bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of levothyroxine treatment on fetal growth among women with mild subclinical hypothyroidism and thyroid peroxidase antibody negative: a cohort study
Authors: Ji Yuelong , Xu Jinhui , Su Tao , Lin Lizi , Zhou Shuang , Bao Heling , Liu Zheng , Luo Shusheng , Xu Xiangrong , Han Na , Wang Hai-Jun
Published: May 2023

Background

Some clinicians used levothyroxine (LT4) treatment for mild subclinical hypothyroidism (SCH) pregnant women (2.5 < thyroid-stimulating hormone (TSH) ≤ the pregnancy-specific reference range with normal free thyroxine (FT4) level) with thyroid peroxidase antibody negative (TPOAb−), although the recent clinical guideline did not recommend it. It is unknown whether LT4 treatment for pregnant women with mild SCH and TPOAb− have impact on fetal growth. Therefore, the aim of the study was to investigate the effect of LT4 treatment on fetal growth and birth weight among mild SCH pregnant women with TPOAb−.

Methods

This was a birth cohort study including 14,609 pregnant women between 2016 and 2019 in Tongzhou Maternal and Child Health Hospital of Beijing, China. Pregnant women were divided into 3 groups as follows: Euthyroid (n = 14,285, 0.03 ≤ TSH ≤ 2.5mIU/L, normal FT4), TPOAb−; Untreated mild SCH with TPOAb− (n = 248, 2.5 < TSH ≤ 2.9mIU/L, normal FT4, without LT4 treatment); Treated mild SCH with TPOAb− (n = 76, 2.5 < TSH ≤ 2.9mIU/L, normal FT4, with LT4 treatment). The main outcome measures were Z-scores of fetal growth indicators (abdominal circumference (AC), biparietal diameter (BPD), femur length (FL), head circumference (HC), estimated fetal weight (EFW)), fetal growth restriction (FGR) and birth weight.

Results

There was no difference in fetal growth indicators and birth weight between the untreated mild SCH women with TPOAb− and the euthyroid pregnant women. But the HC Z-score was lower in the LT4 treated mild SCH women with TPOAb−, compared with the euthyroid pregnant women (β = -0.223, 95%CI: -0.422, -0.023). The LT4 treated mild SCH women with TPOAb− had lower fetal HC Z-score (β = -0.236, 95%CI: -0.457, -0.015), compared with the untreated mild SCH women with TPOAb−.

Conclusions

We observed that LT4 treatment for mild SCH with TPOAb− was associated with decreased fetal HC, which was not observed for untreated mild SCH women with TPOAb−. The adverse effect of LT4 treatment for mild SCH with TPOAb− provided new evidence for the recent clinical guideline.
Experiences of patients on cancer treatment regarding decentralization of oncology services at a tertiary hospital in the Eastern Cape
Authors: Jojo Lumkile Wilmot , Nkutu Nonyaniso Trustina
Published: May 2023

Background

The cancer burden is a global public health concern associated with high morbidities and mortalities. Low and middle-income countries are more affected including South Africa. Limited access to oncology services contributes to the late presentation, late diagnosis, and treatment of cancer. In the Eastern Cape, oncology services were previously centralized with negative effects on the quality of life of the already compromised health status of the oncology patients. To mitigate the situation, a new oncology unit was opened to decentralize oncology services in the province. Little is known about the experiences of patients after this transformation. That prompted this inquiry.

Aim

This study aims to explore the experiences of cancer patients regarding the decentralization of oncology services at a tertiary hospital in the Eastern Cape.

Methodology

A qualitative approach with a descriptive, explorative, and contextual design was undertaken, to obtain the perspective of oncology recipients following the decentralization of oncology services at a selected public tertiary hospital in the Eastern Cape. After obtaining ethical clearance and permission to conduct the study, interviews were conducted with 19 participants. All interviews were transcribed verbatim against their audio recordings. Field notes were taken by the primary researcher. The concept of trustworthiness was used to ensure rigour throughout this study. Thematic analysis was done using Tesch’s approach to open coding in qualitative research.

Results

Three themes emerged from the data analysis: 1) Access to oncology services; 2) Oncology services provided; and 3) Need for improved infrastructural facilities.

Conclusion

The majority of patients had positive experiences with the unit. The waiting time was acceptable, and medication was available. Access to services was improved. The staff had a positive attitude towards patients receiving cancer treatment.
Perineural invasion affects prognosis of patients undergoing colorectal cancer surgery: a propensity score matching analysis
Authors: Qin Le , Heng Yixin , Deng Shenghe , Gu Junnan , Mao Fuwei , Xue Yifan , Jiang Zhenxing , Wang Jun , Cheng Denglong , Wu Ke , Cao Yinghao , Cai Kailin
Published: May 2023

Background

Tumour perineural invasion (PNI) is a predictor of poor prognosis, but its effect on the prognosis of patients with colorectal cancer (CRC) has not yet been elucidated.

Methods

This retrospective study used propensity score matching (PSM). The clinical case data of 1470 patients with surgically treated stage I–IV CRC at Wuhan Union Hospital were collected. PSM was used to analyse and compare the clinicopathological characteristics, perioperative outcomes, and long-term prognostic outcomes of the PNI(+) and PNI(-) groups. The factors influencing prognosis were screened using Cox univariate and multivariate analyses.

