bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary insulin index and insulin load in relation to hypertriglyceridemic waist phenotype and low brain derived neurotrophic factor in adults
Authors: Hajhashemy Zahra , Lotfi Keyhan , Shahdadian Farnaz , Rouhani Parisa , Heidari Zahra , Saneei Parvane
Published: September 2022

Background

The evidence about the relation of the insulinemic potential of food with visceral obesity and brain-derived neurotrophic factor (BDNF) was limited. We aimed to investigate the relation of dietary insulin index (DII) and dietary insulin load (DIL) with hypertriglyceridemic waist phenotype (HTGW) and serum BDNF in Iranian adults.

Methods

This cross-sectional study included 528 middle-aged adults (45.6% women), using a multistage cluster random-sampling method. Dietary intakes were assessed using a validated semi-quantitative 168-item food frequency questionnaire. Blood samples were collected after 12 h of fasting for assessing the serum BDNF and triglyceride concentrations. HTGW was defined as triacylglycerol ≥ 150 mg/dL plus enlarged waist circumference. The values less than the first decile of serum BDNF were considered as the low level.

Results

Individuals in the top tertile of DIL, in comparison to those in the bottom tertile, had higher odds of HTGW in both crude (OR = 1.96, 95% CI: 1.14–3.37) and fully adjusted model (OR = 6.10, 95% CI: 1.58–23.53). However, the relation between DII and odds of HTGW was statistically insignificant in crude (OR = 1.30, 95% CI: 0.78–2.16) and maximally adjusted model (OR = 1.25, 95% CI: 0.65–2.40). After considering confounders, participants in the top tertile of DIL had marginally higher odds of having low BDNF values (OR = 2.00, 95% CI: 0.95–4.21). Nevertheless, the association between DII and odds of low BDNF values was statistically insignificant.

Conclusion

This population-based study demonstrated that adults with higher DIL had significantly higher chance of HTGW phenotype and slightly higher chance for low BDNF level. DII was not associated with HTGW phenotype or BDNF values.
Self-assembly and label-free fluorescent aptasensor based on deoxyribonucleic acid intercalated dyes for detecting lactoferrin in milk powder
Authors: Liu Jiahui , Li Tengfei , Qin Hongwei , Li Linsen , Yan Mengmeng , Zhu Chao , Qu Feng , Abd El-Aty A. M.
Published: September 2022

Lactoferrin (Lf), an iron-binding glycoprotein, regulates the immune system. It has broad-spectrum antimicrobial activity and is critical for child physical growth and development. As a common additive in the dairy industry, it is crucial to quantify LF content. This study established a self-assembly and universal fluorescence aptasensor for detecting LF in milk powder based on structure-selective dyes of PicoGreen intercalated in the label-free aptamer. Herein, the aptamer functions as both a specific recognition element against targets and a fluorescent signal reporter integrated with structure-selective dyes. First, the aptamer folds into a three-dimensional spatial structure based on complementary base pairings and intermolecular weak non-covalent interactions. Then, the dye is intercalated into the minor groove structures of the aptamer and triggers its potential fluorescent property. When the target exists, the aptamer binds to it preferentially, and its space structure unfolds. This causes the freeing of the subsequent dye and decreases the corresponding fluorescence. Hence, the reflected fluorescence signals could directly determine the target concentrations. Under the optimum conditions, a good linear relationship (R2, 0.980) was obtained in the Lf range from 20 to 500 nM with a detection limit of 3 nM (2.4 mg/kg) and good specificity, as well as a reliable recovery of 95.8–105.1% in milk powder. In addition, the universality was also confirmed with a good performance by quickly changing the aptamers against other targets (chlorpyrifos, acetamiprid, bovine thyroglobulin, and human transferrin) or utilizing another fluorescence dye. Therefore, this self-assembly aptasensor provides a universal and concise strategy for effective detection.
Case report: A rare case of acute myeloid leukemia with CPSF6–RARG fusion resembling acute promyelocytic leukemia
Authors: Zhao Junmei , Wang Wentao , Yan Li , Chen Xi , Li Wen , Li Wanying , Chen Tingting , Chen Lunhua
Published: September 2022

Retinoic acid receptor gamma (RARG) gene rearrangement has been reported in several acute myeloid leukemia (AML) patients. They resemble classical acute promyelocytic leukemia (APL) patients in clinical features, morphology, and immunophenotype but do not carry the promyelocytic leukemia (PML)–RARA fusion gene. Importantly, almost all these APL-like AML patients show resistance to all-trans retinoic acid (ATRA), and no effective treatment is recommended for them. Here, we identified a case of AML resembling APL in clinical presentation and experimental findings carrying a rare cleavage and polyadenylation-specific factor 6 (CPSF6)-RARG fusion gene. The patient was insensitive to ATRA and ATO but responded well to homoharringtonine and cytarabine.
CDCA4 as a novel molecular biomarker of poor prognosis in patients with lung adenocarcinoma
Authors: Tan Jianlong , Chen Fengyu , Ouyang Bin , Li Xiuying , Zhang Weidong , Gao Xinglin
Published: September 2022

Background

Because of the high incidence and poor prognoses of lung adenocarcinoma (LUAD), it is essential to identify cost-effective treatment options and accurate and reliable prognostic biomarkers. CDCA4 upregulation has been identified in many cancers. However, the prognostic importance of CDCA4 and its role in LUAD remain unknown.

