bluuebunny/crossref_metadata_2025 huggingface dataset:
Tuning heterologous glucan biosynthesis in yeast to understand and exploit plant starch diversity
Authors: Pfister Barbara , Shields Jessica M. , Kockmann Tobias , Grossmann Jonas , Abt Melanie R. , Stadler Martha , Zeeman Samuel C.
Published: September 2022

Background

Starch, a vital plant-derived polysaccharide comprised of branched glucans, is essential in nutrition and many industrial applications. Starch is often modified post-extraction to alter its structure and enhance its functionality. Targeted metabolic engineering of crops to produce valuable and versatile starches requires knowledge of the relationships between starch biosynthesis, structure, and properties, but systematic studies to obtain this knowledge are difficult to conduct in plants. Here we used Saccharomyces cerevisiae as a testbed to dissect the functions of plant starch biosynthetic enzymes and create diverse starch-like polymers.

Results

We explored yeast promoters and terminators to tune the expression levels of the starch-biosynthesis machinery from Arabidopsis thaliana. We systematically modulated the expression of each starch synthase (SS) together with a branching enzyme (BE) in yeast. Protein quantification by parallel reaction monitoring (targeted proteomics) revealed unexpected effects of glucan biosynthesis on protein abundances but showed that the anticipated broad range of SS/BE enzyme ratios was maintained during the biosynthetic process. The different SS/BE ratios clearly influenced glucan structure and solubility: The higher the SS/BE ratio, the longer the glucan chains and the more glucans were partitioned into the insoluble fraction. This effect was irrespective of the SS isoform, demonstrating that the elongation/branching ratio controls glucan properties separate from enzyme specificity.

Conclusions

Our results provide a quantitative framework for the in silico design of improved starch biosynthetic processes in plants. Our study also exemplifies a workflow for the rational tuning of a complex pathway in yeast, starting from the selection and evaluation of expression modules to multi-gene assembly and targeted protein monitoring during the biosynthetic process.
TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma
Authors: Jiang Vivian Changying , Hao Dapeng , Jain Preetesh , Li Yijing , Cai Qingsong , Yao Yixin , Nie Lei , Liu Yang , Jin Jingling , Wang Wei , Lee Heng-Huan , Che Yuxuan , Dai Enyu , Han Guangchun , Wang Ruiping , Rai Kunal , Futreal Andrew , Flowers Christopher , Wang Linghua , Wang Michael
Published: September 2022

Background

Chimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the only CAR T-cell therapy approved by the FDA for MCL. However, development of relapses to BA is recognized with poor patient outcomes. Multiple CAR T-cell therapies have been approved for other lymphomas and the resistance mechanisms have been investigated. However, the mechanisms underlying BA relapse in MCL have not been investigated and whether any previously reported resistance mechanisms apply to BA-relapsed patients with MCL is unknown.

Methods

To interrogate BA resistance mechanisms in MCL, we performed single-cell RNA sequencing on 39 longitudinally collected samples from 15 BA-treated patients, and multiplex cytokine profiling on 80 serial samples from 20 patients.

Results

We demonstrate that after BA relapse, the proportion of T cells, especially cytotoxic T cells (CTLs), decreased among non-tumor cells, while the proportion of myeloid cells correspondingly increased. TIGIT, LAG3, and CD96 were the predominant checkpoint molecules expressed on exhausted T cells and CTLs; only TIGIT was significantly increased after relapse. CTLs expanded during remission, and then contracted during relapse with upregulated TIGIT expression. Tumor cells also acquired TIGIT expression after relapse, leading to the enhanced interaction of tumor cell TIGIT with monocyte CD155/PVR. In myeloid cells, post-relapse HLA-II expression was reduced relative to pretreatment and during remission. Myeloid-derived suppressor cells (MDSCs) were enriched after relapse with elevated expression of activation markers, including CLU (clusterin) and VCAN (versican). Extracellular chemokines (CCL4, CXCL9, CXCL13), soluble checkpoint inhibitors (sPD-L1, sTIM3, s4-1BB), and soluble receptors (sIL-2R, sTNFRII) were decreased during remission but elevated after relapse.

Conclusions

Our data demonstrate that multiple tumor-intrinsic and -extrinsic factors are associated with T-cell suppression and BA relapse. Among these, TIGIT appears to be the central player given its elevated expression after BA relapse in not only CTLs but also MCL cells. The acquisition of TIGIT expression on tumor cells is MCL-specific and has not been reported in other CAR T-treated diseases. Together, our data suggest that co-targeting TIGIT may prevent CAR T relapses and thus promote long-term progression-free survival in MCL patients.
A bimodal type of AgPd Plasmonic Blackbody Nanozyme with boosted catalytic efficacy and synergized photothermal therapy for efficacious tumor treatment in the second biological window
Authors: Jia Tao , Li Dan , Du Jiarui , Fang Xikui , Gerasimov Valeriy , Ågren Hans , Chen Guanying
Published: September 2022