Results

After PSM, 548 patients were included in the study (n = 274 in each group). Multifactorial analysis showed that neurological invasion was an independent prognostic factor affecting patients’ OS and DFS (hazard ratio [HR], 1.881; 95% confidence interval [CI], 1.35–2.62; P = 0.0001; HR, 1.809; 95% CI, 1.353–2.419; P < 0.001). Compared to PNI(+) patients without chemotherapy, those who received chemotherapy had a significant improvement in OS (P < 0.01). The AUROC curve of OS in the PNI(+) subgroup (0.802) was higher than that after PSM (0.743), while that of DFS in the PNI(+) subgroup (0.746) was higher than that after PSM (0.706). The independent predictors of PNI(+) could better predict the prognosis and survival of patients with PNI(+).

Conclusions

PNI significantly affects the long-term survival and prognosis of patients with CRC undergoing surgery and is an independent risk factor for OS and DFS in patients with CRC undergoing surgery. Postoperative chemotherapy significantly improved the OS of PNI(+) patients.
Biliary-enteric reconstruction in laparoscopic radical resection of hilar cholangiocarcinoma: a single-center retrospective cohort study
Authors: Liu Wenzheng , Xiong Fei , Wu Guanhua , Wang Qi , Wang Bing , Chen Yongjun
Published: May 2023

Objective

To evaluate the feasibility and quality of biliary-enteric reconstruction (BER) in laparoscopic radical resection of hilar cholangiocarcinoma (LsRRH) versus open surgery and propose technical recommendations.

Methods

Data of 38 LsRRH and 54 radical laparotomy resections of hilar cholangiocarcinoma (LtRRH) cases were collected from our institution. BER was evaluated via biliary residuals numbers, number of anastomoses, anastomosis manner, suture method, time consumption, and postoperative complication.

Results

In the LsRRH group, patients were relatively younger; Bismuth type I had a higher proportion while type IIIa and IV were less and required no revascularization. In LsRRH and LtRRH groups, respectively, the biliary residuals number was 2.54 ± 1.62 and 2.47 ± 1.46 (p > 0.05); the number of anastomoses was 2.04 ± 1.27 and 2.57 ± 1.33 (p > 0.05); the time of BER was 65.67 ± 21.53 and 42.5 ± 19.77 min (p < 0.05), 15.08 ± 3.64% and 11.76 ± 2.54% of the total operation time (p < 0.05); postoperative bile leakage incidence was 15.79% and 16.67% (p > 0.05); 14 ± 10.28 and 17 ± 9.73 days for healing (p < 0.05); anastomosis stenosis rate was 2.63% and 1.85% (p > 0.05). Neither group had a biliary hemorrhage or bile leakage-related death.

Conclusion

The selection bias in LsRRH mainly affects tumor resection than BER. Our cohort study indicates that BER in LsRRH is technically feasible and equals anastomotic quality to open surgery. However, its longer and a more significant proportion of total operation time represent that BER has higher technical requirements and is one of the critical rate-limiting steps affecting the minimal invasiveness of LsRRH.
Qualitative assessment of infant sleep practices and other risk factors of sudden infant death syndrome (SIDS) among mothers in Lusaka, Zambia
Authors: Osei-Poku Godwin K. , Mwananyanda Lawrence , Elliott Patricia A. , MacLeod William B. , Somwe Somwe Wa , Pieciak Rachel C. , Hamapa Arnold , Gill Christopher J.
Published: May 2023

Background

There is very little information on the beliefs and perceptions of mothers about SIDS and its related risk factors in Africa. To better understand parental decisions about infant sleep practices and other risk factors for SIDS, we conducted focus group discussions (FGDs) with mothers of infants in Lusaka, Zambia.

Methods

FGDs involved 35 purposively sampled mothers aged 18–49 years. FGDs were conducted using a semi-structured interview guide in the local language, Nyanja. These were translated, transcribed verbatim into English, and then coded and analyzed using thematic analysis in NVivo 12.

Results

Six FGDs were conducted with 35 mothers in April-May 2021 across two study sites. FGD Participants were generally aware of sudden unexplained infant deaths, with several describing stories of apparent SIDS in the community. The side sleeping position was preferred and perceived to be safer for the infant with most believing the supine position posed an aspiration or choking risk to the infant. Bedsharing was also preferred and perceived to be convenient for breastfeeding and monitoring of the infant. Experienced family members such as grandmothers and mothers-in-law, and health care workers were frequently cited as sources of information on infant sleep position. A heightened awareness of the infant’s sleeping environment was suggested as a mechanism to prevent SIDS and smothering.

Conclusions

Decisions about bedsharing and infant sleep position were guided by maternal beliefs and perceptions about what is convenient for breastfeeding and safer for the infant. These concerns are vital to designing tailored interventions to address sleep-related sudden infant losses in Zambia. Public health campaigns with tailored messages that address these concerns are likely to be effective at ensuring optimal uptake of safe sleep recommendations.
MiR-210 improves postmenopausal osteoporosis in ovariectomized rats through activating VEGF/Notch signaling pathway
Authors: Ren Li-Jue , Zhu Xiao-Hui , Tan Jiu-Ting , Lv Xiang-Yu , Liu Yan
Published: May 2023

Background

To explore the effect and mechanism of action of miR-210 on postmenopausal osteoporosis (PMPO) in ovariectomized rats in vivo.