Methods

CDCA4 expression was assessed through IHC, Western blotting (WB) and RT-PCR. The Cancer Genome Atlas (TCGA) provided data from 513 patients to study the expression and prognostic relevance of CDCA4 in LUAD. This study used gene set enrichment analyses (GSEA), gene ontology and KEGG pathway analyses for elucidating potential mechanisms underpinning the function of CDCA4 in LUAD. We also investigated correlations between immune infiltration and CDCA4 expression with single specimen GSEA (ssGSEA).

Results

According to database analysis and identification of patient tissue samples, CDCA4 expression in tumour tissues surpassed that in normal tissues (P< 0.001). Increased CDCA4 expression was positively correlated with a higher T, N, pathologic stage and poor primary therapy outcome. In addition, the Kaplan–Meier plotter exhibited that an elevated CDCA4 expression was related to worse disease-specific survival(DSS) and overall survival (OS) (DSS HR= 5.145, 95% CI=3.413-7.758, P<0.001; OS HR=3.570, 95% CI=2.472-5.155, P<0.001). Then multivariate COX regression analyses indicated that the CDCA4 gene was an independent risk consideration for prognoses. GO and KEGG results showed that CDCA4 and its neighbouring genes were enriched in the cell cycle and DNA replication. As determined by GSEA, CDCA4 was related to various immune-related signalling pathways (SPs), Homologous recombination, DNA replication and the cell cycle. SsGSEA analysis showed a significant association between CDCA4 expression and Th2 cells, mast cells, eosinophils and Th17 cells.

Conclusions

CDCA4 expression is increased in LUAD and is a potential predictive biomarker and therapeutic target.
Predicting lymphovascular invasion in clinically node-negative breast cancer detected by abbreviated magnetic resonance imaging: Transfer learning vs. radiomics
Authors: Feng Bao , Liu Zhuangsheng , Liu Yu , Chen Yehang , Zhou Haoyang , Cui Enming , Li Xiaoping , Chen Xiangmeng , Li Ronggang , Yu Tianyou , Zhang Ling , Long Wansheng
Published: September 2022

Objective

To compare the performance of abbreviated breast magnetic resonance imaging (AB-MRI)-based transfer learning (TL) algorithm and radionics analysis for lymphovascular invasion (LVI) prediction in patients with clinically node-negative invasive breast cancer (IBC).

Methods

Between November 2017 and October 2020, 233 clinically node-negative IBCs detected by AB-MRI were retrospectively enrolled. One hundred thirty IBCs from center 1 (37 LVI-positive and 93 LVI-negative) were assigned as the training cohort and 103 from center 2 (25 LVI-positive and 78 LVI-negative) as the validation cohort. Based on AB-MRI, a TL signature (TLS) and a radiomics signature (RS) were built with the least absolute shrinkage and selection operator (LASSO) logistic regression. Their diagnostic performances were validated and compared using areas under the receiver operating curve (AUCs), net reclassification improvement (NRI), integrated discrimination improvement (IDI), decision curve analysis (DCA), and stratification analysis. A convolutional filter visualization technique was used to map the response areas of LVI on the AB-MRI.

Results

In the validation cohort, compared with RS, the TLS showed better capability in discriminating LVI-positive from LVI-negative lesions (AUC: 0.852 vs. 0.726, p < 0.001; IDI = 0.092, p < 0.001; NRI = 0.554, p < 0.001). The diagnostic performance of TLS was not affected by the menstrual state, molecular subtype, or contrast agent type (all p > 0.05). Moreover, DCA showed that the TLS added more net benefit than RS for clinical utility.

Conclusions

An AB-MRI-based TLS was superior to RS for preoperative LVI prediction in patients with clinically node-negative IBC.
Clinical value of ultrasound for the evaluation of local recurrence of primary bone tumors
Authors: Wang Yu , Yu Ping , Liu Feifei , Wang Yuqin , Zhu Jiaan
Published: September 2022

Background

Early detection of local recurrence would improve the survival rate of patients with recurrent bone tumors. There is still no consensus on how to follow up after surgery of primary malignant bone tumors. Therefore, the purpose of this study is to evaluate the diagnostic value of ultrasound (US) for local recurrence after limb salvage by comparing it with other imaging modalities.

Methods

We retrospectively reviewed the medical records of patients who were regularly examined by US in our hospital after primary bone tumor surgery from January 2016 to December 2019, some of which underwent x-ray, computed tomography (CT), or 99mTc-MDP bone scan. Recurrence was determined by pathologic confirmation. The cases were considered a true negative for no recurrence if no clinical or pathologic evidence for recurrence was found at least 6 months after the US examination. The Chi-square test or Fisher exact test was used to compare categorical data. p-values < 0.0083 were considered statistically significant.

Results

A total of 288 cases were finally enrolled in our research, including 66 cases with pathologic results. The sensitivity of US was 95.0%, higher than that of x-ray (29.6%) (p = 0.000). The accuracy of US was 96.9%, higher than that of x-ray (85.6%) (p = 0.000).

