bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of protocolized fluid management on electrolyte stability in patients undergoing continuous renal replacement therapy
Authors: Baeg Song In , Jeon Junseok , Kang Danbee , Na Soo Jin , Cho Juhee , Kim Kyunga , Yang Jeong Hoon , Chung Chi Ryang , Lee Jung Eun , Huh Wooseong , Suh Gee Young , Kim Yoon-Goo , Kim Dae Joong , Jang Hye Ryoun
Published: August 2022

Objective

Continuous renal replacement therapy (CRRT) is the standard treatment for critically ill patients with acute kidney injury (AKI). Electrolyte disturbance such as hypokalemia or hypophosphatemia occurs paradoxically in patients undergoing CRRT due to high clearance. We developed a fluid management protocol for dialysate and replacement fluid that depends on serum electrolytes and focuses on potassium and phosphate levels to prevent electrolyte disturbance during CRRT. The impact of our new fluid protocol on electrolyte stability was evaluated.

Methods

Adult patients who received CRRT between 2013 and 2017 were included. Patients treated 2 years before (2013–2014; pre-protocol group) and 2 years following development of the fluid protocol (2016–2017; protocol group) were compared. The primary outcomes were individual coefficient of variation (CV) and abnormal event rates of serum phosphate and potassium. Secondary outcomes were frequency of electrolyte replacement and incidence of cardiac arrhythmias. Individual CV and abnormal event rates for each electrolyte were analyzed using the Wilcoxon rank-sum test and Chi-square test with Yates’ continuity correction.

Results

A total of 1,448 patients was included. Both serum phosphate and potassium were higher in the protocol group. The CVs of serum phosphate (pre-protocol vs. protocol, 0.275 [0.207–0.358] vs. 0.229 [0.169–0.304], p < 0.01) and potassium (0.104 [0.081–0.135] vs. 0.085 [0.064–0.110], p < 0.01) were significantly lower in the protocol group. The abnormal event rates of serum phosphate (rate [95% CI], 0.410 [0.400–0.415] vs. 0.280 [0.273–0.286], p < 0.01) and potassium (0.205 [0.199–0.211] vs. 0.083 [0.079–0.087], p < 0.01) were also significantly lower in the protocol group.

Conclusion

The protocolized management of fluid in CRRT effectively prevented hypophosphatemia and hypokalemia by inducing excellent stability of serum phosphate and potassium levels.
Prognostic value of soluble endoglin in patients with septic shock and severe COVID-19
Authors: Tomášková Veronika , Mýtniková Alexandra , Hortová Kohoutková Marcela , Mrkva Ondřej , Skotáková Monika , Šitina Michal , Helánová Kateřina , Frič Jan , Pařenica Jiří , Šrámek Vladimír , Helán Martin
Published: August 2022

Sepsis is a clinical syndrome characterized by a dysregulated response to infection. It represents a leading cause of mortality in ICU patients worldwide. Although sepsis is in the point of interest of research for several decades, its clinical management and patient survival are improving slowly. Monitoring of the biomarkers and their combinations could help in early diagnosis, estimation of prognosis and patient's stratification and response to the treatment. Circulating soluble endoglin (sEng) is the cleaved extracellular part of transmembrane glycoprotein endoglin. As a biomarker, sEng has been tested in several pathologic conditions where its elevation was associated with endothelial dysfunction. In this study we have tested the ability of sEng to predict mortality and its correlation with other clinical characteristics in the cohort of septic shock patients (n= 37) and patients with severe COVID-19 (n= 40). In patients with COVID-19 sEng did not predict mortality or correlate with markers of organ dysfunction. In contrast, in septic shock the level of sEng was significantly higher in patients with early mortality (p= 0.019; AUC = 0.801). Moreover, sEng levels correlated with signs of circulatory failure (required dose of noradrenalin and lactate levels;p= 0.002 and 0.016, respectively). The predominant clinical problem in patients with COVID-19 was ARDS, and although they often showed signs of other organ dysfunction, circulatory failure was exceptional. This potentially explains the difference between sEng levels in COVID-19 and septic shock. In conclusion, we have confirmed that sEng may reflect the extent of the circulatory failure in septic shock patients and thus could be potentially used for the early identification of patients with the highest degree of endothelial dysfunction who would benefit from endothelium-targeted individualized therapy.
Recirculation in single lumen cannula venovenous extracorporeal membrane oxygenation: A non-randomized bi-centric trial
Authors: Fisser Christoph , Palmér Oscar , Sallisalmi Marko , Paulus Michael , Foltan Maik , Philipp Alois , Malfertheiner Maximilian V. , Lubnow Matthias , Müller Thomas , Broman Lars Mikael
Published: August 2022

Background

Recirculation is a common problem in venovenous (VV) extracorporeal membrane oxygenation (ECMO). The aims of this study were to compare recirculation fraction (Rf) between femoro-jugular and jugulo-femoral VV ECMO configurations, to identify risk factors for recirculation and to assess the impact on hemolysis.

Methods

Patients in the medical intensive care unit (ICU) at the University Medical Center Regensburg, Germany receiving VV ECMO with femoro-jugular, and jugulo-femoral configuration at the ECMO Center Karolinska, Sweden, were included in this non-randomized prospective study. Total ECMO flow (QEC), recirculated flow (QREC), and recirculation fraction Rf= QREC/QECwere determined using ultrasound dilution technology. Effective ECMO flow (QEFF) was defined as QEFF= QEC* (1–Rf). Demographics, cannula specifics, and markers of hemolysis were assessed. Survival was evaluated at discharge from ICU.