Nanozymes are promising for precise cancer treatment, but are typically limited in terms of the low catalytic efficiency and the complexity in tumor microenvironment (TME). Herein, we describe a bimodal type of AgPd plasmonic blackbody (AgPd PB) nanozyme of compact sizes (< 30 nm), which presents not only boosted enzyme efficacy but also efficient photothermal therapy (PTT) for synergized therapy through tissue-penetrating light in the second biological window (1000–1700 nm). The synthesized hyperbranched AgPd PB nanozymes possess intense and broadband localized surface plasmonic resonance absorption of 400–1300 nm, entailing prominent photothermal efficiency (η = 45.1% at 1064 nm) for PTT. Importantly, PTT was found to significantly boost the nanozyme efficacy of both catalase (CAT) and peroxidase (POD) processes, which correspondingly decompose H2O2 to into O2 to relieve tumor hypoxia, and activate H2O2 to generate oxidative •OH radical. While the generated •OH was found to be able to minimize heat shock proteins (HSPs), which plays a vital role to counterbalance PTT effect both in vitro and in vivo. As compared to control ground without treatment, the synergized nanozyme and PTT activities resulted in about 7-fold reduction of tumor volume, thus elevating the survival rate from 0 to 80% at 30 days posttreatment. Besides the synergistic therapy, the AgPd PB nanozyme were shown to own fluorescence, computed tomography (CT), and photoacoustic (PA) imaging abilities, thus having implications for uses in imaging-guided precise cancer therapy. This study provides a paradigm of TME responsive theranostics under NIR-II light irradiation.

Graphical Abstract
A physicochemical double-cross-linked gelatin hydrogel with enhanced antibacterial and anti-inflammatory capabilities for improving wound healing
Authors: Lu Yapeng , Zhao Meihui , Peng Ye , He Sizhe , Zhu Xiaopeng , Hu Chao , Xia Guanghua , Zuo Tao , Zhang Xueying , Yun Yonghuan , Zhang Weimin , Shen Xuanri
Published: September 2022

Background

Skin tissue is vital in protecting the body from injuries and bacterial infections. Wound infection caused by bacterial colonization is one of the main factors hindering wound healing. Wound infection caused by colonization of a large number of bacteria can cause the wound to enter a continuous stage of inflammation, which delays wound healing. Hydrogel wound dressing is composed of natural and synthetic polymers, which can absorb tissue fluid, improve the local microenvironment of wound, and promote wound healing. However, in the preparation process of hydrogel, the complex preparation process and poor biological efficacy limit the application of hydrogel wound dressing in complex wound environment. Therefore, it is particularly important to develop and prepare hydrogel dressings with simple technology, good physical properties and biological effects by using natural polymers.

Results

In this study, a gelatin-based (Tsg-THA&Fe) hydrogel was created by mixing trivalent iron (Fe3+) and 2,3,4-trihydroxybenzaldehyde (THA) to form a complex (THA&Fe), followed by a simple Schiff base reaction with tilapia skin gelatin (Tsg). The gel time and rheological properties of the hydrogels were adjusted by controlling the number of complexes. The dynamic cross-linking of the coordination bonds (o-phthalmictriol-Fe3+) and Schiff base bonds allows hydrogels to have good self-healing and injectable properties. In vitro experiments confirmed that the hydrogel had good biocompatibility and biodegradability as well as adhesion, hemostasis, and antibacterial properties. The feasibility of Tsg-THA&Fe hydrogel was studied by treating rat skin trauma model. The results showed that compared with Comfeel® Plus Transparent dressing, the Tsg-THA&Fe hydrogel could obvious reduce the number of microorganisms, prevent bacterial colonization, reduce inflammation and accelerate wound healing. Local distribution of the Tsg-THA&Fe hydrogel in the skin tissue did not cause organ toxicity.

Conclusions

In summary, the preparation process of Tsg-THA&Fe hydrogel is simple, with excellent performance in physical properties and biological efficacy. It can effectively relieve inflammation and control the colonization of wound microbes, and can be used as a multi-functional dressing to improve wound healing.

Graphical Abstract
Pathological and oncological outcomes of pylorus-preserving versus conventional distal gastrectomy in early gastric cancer: a systematic review and meta-analysis
Authors: Hou Sen , Liu Fan , Gao Zhidong , Ye Yingjiang
Published: September 2022

Background

Pylorus-preserving gastrectomy (PPG) is a function-preserving surgery for the treatment of early gastric cancer (EGC) in the middle third of the stomach. According to the literature reports, PPG decreases the incidence of dumping syndrome, bile reflux, gallstone formation, and nutritional deficit compared with conventional distal gastrectomy (CDG). However, the debates about PPG have been dominated by the incomplete lymphadenectomy and oncological safety. We carried out a systematic review and meta-analysis to evaluate the pathological and oncological outcomes of PPG.

Methods

The protocol was registered in PROSPERO under number CRD42022304677. Databases including PubMed, Embase, Web of Science, and the Cochrane Register of Controlled Trials were searched before February 21, 2022. The outcomes included the pooled odds ratios (ORs) for dichotomous variables and weighted mean differences (WMDs) for continuous variables. For all outcomes, 95% confidence intervals (CIs) were calculated. Meta-analysis was performed using STATA software (Stata 14, Stata Corporation, Texas) and Review Manager 5.4.