Conclusion

As a nonradiative and cost-effective examination, US may be used as a routine imaging method for postoperative surveillance of primary bone tumors, especially those with metal implants, if more multicenter prospective studies can be done in the future.
A machine learning model for grade 4 lymphopenia prediction during pelvic radiotherapy in patients with cervical cancer
Authors: Xu Zhiyuan , Yang Li , Yu Hao , Guo Linlang
Published: September 2022

Background/purpose

Severe lymphopenia during pelvic radiotherapy (RT) predicts poor survival in patients with cervical cancer. However, the risk of severe lymphopenia has not been well predicted. We developed a machine learning model using clinical and dosimetric information to predict grade 4 (G4) lymphopenia during pelvic RT in patients with cervical cancer.

Methods

This retrospective study included cervical cancer patients treated with definitive pelvic RT ± induction/concurrent chemotherapy. Clinical information and a set of dosimetric parameters of external beam radiotherapy plan were collected. G4 lymphopenia during RT, which was also referred to as G4 absolute lymphocyte count (ALC) nadir, was defined as ALC nadir <0.2 × 109cells/L during RT according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Elastic-net logistic regression models were constructed for the prediction of G4 lymphopenia during pelvic RT using a repeated cross-validation methodology.

Results

A total of 130 patients were eligible, and 43 (33.1%) patients had G4 lymphopenia during RT. On multivariable analysis, G4 ALC nadir was associated with poor overall survival (OS) [hazard ratio (HR), 3.91; 95% confidence interval (CI), 1.34–11.38, p = 0.01]. Seven significant factors [Eastern Cooperative Oncology Group (ECOG) performance score, pre-RT hemoglobin, pre-RT lymphocytes, concurrent chemotherapy, gross tumor volume of regional lymphadenopathy (GTV_N volume), body volume, and maximum dose of planning target volume receiving at least 55 Gy (PTV_5500 Dmax)] were obtained by elastic-net logistic regression models and were included in the final prediction model for G4 ALC nadir. The model’s predicting ability in test set was area under the curve (AUC) = 0.77 and accuracy = 0.76. A nomogram of the final predicting model was constructed.

Conclusions

This study developed and validated a comprehensive model integrating clinical and dosimetric parameters by machine learning method, which performed well in predicting G4 lymphopenia during pelvic RT for cervical cancer and will facilitate physicians to identify patients at high risk of G4 lymphopenia who might benefit from modified treatment approaches.
Rationale for combination of paclitaxel and CDK4/6 inhibitor in ovarian cancer therapy — non-mitotic mechanisms of paclitaxel
Authors: Smith Elizabeth R. , Huang Marilyn , Schlumbrecht Matthew P. , George Sophia H.L. , Xu Xiang-Xi
Published: September 2022

Taxanes and CDK4/6 inhibitors (CDK4/6i) are two families of successful anti-mitotic drugs used in the treatment of solid tumors. Paclitaxel, representing taxane compounds, has been used either alone or in combination with other agents (commonly carboplatin/cisplatin) in the treatment of many solid tumors including ovarian, breast, lung, prostate cancers, and Kaposi’s sarcoma. Paclitaxel has been routinely prescribed in cancer treatment since the 1990s, and its prominent role is unlikely to be replaced in the foreseeable future. Paclitaxel and other taxanes work by binding to and stabilizing microtubules, causing mitotic arrest, aberrant mitosis, and cell death. CDK4/6i (palbociclib, ribociclib, abemaciclib) are relatively new cell cycle inhibitors that have been found to be effective in breast cancer treatment, and are currently being developed in other solid tumors. CDK4/6i blocks cell cycle progression at the G1 phase, resulting in cell death by mechanisms not yet fully elucidated. At first glance, paclitaxel and CDK4/6i are unlikely synergistic agents as both are cell cycle inhibitors that work at different phases of the cell cycle, and few clinical trials have yet considered adding CDK4/6i to existing paclitaxel chemotherapy. However, recent findings suggest the importance of a non-mitotic mechanism of paclitaxel in cancer cell death and pre-clinical data support rationale for a strategic paclitaxel and CDK4/6i combination. In mouse tumor model studies, drug sequencing resulted in differential efficacy, indicating complex biological interactions of the two drugs. This article reviews the rationales of combining paclitaxel with CDK4/6i as a potential therapeutic option in recurrent ovarian cancer.
lncRNA NEAT1 promotes the proliferation and metastasis of hepatocellular carcinoma by regulating the FOXP3/PKM2 axis
Authors: Pan Junping , Hu Yingzhe , Yuan Chenlu , Wu Yafu , Zhu Xinhua
Published: September 2022

Objective

Hepatocellular carcinoma (HCC) is a malignant tumor. The occurrence of HCC is involved in the alteration of a variety of oncogenes or tumor suppressor genes, but the specific molecular mechanism remains unknown. This research proved the effects of long non-coding RNA NEAT1 (lncRNA NEAT1) on the viability, proliferation, migration, and invasion of hepatocellular carcinoma cells and explored the mechanism behind these effects.

Methods

NEAT1 in 97H and Huh7 cell lines was overexpressed or knocked down, respectively. The expression of FOXP3 and its target gene PKM2 was hinged on qRT-PCR and Western blot, respectively. RNA pulldown and RNA immunoprecipitation experiments were carried out to detect the interaction between NEAT1 and proteins. Finally, the effect of NEAT1 on the tumor volume of HCC was verified by animal experiments.