Results

Thirty-seven patients with femoro-jugular configuration underwent 595 single-point measurements and 18 patients with jugulo-femoral configuration 231 measurements. Rfwas lower with femoro-jugular compared to jugulo-femoral configuration [5 (0, 11) vs. 19 (13, 28) %, respectively (p< 0.001)], resulting in similar QEFF[2.80 (2.21, 3.39) vs. 2.79 (2.39, 3.08) L/min (p= 0.225)] despite lower QECwith femoro-jugular configuration compared to jugulo-femoral [3.01 (2.40, 3.70) vs. 3.57 (3.05, 4.06) L/min, respectively (p< 0.001)]. In multivariate regression analysis, the type of configuration, distance between the two cannula tips, ECMO flow, and heart rate were significantly associated with Rf [B (95% CI): 25.8 (17.6, 33.8), p < 0.001; 960.4 (960.7, 960.1),p= 0.009; 4.2 (2.5, 5.9), p < 0.001; 960.1 (960.2, 0.0), p = 0.027]. Hemolysis was similar in subjects with Rf > 8 vs. ≤ 8%. Explorative data on survival showed comparable results in the femoro-jugular and the jugulo-femoral group (81 vs. 72%,p= 0.455).

Conclusion

VV ECMO with femoro-jugular configuration caused less recirculation. Further risk factors for higher Rfwere shorter distance between the two cannula tips, higher ECMO flow, and lower heart rate. Rfdid not affect hemolysis.
Persisting sicca complaints in sarcoidosis
Authors: Hofauer Benedikt , Wiesner Miriam , Zhu Zhaojun , Stock Konrad , Peltz Friedhelm , Thuermel Klaus , Strassen Ulrich , Johnson Felix , Knopf Andreas
Published: August 2022

Background

Sarcoidosis is a systemic inflammatory disease that is characterized by non-caseating granulomas. Besides the lung as classical site of involvement, extrapulmonary manifestations are common, for example cervical lymph nodes or the salivary glands. The aim of this investigation is the analysis of the long-term course of glandular symptoms with a focus on persisting sicca symptoms.

Materials and methods

All patients with the diagnosis of sarcoidosis over a period of 20 years in the departments of otorhinolaryngology, nephrology and pneumology were identified. In addition to clinical examinations and functional evaluation of the salivary glands, a sonographic examination of the salivary glands was carried out.

Results

A total of 76 patients were included in the study (age 35.1 ± 21.6 years). At baseline, 32 out of 76 patients were suffering from xerostomia, 36 from dry eyes. While other salivary gland symptoms, such as gland enlargement, pain or facial nerve impairment, dissolved during the further course of the disease, xerostomia was still present in 29 and dry eyes in 35 out of 76 patients at the time of follow-up (which took place on average after 88.2 months).

Conclusion

Sicca symptoms persist in patients with the diagnosis of sarcoidosis, while other salivary gland symptoms completely dissolve during the further course of the disease. This development appears to be independent of the type of therapy and should be considered during the follow-up of these patients, since sicca symptoms can cause further ocular, oral and dental damage.
Enhancement of violaxanthin accumulation in Nannochloropsis oceanica by overexpressing a carotenoid isomerase gene from Phaeodactylum tricornutum
Authors: Sun Yan , Xin Yi , Zhang Luyao , Wang Ying , Liu Ruolan , Li Xiaohui , Zhou Chengxu , Zhang Lin , Han Jichang
Published: August 2022

Nannochloropsis has been considered as a promising feedstock for the industrial production of violaxanthin. However, a rational breeding strategy for the enhancement of violaxanthin content in this microalga is still vacant, thereby limiting its industrial application. All-trans-lycopene locates in the first branch point of carotenogenesis. The carotenoid isomerase (CRTISO), catalyzing the lycopene formation, is thus regarded as a key enzyme for carotenogenesis. Phaeodactylum tricornutum can accumulate high-level carotenoids under optimal conditions. Therefore, it is feasible to improve violaxanthin level in Nannochloropsis by overexpression of PtCRTISO. Protein targeting analysis of seven PtCRTISO candidates (PtCRTISO1–6 and PtCRTISO-like) demonstrated that PtCRTISO4 was most likely the carotenoid isomerase of P. tricornutum. Moreover, the transcriptional pattern of PtCRTISO4 at different cultivation periods was quite similar to other known carotenogenesis genes. Thus, PtCRTISO4 was transformed into N. oceanica. Compared to the wild type (WT), all three transgenic lines (T1–T3) of N. oceanica exhibited higher levels of total carotenoid and violaxanthin. Notably, T3 exhibited the peak violaxanthin content of 4.48 mg g–1 dry cell weight (DCW), which was 1.68-folds higher than WT. Interestingly, qRT-polymerase chain reaction (PCR) results demonstrated that phytoene synthase (NoPSY) rather than ζ-carotene desaturase (NoZDS) and lycopene β-cyclase (NoLCYB) exhibited the highest upregulation, suggesting that PtCRTISO4 played an additional regulatory role in terms of carotenoid accumulation. Moreover, PtCRTISO4 overexpression increased C18:1n-9 but decreased C16:1n-7, implying that C18:1 may serve as a main feedstock for xanthophyll esterification in Nannochloropsis. Our results will provide valuable information for the violaxanthin production from Nannochloropsis.
Non-antibiotic strategies for prevention and treatment of internalized Staphylococcus aureus
Authors: Li Jiangbi , Wen Qiangqiang , Gu Feng , An Lijuan , Yu Tiecheng
Published: August 2022