Methods

An ovariectomized (OVX) rat model was established by ovariectomy. Tail vein injection was performed to overexpress and knock down miR-210 in OVX rats, followed by the collection of blood and femoral tissues from each group of rats. And quantitative real-time polymerase chain reaction (qRT-PCR) was applied to assess the expression level of miR-210 in femoral tissues of each group. Micro computed tomography (Micro CT) was adopted to scan the microstructure of the femoral trabecula in each group to obtain relevant data like bone mineral density (BMD), bone mineral content (BMC), trabecular bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone surface-to-volume ratio (BS/BV), and trabecular separation (Tb.Sp). ELISA was used for determining the level of bone alkaline phosphatase (BALP), amino-terminal propeptide of type I procollagen (PINP), osteocalcin (OCN), and C-terminal telopeptide of type I collagen (CTX-1) in serum; and Western blot for the protein level of Runt-related transcription factor 2 (Runx2), osteopontin (OPN), and collagen type I alpha 1 (COL1A1) in femoral tissues.

Results

MiR-210 expression was significantly decreased in femoral tissues of OVX rats. Overexpression of miR-210 could obviously increase BMD, BMC, BV/TV and Tb.Th, whereas significantly decrease BS/BV and Tb.Sp in femurs of OVX rats. Moreover, miR-210 also downregulated BALP and CTX-1 level, upregulated PINP and OCN level in the serum of OVX rats promoted the expression of osteogenesis-related markers (Runx2, OPN and COL1A1) in the femur of OVX rats. Additionally, further pathway analysis revealed that high expression of miR-210 activated the vascular endothelial growth factor (VEGF)/Notch1 signaling pathway in the femur of OVX rats.

Conclusion

High expression of miR-210 may improve the micromorphology of bone tissue and modulate bone formation and resorption in OVX rats by activating the VEGF/Notch1 signaling pathway, thereby alleviating osteoporosis. Consequently, miR-210 can serve as a biomarker for the diagnosis and treatment of osteoporosis in postmenopausal rats.
Cantharidin suppresses hepatocellular carcinoma development by regulating EZH2/H3K27me3-dependent cell cycle progression and antitumour immune response
Authors: Yan Jia , Deng Xiu ling , Ma Shi qi , hui Li Yu , Gao Yu min , Shi Gui tao , Wang Hai sheng
Published: May 2023

Background

Cantharidin (CTD) is a major ingredient of cantharis (Mylabris phalerata Pallas) and has been used extensively in traditional Chinese medicines. It has been shown to exhibit anticancer activity in multiple types of cancer, especially hepatocellular carcinoma (HCC). However, there is no systematic study on the relationships among the regulatory networks of its targets in HCC therapy. We focused on histone epigenetic regulation and the influence of CTD on the immune response in HCC.

Methods

We performed a comprehensive analysis of novel CTD targets in HCC based on network pharmacology and RNA-seq approaches. The mRNA levels of target genes were analyzed by qRT-PCR, and the corresponding protein levels were confirmed using enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining (IHC). ChIP-seq data were visualized by IGV software. The associations of gene transcript levels with the cancer immune score and infiltration level were investigated using TIMER. In vivo, the H22 mouse model of hepatocellular carcinoma was established by treatment with CTD and 5-Fu. The immune cell proportions in the blood were elevated in model mice, as shown by flow cytometry.

Results

We identified 58 targets of CTD, which were involved in various pathways in cancer, including apoptosis, the cell cycle, EMT and immune pathways. Moreover, we found that 100 EMT-related genes were differentially expressed after CTD treatment in HCC cells. Interestingly, our results confirmed that the EZH2/H3K27me3 -related cell cycle pathway is a therapeutic target of CTD in antitumour. In addition, we evaluated the influence of CTD on the immune response. Our data showed that the significantly enriched gene sets were positively correlated with the chemokine biosynthetic and chemokine metabolic modules. The proportions of CD4+/CD8 + T cells and B cells were increased, but the proportion of Tregs was decreased after treatment with CTD in vivo. Moreover, we found that the expression of the inflammatory factor and immune checkpoint genes PD­1/PD-L1 was significantly reduced in the mouse model.

Conclusion

We performed a novel integrated analysis of the potential role of CTD in HCC treatment. Our results provide innovative insight into the mechanism by which cantharidin exerts antitumour effects by regulating target genes expression to mediate apoptosis, EMT, cell cycle progression and the immune response in HCC. Based on the effect of CTD on the immune response, it can be used as a potential effective drug to activate antitumour immunity for the treatment of liver cancer.
Comprehensive chemical profiling of Bassia indica Wight. aerial parts extract using UPLC-ESI–MS/MS, and its antiparasitic activity in Trichinella spiralis infected mice: in silico supported in vivo study
Authors: Mohammed Magdy M. D. , Heikal Elham A. , Ellessy Fatma M. , Aboushousha Tarek , Ghareeb Mosad A.
Published: May 2023

Background

Trichinellosis is a public health threat infected both animals and humans as a result of eating undercooked meat. It caused by Trichinella spiralis that has widespread drug resistance and even developed many sophisticated strategies for their survival, this increases the demand in searching for new anthelmintic drugs from natural source.

Methods

Our objectives were to test the in vitro and in vivo anthelmintic activity of Bassia indica BuOH frac., and to characterize its chemical composition using UPLC-ESI–MS/MS. Besides an in silico molecular docking study with the prediction of the PreADMET properties.