Results

A series of experiments have shown that NEAT1 knockdown can inhibit the viability, proliferation, migration, and invasion of HCC cells; NEAT1 can bind FOXP3 to promote PKM2 transcription; PKM2 knockdown can inhibit the viability, proliferation, migration, and invasion of HCC cells; and PKM2 knockdown reversed the function of NEAT1.

Conclusion

lncRNA NEAT1 can promote the malignant behavior of HCC cells, while silencing of NEAT1 can inhibit that behavior of HCC cells. Mechanically, NEAT1 promotes the transcriptional activation of PKM2 by binding FOXP3, and PKM2 knockout reverses the function of NEAT1.
Differentiation of glioblastoma tissues using spontaneous Raman scattering with dimensionality reduction and data classification
Authors: Romanishkin Igor , Savelieva Tatiana , Kosyrkova Alexandra , Okhlopkov Vladimir , Shugai Svetlana , Orlov Arseniy , Kravchuk Alexander , Goryaynov Sergey , Golbin Denis , Pavlova Galina , Pronin Igor , Loschenov Victor
Published: September 2022

The neurosurgery of intracranial tumors is often complicated by the difficulty of distinguishing tumor center, infiltration area, and normal tissue. The current standard for intraoperative navigation is fluorescent diagnostics with a fluorescent agent. This approach can be further enhanced by measuring the Raman spectrum of the tissue, which would provide additional information on its composition even in the absence of fluorescence. However, for the Raman spectra to be immediately helpful for a neurosurgeon, they must be additionally processed. In this work, we analyzed the Raman spectra of human brain glioblastoma multiforme tissue samples obtained during the surgery and investigated several approaches to dimensionality reduction and data classificatin to distinguish different types of tissues. In our study two approaches to Raman spectra dimensionality reduction were approbated and as a result we formulated new technique combining both of them: feature filtering based on the selection of those shifts which correspond to the biochemical components providing the statistically significant differences between groups of examined tissues (center of glioblastoma multiforme, tissues from infiltration area and normally appeared white matter) and principal component analysis. We applied the support vector machine to classify tissues after dimensionality reduction of registered Raman spectra. The accuracy of the classification of malignant tissues (tumor edge and center) and normal ones using the principal component analysis alone was 83% with sensitivity of 96% and specificity of 44%. With a combined technique of dimensionality reduction we obtained 83% accuracy with 77% sensitivity and 92% specificity of tumor tissues classification.
Ferroptosis: A novel therapeutic strategy and mechanism of action in glioma
Authors: Zhang Gaosen , Fang Yi , Li Xiang , Zhang Zhen
Published: September 2022

Glioma is the most common malignant tumor of the central nervous system and resistance is easily developed to chemotherapy drugs during the treatment process, resulting in high mortality and short survival in glioma patients. Novel therapeutic approaches are urgently needed to improve the therapeutic efficacy of chemotherapeutic drugs and to improve the prognosis of patients with glioma. Ferroptosis is a novel regulatory cell death mechanism that plays a key role in cancer, neurodegenerative diseases, and other diseases. Studies have found that ferroptosis-related regulators are closely related to the survival of patients with glioma, and induction of ferroptosis can improve glioma resistance to chemotherapy drugs. Therefore, induction of tumor cell ferroptosis may be an effective therapeutic strategy for glioma. This review summarizes the relevant mechanisms of ferroptosis, systematically summarizes the key role of ferroptosis in the treatment of glioma and outlines the relationship between ferroptosis-related ncRNAs and the progression of glioma.
N7-methylguanosine-related lncRNAs: Distinction between hot and cold tumors and construction of predictive models in colon adenocarcinoma
Authors: Cheng Zhichao , Wang Jiaqi , Xu Yixin , Jiang Tao , Xue Zhenyu , Li Shuai , Zhao Ying , Song Hu , Song Jun
Published: September 2022

Colon adenocarcinoma (COAD) is a prevalent malignant tumor that severely threatens human health across the globe. Immunotherapy is an essential need for patients with COAD. N7-methylguanosine (m7G) has been associated with human diseases, and non-coding RNAs (lncRNAs) regulate various tumor-related biological processes. Nonetheless, the m7G-related lncRNAs involved in COAD regulation are limited. This study aims to construct the clustering features and prognostic model of m7G-related lncRNAs in COAD. First, The Cancer Genome Atlas (TCGA) database was used to identify m7G-related differentially expressed lncRNAs (DELs), based on which COAD cases could be classified into two subtypes. Subsequently, univariate Cox analysis was used to identify 9 prognostic m7G-related lncRNAs. Further, Five candidates were screened by LASSO-Cox regression to develop new models. The patients were divided into high-risk and low-risk groups based on the median risk score. Consequently, the Kaplan-Meier survival curve demonstrated a statistically significant overall survival (OS) between the high- and low-risk groups (P<0.001). Multivariate Cox regression analysis revealed that risk score is an independent prognostic factor in COAD patients (P<0.001). This confirms the clinical applicability of the model. Additionally, we performed Gene Set Enrichment Analysis (GSEA), which uncovered the biological and functional differences between risk subgroups, i.e., enrichment of immune-related diseases in the high-risk group and enrichment of metabolic-related pathways in the low-risk group. In a drug sensitivity analysis, high-risk group were more sensitive to some chemotherapeutics and targeted drugs than low-risk group. Eventually, the stability of the model was confirmed by qRT-PCR. Our study unraveled the features of different immune states of COAD and established a prognostic model, including five m7G-related lncRNAs for COAD patients. These results will bolster clinical treatment and survival prediction of COAD.
The origin of gastric cancer stem cells and their effects on gastric cancer: Novel therapeutic targets for gastric cancer
Authors: Yang Ying , Meng Wen-Jian , Wang Zi-Qiang
Published: September 2022