Staphylococcus aureus (S. aureus) infections are often difficult to cure completely. One of the main reasons for this difficulty is that S. aureus can be internalized into cells after infecting tissue. Because conventional antibiotics and immune cells have difficulty entering cells, the bacteria can survive long enough to cause recurrent infections, which poses a serious burden in healthcare settings because repeated infections drastically increase treatment costs. Therefore, preventing and treating S. aureus internalization is becoming a research hotspot. S. aureus internalization can essentially be divided into three phases: (1) S. aureus binds to the extracellular matrix (ECM), (2) fibronectin (Fn) receptors mediate S. aureus internalization into cells, and (3) intracellular S. aureus and persistence into cells. Different phases require different treatments. Many studies have reported on different treatments at different phases of bacterial infection. In the first and second phases, the latest research results show that the cell wall-anchored protein vaccine and some microbial agents can inhibit the adhesion of S. aureus to host cells. In the third phase, nanoparticles, photochemical internalization (PCI), cell-penetrating peptides (CPPs), antimicrobial peptides (AMPs), and bacteriophage therapy can effectively eliminate bacteria from cells. In this paper, the recent progress in the infection process and the prevention and treatment of S. aureus internalization is summarized by reviewing a large number of studies.
Cognitive and contextual factors modulating grammar learning at older ages
Authors: Rivera Marta , Paolieri Daniela , Iniesta Antonio , Bajo Teresa
Published: August 2022

Second language learning has been shown more difficult for older than younger adults, however, the research trying to identify the sources of difficulty and possible modulating factors is scarce. Extrinsic (learning condition and complexity) and intrinsic factors (executive control) have been related to L2-grammar learning in younger adults. In the present study, we aim to assess whether extrinsic and intrinsic factors are also modulating grammar learning in older adults. We compared the learning performance of younger and older adults in a L2 learning task. 162 Spanish native-speakers (81 young) learnt Japañol (Japanese syntaxis and Spanish lexicon) in either an intentional (metalinguistic explanation) or an incidental (comprehension of sentences) context. The complexity of the sentences was also manipulated by introducing (or not) a subordinate clause. Individual differences in proactivity were measured with the AX-CPT task. After the learning phase, participants performed a Grammatical Judgment Task where they answered if the presented sentences were grammatically correct. No differences between older and younger adults were found. Overall, better results were found for the intentional-condition than for the incidental-condition. A significant interaction between learning context and the proactivity index in the AX-CPT task showed that more proactive participants were better when learning in the incidental-condition. These results suggest that both extrinsic and intrinsic factors are important during language learning and that they equally affect younger and older adults.
Advances in nano-based materials for glioblastoma multiforme diagnosis: A mini-review
Authors: Gusmão Luiza Araújo , Matsuo Flávia Sayuri , Barbosa Hellen Franciane Gonçalves , Tedesco Antonio Claudio
Published: August 2022

The development of nano-based materials for diagnosis enables a more precise prognosis and results. Inorganic, organic, or hybrid nanoparticles using nanomaterials, such as quantum dots, extracellular vesicle systems, and others, with different molecular compositions, have been extensively explored as a better strategy to overcome the blood-brain barrier and target brain tissue and tumors. Glioblastoma multiforme (GBM) is the most common and aggressive primary tumor of the central nervous system, with a short, established prognosis. The delay in early detection is considered a key challenge in designing a precise and efficient treatment with the most encouraging prognosis. Therefore, the present mini-review focuses on discussing distinct strategies presented recently in the literature regarding nanostructures’ use, design, and application for GBM diagnosis.
A bibliometric analysis and visualization of tension-type headache
Authors: Fan Xueming , Fu Guojing , Wang Liuding , Shen Wei , Zhang Yunling
Published: August 2022

Background

Tension-type headache (TTH) is the most prevalent headache in the clinical practice, leading to impaired social activities, work-related disability, and heavy financial burdens. Previous studies have described possible inducement, potential pathophysiology, and clinical management of TTH; however, due to the lack of attention, literature involving bibliometric analysis is sporadic. Therefore, this study aimed to explore the current hotspots and future directions of the TTH field by bibliometric analysis.

Methods

By using CiteSpace and VOSviewer, literature regarding TTH between 2002 and 2021 from the Web of Science database was summarized and extracted. Annual publication trend, the most productive countries/regions and institutions, distribution of categories, co-citation of journals and references, and co-occurrence of keywords were analyzed.

Results

A total of 3,379 publications were included in the final visualization, indicating a stable trend in current research and a lack of breakthroughs over the past decades. These studies were mainly conducted in 120 countries/regions led by the United States and more than 600 institutions. Four eternal core themes were identified in TTH, including neurosciences, nursing, developmental psychology, and general/internal medicine. Cephalalgia ranked first, with the highest number of literature, and is the most influential journal in this area. Keyword analysis demonstrated that the similarities and differences between migraine and TTH, epidemiological studies, clinical double-blind trials, and potential populations have become key issues in the TTH field.