Results

A total of 4500 patients from 16 studies were included. Compared with the CDG group, the PPG group had fewer lymph nodes harvested (WMD= −3.09; 95% CI −4.75 to −1.43; P < 0.001). Differences in the number of resected lymph nodes were observed at stations No. 5, No. 6, No. 9, and No. 11p. There were no differences in lymph node metastasis at each station. Shorter proximal resection margins (WMD = −0.554; 95% CI −0.999 to −0.108; P = 0.015) and distal resection margins (WMD = −1.569; 95% CI −3.132 to −0.007; P = 0.049) were observed in the PPG group. There were no significant differences in pathological T1a stage (OR = 0.99; 95% CI 0.80 to 1.23; P = 0.88), T1b stage (OR = 1.01; 95% CI 0.81 to 1.26; P = 0.88), N0 stage (OR = 0.97; 95% CI 0.63 to 1.48; P = 0.88), tumor size (WMD = −0.10; 95% CI −0.25 to 0.05; P = 0.187), differentiated carcinoma (OR = 1.04; 95% CI 0.74 to 1.47; P = 0.812) or signet ring cell carcinoma (OR = 1.22; 95% CI 0.90 to 1.64; P = 0.198). No significant differences were observed between the groups in terms of overall survival (HR = 0.63; 95% CI 0.24 to 1.67; P = 0.852) or recurrence-free survival (HR = 0.29; 95% CI 0.03 to 2.67; P = 0.900).

Conclusions

The meta-analysis of existing evidence demonstrated that the survival outcomes of PPG may be comparable to those of CDG. However, fewer lymph nodes at stations in No. 5, No. 6, No. 9, and No. 11p were harvested with PPG. We also found shorter proximal resection margins and distal resection margins for PPG, meaning more remnant stomachs would be preserved in PPG.
Preoperative low absolute lymphocyte count to fibrinogen ratio correlated with poor survival in nonmetastatic colorectal cancer
Authors: Huang Xiang , Huan Yu , Liu Long , Ye Qianwen , Guo Jian , Yan Bing
Published: September 2022

Background

Preoperative absolute lymphocyte count (LC) and fibrinogen (FIB) are useful prognostic indicators in colorectal cancer (CRC). However, the prognostic value of the LC to FIB ratio (LFR) has never been addressed.

Methods

A total of 189 nonmetastatic CRC patients after resection were enrolled retrospectively. The significance of the LFR in predicting disease-free survival (DFS) and overall survival (OS) was estimated by receiver operating characteristic curve analysis, and the prognostic efficacy was compared with individual LC and FIB. Patients were assigned to LFR low or high subgroups. Differences in clinicopathological features among these subgroups were calculated, and the survival differences of these subgroups were determined by the Kaplan-Meier analysis. A Cox proportional hazards model was applied to test the risk factors for survival.

Results

Taking 0.54 as the optimal cutoff point, the LFR had sensitivities of 79.70% and 86.40% and specificities of 52.30% and 51.00% in predicting the DFS and OS, respectively. A total of 109/189 (57.67%) patients were assigned to the LFR low group, and these patients were more likely to be characterized by criteria such as T3 + T4 (P < 0.01), stage 3 (P < 0.01), tumor deposits (P = 0.01), high CEA (P < 0.01), or CA19-9 levels (P = 0.04). And they also displayed worse DFS (log rank = 18.57, P < 0.01) and OS (log rank = 20.40, P < 0.01) than the high LFR group. Finally, the LFR was independently associated with inferior DFS (HR = 0.32, 95% CI: 0.16–0.61, P < 0.01) and OS (HR = 0.23, 95% CI: 0.09–0.55, P < 0.01).

Conclusions

The LFR is a useful prognostic indicator in nonmetastatic CRC, and patients with a relatively low LFR had poor survival.
The renal pelvis urobiome in the unilateral kidney stone patients revealed by 2bRAD-M
Authors: Hong Sen-Yuan , Yang Yuan-Yuan , Xu Jin-Zhou , Xia Qi-Dong , Wang Shao-Gang , Xun Yang
Published: September 2022

Background

The pathogenesis of kidney stone disease (KSD) is not fully understood, and potential contributing factors remain to be explored. Several studies have revealed that the urinary microbiome (urobiome) of stone formers was distinct from that of healthy individuals using 16S rRNA gene sequencing, most of which only provided microbial identification at the genus level. 2bRAD sequencing for Microbiome (2bRAD-M) is a novel sequencing technique that enables accurate characterization of the low-biomass microbiome at the species resolution. We aimed to apply 2bRAD-M to profile the renal pelvis urobiome of unilateral kidney stone patients and compared the urobiome with and without stone(s).

Method

A total of 30 patients with unilateral stones were recruited, and their renal pelvis urine from both sides was collected. A ureteroscope was inserted into the renal pelvis with stone(s) and a ureteral catheter was placed into the ureteroscope to collect renal pelvis urine. This procedure was repeated again with new devices to collect the urine of the other side. 2bRAD-M was performed to characterize the renal pelvis urobiome of unilateral stone formers to explore whether microbial differences existed between the stone side and the non-stone side.

Results

The microbial community composition of the stone side was similar to that of the non-stone side. Paired comparison showed that Corynebacterium was increased and Prevotella and Lactobacillus were decreased in the stone side. Four species (Prevotella bivia, Lactobacillus iners, Corynebacterium aurimucosum, and Pseudomonas sp_286) were overrepresented in the non-stone side. 24 differential taxa were also identified between two groups by linear discriminant analysis effect size (LEfSe). Extensive and close connections among genera and species were observed in the correlation analysis. Moreover, a random forest classifier was constructed using specific enriched species, which can distinguish the stone side from the non-stone side with an accuracy of 71.2%.

