bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of cognitive impairment and diabetes on survival in Chinese older people with hypertension: a 10-year prospective study
Authors: Cai Shuang , Cheng Bokai , Li Kailiang , Li Yun , Zhang Anhang , Sun Jin , Su Yongkang , Li Man , Bao Qiligeer , Zhang Yan , Ma Shouyuan , Zhu Ping , Wang Shuxia
Published: September 2023

Background

Older people with hypertension may have more complex multisystem problems and a higher risk of morbidity and mortality. We aimed to examine the association of cognitive impairment (CI) and diabetes mellitus (DM) on all-cause mortality in the aged with hypertension (HTN).

Methods

This is a prospective cohort study with a sample of 1017 older people with hypertension aged 60 years or older who completed baseline examinations in 2009–2010 and followed up for ten years in 2020. The endpoint was death from any cause. Subjects were categorized as HTN only, HTN + DM, HTN + CI, and HTN + DM + CI. Cox regression model was used to determine the association of comorbidities on all-cause mortality.

Results

During the 10-year follow-up period, 196 deaths occurred. After adjusted for covariates, risk of death from any cause was significantly increased in the older people with increased comorbidities (P = 0.003). Compared with the HTN only, with HTN + CI, and HTN + DM + CI, the HRs (95% confidence intervals) for all-cause mortality were 1.61(1.13–2.30) and 1.79(1.07–2.99), respectively. In stratified analyses, the relationship between comorbidities level and the risk of all-cause mortality persisted.

Conclusion

All-cause mortality risks increased with increasing the comorbidities. This study emphasizes the importance of comprehensive management of the older people with HTN in clinical practice and public health policy.
Automated cervical cell segmentation using deep ensemble learning
Authors: Ji Jie , Zhang Weifeng , Dong Yuejiao , Lin Ruilin , Geng Yiqun , Hong Liangli
Published: September 2023

Background

Cervical cell segmentation is a fundamental step in automated cervical cancer cytology screening. The aim of this study was to develop and evaluate a deep ensemble model for cervical cell segmentation including both cytoplasm and nucleus segmentation.

Methods

The Cx22 dataset was used to develop the automated cervical cell segmentation algorithm. The U-Net, U-Net +  + , DeepLabV3, DeepLabV3Plus, Transunet, and Segformer were used as candidate model architectures, and each of the first four architectures adopted two different encoders choosing from resnet34, resnet50 and denseNet121. Models were trained under two settings: trained from scratch, encoders initialized from ImageNet pre-trained models and then all layers were fine-tuned. For every segmentation task, four models were chosen as base models, and Unweighted average was adopted as the model ensemble method.

Results

U-Net and U-Net +  + with resnet34 and denseNet121 encoders trained using transfer learning consistently performed better than other models, so they were chosen as base models. The ensemble model obtained the Dice similarity coefficient, sensitivity, specificity of 0.9535 (95% CI:0.9534–0.9536), 0.9621 (0.9619–0.9622),0.9835 (0.9834–0.9836) and 0.7863 (0.7851–0.7876), 0.9581 (0.9573–0.959), 0.9961 (0.9961–0.9962) on cytoplasm segmentation and nucleus segmentation, respectively. The Dice, sensitivity, specificity of baseline models for cytoplasm segmentation and nucleus segmentation were 0.948, 0.954, 0.9823 and 0.750, 0.713, 0.9988, respectively. Except for the specificity of cytoplasm segmentation, all metrics outperformed the best baseline models (P < 0.05) with a moderate margin.

Conclusions

The proposed algorithm achieved better performances on cervical cell segmentation than baseline models. It can be potentially used in automated cervical cancer cytology screening system.
The minimum number of examined lymph nodes was 24 for optimal survival of pathological T2-4 gastric cancer: a multi-center, hospital-based study covering 20 years of data
Authors: Zhao Lulu , Zhang Fan , Jiao Fuzhi , Zhou Xiadong , Niu Penghui , Han Xue , Wang Wanqing , Luan Xiaoyi , He Mingyan , Guan Quanlin , Li Yumin , Zhao Dongbing , Gao Jidong , Chen Yingtai
Published: September 2023

Introduction

The current National Comprehensive Cancer Network (NCCN) guidelines recommend that at least 16 lymph nodes should be examined for gastric cancer patients to reduce staging migration. However, there is still debate regarding the optimal management of examined lymph nodes (ELNs) for gastric cancer patients. In this study, we aimed to develop and test the minimum number of ELNs that should be retrieved during gastrectomy for optimal survival in patients with gastric cancer.

Methods

We used the restricted cubic spline (RCS) to identify the optimal threshold of ELNs that should be retrieved during gastrectomy based on the China National Cancer Center Gastric Cancer (NCCGC) database. Northwest cohort, which sourced from the highest gastric cancer incidence areas in China, was used to verify the optimal cutoff value. Survival analysis was performed via Kaplan-Meier estimates and Cox proportional hazards models.

Results

In this study, 12,670 gastrectomy patients were included in the NCCGC cohort and 4941 patients in the Northwest cohort. During 1999–2019, the average number of ELNs increased from 17.88 to 34.45 nodes in the NCCGC cohort, while the number of positive lymph nodes remained stable (5–6 nodes). The RCS model showed a U-curved association between ELNs and the risk of all-cause mortality, and the optimal threshold of ELNs was 24 [Hazard ratio (HR) = 1.00]. The ELN ≥ 24 group had a better overall survival (OS) than the ELN < 24 group clearly (P = 0.003), however, with respect to the threshold of 16 ELNs, there was no significantly difference between the two groups (P = 0.101). In the multivariate analysis, ELN ≥ 24 group was associated with improved survival outcomes in total gastrectomy patients [HR = 0.787, 95% confidence interval (CI): 0.711–0.870, P < 0.001], as well as the subgroup analysis of T2 patients (HR = 0.621, 95%CI: 0.399–0.966, P = 0.035), T3 patients (HR = 0.787, 95%CI: 0.659–0.940, P = 0.008) and T4 patients (HR = 0.775, 95%CI: 0.675–0.888, P < 0.001).