Conclusion

TTH has received less attention and breakthroughs in the past 20 years. To promote coordinated development between regions to fight headaches, cooperation and exchanges between countries and institutions are essential in the future. Relevant studies about headaches in children and adolescents, inducing factors such as emotional triggers and sleep disorders, concomitant diseases, possible pathogenesis, and headache treatments, are in the spotlight in recent years. This study offers a powerful roadmap for further research in this field.
Treatment of depression in the elderly with repetitive transcranial magnetic stimulation using theta-burst stimulation: Study protocol for a randomized, double-blind, controlled trial
Authors: Valiengo Leandro , Pinto Bianca S. , Marinho Kalian A. P. , Santos Leonardo A. , Tort Luara C. , Benatti Rafael G. , Teixeira Bruna B. , Miranda Cristiane S. , Cardeal Henriette B. , Suen Paulo J. C. , Loureiro Julia C. , Vaughan Renata A. R. , Dini Mattar Roberta A. M. P. F. , Lessa Maíra , Oliveira Pedro S. , Silva Valquíria A. , Gattaz Wagner Farid , Brunoni André R. , Forlenza Orestes Vicente
Published: August 2022

Introduction

Transcranial magnetic stimulation (TMS) is a consolidated procedure for the treatment of depression, with several meta-analyses demonstrating its efficacy. Theta-burst stimulation (TBS) is a modification of TMS with similar efficacy and shorter session duration. The geriatric population has many comorbidities and a high prevalence of depression, but few clinical trials are conducted specifically for this age group. TBS could be an option in this population, offering the advantages of few side effects and no pharmacological interactions. Therefore, our aim is to investigate the efficacy of TBS in geriatric depression.

Clinical trial registration

[https://clinicaltrials.gov/ct2/], identifier [NCT04842929].
Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies
Authors: Yang Hai , Li Jinping , Li Xiaoxiong , Ma Linqiu , Hou Mingliang , Zhou Huadong , Zhou Rui
Published: August 2022

Amyloid-β (Aβ) has long been considered as one of the most important pathogenic factors in Alzheimer’s disease (AD), but the specific pathogenic mechanism of Aβ is still not completely understood. In recent years, the development of structural biology technology has led to new understandings about Aβ molecular structures, Aβ generation and clearance from the brain and peripheral tissues, and its pathological toxicity. The purpose of the review is to discuss Aβ metabolism and toxicity, and the therapeutic strategy of AD based on the latest progress in molecular structures of Aβ. The Aβ structure at the atomic level has been analyzed, which provides a new and refined perspective to comprehend the role of Aβ in AD and to formulate therapeutic strategies of AD.
Efficacy of a vegetal mixture composed of Zingiber officinale, Echinacea purpurea, and Centella asiatica in a mouse model of neuroinflammation: In vivo and ex vivo analysis
Authors: Micheli Laura , Toti Alessandra , Lucarini Elena , Ferrara Valentina , Ciampi Clara , Olivero Guendalina , Pittaluga Anna , Mattoli Luisa , Pelucchini Caroline , Burico Michela , Lucci Jacopo , Carrino Donatello , Pacini Alessandra , Pallanti Stefano , Di Cesare Mannelli Lorenzo , Ghelardini Carla
Published: August 2022

Experimental evidence suggests that neuroinflammation is a key pathological event of many diseases affecting the nervous system. It has been well recognized that these devastating illnesses (e.g., Alzheimer’s, Parkinson’s, depression, and chronic pain) are multifactorial, involving many pathogenic mechanisms, reason why pharmacological treatments are unsatisfactory. The purpose of this study was to evaluate the efficacy of a vegetal mixture capable of offering a multiple approach required to manage the multifactoriality of neuroinflammation. A mixture composed of Zingiber officinale (150 mg kg−1), Echinacea purpurea (20 mg kg−1), and Centella asiatica (200 mg kg−1) was tested in a mouse model of systemic neuroinflammation induced by lipopolysaccharide (LPS, 1 mg kg−1). Repeated treatment with the vegetal mixture was able to completely counteract thermal and mechanical allodynia as reported by the Cold plate and von Frey tests, respectively, and to reduce the motor impairments as demonstrated by the Rota rod test. Moreover, the mixture was capable of neutralizing the memory loss in the Passive avoidance test and reducing depressive-like behavior in the Porsolt test, while no efficacy was shown in decreasing anhedonia as demonstrated by the Sucrose preference test. Finally, LPS stimulation caused a significant increase in the activation of glial cells, of the central complement proteins and of inflammatory cytokines in selected regions of the central nervous system (CNS), which were rebalanced in animals treated with the vegetal mixture. In conclusion, the vegetal mixture tested thwarted the plethora of symptoms evoked by LPS, thus being a potential candidate for future investigations in the context of neuroinflammation.
Structural characterization, antioxidant activity and anti-inflammatory of the phosphorylated polysaccharide from Pholiota nameko
Authors: Zhang Xu , Liu Tingting , Wang Xi , Zhou Lanying , Qi Ji , An Siyu
Published: August 2022

In this study, a novel polysaccharide (SPN) was extracted by high-temperature pressure method and purified by a DEAE-52 column and a Sephadx G-100 gel column. PPN was obtained after phosphorylation of SPN. The differences of structural features, antioxidant activity, and anti-inflammatory effect of the two polysaccharides were investigated by chemical methods and RAW 264.7 cell model. SPN (Mw = 15.8 kDa) and PPN (Mw = 27.7 kDa) are an acidic polysaccharide with β-pyranose configuration, mainly containing rhamnose, mannose, glucose, arabinose, and galacose. FI-IR, NMR, and SEM spectra showed phosphorylation of SPN changed its structure. In methylation analysis, the major chains of SPN and PPN were 1,4-linked Glcp, 1,6-linked Galp, 1,2-linked Rhap, and 1.6-linked Manp with terminals of t-linked Glcp, t-linked Araf. The side chain of SPN was 1,4,6-linked Galp, 1,2,5-linked Araf, while the side chain of PPN was 1,4,6-linked Galp, 1,2,4-linked Glcp. In antioxidant activity experiments, the free radical scavenging rate of PPN was stronger than that of SPN. Also, PPN always has better anti-inflammatory on RAW 264.7 cells induced by LPS than that of SPN in same concentration, and it plays an anti-inflammatory role by inhibiting PI3K/AKT/mTOR pathway. The results indicated polysaccharide could significantly improve its antioxidant and anti-inflammatory function after phosphorylation. This study provides a potentially antioxidant and anti-inflammatory health food and drug.
Physical properties, chemical composition, and nutritional evaluation of common salad dressings
Authors: Yin Mingyu , Chen Min , Yanagisawa Takuya , Matsuoka Ryosuke , Xi Yinci , Tao Ningping , Wang Xichang
Published: August 2022

