) play an important role in the progression of NASH and they stand out as promising targets for NASH therapy. Interestingly, their kinase domains are found to be similar in sequence and topology; therefore, dual inhibition of ROCK1 and ASK1 is expected to be amenable and could achieve a more favourable outcome. To reach this goal, a training set of ROCK1 and ASK1 protein structures co-crystalized with type 1 (ATP-competitive) inhibitors was constructed to manually generate receptor-based pharmacophore models representing ROCK1 and ASK1 inhibitors’ common pharmacophoric features. The models produced were assessed using a test set of both ROCK1 and ASK1 actives and decoys, and their performance was evaluated using different assessment metrics. The best pharmacophore model obtained, showing a Mathew’s correlation coefficient (MCC) of 0.71, was then used to screen the ZINC purchasable database retrieving 6178 hits that were filtered accordingly using several medicinal chemistry and pharmacokinetics filters returning 407 promising compounds. To confirm that these compounds are capable of binding to the target kinases, they were subjected to molecular docking simulations at both protein structures. The results were then assessed individually and filtered, setting the spotlight on various privileged scaffolds that could be exploited as the nucleus for designing novel ROCK1/ASK1 dual inhibitors.
A chemometric approach based on response surface methodology for optimization of antibiotic and organic dyes removal from water samples
Authors: Hsu Chou-Yi , Ali Eyhab , Al-Saedi Haider Falih Shamikh , Mohammed Amjed Qasim , Mustafa Nadia Khalid , Talib Maysm Barzan , Radi Usama Kadem , Ramadan Montather F. , Ami Ahmed Ali , Al-Shuwaili Saeb Jasim , Alawadi Ahmed , Alsalamy Ali , Baharinikoo Leila
Published: January 2024

In this study, the Fe3O4/rGO/Ag magnetic nanocomposite was synthesized and employed as an adsorbent for the removal of tetracycline (TC), crystal violet (CV), and methylene blue (MB) from water samples. The influential parameters in the removal process were identified and optimized using response surface methodology (RSM). Characterization of the product was performed through field emission scanning electron microscopy (FE-SEM), Fourier-transform infrared spectroscopy (FTIR), energy dispersive X-ray spectroscopy (EDX), vibrating-sample magnetometer (VSM), and X-ray diffraction (XRD) analysis. XRD and SEM analysis revealed the successful synthesis of the Fe3O4/rGO/Ag nanocomposite. EDX analysis elucidated the accuracy and clarity of the chemical composition of the magnetic nanocomposite structure. Additionally, the separation of the nano-adsorbent from the solution can be achieved using a magnetic field. Maximum removal of analytes was obtained at pH of 6, amount of nanocomposite 0.014 g, ultrasonic time of 8 min and concentration of 21 mg L−1. Under optimal conditions, the removal efficiencies for TC, CV, and MB were 91.33, 95.82, and 98.19%, respectively. Also, it was observed that after each adsorption–desorption cycle, Fe3O4/rGO/Ag magnetic nanocomposite had good stability to remove TC, CV, and MB. Achieving nearly 98% removal efficiency in optimal conditions showed that Fe3O4/rGO/Ag magnetic nanocomposite is an effective adsorbent for removing TC, CV, and MB from wastewater samples.