Conclusion

In conclusion, the minimum number of ELNs for optimal survival of gastric cancer with pathological T2-4 was 24.
Preoperative treatment with mFOLFIRINOX or Gemcitabine/Nab-paclitaxel +/- isotoxic high-dose stereotactic body Radiation Therapy (iHD-SBRT) for borderline resectable pancreatic adenocarcinoma (the STEREOPAC trial): study protocol for a randomised comparative multicenter phase II trial
Authors: Bouchart Christelle , Navez Julie , Borbath Ivan , Geboes Karen , Vandamme Timon , Closset Jean , Moretti Luigi , Demetter Pieter , Paesmans Marianne , Van Laethem Jean-Luc
Published: September 2023

Background

For patients with pancreatic ductal adenocarcinoma (PDAC), surgical resection remains the only potentially curative treatment. Surgery is generally followed by postoperative chemotherapy associated with improved survival, yet neoadjuvant therapy is a rapidly emerging concept requiring to be explored and validated in terms of treatment options and oncological outcomes. In this context, stereotactic body radiation (SBRT) appears feasible and can be safely integrated into a neoadjuvant chemotherapy regimen of modified FOLFIRINOX (mFFX) with promising benefits in terms of R0 resection, local control and survival. However, the optimal therapeutic sequence is still not known, especially for borderline resectable PDAC, and the role of adding SBRT to chemotherapy in the neoadjuvant setting needs to be evaluated in randomised controlled trials. The aim of the STEREOPAC trial is to assess the impact and efficacy of adding isotoxic high-dose SBRT (iHD-SBRT) to neoadjuvant mFFX or Gemcitabine/Nab-Paclitaxel (Gem/Nab-P) in patients with borderline resectable PDAC.

Methods

This is a randomised comparative multicentre phase II trial, planning to enrol patients (n = 256) diagnosed with a borderline resectable biopsy-confirmed PDAC. Patients will receive 4 cycles of mFFX (or 6 doses of Gem/Nab-P). After full disease restaging, non-progressive patients will be randomised for receiving either 4 additional mFFX cycles (or 6 doses of Gem/Nab-P) (Arm A), or 2 mFFX cycles (or 3 doses of Gem/Nab-P) + iHD-SBRT (35 to 55 Gy in 5 fractions) + 2 mFFX cycles (or 3 doses of Gem/Nab-P) (Arm B). Then curative surgery will be performed followed by adjuvant chemotherapy according to patient’s condition. The co-primary endpoints are R0 resection and disease-free survival after the complete sequence strategy. The secondary endpoints include resection rate, overall survival, locoregional failure / distant metastasis free interval, pathologic complete response, toxicity, postoperative complications and quality of life assessment.

Discussion

This trial will help define the best neoadjuvant treatment sequence for borderline resectable PDAC and aims to evaluate if a total neoadjuvant treatment integrating iHD-SBRT improves the patients’ oncological outcomes.

Trial registration

The study was registered at ClinicalTrails.gov (NCT05083247) on October 19th, 2021, and in the Clinical Trials Information System (CTIS) EU CT database (2022-501181-22-01) on July 2022.
Comparison between P-POSSUM and NELA risk score for patients undergoing emergency laparotomy in Egyptian patients
Authors: Alabbasy Mahmoud Magdy , Elsisy Alaa Abd Elazim , Mahmoud Adel , Alhanafy Saad Soliman
Published: September 2023

Background and aims

The Portsmouth-Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (P-POSSUM) is one of the scores that is used most frequently for determining the likelihood of mortality in patients undergoing emergency laparotomy. National Emergency Laparotomy Audit (NELA) presents a novel and validated score. Therefore, we aimed to compare the performance of the NELA and P-POSSUM mortality risk scores in predicting 30-day and 90-day mortality in patients undergoing emergency laparotomy.

Methods

Between August 2020 and October 2022, this cohort study was undertaken at Menoufia University Hospital. We compared the P-POSSUM, preoperative NELA, and postoperative NELA scores in patients undergoing emergency laparotomy. All variables needed to calculate the used scores were collected. The outcomes included the death rates at 30 and 90 days. By calculating the area under the curve (AUC) for every mortality instrument, the discrimination of the various methods was evaluated and compared.

Results

Data from 670 patients were included. The observed risk of 30-day and 90-day mortality was 10.3% (69/670) and 13.13% (88/670), respectively. Concerning 30-day mortality, the AUC was 0.774 for the preoperative NELA score, 0.763 for the preoperative P-POSSUM score, and 0.780 for the postoperative NELA score. Regarding 90-day mortality, the AUCs for the preoperative NELA score, preoperative P-POSSUM score, and postoperative NELA score were 0.649 (0.581–0.717), 0.782 (0.737–0.828), and 0.663 (0.608–0.718), respectively. There was noticeable difference in the three models' capacity for discrimination, according to pairwise comparisons.