Conclusion

This first 2bRAD-M microbiome survey gave an important hint towards the potential role of urinary dysbiosis in KSD and provided a better understanding of mechanism of stone formation.
Asbestos awareness among the residents of St. Kitts and Nevis: a cross-sectional study
Authors: Jeffers Denrick , Liao Yu-Chi , Takahashi Ken , Lin Ro-Ting
Published: September 2022

Background

High levels of public awareness regarding the hazards of asbestos, rights to health, and benefits of an asbestos-free country can increase advocacy and political commitment to a total ban on asbestos. We aimed to investigate asbestos awareness and associated sociodemographic characteristics among the adult population of St. Kitts and Nevis.

Methods

In this cross-sectional study, 1009 participants completed an online questionnaire with questions about sociodemographic data and asbestos awareness. We applied multiple regression models to estimate associations between sociodemographic factors, levels of asbestos knowledge, and attitudes toward asbestos management.

Results

We found that 70% of residents of St. Kitts and Nevis considered asbestos exposure to be a general public concern and believed the government should prevent it. Of all participants, 54% were in favor of completely banning the use and importation of all asbestos products and materials; those with higher levels of asbestos knowledge were more likely to favor a total ban. Higher proportions and odds of favoring a total asbestos ban were also observed in participants aged ≥ 30 years, women, those with higher education, and those living in St. Kitts (vs. Nevis).

Conclusions

These findings support implementing policies to regulate and outright ban the use of asbestos products and materials in St. Kitts and Nevis. This data can be used to develop tailored campaigns to improve asbestos knowledge among sociodemographic groups with lower asbestos awareness, such as in the wider Caribbean and other under-resourced countries.
A two-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family: clinical presentations, pathological characteristics and genetic analysis: a case report
Authors: Yang Dun , Zheng Jiaoyun , Tang Fei , He Qiongzhi , Huang Hui , Zhou Peng
Published: September 2022

Background

Hyperparathyroidism-Jaw Tumor (HPT-JT) is caused by inactivating germline mutations of CDC73. This hereditary disease can present with a range of symptoms. Jaw ossifying fibroma (OF) is one of the most important clinical presentations, affecting 30% of HPT-JT patients. However, OF is easily confused with other fibro-osseous lesions (FOLs) of the jaw. The correct diagnosis of HPT-JT is a real challenge and must be confirmed by genetic testing.

Case presentation

A female proband and her father suffered from multiple and recurrent FOLs in the jaw. Considering well demarcated margin and heterogeneous calcified substance lying in a variable density of fibrous stroma, we reached the diagnosis of jaw OF through radiologic and microscopic analyses. Additionally, the proband presented with chronic anemia resulting from menorrhagia, as well as renal mixed epithelial and stromal tumor (MEST). Two patients both presented with no evidence of Hyperparathyroidism (HPT). A germline start codon mutation (c.1A > G) of CDC73 was identified in them. Copy number loss at the CDC73 gene locus was verified in the jaw tumor sample of the proband.

Conclusion

Regardless of whether HPT manifestations are present, patients with heritable jaw OF may be at risk for HPT-JT. Genetic testing should be adopted to confirm the diagnosis. Early recognition of HPT-JT helps to better develop tailored treatment plans and surveillance programs.
DICER1-associated central nervous system sarcoma with neural lineage differentiation: a case report
Authors: Yao Kun , Duan Zejun , Feng Jing , Yan Changxiang , Qi Xueling
Published: September 2022

Background

DICER1-associated central nervous system sarcoma (DCS) without evidence of other cancer-related syndromes is rare. Though the morphology of DCS was highly variable, the immunophenotype was predominant myogenic phenotype. Other lineage markers were consistently negative.

Case presentation

We report a case of DCS with neurogenic differentiation proved by immunohistochemical staining and whole-exome sequencing (WES). An 8-year-old female patient presented with 8-day history of headache, nausea and vomiting. Magnetic resonance imaging (MRI) revealed a heterogeneous mass in the left parietal lobe. The patient underwent the craniotomy via left parietal approach to resect the tumor completely. Histologically, the tumor predominately showed fibrosarcoma-like spindle cells with obvious cytoplasmic eosinophilic globules. Immunohistochemically, the tumor stained positively for DICER1, Desmin, and several neurogenic markers. DICER1 somatic hotspot mutation was confirmed by WES, as well as TP53 and RAF1 mutations which were commonly found in DCS, and other sarcoma-associated genes including AR, AXL and ETV5 mutations. Subsequently, the result of Gene Ontology (GO) analysis showed that the mutated genes in this case were involved in neuron development. All of these findings indicated the diagnosis of DCS with neurogenic differentiation. Postoperatively, the patient received high-dose radiotherapy (60 Gy) and chemotherapy. There was no MRI evidence of tumor recurrence at the 21-month postoperative follow-up.