Salad dressings (SDs), a subcategory of flavored sauces with more than 20% fat content and less than 30% moisture content, is favored by consumers due to its delicacy. The physical properties, chemical composition and nutritional evaluation of common SDs on the Chinese market needs to be systematically investigated. This study compared the quality (physical properties, proximate composition, amino acids, fatty acids, and minerals) of six commercially available sweet SDs (SD1, SD2, SD3, SD4, SD5, and SD6) from the Chinese market. The results indicated that the water activity of six SDs was less than 0.60 (0.35–0.41), the moisture content was less than 65% (24.0–60.0%), and the crude fat content was between 23.25 and 64.15%. The essential amino acid index (EAAI) of SD3, SD1, SD2, and SD4 was greater than the FAO/WHO standard (EAAI = 75). Numerous fatty acids were detected, mainly linoleic and oleic acids; n-3 polyunsaturated fatty acids were ranged from 1,090 mg/100 g to 2,520 mg/100 g. In addition, SDs were rich in minerals such as Mg, Ca, and Fe and the atherogenic index and thrombogenic index were 0.03–0.09 and 0.77–0.91, respectively. In summary, this work helps to provide key nutritional information on the composition of common SDs. The availability of this data may help purchasers with different nutritional needs to make informed choices about the use of SD and encourage more moderate consumption of pre-packaged sauces.
Role of mitochondrial translation in remodeling of energy metabolism in ER/PR(+) breast cancer
Authors: Koc Emine C. , Koc Fatih C. , Kartal Funda , Tirona Maria , Koc Hasan
Published: August 2022

Remodeling of mitochondrial energy metabolism is essential for the survival of tumor cells in limited nutrient availability and hypoxic conditions. Defects in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis also cause a switch in energy metabolism from oxidative to aerobic glycolysis contributing to the tumor heterogeneity in cancer. Specifically, the aberrant expressions of mitochondrial translation components such as ribosomal proteins (MRPs) and translation factors have been increasingly associated with many different cancers including breast cancer. The mitochondrial translation is responsible for the synthesis 13 of mitochondrial-encoded OXPHOS subunits of complexes. In this study, we investigated the contribution of mitochondrial translation in the remodeling of oxidative energy metabolism through altered expression of OXPHOS subunits in 26 ER/PR(+) breast tumors. We observed a significant correlation between the changes in the expression of mitochondrial translation-related proteins and OXPHOS subunits in the majority of the ER/PR(+) breast tumors and breast cancer cell lines. The reduced expression of OXPHOS and mitochondrial translation components also correlated well with the changes in epithelial-mesenchymal transition (EMT) markers, E-cadherin (CHD1), and vimentin (VIM) in the ER/PR(+) tumor biopsies. Data mining analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) breast cancer proteome further supported the correlation between the reduced OXPHOS subunit expression and increased EMT and metastatic marker expression in the majority of the ER/PR(+) tumors. Therefore, understanding the role of MRPs in the remodeling of energy metabolism will be essential in the characterization of heterogeneity at the molecular level and serve as diagnostic and prognostic markers in breast cancer.
Phase II INTERACT-ION study: ezabenlimab (BI 754091) and mDCF (docetaxel, cisplatin, and 5-fluorouracil) followed by chemoradiotherapy in patients with Stage III squamous cell anal carcinoma
Authors: Kim Stefano , Boustani Jihane , Vernerey Dewi , Vendrely Véronique , Evesque Ludovic , Francois Eric , Quero Laurent , Ghiringhelli Francois , de la Fouchardière Christelle , Dahan Laëtitia , Bouché Oliver , Chibaudel Benoist , Hajbi Farid El , Vernet Chloé , Rebucci-Peixoto Magali , Feuersinger Alexandra , Maritaz Christophe , Borg Christophe
Published: August 2022

Background

Chemoradiotherapy alone is the standard treatment for locally advanced squamous cell anal carcinoma (SCAC). However, up to 50% of patients will experience recurrence; thus, there is a need for new treatments to improve outcomes. Modified docetaxel, cisplatin and 5-fluorouracil (mDCF) is a treatment option for first-line metastatic SCAC, having shown efficacy in the Epitopes-HPV01 and -02 trials (NCT01845779 and NCT02402842). mDCF treatment also plays a role in the modulation of anti-tumor immunity, suggesting it may be a good combination partner for immunotherapy in patients with SCAC. Anti-programmed death protein-1 (PD-1) immunotherapy has been shown to be effective in metastatic SCAC. We therefore designed the INTERACT-ION study to assess the combination of mDCF with ezabenlimab (BI 754091), an anti-PD-1 antibody, followed by chemoradiotherapy, in patients with Stage III SCAC.