Conclusions

The probability of 30-day and 90-day death across the entire population was underestimated by the NELA and P-POSSUM scores. There was discernible difference in predictive performance between the two scores.
A collision tumor of nasopharyngeal carcinoma and primary mantle cell lymphoma in the nasopharynx: a case report and review of the literature
Authors: Jiang Meng , Yuan Xiao-ping , Zhang Hong , Li Chuang-quan , Mao Yong-lin , Chen Wei-liang
Published: September 2023

Background

Nasopharyngeal carcinoma (NPC) is more common in men aged 40 to 59, and radiotherapy is an effective treatment. Nasopharyngeal lymphoma (NPL) is rare, and the coexistence of nasopharyngeal mantle cell lymphoma (MCL) and NPC is even rarer. A collision tumor is a rare type of tumor that refers to two or more different tumors occurring in the same organ. No reports to date have described a collision tumor of NPC and MCL occurring within the same nasopharyngeal mass. We herein report the successful treatment of a unique case of synchronous coexistence of NPC and MCL occurring in the nasopharynx of a Chinese man.

Case presentation

A 58-year-old man presented with a 5-month history of swallowing discomfort. Biopsy was performed under nasopharyngeal endoscopy, and histopathology revealed NPC. Magnetic resonance imaging revealed lesions in the nasopharynx, oropharynx, and tonsils, as well as enlarged lymph nodes in the parotid gland, posterior ear, and neck. This may be a synchronous dual primary tumor coexisting with NPC and NPL. Pathology consultation confirmed that the biopsy specimen of the nasopharynx was a collision tumor of NPC and MCL. Positron emission tomography computed tomography (PET-CT) revealed thickening of the posterior wall of the nasopharynx, which was considered NPC with lymphoma. The enlargement of the pharyngeal lymph ring and multiple hypermetabolic lymph nodes were evaluated as lymphoma infiltration. The patient received two courses of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by head and neck radiotherapy. At the time of this writing, he had remained alive without recurrence for 61 months since the initial treatment and was still undergoing follow-up.

Conclusions

It is very important to correctly recognize collision tumors. Magnetic resonance imaging helps identify different components of collision tumors. Pathological examination helps to confirm the diagnosis. Histological examination reveals different components, and PET-CT can help determine the extent of the lesion. Dose-adjusted chemotherapy combined with radiotherapy may have promising herapeutic effects, but additional case studies are needed to confirm.
What do I do to avoid sexually transmitted diseases? A scale development study: behavioral scale for protection from sexually transmitted diseases
Authors: Kılavuz Mustafa , Yigit Feride
Published: September 2023

The authors’ aim is to develop and confirm a reliable and valid measurement tool that can measure women’s behavior to prevent sexually transmitted diseases. The study data were collected from adult women aged 18–47 years (n = 505). Explanatory factor analysis (EFA) was applied to the STD scale consisting of 44 items in a 5-point Likert style. According to the results of EFA, 21 items were defined in the scale. The KMO value of the scale is 90.6%. In the study, the varimax rotation method was used to bring the factors together with the related items. As a result of varimax rotation, two factors with eigenvalues greater than 1 were found in the scale. The overall Cronbach’s alpha coefficient of the scale was calculated as 0.911, 0.941 for the first subdimension and 0.889 for the second subdimension. The validity and reliability of this study have been proven according to the results of explanatory factor analysis (EFA) and confirmatory factor analysis (CFA).
Vaccination coverage in rural Burkina Faso under the effects of COVID-19: evidence from a panel study in eight districts
Authors: Cooper Sarah , Bicaba Frank , Tiendrebeogo Cheick Oumar , Bila Alice , Bicaba Abel , Druetz Thomas
Published: September 2023

Background

Improving infant immunization completion and promoting equitable vaccination coverage are crucial to reducing global under-5 childhood mortality. Although there have been hypotheses that the impact of the COVID-19 pandemic would decrease the delivery of health services and immunization campaigns in low- and middle-income countries, the available evidence is still inconclusive. We conducted a study in rural Burkina Faso to assess changes in vaccination coverage during the pandemic. A secondary objective was to examine long-term trends in vaccination coverage throughout 2010–2021.

Methods

Using a quasi-experimental approach, we conducted three rounds of surveys (2019, 2020, 2021) in rural Burkina Faso that we pooled with two previous rounds of demographic and household surveys (2010, 2015) to assess trends in vaccination coverage. The study population comprised infants aged 0–13 months from a sample of 325 households randomly selected in eight districts (n = 736). We assessed vaccination coverage by directly observing the infants’ vaccination booklet. Effects of the pandemic on infant vaccination completion were analyzed using multi-level logistic regression models with random intercepts at the household and district levels.

Results

A total of 736 child-year observations were included in the analysis. The proportion of children with age-appropriate complete vaccination was 69.76% in 2010, 55.38% in 2015, 50.47% in 2019–2020, and 64.75% in 2021. Analyses assessing changes in age-appropriate full-vaccination coverage before and during the pandemic show a significant increase (OR: 1.8, 95% CI: 1.14–2.85). Our models also confirmed the presence of heterogeneity in full vaccination between health administrative districts. The pandemic could have increased inequities in infant vaccination completion between these districts. The analyses suggest no disruption in age-appropriate full vaccination due to COVID-19. Our findings from our sensitivity analyses to examine trends since 2010 did not show any steady trends.