Gastric cancer (GC) is one of the most prevalent malignancies and the most common causes of cancer-related mortality worldwide. Furthermore, the prognosis of advanced GC remains poor even after surgery combined with chemoradiotherapy. As a small group of cells with unlimited differentiation and self-renewal ability in GC, accumulating evidence shows that GC stem cells (GCSCs) are closely associated with the refractory characteristics of GC, such as drug resistance, recurrence, and metastasis. With the extensive development of research on GCSCs, GCSCs seem to be promising therapeutic targets for GC. However, the relationship between GCSCs and GC is profound and intricate, and its mechanism of action is still under exploration. In this review, we elaborate on the source and key concepts of GCSCs, systematically summarize the role of GCSCs in GC and their underlying mechanisms. Finally, we review the latest information available on the treatment of GC by targeting GCSCs. Thus, this article may provide a theoretical basis for the future development of the novel targets based on GCSCs for the treatment of GC.
Corneal perforation associated with ocular graft-versus-host disease
Authors: Xu Yue , Wang Ying-Ming , Sun Zheng-Tai , Yang Xiao-Long , Zhuang Xin-Yu , Ren Ya-Ru , Chen Ying-Jie , Chen Feng , Ma Xiao , Tang Xiao-Wen , Zhang Xiao-Feng
Published: September 2022

Corneal perforation is a rare and serious complication of ocular graft-versus-host disease (oGVHD) patients. This study was to retrospectively report seven corneal perforation patients after allogeneic hematopoietic stem cell transplantation (HSCT). Demographic, hematologic, and ophthalmological data of patients were clarified in detail. Nine eyes of seven corneal perforation patients were clarified (Cases 3 and 6 were bilateral and the others are unilateral). All the cases had other affected GVHD organs, especially skin involvement. The duration between HSCT and corneal perforation was usually long with 21 (17–145) months as median interval, whereas the duration between oGVHD diagnosis and corneal perforation was relatively shorter with 4 (2–81) months as median interval. Most patients presented to ophthalmology department with poor visual acuity, BUT and Schirmer’s test. Eyelid marginal hyperemia and irregularity were observed in most corneal perforation eyes. Keratoplasty or conjunctival flap covering (CFC) surgeries was performed after corneal perforation. After a long-term follow-up for most patients (median 21 months, range: 2–86 months), only two eyes of two patients (22.22%) had a final BCVA of 20/100 or better. Patients involved in both cutaneous GVHD and blepharitis indicate the aggressive development of oGVHD. Early diagnosis, long-term follow-up, and effective multi-disciplinary treatments for oGVHD patients are essential. Corticosteroids and immunosuppressor remain essential, whereas the use of topical corticosteroids should be carefully considered in corneal ulceration patients. In addition, appropriate surgeries should be performed to control oGVHD development in time.
Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA
Authors: Swami Umang , Zimmerman Raquel Mae , Nussenzveig Roberto H. , Hernandez Edgar Javier , Jo Yeonjung , Sayegh Nicolas , Wesolowski Sergiusz , Kiedrowski Lesli A. , Barata Pedro C. , Lemmon Gordon Howard , Bilen Mehmet A. , Heath Elisabeth I. , Nandagopal Lakshminarayan , Babiker Hani M. , Pal Sumanta K. , Lilly Michael , Maughan Benjamin L. , Haaland Benjamin , Yandell Mark , Sartor Oliver , Agarwal Neeraj
Published: September 2022

BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. In a large dataset of 7,707 men with advanced prostate cancer undergoing comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA), 614 men harbored BRCA1 and/or BRCA2 alterations. Differences in the genomic landscape of co-segregating genes was investigated by Fisher’s exact test and probabilistic graphical models (PGMs). Results demonstrated that BRCA1 was significantly associated with six other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. These hypothesis-generating data may explain the differential response to PARP inhibition and guide towards the development of combinatorial drug regimens in those with BRCA1 mutation.
Epigenetics and environment in breast cancer: New paradigms for anti-cancer therapies
Authors: Thakur Chitra , Qiu Yiran , Fu Yao , Bi Zhuoyue , Zhang Wenxuan , Ji Haoyan , Chen Fei
Published: September 2022

Breast cancer remains the most frequently diagnosed cancer in women worldwide. Delayed presentation of the disease, late stage at diagnosis, limited therapeutic options, metastasis, and relapse are the major factors contributing to breast cancer mortality. The development and progression of breast cancer is a complex and multi-step process that incorporates an accumulation of several genetic and epigenetic alterations. External environmental factors and internal cellular microenvironmental cues influence the occurrence of these alterations that drives tumorigenesis. Here, we discuss state-of-the-art information on the epigenetics of breast cancer and how environmental risk factors orchestrate major epigenetic events, emphasizing the necessity for a multidisciplinary approach toward a better understanding of the gene-environment interactions implicated in breast cancer. Since epigenetic modifications are reversible and are susceptible to extrinsic and intrinsic stimuli, they offer potential avenues that can be targeted for designing robust breast cancer therapies.
The feasibility of triggers for the integration of Standardised, Early Palliative (STEP) Care in advanced cancer: A phase II trial
Authors: Collins Anna , Sundararajan Vijaya , Le Brian , Mileshkin Linda , Hanson Susan , Emery Jon , Philip Jennifer
Published: September 2022

Background

While multiple clinical trials have demonstrated benefits of early palliative care for people with cancer, access to these services is frequently very late if at all. Establishing evidence-based, disease-specific ‘triggers’ or times for the routine integration of early palliative care may address this evidence-practice gap.