Results

In vitro investigation of B. indica BuOH frac., showed severe destruction of the adult worm and larvae, marked cuticle swelling, areas with vesicles, blebs and loss of annulations. This was assured via in vivo study, which revealed a significant reduction (P < 0.05) in the mean adult worm count with efficacy of 47.8% along with a significant decrease (P < 0.001) in the mean larval count per gram muscle with efficacy 80.7%. Histopathological examinations of the small intestine and muscular sections showed marked improvement. In addition, immunohistochemical findings demonstrated that B. indica BuOH frac. depressed the proinflammatory cytokines expressions of TNF-α, which was obviously upregulated by T. spiralis. Precise chemical investigation of the BuOH frac. using UPLC-ESI–MS/MS resulted in the identification of 13 oleanolic type triterpenoid saponins; oleanolic acid 3-O-6´-O-methyl-β-D-glucurono-pyranoside (1), chikusetsusaponin-IVa (2) and its methyl ester (3), chikusetsusaponin IV (4) and its methyl ester (5), momordin-Ic (6) and its methyl ester (7), betavulgaroside-I (8), -II (9) -IV (10), -X (11), licorice-saponin-C2 (12) and -J2 (13). In addition, 6 more phenolics were identified as syringaresinol (14), 3,4-di-O-caffeoylquinic acid (15), 3-O-caffeoyl-4-O-dihydrocaffeoylquinic acid (16), 3,4-di-O-caffeoylquinic acid butyl ester (17), 3,5-di-O-galloyl-4-O-digalloylquinic acid (18) and quercetin 3-O-(6´´-feruloyl)-sophoroside (19). The auspicious anthelmintic activity was further ascertained using in silico molecular docking approach that targeted certain protein receptors (β-tubulin monomer, tumor necrosis factor alpha (TNF-α), cysteine protease (Ts-CF1), calreticulin protein (Ts-CRT)), all the docked compounds (1–19) fit into the binding site of the active pocket with binding affinities noteworthy than albendazole. In addition, ADMET properties, drug score and drug likeness were predicted for all compounds.
The impact of non-alcoholic fatty liver disease and liver fibrosis on adverse clinical outcomes and mortality in patients with chronic kidney disease: a prospective cohort study using the UK Biobank
Authors: Hydes Theresa J. , Kennedy Oliver J. , Buchanan Ryan , Cuthbertson Daniel J. , Parkes Julie , Fraser Simon D. S. , Roderick Paul
Published: May 2023

Background

Chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) frequently co-exist. We assess the impact of having NAFLD on adverse clinical outcomes and all-cause mortality for people with CKD.

Methods

A total of 18,073 UK Biobank participants identified to have CKD (eGFR < 60 ml/min/1.73 m2 or albuminuria > 3 mg/mmol) were prospectively followed up by electronic linkage to hospital and death records. Cox-regression estimated the hazard ratios (HR) associated with having NAFLD (elevated hepatic steatosis index or ICD-code) and NAFLD fibrosis (elevated fibrosis-4 (FIB-4) score or NAFLD fibrosis score (NFS)) on cardiovascular events (CVE), progression to end-stage renal disease (ESRD) and all-cause mortality.

Results

56.2% of individuals with CKD had NAFLD at baseline, and 3.0% and 7.7% had NAFLD fibrosis according to a FIB-4 > 2.67 and NFS ≥ 0.676, respectively. The median follow-up was 13 years. In univariate analysis, NAFLD was associated with an increased risk of CVE (HR 1.49 [1.38–1.60]), all-cause mortality (HR 1.22 [1.14–1.31]) and ESRD (HR 1.26 [1.02–1.54]). Following multivariable adjustment, NAFLD remained an independent risk factor for CVE overall (HR 1.20 [1.11–1.30], p < 0.0001), but not ACM or ESRD. In univariate analysis, elevated NFS and FIB-4 scores were associated with increased risk of CVE (HR 2.42 [2.09–2.80] and 1.64 [1.30–2.08]) and all-cause mortality (HR 2.82 [2.48–3.21] and 1.82 [1.47–2.24]); the NFS score was also associated with ESRD (HR 5.15 [3.52–7.52]). Following full adjustment, the NFS remained associated with an increased incidence of CVE (HR 1.19 [1.01–1.40]) and all-cause mortality (HR 1.31 [1.13–1.52]).

Conclusions

In people with CKD, NAFLD is associated with an increased risk of CVE, and the NAFLD fibrosis score is associated with an elevated risk of CVE and worse survival.
Polyamine metabolism patterns characterized tumor microenvironment, prognosis, and response to immunotherapy in colorectal cancer
Authors: Zhang Enkui , Ding Chengsheng , Li Shuchun , Aikemu Batuer , Zhou Xueliang , Fan Xiaodong , Sun Jing , Yang Xiao , Zheng Minhua
Published: May 2023

Background

Changes in Polyamine metabolism (PAM) have been shown to establish a suppressive tumor microenvironment (TME) and substantially influence the progression of cancer in the recent studies. However, newly emerging data have still been unable to fully illuminate the specific effects of PAM in human cancers. Here, we analyzed the expression profiles and clinical relevance of PAM genes in colorectal cancer (CRC).

Methods

Based on unsupervised consensus clustering and principal component analysis (PCA) algorithm, we designed a scoring model to evaluate the prognosis of CRC patients and characterize the TME immune profiles, with related independent immunohistochemical validation cohort. Through comparative profiling of cell communities defined by single cell sequencing data, we identified the distinct characteristics of polyamine metabolism in the TME of CRC.