Conclusion

Our findings in Burkina Faso do not support the predicted detrimental effects of COVID-19 on the immunization schedule for infants in low- and middle-income countries. Analyses comparing 2019 and 2021 show an improvement in age-appropriate full vaccination. Regardless of achieving and sustaining vaccination coverage levels in Burkina Faso, this should remain a priority for health systems and political agendas.
Q fever and toxoplasmosis in South African livestock and wildlife: a retrospective study on seropositivity, sporadic abortion, and stillbirth cases in livestock caused by Coxiella burnetii
Authors: Mangena Maruping L. , Gcebe Nomakorinte , Thompson Peter N. , Adesiyun Abiodun A.
Published: September 2023

Background

Q fever and toxoplasmosis are economically important zoonoses as they cause considerable losses in livestock (cattle, sheep and goats) and wildlife (antelopes, giraffes, lions, and cheetahs) through reproductive disorders such as abortions and stillbirths. Q fever and toxoplasmosis testing in South Africa is conducted by the Agricultural Research Council-Onderstepoort Veterinary Research (ARC-OVR). However, both zoonoses are understudied and not monitored in South Africa as they are not considered controlled or notifiable diseases in the Animal Disease Act 35 of 1984. A retrospective study was conducted on Q fever (2007–2009) and toxoplasmosis (2007–2017) using diagnostic laboratory data at the ARC-OVR. Also, we report on sporadic abortion and stillbirth cases in livestock from diagnostic tissue samples submitted for Coxiella burnetii polymerase chain reaction (PCR) detection at the ARC-OVR.

Results

During 2007 to 2009, 766 animal samples were tested for C. burnetii antibodies and seropositivity was 0.9% (95%CI: 0.3–1.7) with sheep (1.9%; 95%CI: 0.6–4.4) having the highest seropositivity followed by cattle (0.7%; 95%CI: 0.09–2.6), while all goats (0.0%; 95%CI: 0.0–4.2) and wildlife (0.0%; 95%CI: 0.0–2.5) tested were negative. From 2007 to 2017, 567 sera were tested for T. gondii antibodies; overall seropositivity was 12.2% (95%CI: 9.6–15). Wildlife had highest seropositivity to T. gondii antibodies (13.9%; 95%CI: 9.0–19.7) followed by goats (12.9%; 95%CI: 9.2–17.4) and sheep (12.3%; 95%CI: 5.1–23.8) while seropositivity in cattle was 2.4% (95%CI: 0.06–12.9). Of 11 animals tested by C. burnetii PCR detection (2021–2022), 10 (91.0%) were positive. The amplicon sequences showed similarity to Coxiella burnetii strain 54T1 transposase gene partial coding sequence.

Conclusions

We have confirmed the occurrence of the causative agents of Q fever and toxoplasmosis in livestock and wildlife in South Africa, with data limitations. These zoonoses remain of importance with limited information about them in South Africa. This study provides baseline information for future studies on Q fever and toxoplasmosis in South African livestock and wildlife, as well other African countries. Due to limited data collection experienced in this study, it is recommended that improvements in data collection samples tested should include associated factors such as sex, age, and breed of the animals.
A strategy to enhance and modify fatty acid synthesis in Corynebacterium glutamicum and Escherichia coli: overexpression of acyl-CoA thioesterases
Authors: Liu Jin , Mandlaa  , Wang Jia , Sun Ziyu , Chen Zhongjun
Published: September 2023

Background

Fatty acid (FA) is an important platform compound for the further synthesis of high‐value biofuels and oleochemicals, but chemical synthesis of FA has many limitations. One way to meet the future demand for FA could be to use microbial cell factories for FA biosynthesis.

Results

Thioesterase (TE; TesA, TesB, and TE9) of Corynebacterium glutamicum (CG) can potentially improve FA biosynthesis, and tesA, tesB, and te9 were overexpressed in C. glutamicum and Escherichia coli (EC), respectively, in this study. The results showed that the total fatty acid (TFA) production of CGtesB and ECtesB significantly increased to 180.52 mg/g dry cell weight (DCW) and 123.52 mg/g DCW, respectively (P < 0.05). Overexpression strains CG and EC could increase the production of C16:0, C18:1(t), C18:2, C20:1, C16:1, C18:0, and C18:1(c) (P < 0.05), respectively, and the changes of long-chain FA resulted in the enhancement of TFA production. The enzymatic properties of TesA, TesB, and TE9 in vitro were determined: they were specific for long-, broad and short-chain substrates, respectively; the optimal temperature was 30.0 °C and the optimal acid–base (pH) were 8.0, 8.0, and 9.0, respectively; they were inhibited by Fe2+, Cu2+, Zn2+, Mg2+, and K+.

Conclusion

Overexpression TE enhances and modifies FA biosynthesis with multiple productive applications, and the enzyme properties provided useful clues for optimizing FA synthesis.

Graphical Abstract
The novel oncogenic factor TET3 combines with AHR to promote thyroid cancer lymphangiogenesis via the HIF-1α/VEGF signaling pathway
Authors: Yang Liyun , Zhao Runyu , Qiao Peipei , Cui Jiaxin , Chen Xiaoping , Fan Jinping , Hu An , Huang Shuixian
Published: September 2023

Background

Lymphangiogenesis has been reported to play crucial roles in the metastasis of thyroid cancer (THCA), but despite the significant research on lymphangiogenesis in THCA, the precise regulatory mechanism remains unclear.

Methods

Public databases including the Cancer Genome Atlas (TCGA), TIMER, and UALCAN were used to analyze and visualize the expression of TET3 and AHR in THCA, and the correlation between these molecules were used by TIMER. Additionally, RT-PCR and Western Blot were performed to determine the mRNA and protein expression of related proteins. Plate colony formation, wound healing, cell cycle, apoptosis, angiogenesis and transwell assay were used to examine the ability of proliferation, movement, lymphangiogenesis, migration and invasion of THCA cells.