Methods

INTERACT-ION is a pivotal, open-label, single-arm phase II study in patients with treatment-naïve Stage III SCAC. Patients will receive induction treatment with mDCF (docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on Day 1, 5-fluorouracil 1200 mg/m2/day for 2 days) every 2 weeks for 4 cycles and ezabenlimab (240 mg given intravenously) every 3 weeks for 3 cycles. In the absence of disease progression at 2 months, two additional cycles of mDCF and one additional cycle of ezabenlimab will be administered. Patients with radiological objective response, pathological complete/near-complete response and biological complete response will then receive an involved-node radiotherapy with intensity-modulated radiation therapy and concurrent chemotherapy, followed by ezabenlimab alone for seven cycles. All other patients will receive standard chemoradiotherapy. The primary endpoint is the clinical complete response rate 10 months after the first cycle of mDCF plus ezabenlimab. Major secondary endpoints are major pathological response and biological complete response after induction treatment. An extensive ancillary biomarker study in tumor tissue and peripheral blood will also be conducted.

Discussion

The addition of immunotherapy to chemotherapy is an area of active interest in metastatic anal cancer. This pivotal study will evaluate this combination in the locally advanced setting. Ancillary biomarker studies will contribute to the understanding of predictors of response or resistance to treatment.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT04719988, identifier NCT04719988.
Expression and prognosis analysis of PAQR5 in kidney cancer
Authors: Lu Tao , Xu Hai-rong , Dong Wei , Dong Hui
Published: August 2022

Progestin and adipoQ receptor 5 (PAQR5) affects the development of various malignancies and is specifically expressed in kidney. However, the role of PAQR5 in renal carcinoma remains unclear. We assessed the state of PAQR5 expression in kidney renal clear cell carcinoma (KIRC) by The Cancer Genome Atlas and Gene Expression Omnibus datasets. Moreover, immunohistochemistry was performed to observe the expressions of PAQR5 protein in tumor tissues. The relationships between PAQR5 expression and clinical characteristics were investigated by UALCAN. Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter were used to analyze the effect of PAQR5 expression levels on overall survival and relapse-free survival (RFS). The re lationships between clinical characteristics and survival were also evaluated by univariate and multifactorial Cox regression. Gene Ontology term analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and gene set enrichment analysis were performed on PAQR5 to explain the enrichment pathways and functions. Protein and protein interactions were explained by GeneMANIA and STRING. We also explored the relevance of PAQR5 to tumor immune cell infiltration and immunomodulatory molecules by TIMER and GEPIA. Finally, we explored the correlation of PAQR5 with the pathway proteins STATs, HIF-1α, and mTOR using the GSE40435 dataset. PAQR5 expression was low in KIRC and correlated significantly with clinical characteristics including cancer stage, tumor grade, and nodal metastasis status. Low PAQR5 expression was significantly associated with poorer survival. Cox regression analysis indicated that upregulation of PAQR5 was an independent factor for a good prognosis of KIRC. PAQR5 downregulation was associated mainly with STAT3 target upregulation, tumorigenesis, and poor differentiation. PAQR5 expression also correlated positively with B cells, neutrophils, macrophages, and dendritic cells and negatively with the infiltration of FOXP3+ Treg cells and the immune checkpoint molecules PD-1, CTLA4, and LAG3. Moreover, PAQR5 expression in KIRC was negatively correlated with the pathway proteins STAT1/2/3/4/5A, HIF-1α, and mTOR. PAQR5 is an excellent predictor of KIRC prognosis and may be a potential molecular therapeutic target.
Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer
Authors: Zhou Jie , Lai Yiming , Peng Shengmeng , Tang Chen , Chen Yongming , Li Lingfeng , Huang Hai , Guo Zhenghui
Published: August 2022

Background

Although TP53 and SPOP are frequently mutated in metastatic prostate cancer (PCa), their prognostic value is ambiguous, and large sample studies are lacking, especially when they co-occur with other genetic alterations.

Methods

Genomic data and patients’ clinical characteristics in PCa were downloaded from the cBioPortal database. We extensively analyzed other gene alterations in different mutation status of TP53 and SPOP. We further subdivided TP53 and SPOP mutation into subgroups based on different mutation status, and then evaluated the prognostic value. Two classification systems for TP53 survival analysis were used.

Results

A total of 2,172 patients with PCa were analyzed in our study, of which 1,799 were metastatic PCa patients. The mutual exclusivity analysis showed that TP53 and SPOP mutation has a strong mutual exclusion (p<0.001). In multivariable analysis, truncating TP53 mutations (HR=1.773, 95%CI:1.403-2.239, p<0.001) and other TP53 mutations(HR=1.555, 95%CI:1.267-1.908, p<0.001) were independent negative prognostic markers in metastatic PCa, whereas SPOP mutations(HR=0.592, 95%CI:0.427-0.819, p<0.001) were an independent prognostic factor for better prognosis. Mutations in TP53 were significantly associated with wild-type status for SPOP and CDK12, structural variants/fusions for TMPRSS2 and ERG, AR amplification and PTEN deletion (p<0.001). And truncating TP53 mutations have higher AR amplification rates than other TP53 mutations (p=0.022). Consistently, truncating TP53 mutations had a worse prognosis than other TP53 mutations (p<0.05). Then Kaplan-Meier survival curve showed that Co-occurring TP53 mutations in AR amplification or PTEN deletion tumors significantly reduced survival (p<0.05). Furthermore, those with SPOP-mutant tumors with co-occurring TP53 truncating mutations had shorter overall survival than those with SPOP-mutant tumors with wild-type or other TP53 mutations.