Results

Three PAM patterns with distinct prognosis and TME features were recognized from 1224 CRC samples. Moreover, CRC patients could be divided into high- and low-PAMscore subgroups by PCA-based scoring system. High PAMscore subgroup were associated to more advanced stage, higher infiltration level of immunosuppressive cells, and unfavorable prognosis. These results were also validated in CRC samples from other public CRC datasets and our own cohort, which suggested PAM genes were ideal biomarkers for predicting CRC prognosis. Notably, PAMscore also corelated with microsatellite instability-high (MSI-H) status, higher tumor mutational burden (TMB), and increased immune checkpoint gene expression, implying a potential role of PAM genes in regulating response to immunotherapy. To further confirm above results, we demonstrated a high-resolution landscape of TME and cell–cell communication network in different PAM patterns using single cell sequencing data and found that polyamine metabolism affected the communication between cancer cells and several immune cells such as T cells, B cells and myeloid cells.

Conclusion

In total, our findings highlighted the significance of polyamine metabolism in shaping the TME and predicting the prognosis of CRC patients, providing novel strategies for immunotherapy and the targeting polyamine metabolites.
Exploring the role of pyroptosis in shaping the tumor microenvironment of colorectal cancer by bulk and single-cell RNA sequencing
Authors: Ding Chengsheng , Yang Xiao , Li Shuchun , Zhang Enkui , Fan Xiaodong , Huang Ling , He Zirui , Sun Jing , Ma Junjun , Zang Lu , Zheng Minhua
Published: May 2023

Background

Emerging studies have shown that pyroptosis plays a non-negligible role in the development and treatment of tumors. However, the mechanism of pyroptosis in colorectal cancer (CRC) remains still unclear. Therefore, this study investigated the role of pyroptosis in CRC.

Methods

A pyroptosis-related risk model was developed using univariate Cox regression and LASSO Cox regression analyses. Based on this model, pyroptosis-related risk scores (PRS) of CRC samples with OS time > 0 from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database were calculated. The abundance of immune cells in CRC tumor microenvironment (TME) was predicted by single-sample gene-set enrichment analysis (ssGSEA). Then, the responses to chemotherapy and immunotherapy were predicted by pRRophetic algorithm, the tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms, respectively. Moreover, the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing dataset (PRISM) were used to explore novel drug treatment strategies of CRC. Finally, we investigated pyroptosis-related genes in the level of single-cell and validated the expression levels of these genes between normal and CRC cell lines by RT-qPCR.

Results

Survival analysis showed that CRC samples with low PRS had better overall survival (OS) and progression-free survival (PFS). CRC samples with low PRS had higher immune-related gene expression and immune cell infiltration than those with high PRS. Besides, CRC samples with low PRS were more likely to benefit from 5-fluorouracil based chemotherapy and anti-PD-1 immunotherapy. In novel drug prediction, some compounds such as C6-ceramide and noretynodrel, were inferred as potential drugs for CRC with different PRS. Single-cell analysis revealed pyroptosis-related genes were highly expressed in tumor cells. RT-qPCR also demonstrated different expression levels of these genes between normal and CRC cell lines.

Conclusions

Taken together, this study provides a comprehensive investigation of the role of pyroptosis in CRC at the bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) levels, advances our understanding of CRC characteristics, and guides more effective treatment regimens.

Graphical Abstract
Comprehensive analysis of three female patients with different types of X/Y translocations and literature review
Authors: Liu Shanquan , Zheng Jiemei , Liu Xijing , Lai Yi , Zhang Xuan , He Tiantian , Yang Yan , Wang He , Zhang Xuemei
Published: May 2023

Background

X/Y translocations are highly heterogeneity in terms of clinical genetic effects, and most patients lack complete pedigree analysis for clinical and genetic characterization.

Results

This study comprehensively analyzed the clinical and genetic characteristics of three new patients with X/Y translocations. Furthermore, cases with X/Y translocations reported in the literature and studies exploring the clinical genetic effects in patients with X/Y translocations were reviewed. All three female patients were carriers of X/Y translocations with different phenotypes. The karyotype for patient 1 was 46,X,der(X)t(X;Y)(p22.33;q12)mat, patient 2 was 46,X,der(X)t(X;Y)(q21.2;q11.2)dn, and patient 3 was 46,X,der(X)t(X;Y)(q28;q11.223)t(Y;Y)(q12;q11.223)mat. C-banding analysis of all three patients revealed a large heterochromatin region in the terminal region of the X chromosome. All patients underwent chromosomal microarray analysis, which revealed the precise copy number loss or gain. Data on 128 patients with X/Y translocations were retrieved from 81 studies; the phenotype of these patients was related to the breakpoint of the chromosome, size of the deleted region, and their sex. We reclassified the X/Y translocations into new types based on the breakpoints of the X and Y chromosomes.

Conclusion

X/Y translocations have substantial phenotypic diversity, and the genetic classification standards are not unified. With the development of molecular cytogenetics, it is necessary to combine multiple genetic methods to obtain an accurate and reasonable classification. Thus, clarifying their genetic causes and effects promptly will help in genetic counseling, prenatal diagnosis, preimplantation genetic testing, and improvement in clinical treatment strategies.
Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids
Authors: Cesari Eleonora , Ciucci Alessandra , Pieraccioli Marco , Caggiano Cinzia , Nero Camilla , Bonvissuto Davide , Sillano Francesca , Buttarelli Marianna , Piermattei Alessia , Loverro Matteo , Camarda Floriana , Greco Viviana , De Bonis Maria , Minucci Angelo , Gallo Daniela , Urbani Andrea , Vizzielli Giuseppe , Scambia Giovanni , Sette Claudio
Published: May 2023

Background

High grade serous ovarian cancer (HGSOC) is highly lethal, partly due to chemotherapy resistance and limited availability of targeted approaches. Cyclin dependent kinases 12 and 13 (CDK12/13) are promising therapeutic targets in human cancers, including HGSOC. Nevertheless, the effects of their inhibition in HGSOC and the potential synergy with other drugs are poorly known.