Results

Analysis of the TCGA database revealed higher expression levels of TET3 and AHR in tumor tissue compared to normal tissue in THCA. Additionally, a strong correlation was observed between TET3 and AHR. UALCAN database demonstrated that high expression of TET3 and AHR was associated with advanced THCA TNM stages in THCA patients. Furthermore, TET3 activation accelerated THCA cell proliferation by inducing G2/M phase arrest and suppressing apoptosis, while AHR inactivation reduced THCA cell proliferation by decreasing G2/M phase arrest and promoting apoptosis in vitro. Notably, both TET3 and AHR significantly enhanced THCA cell lymphangiogenesis, migration and invasion. Moreover, TET3 activation and AHR inactivation regulated HIF-1α/VEGF signaling pathway, which ultimately, blocked the HIF-1α/VEGF in THCA cells and impaired their movement, migration and invasion abilities.

Conclusions

The combined action of TET3 and AHR to promote lymphangiogenesis in THCA through the HIF-1α/VEGF signaling pathway, and targeting them might provide a potential treatment strategy for THCA.
A Versatile PDA(DOX) Nanoplatform for Chemo-Photothermal Synergistic Therapy against Breast Cancer and Attenuated Doxorubicin-Induced Cardiotoxicity
Authors: Geng Siqi , Feng Qiang , Wang Chujie , Li Ying , Qin Jiaying , Hou Mingsheng , Zhou Jiedong , Pan Xiaoyu , Xu Fei , Fang Baoru , Wang Ke , Yu Zhangsen
Published: September 2023

Photothermal therapy (PTT) is a highly clinical application promising cancer treatment strategy with safe, convenient surgical procedures and excellent therapeutic efficacy on superficial tumors. However, a single PTT is difficult to eliminate tumor cells completely, and tumor recurrence and metastasis are prone to occur in the later stage. Chemo-photothermal synergistic therapy can conquer the shortcomings by further killing residual tumor cells after PTT through systemic chemotherapy. Nevertheless, chemotherapy drugs' extreme toxicity is also a problematic issue to be solved, such as anthracycline-induced cardiotoxicity. Herein, we selected polydopamine nanoparticles (PDA) as the carrier of the chemotherapeutic drug doxorubicin (DOX) to construct a versatile PDA(DOX) nanoplatform for chemo-photothermal synergistic therapy against breast cancer and simultaneously attenuated DOX-induced cardiotoxicity (DIC). The excellent photothermal properties of PDA were used to achieve the thermal ablation of tumors. DOX carried out chemotherapy to kill residual and occult distant tumors. Furthermore, the PDA(DOX) nanoparticles significantly alleviate DIC, which benefits from PDA's excellent antioxidant enzyme activity. The experimental data of the chemotherapy groups showed that the results of the PDA(DOX) group were much better than the DOX group. This study not only effectively inhibits cancer but tactfully attenuates DIC, bringing a new perspective into synergistic therapy against breast cancer.

Graphical Abstract
Nestin and Notch3 collaboratively regulate angiogenesis, collagen production, and endothelial–mesenchymal transition in lung endothelial cells
Authors: Daido Wakako , Nakashima Taku , Masuda Takeshi , Sakamoto Shinjiro , Yamaguchi Kakuhiro , Horimasu Yasushi , Miyamoto Shintaro , Iwamoto Hiroshi , Fujitaka Kazunori , Hamada Hironobu , Hattori Noboru
Published: September 2023

Background

Nestin, an intermediate filament protein, participates in various pathophysiological processes, including wound healing, angiogenesis, endothelial–mesenchymal transition (EndoMT), and fibrosis. However, the pathophysiological roles of lung nestin-expressing cells remain unclear due to conflicting reports. The objective of this study is to elucidate the characteristics and functions of lung nestin-expressing cells.

Methods

We conducted a series of in vitro and in vivo experiments using endothelial cell line MS1 and nestin-GFP mice. This animal model allows for nestin-expressing cell detection without the use of anti-nestin antibodies.

Results

Lung nestin-expressing cells occurred in approximately 0.2% of CD45− cells and was co-expressed with epithelial, endothelial, and mesenchymal cell-surface markers. Importantly, virtually all nestin-expressing cells co-expressed CD31. When compared to lung nestin-nonexpressing endothelial cells, nestin-expressing endothelial cells showed robust angiogenesis with frequent co-expression of PDGFRβ and VEGFR2. During TGFβ-mediated EndoMT, the elevation of Nes mRNA expression preceded that of Col1a1 mRNA, and nestin gene silencing using nestin siRNA resulted in further upregulation of Col1a1 mRNA expression. Furthermore, Notch3 expression was regulated by nestin in vitro and in vivo; nestin siRNA resulted in reduced Notch3 expression accompanied with enhanced EndoMT. Contrary to previous reports, neither Nes mRNA expression nor nestin-expressing cells were increased during pulmonary fibrosis.