Aim

To test the feasibility of using defined triggers for the integration of standardised, early palliative (STEP) care across three advanced cancers.

Method

Phase II, multi-site, open-label, parallel-arm, randomised trial of usual best practice cancer care +/- STEP Care conducted in four metropolitan tertiary cancer services in Melbourne, Australia in patients with advanced breast, prostate and brain cancer. The primary outcome was the feasibility of using triggers for times of integration of STEP Care, defined as enrolment of at least 30 patients per cancer in 24 months. Triggers were based on hospital admission with metastatic disease (for breast and prostate cancer), or development of disease recurrence (for brain tumour cohort). A mixed method study design was employed to understand issues of feasibility and acceptability underpinning trigger points.

Results

The triggers underpinning times for the integration of STEP care were shown to be feasible for brain but not breast or prostate cancers, with enrolment of 49, 6 and 10 patients across the three disease groups respectively. The varied feasibility across these cancer groups suggested some important characteristics of triggers which may aid their utility in future work.

Conclusions

Achieving the implementation of early palliative care as a standardized component of quality care for all oncology patients will require further attention to defining triggers. Triggers which are 1) linked to objective points within the illness course (not dependent on recognition by individual clinicians), 2) Identifiable and visible (heralded through established service-level activities) and 3) Not reliant upon additional screening measures may enhance their feasibility.
Effects of a therapeutic exercise program in children with non-cystic fibrosis bronchiectasis: A pilot randomized controlled trial
Authors: Joschtel Barbara , Gomersall Sjaan R. , Tweedy Sean , Petsky Helen , Chang Anne B. , Trost Stewart G.
Published: September 2022

Background

In the absence of randomized controlled trials (RCTs) on the benefits of therapeutic exercise programs involving children with bronchiectasis, we undertook a pilot RCT to evaluate the effects of a play-based therapeutic exercise program on fundamental movement skill (FMS) proficiency. The effects of the program on cardiorespiratory fitness, perceived competence, and health-related quality of life (HR-QoL) were examined as secondary outcomes.

Methods

Children [median (IQR) age: 6.8 (5.3–8.8) years] with bronchiectasis unrelated to cystic fibrosis were randomized to a 7-week therapeutic exercise program (n = 11) or wait-list control (n = 10). The exercise program comprised 7 × 60-min weekly sessions and was supplemented by a home-based program 2-days/week. Participants were assessed on: FMS (locomotor and object control skills) using the Test of Gross Motor Development 2nd Edition (TGMD-2); cardiovascular fitness by calculating the percent change in heart rate (%ΔHR) from rest to completion of the first stage of a submaximal treadmill test; perceived competence using Harter’s athletic competence subscale; and QoL with the PedsQL.

Results

Significant group by time interactions were observed for locomotor and object control skills. Children completing the therapeutic exercise program exhibited significant improvements in both locomotor (pre 29.0 ± 2.0, post 35.2 ± 2.2, p = 0.01) and object control (pre 27.0 ± 2.0, post 35.5 ± 2.2, p = 0.01) skills, with no significant change in controls (pre 31.6 ± 2.1, post 31.8 ± 2.3 and pre 31.0 ± 2.1, post 32.3 ± 2.3, respectively). Among children completing the program, %ΔHR declined by 6% points, while %ΔHR declined only marginally among controls (0.9% points), but the group by time interaction was not statistically significant. The program had a small positive impact on competence perceptions (Cohen’s d = 0.2) and HR-QoL (Cohen’s d = 0.3).

Conclusion

This pilot RCT provides preliminary evidence for the efficacy of a play-based therapeutic exercise program to improve proficiency in FMS and fitness in children with bronchiectasis. The results are sufficiently positive to warrant conducting a larger RCT testing the efficacy of the exercise program in children with bronchiectasis and/or other chronic respiratory conditions.
An Ethnopharmaceutical Study on the Hypolipidemic Formulae in Taiwan Issued by Traditional Chinese Medicine Pharmacies
Authors: Chi Min-Han , Chao Jung , Ko Chien-Yu , Huang Shyh-Shyun
Published: September 2022