Methods

We analyzed the effects of the CDK12/13 inhibitor THZ531 in HGSOC cells and patient-derived organoids (PDOs). RNA sequencing and quantitative PCR analyses were performed to identify the genome-wide effects of short-term CDK12/13 inhibition on the transcriptome of HGSOC cells. Viability assays with HGSOC cells and PDOs were performed to assess the efficacy of THZ531 as single agent or in combination with clinically relevant drugs.

Results

The CDK12 and CDK13 genes are deregulated in HGSOC and their concomitant up-regulation with the oncogene MYC predicts poor prognosis. HGSOC cells and PDOs display high sensitivity to CDK12/13 inhibition, which synergizes with drugs in clinical use for HGSOC. Transcriptome analyses revealed cancer-relevant genes whose expression is repressed by dual CDK12/13 inhibition through impaired splicing. Combined treatment with THZ531 and inhibitors of pathways regulated by these cancer relevant genes (EGFR, RPTOR, ATRIP) exerted synergic effects on HGSOC PDO viability.

Conclusions

CDK12 and CDK13 represent valuable therapeutic targets for HGSOC. We uncovered a wide spectrum of CDK12/13 targets as potential therapeutic vulnerabilities for HGSOC. Moreover, our study indicates that CDK12/13 inhibition enhances the efficacy of approved drugs that are already in use for HGSOC or other human cancers.
CircZNF215 promotes tumor growth and metastasis through inactivation of the PTEN/AKT pathway in intrahepatic cholangiocarcinoma
Authors: Liao Wenwei , Du Jinpeng , Li Lian , Wu Xianquan , Chen Xing , Feng Qingbo , Xu Lin , Chen Xiangzheng , Liao Mingheng , Huang Jiwei , Yuan Kefei , Zeng Yong
Published: May 2023

Background

Increasing evidence shows that circular RNAs (circRNAs), a novel class of noncoding RNAs, play a crucial role in the development of cancers, including intrahepatic cholangiocarcinoma (iCCA). Nevertheless, their functions and exact mechanisms in iCCA progression and metastasis are still unclear. Ipatasertib is a highly selective inhibitor of AKT that inhibits tumor growth by blocking the PI3K/AKT pathway. In addition, phosphatase and tensin homolog (PTEN) can also inhibit the activation of the PI3K/AKT pathway, but it is not clear whether the cZNF215-PRDX-PTEN axis plays a role in the antitumor activity of ipatasertib.

Methods

We identified a new circRNA (circZNF215, termed cZNF215) through high-throughput circRNA sequencing (circRNA-seq). In addition, RT‒qPCR, immunoblot assay, RNA pull-down assay, RNA immunoprecipitation (RIP) assay, and fluorescence in situ hybridization assay (FISH) were used to investigate the interaction of cZNF215 with peroxiredoxin 1 (PRDX1). Coimmunoprecipitation (Co-IP) assays and duolink in situ proximity ligation assays (PLAs) were conducted to analyze the effects of cZNF215 on the interaction between PRDX1 and PTEN. Finally, we tested the potential effects of cZNF215 on the antitumor activity of ipatasertib with in vivo experiments.

Results

We found that cZNF215 expression was obviously upregulated in iCCA tissues with postoperative metastases and was correlated with iCCA metastasis and poor outcome in patients with iCCA. We further revealed that overexpression of cZNF215 promoted iCCA cell growth and metastasis in vitro and in vivo, while cZNF215 knockdown had the opposite effect. Mechanistic studies suggested that cZNF215 competitively interacted with PRDX1, which blocked the association between PRDX1 and PTEN, subsequently leading to oxidation-induced inactivation of the PTEN/AKT pathway and finally contributing to iCCA progression and metastasis. Additionally, we also revealed that silencing cZNF215 in iCCA cells had the potential to enhance the antitumor effect of ipatasertib.

Conclusions

Our study demonstrates that cZNF215 facilitates iCCA progression and metastasis by regulating the PTEN/AKT pathway and may serve as a novel prognostic predictor in patients with iCCA.
SPUMONI 2: improved classification using a pangenome index of minimizer digests
Authors: Ahmed Omar Y. , Rossi Massimiliano , Gagie Travis , Boucher Christina , Langmead Ben
Published: May 2023

Genomics analyses use large reference sequence collections, like pangenomes or taxonomic databases. SPUMONI 2 is an efficient tool for sequence classification of both short and long reads. It performs multi-class classification using a novel sampled document array. By incorporating minimizers, SPUMONI 2’s index is 65 times smaller than minimap2’s for a mock community pangenome. SPUMONI 2 achieves a speed improvement of 3-fold compared to SPUMONI and 15-fold compared to minimap2. We show SPUMONI 2 achieves an advantageous mix of accuracy and efficiency in practical scenarios such as adaptive sampling, contamination detection and multi-class metagenomics classification.
In vitro anti-Toxoplasma gondii activity of Ganoderma lucidum extracts
Authors: ahmadi Mohammad , Salimi Mahboobeh , Saraei Mehrzad , Nezhad Niloofar Salavati , Javadi Amir , Mohammadi Faezeh , Heydarian Peyman , Ali Ehsan , Hajialilo Elham
Published: May 2023

Objective

Ganoderma extracts have the potential to be used as anti-cancer, anti-inflammatory, immunomodulator, and antimicrobial agents, as evaluated in numerous studies. This study was aimed to determine the lethal and inhibitory effects of aqueous, hydroalcoholic, and alcoholic extracts of Ganoderma lucidum on Toxoplasma gondii RH strain tachyzoites, in vitro.