Conclusions

This unusual DCS case with neuronal differentiation is an important addition to the immuno-phenotypic spectrum of DCS. Although the prognosis for DCS is poor, gross tumor resection with high dose radiotherapy and chemotherapy may assist in prolonging survival.
The genomic stability regulator PTIP is required for proper chromosome segregation in mitosis
Authors: Zhang Fengxia , Wei Mingxuan , Chen Haoran , Ji Liting , Nie Yan , Kang Jungseog
Published: September 2022

Background

The Pax transcription activation domain-interacting protein (PTIP) is a nuclear protein that is an essential component of H3K4 methylation for gene activation in vascular, kidney, B cell, and adipocyte development. Furthermore, it plays a key role in genomic stability in higher eukaryotic cells. It binds to 53BP1 and antagonizes inappropriate homologous recombination for a proper DNA damage response. Interestingly, an early study reported mitotic defects after PTIP inactivation, but it is not clear whether PTIP directly facilitates mitotic processes.

Results

Here, we showed that PTIP is essential for the mitotic integrity of HeLa cells. PTIP inactivation increases cell death during mitotic exit, which appears to result from direct mitotic defects. PTIP inactivation did not affect the G2M DNA damage checkpoint during interphase upon etoposide treatment. However, in mitosis, PTIP inactivation results in prolonged mitotic time, inefficient chromosome alignment, and increased cell death. Furthermore, PTIP localizes to the mitotic centrosome via BRCT domains at the C-terminus.

Conclusion

This study reveals a novel function of PTIP in maintaining the genomic stability of higher eukaryotes during mitosis. Therefore, its deregulation, which occurs in various tumors, may destabilize the genome by introducing an abnormal DNA damage response, as well as erroneous chromosome segregation.
Circ_0051079 functions as an oncogenic regulator in osteosarcoma by leading to MAFB expression upregulation by competitively interacting with miR-1286
Authors: Huang Zhong , Chen Pengcheng , Jia Ruipeng , Liu Yiheng
Published: September 2022

Background

Circular RNAs are involved in various cellular processes of bone diseases by acting as miRNA sponges to regulate gene expression levels, including osteosarcoma (OS). This research concentrated on the molecular mechanism of circ_0051079 in OS progression.

Methods

Reverse transcription-quantitative polymerase chain reaction assay was used for expression detection of circ_0051079, microRNA-1286 (miR-1286), and musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB). Cell Counting Kit-8 assay and Edu assay were used for cell proliferation analysis. Cell apoptosis was evaluated using flow cytometry. Western blot was performed to measure protein levels. Migration and invasion were assessed via transwell assay. Interaction of circ_0051079/miR-1286 or miR-1286/MAFB was explored through a dual-luciferase reporter assay. In vivo research was carried out via tumor xenograft assay and immunohistochemistry staining.

Results

Circ_0051079 expression was upregulated in OS. Downregulation of circ_0051079 reduced OS cell proliferation, migration, invasion, and accelerated apoptosis. Circ_0051079 interacted with miR-1286, and the tumor-inhibitory function of si-circ_0051079 was abolished by miR-1286 inhibition in OS cells. MAFB served as a target for miR-1286. OS cell progression was suppressed by miR-1286 overexpression via downregulating MAFB. Circ_0051079/miR-1286 resulted in expression change of MAFB in OS cells. Silencing circ_0051079 inhibited tumor growth in vivo via regulating the miR-1286/MAFB axis.

Conclusion

The collective results elucidated that circ_0051079 contributed to OS progression via miR-1286-mediated upregulation of MAFB, confirming the interaction of circ_0051079/miR-1286/MAFB axis in OS.
Characterization of a novel polysaccharide from red ginseng and its ameliorative effect on oxidative stress injury in myocardial ischemia
Authors: Lian Yuanpei , Zhu Maomao , Yang Bing , Wang Xianfeng , Zeng Jingqi , Yang Yanjun , Guo Shuchen , Jia Xiaobin , Feng Liang
Published: September 2022

Background

Red ginseng (RG) was widely used as traditional Chinese medicine (TCM) or dietary supplement. However, few researches had been reported on the red ginseng polysaccharide (RGP).

Methods

In this study, a novel heteropolysaccharide named RGP1-1 was fractionated sequentially by DEAE-52 column and Sephadex G-100 gel column. The primary structure of RGP1-1, including glycosyl linkages, molecular weight, monosaccharide composition, morphology and physicochemical property were conducted by nuclear magnetic resonance (NMR), gas chromatography-mass spectrometer (GC–MS), atomic force microscope (AFM), scanning electron microscope (SEM), differential scanning calorimetry-thermogravimetric analysis (DSC-TG) and so on. The effect of RGP1-1 in preventing and treating myocardial ischemia was evaluated by an animal model isoprenaline (ISO) induced mice.

Results

RGP1-1, with a homogeneous molecular weight of 5655 Da, was composed of Glc and Gal in the ratio of 94.26:4.92. The methylation and NMR analysis indicated the backbone was composed of → 1)-Glcp-(4 → and → 1)-Galp-(4 →, branched partially at O-4 with α-D-Glcp-(1 → residue. Morphology and physicochemical property analysis revealed a triple-helical conformation, flaky and irregular spherical structure with molecule aggregations and stable thermal properties of RGP1-1. And it contained 6.82 mVzetapotential, 117.4 nm partical size and polymerization phenomenon. Furthermore, RGP1-1 possessed strong antioxidant activity in vitro and in vivo, RGP1-1 could decrease cardiomyocyte apoptosis and myocardium fibrosis of mice in histopathology and it could decrease significantly the serum levels of cardiac troponin (cTnI), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), malondialdehyde (MDA). Western blot analysis showed that RGP1-1 can increase the expression of main protein Nuclear factor E2-related factor 2(Nrf2), NAD(P)H:quinone oxidoreductase 1 (NQO1), heme oxygenase-1(HO-1) and kelch-like ECH-associated protein1(keap1) in oxidative stress injure progress, and therefore regulate the pathway of Nrf2/HO-1.