Conclusions

Our study showed that (1) lung nestin-expressing cells are an endothelial lineage but are distinct from nestin-nonexpressing endothelial cells; (2) nestin regulates Notch3 and they act collaboratively to regulate angiogenesis, collagen production, and EndoMT; and (3) nestin plays novel roles in lung angiogenesis and fibrosis.
Sirtuin1, not NAMPT, possesses anti-inflammatory effects in epicardial, pericardial and subcutaneous adipose tissue in patients with CHD
Authors: Opstad Trine Baur , Papotti Bianca , Åkra Sissel , Hansen Charlotte Holst , Braathen Bjørn , Tønnessen Theis , Solheim Svein , Seljeflot Ingebjørg
Published: September 2023

Background

Inflammation in cardiac adipose tissue (AT) is associated with atherosclerosis. We investigated whether the epicardial-, pericardial and pre-sternal subcutaneous AT (EAT, PAT and SAT) expression of Sirtuin1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) are involved in the inflammatory process in coronary heart disease (CHD), and potentially associated to nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-related markers, macrophage polarization markers, cell markers and the cardiometabolic profile.

Methods

In this cohort study performed between 2016 and 2018, EAT, PAT and SAT biopsies were retrieved from 52 CHD patients (77% men, median age 67) undergoing open-chest coronary artery bypass grafting (CABG), and 22 patients (50% men, median age 69) undergoing aortic valve replacement serving as controls. AT samples were snap-frozen at – 80 °C until RNA extraction and AT expression of actual markers, relatively quantified by PCR. Circulating SIRT1 and NAMPT were measured with Enzyme-linked immunosorbent assays (ELISAs). Non-parametric statistical tests were mainly used, including Friedman’s test coupled to Wilcoxon signed-rank test and Spearman Correlation.

Results

SIRT1 and NAMPT levels were similar in CHD and controls. In CHD, SIRT1 and NAMPT were inter-correlated in all AT compartments (r = 0.37–0.56, p < 0.01, all), and differently expressed between compartments, with the highest expression in SAT, significantly different from EAT (p < 0.01, both). Circulating SIRT1 and NAMPT levels were inversely associated (r = − 0.32, p = 0.024). In EAT and SAT, SIRT1 expression was inversely associated with IL-18 (r = − 0.43 and r = − 0.38, p < 0.01, both), whereas NAMPT expression was positively associated with the NLRP3 inflammasome-related markers in all compartments (r = 0.37–0.55, p < 0.01, all). While SIRT1 and NAMPT correlated to nitric oxide synthase 2 (NOS2), especially in SAT (r = 0.50–0.52, p ≤ 0.01, both), SIRT1 expression was related to endothelial cells, and NAMPT to macrophages. SIRT1 levels were correlated to weight and waist (r = 0.32 and r = 0.38, p < 0.03, both) and inversely to triglycerides and glycated haemoglobin (HbA1c) (r = − 0.33–− 0.37, p < 0.03, all), the latter positively correlated to NAMPT concentration (r = 0.39, p = 0.010).

Conclusion

The study indicates that targeting SIRT1, with its anti-inflammatory properties, may be a novel anti-inflammatory strategy in preventing atherosclerosis and CHD progression. NAMPT may be an early player in AT inflammation, mediating/reflecting a pro-inflammatory state.

Trial Registration: Registration: Clinicaltrials.gov ID: NCT02760914, registered the 5th of February 2016, http://clinicaltrials.gov/NCT02760914

Graphical Abstract
Screw fixation after tripe pelvic osteotomy is reliable: changes of acetabular correction are rare and do not correlate with risk factors
Authors: Dornacher Daniel , Kelsch Maximilian , Sgroi Mirco , Reichel Heiko , Lutz Bernd
Published: September 2023

Purpose

The aim of this examination was to assess whether there is a change of acetabular correction after triple pelvic osteotomy (TPO) and if so, whether there is a correlation with patient-specific risk factors or with certain periods in the postoperative course.

Methods

A consecutive series of 241 TPO was reviewed retrospectively. The close-meshed radiographic follow-up of the first 12 weeks comprised pelvic radiographs performed immediately after the procedure, 5 days, 6 and 12 weeks after TPO. Three observers measured the lateral center edge angle, acetabular index and the craniocaudal offset of the pubic osteotomy. Patient-specific risk factors (e. g. age, gender, body mass index, nicotine abuse) and certain periods in the postoperative course were correlated with a change of acetabular correction.

Results

After application of the exclusion criteria, 225 hips were available for further examination. Intraclass correlation coefficient resulted in predominantly excellent agreement between the measurements of the three observers (0.74–0.91). In 27 cases (12%), the three observers agreed on a change of acetabular correction. In 18 cases (8%), there was a slight change, in 9 cases (4%), a relevant change. The latter entailed consequences in the postoperative aftercare. General equation estimation did not show any correlation between a change of acetabular correction and patient-specific risk factors or certain periods in the postoperative course (p = 0.79–0.99).

Conclusion

Every once treated hip should be followed-up with the same attention, irrespective of the apparent risk profile. There is no rationale to skip a radiographic follow-up in the first 12 weeks after TPO.
Z-ligustilide preferentially caused mitochondrial dysfunction in AML HL-60 cells by activating nuclear receptors NUR77 and NOR1
Authors: Liu Gen , Chen Zhi-gang , Yang Li-rong , Rong Yu-xia , Wang Qin , Li Li , Lu Qian-wei , Jiang Ming-dong , Qi Hong-yi
Published: September 2023

Background

Nuclear receptors NUR77 and NOR1 were identified as critical targets in acute myeloid leukemia (AML) therapy. Previously, we showed that Z-ligustilide (Z-LIG) selectively targeted AML by restoring NUR77 and NOR1. However, its downstream mechanisms are yet to be elucidated.

Methods

SRB staining assay was used to measure cell viability. Cell apoptosis, mitochondrial membrane potential and mitochondrial reactive oxygen species were analyzed using flow cytometry. The potential targets of Z-LIG in AML HL-60 cells were evaluated by RNA sequencing. Changes in RNA levels were measured using quantitative RT-qPCR and western blot analysis was used to detect the expression of proteins.