Results

All three types of extracts showed toxoplasmacidal effects. The highest percentage of mortality was related to hydroalcoholic extract. The EC50 of Ganoderma extracts for tachyzoites were 76.32, 3.274, and 40.18 for aqueous, hydroalcoholic and alcoholic extracts, respectively. The selectivity index obtained for hydroalcoholic extract was 71.22, showing the highest activity compared to other extracts. According to our findings, the hydroalcoholic part was the most effective substance among the extracts. This basic study showed obvious anti-toxoplasma effect of Ganoderma lucidum extracts. These extracts can be used as candidates for further in-depth and comprehensive studies especially In vivo experiments to prevent toxoplasmosis.
Automatic and standardized quality assurance of digital mammography and tomosynthesis with deep convolutional neural networks
Authors: Hejduk Patryk , Sexauer Raphael , Ruppert Carlotta , Borkowski Karol , Unkelbach Jan , Schmidt Noemi
Published: May 2023

Objectives

The aim of this study was to develop and validate a commercially available AI platform for the automatic determination of image quality in mammography and tomosynthesis considering a standardized set of features.

Materials and methods

In this retrospective study, 11,733 mammograms and synthetic 2D reconstructions from tomosynthesis of 4200 patients from two institutions were analyzed by assessing the presence of seven features which impact image quality in regard to breast positioning. Deep learning was applied to train five dCNN models on features detecting the presence of anatomical landmarks and three dCNN models for localization features. The validity of models was assessed by the calculation of the mean squared error in a test dataset and was compared to the reading by experienced radiologists.

Results

Accuracies of the dCNN models ranged between 93.0% for the nipple visualization and 98.5% for the depiction of the pectoralis muscle in the CC view. Calculations based on regression models allow for precise measurements of distances and angles of breast positioning on mammograms and synthetic 2D reconstructions from tomosynthesis. All models showed almost perfect agreement compared to human reading with Cohen’s kappa scores above 0.9.

Conclusions

An AI-based quality assessment system using a dCNN allows for precise, consistent and observer-independent rating of digital mammography and synthetic 2D reconstructions from tomosynthesis. Automation and standardization of quality assessment enable real-time feedback to technicians and radiologists that shall reduce a number of inadequate examinations according to PGMI (Perfect, Good, Moderate, Inadequate) criteria, reduce a number of recalls and provide a dependable training platform for inexperienced technicians.
Efficient pulmonary nodules classification using radiomics and different artificial intelligence strategies
Authors: Saied Mohamed , Raafat Mourad , Yehia Sherif , Khalil Magdy M.
Published: May 2023

Objectives

This study aimed to explore and develop artificial intelligence approaches for efficient classification of pulmonary nodules based on CT scans.

Materials and methods

A number of 1007 nodules were obtained from 551 patients of LIDC-IDRI dataset. All nodules were cropped into 64 × 64 PNG images , and preprocessing was carried out to clean the image from surrounding non-nodular structure. In machine learning method, texture Haralick and local binary pattern features were extracted. Four features were selected using principal component analysis (PCA) algorithm before running classifiers. In deep learning, a simple CNN model was constructed and transfer learning was applied using VGG-16 and VGG-19, DenseNet-121 and DenseNet-169 and ResNet as pre-trained models with fine tuning.

Results

In statistical machine learning method, the optimal AUROC was 0.885 ± 0.024 with random forest classifier and the best accuracy was 0.819 ± 0.016 with support vector machine. In deep learning, the best accuracy reached 90.39% with DenseNet-121 model and the best AUROC was 96.0%, 95.39% and 95.69% with simple CNN, VGG-16 and VGG-19, respectively. The best sensitivity reached 90.32% using DenseNet-169 and the best specificity attained was 93.65% when applying the DenseNet-121 and ResNet-152V2.

Conclusion

Deep learning methods with transfer learning showed several benefits over statistical learning in terms of nodule prediction performance and saving efforts and time in training large datasets. SVM and DenseNet-121 showed the best performance when compared with their counterparts. There is still more room for improvement, especially when more data can be trained and lesion volume is represented in 3D.

Clinical relevance statement

Machine learning methods offer unique opportunities and open new venues in clinical diagnosis of lung cancer. The deep learning approach has been more accurate than statistical learning methods. SVM and DenseNet-121 showed superior performance in pulmonary nodule classification.

Graphical abstract
Technical aspects of inter-recti distance measurement with ultrasonographic imaging for physiotherapy purposes: the scoping review
Authors: Opala-Berdzik Agnieszka , Rudek-Zeprzałka Magdalena , Niesporek Justyna , Cebula Maciej , Baron Jan , Gruszczyńska Katarzyna , Pascoal Augusto Gil , Mota Patrícia , Chmielewska Daria
Published: May 2023

Background

Inter-recti distance (IRD) measurement using musculoskeletal USI has been used in physiotherapy research, in particular, to investigate pregnancy-related diastasis recti abdominis (DRA) and to seek its effective treatment methods. Severe and untreated diastasis may result in the formation of umbilical or epigastric hernias.

Objective

This study aimed to systematically map physiotherapy-related research articles that included descriptions of IRD measurement procedures using USI to present their similarities and differences, and formulate recommendations on the procedure.