Globally, approximately one-third of ischemic heart diseases are due to hyperlipidemia, which has been shown to cause various metabolic disorders. This study was aimed to disassemble and analyze hypolipidemic formulae sold by traditional Chinese medicine (TCM) pharmacies. Using commonly used statistical parameters in ethnopharmacology, we identified the core drug combination of the hypolipidemic formulae, thereby exploring the strategy by which the Taiwanese people select hypolipidemic drugs. Most important of all, we preserved the inherited knowledge of TCM. We visited 116 TCM pharmacies in Taiwan and collected 91 TCM formulae. The formulae were mainly disassembled by macroscopical identification, and the medicinal materials with a relative frequency of citation (RFC) >0.2 were defined as commonly used medicinal materials. Subsequently, we sorted the information of medicinal materials recorded in the Pharmacopeia, searched for modern pharmacological research on commonly used medicinal materials using PubMed database, and visualized data based on the statistical results. Finally, the core hypolipidemic medicinal materials used in folk medicine were obtained. Of the 91 TCM formulae collected in this study, 80 traditional Chinese medicinal materials were used, belonging to 43 families, predominantly Lamiaceae. Roots were the most commonly used part as a medicinal material. There were 17 commonly used medicinal materials. Based on medicinal records in Pharmacopeia, most flavors and properties were warm and pungent, the majority traditional effects were “tonifying and replenishing” and “blood-regulating.” Besides, the targeted diseases searching from modern pharmacological studies were diabetes mellitus and dyslipidemia. The core medicinal materials consisted of Astragalus mongholicus Bunge and Crataegus pinnatifida Bunge, and the core formulae were Bu-Yang-Huan-Wu-Tang and Xie-Fu-Zhu-Yu-Tang. In addition, 7 groups of folk misused medicinal materials were found. Although these TCMs have been used for a long period of time, their hypolipidemic mechanisms remain unclear, and further studies are needed to validate their safety and efficacy.
Bcl-xL activity influences outcome of the mitotic arrest
Authors: Suleimenov M. , Bekbayev S. , Ten M. , Suleimenova N. , Tlegenova M. , Nurmagambetova A. , Kauanova S. , Vorobjev I.
Published: September 2022

Microtubule-targeting (MT) drugs taxanes and vinca alkaloids are widely used as chemotherapeutic agents against different tumors for more than 30 years because of their ability to block mitotic progression by disrupting the mitotic spindle and activating the spindle assembly checkpoint (SAC) for a prolonged period of time. However, responses to mitotic arrest are different—some cells die during mitotic arrest, whereas others undergo mitotic slippage and survive becoming able for proliferation. Using normal fibroblasts and several cancer cell types we determined two critical doses, T1 and T2, of mitotic inhibitors (nocodazole, Taxol, and vinorelbine). T1 is the maximal dose cells can tolerate undergoing normal division, and T2 is the minimal mitostatic dose, wherein > 90% of mitotic cells are arrested in mitosis. In all studied cell lines after treatment with mitotic inhibitors in a dose above T2 cells had entered mitosis either die or undergo mitotic slippage. We show that for all three drugs used cell death during mitotic arrest and after slippage proceeded via mitochondria-dependent apoptosis. We determined two types of cancer cells: sensitive to mitotic arrest, that is, undergoing death in mitosis (DiM) frequently, and resistant to mitotic arrest, that is, undergoing mitotic slippage followed by prolonged survival. We then determined that inhibition of Bcl-xL, but not other anti-apoptotic proteins of the Bcl-2 group that regulate MOMP, make resistant cells susceptible to DiM induced by mitotic inhibitors. Combined treatment with MT drugs and highly specific Bcl-xL inhibitors A-1155643 or A-1331852 allows achieving 100% DiM in a time significantly shorter than maximal duration of mitotic arrest in all types of cultured cells tested. We further examined efficacy of sequential treatment of cultured cells using mitotic inhibitors followed by inhibitors of Bcl-xL anti-apoptotic protein and for the first time show that sensitivity to Bcl-xL inhibitors rapidly declines after mitotic slippage. Thus sequential use of mitotic inhibitors and inhibitors of Bcl-xL anti-apoptotic protein will be efficient only if the Bcl-xL inhibitor will be added before mitotic slippage occurs or soon afterward. The combined treatment proposed might be an efficient approach to anti-cancer therapy.
Investigation into the potential mechanism and molecular targets of Fufang Xueshuantong capsule for the treatment of ischemic stroke based on network pharmacology and molecular docking
Authors: Wang Lei , Wang Liping , Wang Hui , Zhu Ting
Published: September 2022

Fufang Xueshuantong (FFXST) capsule is a traditional Chinese medicine (TCM) preparation used to activate blood circulation, resolve stasis, benefit qi, and nourish yin in clinical practice. However, its potential mechanism and molecular targets after ischemic stroke (IS) have not been investigated. The aim of this research was to investigate the molecular mechanisms of FFXST in the treatment of IS based on network pharmacology and molecular docking. We used the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) to collect candidate compounds of four herbs in FFXST; disease-related differential genes were screened using the Gene Expression Omnibus (GEO) database, and a compound–disease network was created using Cytoscape 3.8.2 software. The topological analysis of the protein–protein interaction (PPI) network was then created to determine the candidate targets of FFXST against IS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the clusterProfiler package in R. The gene–pathway network of FFXST against IS was created to obtain the key target genes. Molecular docking was used to validate the core targets using AutoDock Vina 1.1.2. A total of 455 candidate compounds of FFXST and 18,544 disease-related differential genes were screened. Among them, FFXST targets for IS treatment had 67 active compounds and 10 targets in the PPI network related to STAT1, STAT3, and HIF1A. The biological processes of GO analysis included the regulation of reactive oxygen species metabolic process, cellular response to chemical stress, regulation of angiogenesis, regulation of vasculature development, positive regulation of cytokine production, and response to oxidative stress. The KEGG enrichment analysis showed that Kaposi sarcoma-associated herpesvirus infection, microRNAs in the cancer signaling pathway, Th17 cell differentiation, and HIF-1 signaling pathway were significantly enriched. The network pharmacology outcomes were further verified by molecular docking. We demonstrated that FFXST protection against IS may relate to the regulation of oxidative stress, immune inflammatory response, and angiogenesis through the relevant signaling pathways. Our study systematically illustrated the application of network pharmacology and molecular docking in evaluating characteristics of multi-component, multi-target, and multi-pathway of FFXST for IS.
The microtubule cytoskeleton: An old validated target for novel therapeutic drugs
Authors: Lafanechère Laurence
Published: September 2022