Results

Z-LIG preferentially induced mitochondrial dysfunction in HL-60 cells compared with 293T cells. Furthermore, RNA sequencing revealed that mitochondrial transcription and translation might be potential Z-LIG targets inhibiting HL-60 cells. NUR77/NOR1 overexpression significantly reduced the mitochondrial ATP and mitochondrial membrane potential and increased mitochondrial reactive oxygen species in HL-60 cells but not in 293T cells. Moreover, Z-LIG induced mitochondrial dysfunction by restoring NUR77 and NOR1 in HL-60 cells. Compared with HL-60 cells, the apoptosis-inducing activities of NUR77/NOR1 and Z-LIG were significantly reduced in HL-60 ρ0 cells depleted in mitochondrial DNA (mt-DNA). Moreover, NUR77/NOR1 and Z-LIG downregulated mitochondrial transcription and translation related proteins in HL-60 cells. Notably, Z-LIG remarkably reduced mitochondrial ATP in primary AML cells and showed anti-AML activity in mouse models of human AML.

Conclusions

Collectively, our findings suggested that Z-LIG selectively induces mitochondrial dysfunction in AML HL-60 cells by restoring NUR77 and NOR1, a process associated with interference in mtDNA transcription.
Curdione induces ferroptosis mediated by m6A methylation via METTL14 and YTHDF2 in colorectal cancer
Authors: Wang Fang , Sun Zheng , Zhang Qunyao , Yang Hao , Yang Gang , Yang Qi , Zhu Yimiao , Wu Wenya , Xu Wenwen , Wu Xiaoyu
Published: September 2023

Background

Curdione is a sesquiterpene isolated from Curcumae Rhizoma that possesses high biological activity and extensive pharmacological effects. As a traditional Chinese medicine, Curcumae Rhizoma can inhibit the development of many types of cancer, especially colorectal cancer. However, the anti-colorectal mechanism of its monomer curdione remains unclear.

Methods

Colorectal cancer (CRC) cells were treated with curdione at doses of 12.5 μM, 25 μM, and 50 μM, and then the cells’ activity was measured with methyl thiazolyl tetrazolium (MTT). Nude mice were administered different doses of curdione subcutaneously and oxaliplatin by tail vein injection, and then hematoxylin–eosin (HE) staining was adopted to examine tumor histology. Moreover, flow cytometry was applied to detect reactive oxygen species in cells and tissues. Kits were employed to detect the levels of iron ions, malondialdehyde, lipid hydroperoxide, and glutathione. Polymerase chain reaction (PCR) and Western blotting were adopted to detect ferroptosis and m6A modification-related factors. A methylation spot hybridization assay was performed to measure changes in overall methylation. SLC7A11 and HOXA13 were measured by MeRIP-qPCR. The shRNA-METTL14 plasmid was constructed to verify the inhibitory effect of curdione on CRC.

Results

A dose-dependent decrease in activity was observed in curdione-treated cells. Curdione increased the accumulation of reactive oxygen species in CRC cells and tumor tissues, greatly enhanced the levels of malondialdehyde, lipid hydroperoxide and Fe2+, and lowered the activity of glutathione. According to the qPCR and Western blot results, curdione promoted the expression of METTL14 and YTHDF2 in CRC cells and tissues, respectively, and decreased the expression of SLC7A11, SLC3A2, HOXA13, and glutathione peroxidase 4. Additionally, in animal experiments, the curdione-treated group showed severe necrosis of tumor cells, as displayed by HE staining. Furthermore, compared with the control group, levels of m6A modifying factors (namely, SLC7A11 and HOXA13) were increased in the tissues after drug intervention. METTL14 knockdown was followed by an increase in CRC cell activity and glutathione levels. However, the levels of reactive oxygen species, malondialdehyde, and iron ions decreased. The expression levels of SLC7A11, SLC3A2, HOXA13, and GPX4 were all increased after METTL14 knockdown.

Conclusion

The results suggest that curdione induces ferroptosis in CRC by virtue of m6A methylation.
Electrophysiological characterization of a Cav3.2 calcium channel missense variant associated with epilepsy and hearing loss
Authors: Stringer Robin N. , Cmarko Leos , Zamponi Gerald W. , De Waard Michel , Weiss Norbert
Published: September 2023

T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Cav3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss—apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition. This mutation leads to the substitution of an arginine at position 132 with a histidine (R132H) in the proximal extracellular end of the second transmembrane helix of Cav3.2. In this study, we report the electrophysiological characterization of this new variant using whole-cell patch clamp recordings in tsA-201 cells. Our data reveal minor gating alterations of the channel evidenced by a mild increase of the T-type current density and slower recovery from inactivation, as well as an enhanced sensitivity of the channel to external pH change. To what extend these biophysical changes and pH sensitivity alterations induced by the R132H mutation contribute to the observed pathogenicity remains an open question that will necessitate the analysis of additional CACNA1H variants associated with the same pathologies.
Feasibility of delivering supervised exercise training following surgical resection and during adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PRECISE): a case series
Authors: Brown Malcolm , O’Connor Dominic , Turkington Richard , Eatock Martin , Vince Rebecca , Hulme Claire , Bowdery Roy , Robinson Rebecca , Wadsley Jonathan , Maraveyas Anthony , Prue Gillian
Published: September 2023

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm, with surgical resection and adjuvant chemotherapy the only curative treatment. Treatment-related toxicities place a considerable burden on patients although exercise training has shown promise is helping to manage such adversities and facilitate rehabilitation. The feasibility and safety of exercise training as a supportive therapy during adjuvant chemotherapy remains unknown.