Conclusions

This study found that TP53 and SPOP mutations were mutually exclusive and both were independent prognostic markers for metastatic PCa. Genomic alteration and survival analysis revealed that TP53 and SPOP mutations represented distinct molecular subtypes. Our data suggest that molecular stratification on the basis of TP53 and SPOP mutation status should be implemented for metastatic PCa to optimize and modify clinical decision-making.
Neuregulin-1, a potential therapeutic target for cardiac repair
Authors: Wang Yan , Wei Jianliang , Zhang Peng , Zhang Xin , Wang Yifei , Chen Wenjing , Zhao Yanan , Cui Xiangning
Published: August 2022

NRG1 (Neuregulin-1) is an effective cardiomyocyte proliferator, secreted and released by endothelial vascular cells, and affects the cardiovascular system. It plays a major role in heart growth, proliferation, differentiation, apoptosis, and other cardiovascular processes. Numerous experiments have shown that NRG1 can repair the heart in the pathophysiology of atherosclerosis, myocardial infarction, ischemia reperfusion, heart failure, cardiomyopathy and other cardiovascular diseases. NRG1 can connect related signaling pathways through the NRG1/ErbB pathway, which form signal cascades to improve the myocardial microenvironment, such as regulating cardiac inflammation, oxidative stress, necrotic apoptosis. Here, we summarize recent research advances on the molecular mechanisms of NRG1, elucidate the contribution of NRG1 to cardiovascular disease, discuss therapeutic approaches targeting NRG1 associated with cardiovascular disease, and highlight areas for future research.
Effect of corticosteroids combined with cyclophosphamide or mycophenolate mofetil therapy for IgA nephropathy with stage 3 or 4 chronic kidney disease: A retrospective cohort study
Authors: Jia Qing , Ma Feng , Zhao Jin , Yang Xiaoxia , Sun Ruiling , Li Rong , Sun Shiren
Published: August 2022

Background: To determine the safety and efficacy of corticosteroids (CS) combined with cyclophosphamide (CTX), compared with CS combined with mycophenolate mofetil (MMF) for IgA nephropathy (IgAN) patients with stage 3 and 4 CKD and proteinuria ≥1.0 g/24 h in a 10-year real-world study.

Methods: We recruited 296 IgAN patients with renal insufficiency and proteinuria ≥1.0 g/24 h who received uncontrolled supportive care (USC) (n = 44), CS + CTX therapy (n = 164) and CS + MMF therapy (n = 88) in Xijing Hospital from July 2008 to December 2019. The combined event was defined as a ≥50% decrease in eGFR, ESRD, or death.

Results: The median of the follow-up period was 39.3 months. One hundred and twenty-five patients experienced the combined event, 65.9, 37.8, and 38.6% in the USC, CS + CTX, and CS + MMF group, respectively. In multivariate Cox regression analyses, CS combined with CTX (HR = 0.457, 95% CI 0.238-0.878, p = 0.019) significantly reduced the incidence of the combined event, whereas CS + MMF (HR = 0.523, 95% CI 0.246-1.109, p = 0.091) did not reduce the risk of the combined event, compared with USC. The incidence of pneumonia and death due to infection in the CS + MMF group was higher than other two groups.

Conclusion: Compared with USC and CS + MMF therapy, CS + CTX therapy was more safety and possibly more effective. The results need to be further confirmed by large randomized controlled studies.
Novel Sigma-2 receptor ligand A011 overcomes MDR in adriamycin-resistant human breast cancer cells by modulating ABCB1 and ABCG2 transporter function
Authors: Zeng Zhanwei , Liao Shiyi , Zhou Huan , Liu Hongyu , Lin Jiantao , Huang Yunsheng , Zhou Chenhui , Xu Daohua
Published: August 2022

Multidrug resistance (MDR) is thought to be one of the main reasons for the failure of chemotherapy in cancers. ATP-binding cassette subfamily B member 1 (ABCB1) or P-glycoprotein (P-gp) and ATP-binding cassette subfamily G member 2 (ABCG2) play indispensable roles in cancer cell MDR. Sigma-2 (σ2) receptor is considered to be a cancer biomarker and a potential therapeutic target due to its high expression in various proliferative tumors. Recently, σ2 receptor ligands have been shown to have promising cytotoxic effects against cancer cells and to modulate the activity of P-glycoprotein (ABCB1) in vitro experiments, but their specific effects and mechanisms remain to be elucidated. We found that A011, a σ2 receptor ligand with the structure of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, showed promising cytotoxicity against breast cancer MCF-7 and adriamycin-resistant MCF-7 (MCF-7/ADR), induced apoptosis, and reversed adriamycin (ADR) and paclitaxel resistance in MCF-7/ADR cells. Furthermore, we demonstrated that A011 increased the accumulation of rhodamine 123 and mitoxantrone in MCF-7/ADR cells. A011 significantly decreased the ATPase activity of the ABCB1 and down-regulated ABCG2 protein expression. In addition, A011, administered alone or in combination with ADR, significantly inhibited tumor growth in the MCF-7/ADR tumor-bearing nude mouse model. A011 may be a potential therapeutic agent for the treatment of tumor resistance.
Nontargeted metabolomics to characterize the effects of isotretinoin on skin metabolism in rabbit with acne
Authors: Ou-Yang Xiao-Liang , Zhang Deng , Wang Xiu-Ping , Yu Si-Min , Xiao Zhen , Li Wei , Li Chun-Ming
Published: August 2022

Background: Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit. This study aimed to explore the pathogenesis of acne and the therapeutic mechanism of isotretinoin from the metabolic perspective in coal tar-induced acne in rabbits.