Design

A scoping review was conducted according to PRISMA-ScR guidelines, including 49 of 511 publications from three major databases. Publications were selected and screened by two independent reviewers whose decisions were consulted with a third reviewer. The main synthesized data items were: the examinees’ body position, breathing phase, measurement sites, and DRA screening methods. The final conclusions and recommendations were the result of a consensus between seven reviewers from four research centers.

Results

Studies used 1–5 measurement sites that were differently determined. IRD was measured at the umbilicus (n = 3), at its superior (n = 16) and/or inferior border (n = 9), and at different levels: between 2 and 12 cm above the umbilicus, or a third of the distance and halfway between the umbilicus and xiphoid (n = 37); between 2 and 4.5 cm below the umbilicus or halfway between the umbilicus and pubis (n = 27). Different approaches were used to screen subjects for DRA.

Conclusions

The discrepancies between the measurement procedures prevent between-study comparisons. The DRA screening method should be standardized. IRD measurement protocol standardization has been proposed.

Critical relevance statement

This scoping review indicates that the inter-recti distance measurement procedures using ultrasound imaging differ between studies, preventing between-study comparisons. Based on the results synthesis, the measurement protocol standardization has been proposed.

Key points

The inter-recti distance measurement procedures using USI differ between studies.

Proposed standardization concerns body position, breathing phase, measurements number per location.

Determination of measurement locations considering individual linea alba length is suggested.

Recommended locations: umbilical top, ½ of umbilical top-xiphoid, ¼ of umbilical top-xiphoid/pubis distances.

Diastasis recti abdominis diagnostic criteria are needed for proposed measurement locations.

Graphical Abstract
Hospital-based clinicians lack knowledge and comfort in initiating medications for opioid use disorder: opportunities for training innovation
Authors: Jakubowski Andrea , Singh-Tan Sumeet , Torres-Lockhart Kristine , Nahvi Shadi , Stein Melissa , Fox Aaron D. , Lu Tiffany
Published: May 2023

Background

Hospital-based clinicians infrequently initiate medications for opioid use disorder (MOUD) for hospitalized patients. Our objective was to understand hospital-based clinicians’ knowledge, comfort, attitudes, and motivations regarding MOUD initiation to target quality improvement initiatives.

Methods

General medicine attending physicians and physician assistants at an academic medical center completed questionnaires eliciting barriers to MOUD initiation, including knowledge, comfort, attitudes and motivations regarding MOUD. We explored whether clinicians who had initiated MOUD in the prior 12 months differed in knowledge, comfort, attitudes, and motivations from those who had not.

Results

One-hundred forty-three clinicians completed the survey with 55% reporting having initiated MOUD for a hospitalized patient during the prior 12 months. Common barriers to MOUD initiation were: (1) Not enough experience (86%); (2) Not enough training (82%); (3) Need for more addiction specialist support (76%). Overall, knowledge of and comfort with MOUD was low, but motivation to address OUD was high. Compared to MOUD non-initiators, a greater proportion of MOUD initiators answered knowledge questions correctly, agreed or strongly agreed that they wanted to treat OUD (86% vs. 68%, p = 0.009), and agreed or strongly agreed that treatment of OUD with medication was more effective than without medication (90% vs. 75%, p = 0.022).

Conclusions

Hospital-based clinicians had favorable attitudes toward MOUD and are motivated to initiate MOUD, but they lacked knowledge of and comfort with MOUD initiation. To increase MOUD initiation for hospitalized patients, clinicians will need additional training and specialist support.
Genetic mutations in HER2-positive breast cancer: possible association with response to trastuzumab therapy
Authors: Zakaria Nermine H. , Hashad Doaa , Saied Marwa H. , Hegazy Neamat , Elkayal Alyaa , Tayae Eman
Published: May 2023

Background

HER2-positive breast cancer occurs in 15–20% of breast cancer patients and is characterized by poor prognosis. Trastuzumab is considered the key drug for treatment of HER2-positive breast cancer patients. It improves patient survival; however, resistance to trastuzumab remains a challenge in HER2-positive breast cancer patients. Therefore, the prediction of response to trastuzumab is crucial to choose optimal treatment regimens. The aim of the study was to identify genetic variants that could predict response to anti-HER2-targeted therapy (trastuzumab) using next-generation sequencing.

Method

Genetic variants in the hotspot regions of 17 genes were studied in 24 Formalin-Fixed Paraffin-Embedded (FFPE) samples using Ion S5 next-generation sequencing system. FFPE samples were collected from HER2‑positive breast cancer patients previously treated with anti‑HER2‑targeted treatment (Trastuzumab). Patients were divided into two groups; trastuzumab-sensitive group and trastuzumab-resistant group based on their response to targeted therapy.

Results

We identified 29 genetic variants in nine genes that only occurred in trastuzumab-resistant patients and could be associated with resistance to targeted therapy including TP53, ATM, RB1, MLH1, SMARCB1, SMO, GNAS, CDH1, and VHL. Four variants out of these 29 variants were repeated in more than one patient; two variants in TP53, one variant in ATM gene, and the last variant in RB1 gene. In addition, three genes were found to be mutated only in resistant patients; MLH1, SMARCB1 and SMO genes. Moreover, one novel allele (c.407A > G, p. Gln136Arg) was detected within exon 4 of TP53 gene in one resistant patient.

Conclusion

NGS sequencing is a useful tool to detect genetic variants that could predict response to trastuzumab therapy.