Conclusion

The above findings indicated that RGP1-1 had an improving effect on ISO-induced myocardial ischemia injury in mice, as novel natural antioxidant and heart-protecting drugs.
AADAC protects colorectal cancer liver colonization from ferroptosis through SLC7A11-dependent inhibition of lipid peroxidation
Authors: Sun Rongquan , Lin Zhifei , Wang Xiangyu , Liu Lu , Huo Meisi , Zhang Rui , Lin Jing , Xiao Chao , Li Yitong , Zhu Wenwei , Lu Lu , Zhang Jubo , Chen Jinhong
Published: September 2022

Background

Oxidative stress is a highly active metabolic process in the liver, that poses great threats to disseminated tumor cells during their colonization. Here, we aimed to investigate how colorectal cancer (CRC) cells overcome lipid peroxidation to sustain their metastatic colonization in the liver.

Methods

Orthotopic colorectal liver metastasis (CRLM) and CRC liver colonization mouse models were constructed to determine the roles of lipid peroxidation and AADAC in CRC liver colonization. The levels of lipid peroxidation were detected in cells or tissues. AADAC overexpression in LMs and its clinical relevance were analyzed. The oncogenic role of AADAC in CRC liver colonization was evaluated in cell experiments.

Results

Compared with primary tumors (PTs), liver metastases (LMs) showed significantly lower glutathione to oxidized glutathione (GSH/GSSG) ratio and higher malondialdehyde (MDA) levels in CRLM patients and orthotopic mouse models. Inhibition of lipid peroxidation by liproxstatin-1 promoted CRC liver colonization in mouse models. RNA-seq results revealed AADAC as the most significantly upregulated lipid metabolism related gene in LMs compared with PTs. Analyses of datasets and patient and mouse model samples confirmed that AADAC was upregulated in LMs compared with PTs, and was correlated with poor prognosis. AADAC promoted cell proliferation, and facilitated liver colonization in a mouse model by reducing ROS accumulation, which led to lipid peroxidation and ferroptosis. Mechanistically, AADAC upregulated SLC7A11 by activating NRF2 to inhibit lipid peroxidation, thereby protecting metastatic cells from ferroptosis.

Conclusions

AADAC protects metastatic CRC cells from ferroptosis by inhibiting lipid peroxidation in an SLC7A11-dependent manner, thus effectively promoting their metastatic colonization and growth in the liver. Together, our findings suggest that AADAC can act as a prognostic indicator and potential therapeutic target for CRLM.
Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation
Authors: Gámez-Chiachio Manuel , Molina-Crespo Ángela , Ramos-Nebot Carmen , Martinez-Val Jeannette , Martinez Lidia , Gassner Katja , Llobet Francisco J. , Soriano Mario , Hernandez Alberto , Cordani Marco , Bernadó-Morales Cristina , Diaz Eva , Rojo-Sebastian Alejandro , Triviño Juan Carlos , Sanchez Laura , Rodríguez-Barrueco Ruth , Arribas Joaquín , Llobet-Navás David , Sarrió David , Moreno-Bueno Gema
Published: September 2022

Background

Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors.

Methods

Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples.

Results

GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers.

Conclusion

Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome.
Structured implementation of digital, systematically updated guideline recommendations for enhanced adherence in schizophrenia (SISYPHOS)—protocol of a cluster-randomized trial
Authors: Lorenz Carolin , Gaigl Gabriele , Güler Duygu , Halms Theresa , Khorikian-Ghazari Naiiri , Röh Astrid , Schneider Marco , Wagner Elias , Schneider-Axmann Thomas , Kapfhammer Angelika , Flick Marisa , Pielenz Charline , Salveridou-Hof Eva , Falkai Peter , Gaebel Wolfgang , Hasan Alkomiet , Leucht Stefan
Published: September 2022

Background

Despite high acceptance rates in the field, the implementation of the 2019 published German evidence and consensus-based S3 guideline is unsatisfactory. This study aims to assess the superiority of an adaptive online version with a better visualization of the recommendations in terms of guideline conformity, application of shared decision making, and digital health expertise compared to the classic pdf print version of the guideline.

Methods

The study is a multicenter, controlled, cluster-randomized trial with two arms: one arm investigating the implementation of the German schizophrenia guideline in form of a digital format (intervention group using the evidence ecosystem MAGICapp), the other arm in form of the classic print pdf version (control group). Physicians and psychologists working in specialized hospitals will be included in the study. The guideline-knowledge before and after the intervention is defined as primary outcome measure. Secondary endpoints include digital health expertise and application of shared decision making.