Methods: Ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-qTOF-MS) based metabolomics was used to identify skin metabolites in groups C (blank control), M (model group) and T (isotretinoin group). Multivariate statistical analysis was used to process the metabolomics data.

Results: 98 differential metabolites in group C and group M were identified. The highest proportion of differential metabolites were organic acids and derivatives, lipid metabolites, organic heterocyclic compounds, and nucleoside metabolites. The most significant metabolic pathways included protein digestion and absorption, central carbon metabolism in cancer, ABC transporters, aminoacyl-tRNA biosynthesis, biosynthesis of amino acids, and sphingolipid signaling pathway. Isotretinoin treatment normalized eight of these metabolites.

Conclusions: Our study will help to further elucidate the pathogenesis of acne, the mechanism of isotretinoin at the metabolite level, and identify new therapeutic targets for treating acne.
New roles of N6-methyladenosine methylation system regulating the occurrence of non-alcoholic fatty liver disease with N6-methyladenosine-modified MYC
Authors: Cheng Wenli , Li Min , Zhang Luyun , Zhou Cheng , Yu Susu , Peng Xinyue , Zhang Wenji , Zhang Wenjuan
Published: August 2022

Non-alcoholic fatty liver disease (NAFLD) has become a major chronic disease in contemporary society, affected by N6-methyladenosine (m6A) RNA methylation, one of the most common RNA modifications. Compared with healthy control, m6A RNA methyltransferase 3 (METTL3) and METTL14 increased, while Wilms tumor 1-associated protein (WTAP) and RNA-binding motif protein 15 (RBM15) decreased significantly in NAFLD, and the m6A demethylases fat mass and obesity-associated protein (FTO) elevated. Meanwhile, the m6A binding proteins, YT521-B homology (YTH) domain-containing 1 (YTHDC1), YTHDC2, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), and HNRNPA2B1 were decreased, while eukaryotic translation initiation factor 3 subunit H (EIF3H) was increased significantly. All these changes of m6A regulators had significant differences between healthy control and NAFLD, but no differences between the NAFL and NASH group. The expression level of RBM15, HNRNPC, and HNRNPA2B1 were related to body fat index. RBM15, YTHDC2, HNRNPC, HNRNPA2B1, and EIF3H were related to steatosis. Also, KIAA1429 and YTH domain family 1 (YTHDF1) were related to lobular inflammation. Taken together, m6A regulators were involved in the occurrence of NAFLD. More importantly, abnormal MYC was determined as a key link to m6A regulation of NAFLD. The higher MYC mRNA level was accompanied by higher HDL cholesterol and unsaturated fatty acid proportions, as well as lower fat mass, glucose, and transaminase. Taken together, dysregulation of m6A methylation caused steatosis and fibrosis, affecting the occurrence of NAFLD, and MYC might be its potential target.
Magnetic resonance elastography of malignant tumors
Authors: Pagé Gwenaël , Garteiser Philippe , Van Beers Bernard E.
Published: August 2022

Cancer biomechanical properties, including high stiffness, solid stress, and interstitial pressure, as well as altered micro-architecture, are drivers of tumorigenesis, invasiveness and resistance to treatment. Magnetic resonance elastography is an emergent non-invasive imaging method to assess the tumor mechanical properties in a spatially resolved fashion. Several MRE acquisition and reconstruction methods have been developed to assess tumors and surrounding tissues. It is increasingly recognized that the visco-elastic properties assessed with MRE are useful for characterizing malignant tumors and evaluating treatment response in various organs. Generally, malignant tumors, except brain tumors, have high stiffness and high visco-elastic ratio or fluidity. MRE transducers, acquisition sequences and reconstruction algorithms are continuously improved to increase depth penetration and spatial resolution, and limit artifacts at spatial discontinuities. Moreover, assessment of compression stiffening might provide new biomarkers of the altered physical traits of cancer. Increasing research and clinical validation will improve the efficacy of MRE for cancer characterization.
Circadian signatures of adipose tissue in diet-induced obesity
Authors: Xin Haoran , Zhang Jianxin , Huang Rongfeng , Li Lihua , Lam Sin Man , Shui Guanghou , Deng Fang , Zhang Zhihui , Li Min-Dian
Published: August 2022

High-fat diet (HFD) feeding rewires circadian rhythms of peripheral organs including the liver and adipose tissue. While the liver has been extensively studied, it remains largely unknown whether and how HFD organizes circadian biology in adipose tissue. Here, we took a systems approach to profile the diurnal transcriptome of adipose tissue in diet-induced obese mice either fed a low-fat diet (LFD) that reduces weight or still fed HFD. We detected about 200 and 2,500 diurnal genes in HFD and LFD, respectively. Pathway analysis revealed that rhythmic pathways in HFD are represented by circadian rhythm, ribosome biogenesis, and nucleosome organization, whereas those in LFD are represented by myeloid cell function. Remarkably, the majority of the circadian clock genes, except Clock, exhibited robust diurnal rhythm in the adipose tissue of HFD-fed mice. Analysis of mRNAs and proteins in another cohort of HFD-fed mice confirmed that Clock lost rhythmicity at the transcript, but not protein level. Diet reversal to LFD specifically restored diurnal difference of the Clock transcripts in adipose tissue. We matched transcriptomics data with global profiling of neutral lipids and found that lipid metabolism catalyzed by triglycerol hydrolase Ces1d is a key circadian feature that is activated by diet reversal. Together, our work defines the circadian signatures in the adipose tissue of diet-induced obese mice, and their flexibility upon dietary intervention, thereby shedding light on potential clock-modulated tissue-specific pathways during obesity.