Compounds targeting microtubules are widely used in cancer therapy with a proven efficacy. However, because they also target non-cancerous cells, their administration leads to numerous adverse effects. With the advancement of knowledge on the structure of tubulin, the regulation of microtubule dynamics and their deregulation in pathological processes, new therapeutic strategies are emerging, both for the treatment of cancer and for other diseases, such as neuronal or even heart diseases and parasite infections. In addition, a better understanding of the mechanism of action of well-known drugs such as colchicine or certain kinase inhibitors contributes to the development of these new therapeutic approaches. Nowadays, chemists and biologists are working jointly to select drugs which target the microtubule cytoskeleton and have improved properties. On the basis of a few examples this review attempts to depict the panorama of these recent advances.
Analysis of clinical characteristics of mesalazine-induced cardiotoxicity
Authors: Chen Junyu , Duan Tengfei , Fang Weijin , Liu Shikun , Wang Chunjiang
Published: September 2022

Background: Mesalazine is the first-line inflammatory bowel disease (IBD) treatment. However, it can cause fatal cardiotoxicity. We aimed to analyze the clinical characteristics of mesalazine-induced cardiotoxicity and provide evidence for clinical diagnosis, treatment, and prevention.

Methods: We collected Chinese and English literature on mesalazine-induced cardiotoxicity from 1970 to 2021 for retrospective analysis.

Results: A total of 52 patients (40 males and 12 females) were included, with a median age of 24.5 years (range 9–62) and a median onset time of 14 days (range 2–2880). Cardiotoxicity manifested as myocarditis, pericarditis, and cardiac pericarditis. The main clinical manifestations are chest pain (82.7%), fever (46.2%), and respiratory symptoms such as dyspnea and cough (40.4%). The levels of troponin T, creatine kinase, C-reactive protein, leukocyte count, erythrocyte sedimentation rate, and other biochemical markers were significantly increased. Cardiac imaging often suggests myocardial infarction, pericardial effusion, myocardial necrosis, and other symptoms of cardiac injury. It is essential to discontinue mesalamine immediately in patients with cardiotoxicity. Although corticosteroids are a standard treatment option, the benefits remain to be determined. Re-challenge of mesalamine should be carefully considered as cardiotoxic symptoms may reoccur.

Conclusion: Mesalazine may cause cardiotoxicity in patients with inflammatory bowel disease, which should be comprehensively diagnosed based on clinical manifestations, biochemical indicators, and cardiac function imaging examinations. Mesalazine should be immediately discontinued, and corticosteroids may be an effective treatment for cardiotoxicity.
Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes
Authors: Jin Chao , Gao Bei-Bei , Zhou Wen-Jing , Zhao Bao-Jing , Fang Xing , Yang Chun-Lan , Wang Xiao-Hua , Xia Quan , Liu Ting-Ting
Published: September 2022

Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (Treg) and down-regulated CD8+T cell differentiation in AIH mice induced by S-100 antigen. In vitro, HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-β1) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote Treg differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate Treg differentiation and function.
A pharmacodynamic investigation to assess the synergism of orbifloxacin and propyl gallate against Escherichia coli
Authors: Abbas Muhammad Aleem , Lee Eon-Bee , Boby Naila , Biruhanu Biruk Tesfaye , Park Seung-Chun
Published: September 2022

Escherichia coli (E. coli) infections are becoming increasingly difficult to treat, as antibiotic-resistant variants proliferate. Studies on novel methods to combat the spread of resistance and improve the performance of current antibiotics are vital. We aimed to boost the efficacy of the antibiotic orbifloxacin (ORB) against E. coli by combining it with a phenolic component, propyl gallate (PG). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ORB against the E. coli KVCC 1423 resistant strain were 128 μg/ml and 256 μg/ml, respectively. However, the MIC of ORB for the remaining E. coli strains was 0.5 μg/ml–2 μg/ml. For the combination of PG and ORB, the lowest fractional inhibitory concentration (FIC) index was less than 0.5, and the combination decreased the MIC of both drugs by 74%. The time-kill assay revealed the killing properties of both the drugs and the pharmacodynamic model (PD model) confirmed the strong killing properties of the combination as compared to the individual activities of the drugs. The ratio between MIC and mutant prevention concentration of ORB against E. coli 1400306 and 1,423 were 1:32 and 1:8, respectively. The combination of ORB and PG showed strong biofilm eradication and inhibited the motility of bacteria. The cell viability of the combination was > 80%. Therefore, we believe that ORB and PG in combination could be a possible antibacterial candidate that could minimize resistance and improve antibiotic potential.