Discussion

This is the first study evaluating if an adaptive-digital version of the schizophrenia guideline is superior to the classic pdf print version. Therefore, the guideline is digitally prepared in the evidence-ecosystem MAGICapp, which covers the whole process of the development of a living guideline. We intend to use the results of the cluster-randomized trial for developing the German S3 guideline for schizophrenia in form of a living guideline in future.

Trial registration

The study is registered (10 May 2022) in the German Clinical Trials Register (DRKS) and the WHO International Clinical Trials Registry Platform (ICTRP) under registration numberDRKS00028895.
A validated LC–MS/MS method for analysis of Cabergoline in human plasma with its implementation in a bioequivalent study: investigation of method greenness
Authors: Shalaby Khaled , Alghamdi Saleh , Gamal Mohammed , Elhalim Lobna Mohammed Abd , Tony Rehab Moussa
Published: September 2022

Cabergoline (CAB) is effective prolactin lowering drug. Evaluation of the bioequivalence for the new test product (0.5 mg CAB film-coated tablets) in Egypt is strongly needed for approval of the drug by the official health authority. Therefore, a highly sensitive and rapid (LC–MS/MS) method was validated for CAB analysis in human plasma. CAB was extracted from plasma via diethyl ether using Quetiapine (QUE) as an internal standard. Multiple reaction monitoring (MRM) in positive ion mode was used, m/z 452.3 → 381.2 for CAB and 384.2 → 253.1 for QUE. Separation was accomplished on a reversed-phase C18. FDA procedures for the bio-analytical method were followed. The method was used in the bioequivalence study to compare the test product (0.5 mg CAB) versus Dostinex tablets, on 24 healthy Egyptian volunteers. The total analysis time was 5.5 min for each sample which permits analysis of various samples per day. The linearity range was from 2.00 to 200.00 pg/mL for CAB. LOD and LOQ were found to be 0.5 and 1.6 pg/mL, respectively. The final greenness numerical value was 0.63 using AGREE tool. The results of pharmacokinetic parameter Tmax were 2.17, and 2.33 h; for test and reference products, respectively. The generic formulation of test product is considered bioequivalent to the reference product Dostinex 0.5 mg tablets and satisfies the requirements of the Egyptian market. The merits of the method over the previous published methods are low cost; availability of cheap internal standard; rapidness; use of acetonitrile-free solvents mobile phase.
Spatial and temporal parasite dynamics: microhabitat preferences and infection progression of two co-infecting gyrodactylids
Authors: Twumasi Clement , Jones Owen , Cable Joanne
Published: September 2022

Background

Mathematical modelling of host-parasite systems has seen tremendous developments and broad applications in theoretical and applied ecology. The current study focuses on the infection dynamics of a gyrodactylid-fish system. Previous experimental studies have explored the infrapopulation dynamics of co-infecting ectoparasites,Gyrodactylus turnbulliandG. bullatarudis, on their fish host,Poecilia reticulata, but questions remain about parasite microhabitat preferences, host survival and parasite virulence over time. Here, we use more advanced statistics and a sophisticated mathematical model to investigate these questions based on empirical data to add to our understanding of this gyrodactylid-fish system.

Methods

A rank-based multivariate Kruskal-Wallis test coupled with its post-hoc tests and graphical summaries were used to investigate the spatial and temporal parasite distribution of different gyrodactylid strains across different host populations. By adapting a multi-state Markov model that extends the standard survival models, we improved previous estimates of survival probabilities. Finally, we quantified parasite virulence of three different strains as a function of host mortality and recovery across different fish stocks and sexes.

Results

We confirmed that the captive-bredG. turnbulliand wildG. bullatarudisstrains preferred the caudal and rostral regions respectively across different fish stocks; however, the wildG. turnbullistrain changed microhabitat preference over time, indicating microhabitat preference of gyrodactylids is host and time dependent. The average time of host infection before recovery or death was between 6 and 14 days. For this gyrodactylid-fish system, a longer period of host infection led to a higher chance of host recovery. Parasite-related mortalities are host, sex and time dependent, whereas fish size is confirmed to be the key determinant of host recovery.

Conclusion

From existing empirical data, we provided new insights into the gyrodactylid-fish system. This study could inform the modelling of other host-parasite interactions where the entire infection history of the host is of interest by adapting multi-state Markov models. Such models are under-utilised in parasitological studies and could be expanded to estimate relevant epidemiological traits concerning parasite virulence and host survival.

Graphical Abstract
Co-fitness analysis identifies a diversity of signal proteins involved in the utilization of specific c-type cytochromes
Authors: Ding De-wu , Huang Wei-fan , Lei Li-lan , Wu Pu
Published: September 2022

Purpose

c-Type cytochromes are essential for extracellular electron transfer (EET) in electroactive microorganisms. The expression of appropriate c-type cytochromes is an important feature of these microorganisms in response to different extracellular electron acceptors. However, how these diverse c-type cytochromes are tightly regulated is still poorly understood.

Methods

In this study, we identified the high co-fitness genes that potentially work with different c-type cytochromes by using genome-wide co-fitness analysis. We also constructed and studied the co-fitness networks that composed of c-type cytochromes and the top 20 high co-fitness genes of them.

Results

We found that high co-fitness genes of c-type cytochromes were enriched in signal transduction processes in Shewanella oneidensis MR-1 cells. We then checked the top 20 co-fitness proteins for each of the 41 c-type cytochromes and identified the corresponding signal proteins for different c-type cytochromes. In particular, through the analysis of the high co-fitness signal protein for CymA, we further confirmed the cooperation between signal proteins and c-type cytochromes and identified a novel signal protein that is putatively involved in the regulation of CymA. In addition, we showed that these signal proteins form two signal transduction modules.

Conclusion

Taken together, these findings provide novel insights into the coordinated utilization of different c-type cytochromes under diverse conditions.
Recent findings on chimeric antigen receptor (CAR)-engineered immune cell therapy in solid tumors and hematological malignancies
Authors: Keshavarz Ali , Salehi Ali , Khosravi Setareh , Shariati Yasaman , Nasrabadi Navid , Kahrizi Mohammad Saeed , Maghsoodi Sairan , Mardi Amirhossein , Azizi Ramyar , Jamali Samira , Fotovat Farnoush
Published: September 2022

Advancements in adoptive cell therapy over the last four decades have revealed various new therapeutic strategies, such as chimeric antigen receptors (CARs), which are dedicated immune cells that are engineered and administered to eliminate cancer cells. In this context, CAR T-cells have shown significant promise in the treatment of hematological malignancies. However, many obstacles limit the efficacy of CAR T-cell therapy in both solid tumors and hematological malignancies. Consequently, CAR-NK and CAR-M cell therapies have recently emerged as novel therapeutic options for addressing the challenges associated with CAR T-cell therapies. Currently, many CAR immune cell trials are underway in various human malignancies around the world to improve antitumor activity and reduce the toxicity of CAR immune cell therapy. This review will describe the comprehensive literature of recent findings on CAR immune cell therapy in a wide range of human malignancies, as well as the challenges that have emerged in recent years.
Validation of the flow index to detect low inspiratory effort during pressure support ventilation
Authors: Miao Ming-Yue , Chen Wei , Zhou Yi-Min , Gao Ran , Song De-Jing , Wang Shu-Peng , Yang Yan-Lin , Zhang Linlin , Zhou Jian-Xin
Published: September 2022

Background

Bedside assessment of low levels of inspiratory effort, which are probably insufficient to prevent muscle atrophy, is challenging. The flow index, which is derived from the analysis of the inspiratory portion of the flow–time waveform, has been recently introduced as a non-invasive parameter to evaluate the inspiratory effort. The primary objective of the present study was to provide an external validation of the flow index to detect low inspiratory effort.

Methods

Datasets containing flow, airway pressure, and esophageal pressure (Pes)–time waveforms were obtained from a previously published study in 100 acute brain-injured patients undergoing pressure support ventilation. Waveforms data were analyzed offline. A low inspiratory effort was defined by one of the following criteria, work of breathing (WOB) less than 0.3 J/L, Pes–time product (PTPes) per minute less than 50 cmH2O•s/min, or inspiratory muscle pressure (Pmus) less than 5 cmH2O, adding “or occurrence of ineffective effort more than 10%” for all criteria. The flow index was calculated according to previously reported method. The association of flow index with Pes-derived parameters of effort was investigated. The diagnostic accuracy of the flow index to detect low effort was analyzed.

Results

Moderate correlations were found between flow index and WOB, Pmus, and PTPesper breath and per minute (Pearson’s correlation coefficients ranged from 0.546 to 0.634,P < 0.001). The incidence of low inspiratory effort was 62%, 51%, and 55% using the definition of WOB, PTPesper minute, and Pmus, respectively. The area under the receiver operating characteristic curve for flow index to diagnose low effort was 0.88, 0.81, and 0.88, for the three respective definition. By using the cutoff value of flow index less than 2.1, the diagnostic performance for the three definitions showed sensitivity of 0.95–0.96, specificity of 0.57–0.71, positive predictive value of 0.70–0.84, and negative predictive value of 0.90–0.93.

Conclusions

The flow index is associated with Pes-based inspiratory effort measurements. Flow index can be used as a valid instrument to screen low inspiratory effort with a high probability to exclude cases without the condition.
An architecture and performance evaluation framework for artificial intelligence solutions in beyond 5G radio access networks
Authors: Koudouridis Georgios P. , He Qing , Dán György
Published: September 2022

The evolution of mobile communications towards beyond 5th-generation (B5G) networks is envisaged to incorporate high levels of network automation. Network automation requires the development of a network architecture that accommodates multiple solutions based on artificial intelligence (AI) and machine learning (ML). Consequently, integrating AI into the 5th-generation (5G) systems such that we could leverage the advantages of ML techniques to optimize and improve the networks is one challenging topic for B5G networks. Based on a review of 5G system architecture, the state-of-the-art candidate AI/ML techniques, and the progress of the state of the art, and the on AI/ML for 5G in standards we define an AI architecture and performance evaluation framework for the deployment of the AI/ML solution in B5G networks. The suggested framework proposes three AI architectures alternatives, a centralized, a completely decentralized and an hybrid AI architecture. More specifically, the framework identifies the logical AI functions, determines their mapping to the B5G radio access network architecture and analyses the associated deployment cost factors in terms of compute, communicate and store costs. The framework is evaluated based on a use case scenario for heterogeneous networks where it is shown that the deployment cost profiling is different for the different AI architecture alternatives, and that this cost should be considered for the deployment and selection of the AI/ML solution.