Methods

Patients with PDAC were screened post-surgical resection and enrolled in a 16-week, progressive, concurrent exercise programme alongside their chemotherapy regimen. Feasibility was the primary objective detailing recruitment, retention and adherence rates throughout as well as the safety and fidelity of the intervention. Secondarily, the impact on functional fitness and patient-reported outcomes was captured at baseline, post-intervention and 3-month follow up.

Results

Eight patients consented to participate in this trial, with five proceeding to enrol in exercise training. Concurrent exercise training is feasible and safe during adjuvant chemotherapy and prevented an expected decline in functional fitness and patient-reported outcomes during this time.

Discussion

This case series provides preliminary evidence that concurrent exercise training during adjuvant therapy is safe, feasible and well tolerated, preventing an expected decline in functional fitness, muscular strength and health-related quality of life (HRQoL). Given the adverse effects of treatment, these findings are promising and provide further evidence for the inclusion of exercise training as a standard of care for surgical rehabilitation and managing treatment-related toxicities. Future research should explore the impact of exercise training during neoadjuvant chemotherapy, with prehabilitation now standard practice for borderline resectable disease.

Trial registration

ClinicalTrials.gov Identifier: NCT04305067, prospectively registered 12/03/2020, https://classic.clinicaltrials.gov/ct2/show/NCT04305067.
A rare presentation of large bowel obstruction post haemorrhoidectomy: a case report
Authors: Comella Assia , Mogridge Emily , Arachchi Asiri
Published: September 2023

Background

Hemorrhoidal disease is a common anorectal pathology. Complications post hemorrhoidectomy are rare. Postoperative complications following hemorrhoidectomy include bleeding (2%), infection (0.4–8%), urinary retention (15%), and constipation (15–30%).

Case presentation

A 40-year-old of Asian background female presented to a tertiary colorectal service with large bowel obstruction post hemorrhoidectomy. This is the first case in the surgical literature describing large bowel obstruction secondary to extrinsic compression from urinary retention following hemorrhoidectomy. The patient developed urinary retention and obstructed defecation in setting of inadequate analgesia post hemorrhoidectomy. The patient required indwelling catheter insertion and aggressive constipation management to resolve symptoms. Histopathology from the hemorrhoidectomy did not reveal a malignancy.

Conclusion

Anesthetic choice and postoperative analgesia are important factors to avoid the development of complications. A missed malignancy diagnosis must always be excluded with patients presenting post hemorroidectomy with bowel obstruction.
Extract of the bioconverted fine root of ginseng induces apoptosis and cell cycle arrest in mouse colon cancer cells
Authors: Seo Yeonju , Chae Jongbeom , Nam Ju-Ock
Published: September 2023

Cancer is the major cause of death worldwide, and the anticancer effect of ginseng and its main root has been studied. However, study of fine root of ginseng (FRG) is still insufficient. The purpose of this study was to discover a new anticancer effect from FRG, which does not show an anticancer effect, through a bioconversion technique. We measured and compared cell viability in FRG- and bioconverted fine root of ginseng (BFRG)-stimulated CT26 cells to investigate differences caused by bioconversion. Cell viability of CT26 was suppressed upon treatment with BFRG, unlike FRG. The effect of BFRG on apoptosis and cell cycle arrest was investigated by flow cytometry. BFRG-stimulated CT26 cells showed an increased apoptotic cells and cell cycle arrest. Additionally, BFRG induced mitochondrial impairment by reducing the expression of anti-apoptosis protein Bcl-2. When confirming the signaling pathway, it was found that the p38 MAPK pathway was activated by BFRG. Collectively, our results reveal anticancer effects against colorectal cancer and represent potential targets for anticancer drug development.
Postoperative ratio of C-reactive protein to albumin is an independent prognostic factor for gastric cancer
Authors: Li Chenxi , Yang Xuhui , Li Hui , Fu Yan , Wang Wenying , Jin Xin , Bian Lihua , Peng Liang
Published: September 2023

Objective

The role of postoperative of the ratio of c-reactive protein to albumin (CRP/Alb ratio) in the prognosis of gastric cancer is rarely evaluated. Our purpose was to investigate the correlation of the postoperative CRP/Alb ratio and long-term prognosis of gastric cancer.

Methods

We enrolled 430 patients who suffered from radical gastrectomy. The commonly used inflammatory indices, clinical-pathological characteristics and oncologic outcomes were recorded. The median was used to the cut-off value for preoperative and postoperative CRP/Alb ratio, respectively. Kaplan–Meier analysis and Cox proportional hazards regression model were performed to determine its prognostic significance.

Results

In univariate analysis, there were significant differences were observed in overall survival (OS) according to perioperative CRP/Alb ratio, c-reactive protein (CRP), serum albumin (Alb), respectively. According to the multivariate analysis, higher postoperative CRP/Alb ratio (HR 2.03, 95% CI 1.55–2.66, P < 0.001), lower postoperative albumin (Alb), higher preoperative c-reactive protein (CRP) and higher postoperative CRP were indicated a shorter overall survival.

Conclusion

Postoperative inflammatory factors in patients with gastric cancer should be pay attention, especially postoperative CRP/Alb ratio may be an independent predictor of long-term prognosis of gastric cancer.
Tackling barriers to scale up human papillomavirus vaccination in China: progress and the way forward
Authors: Zhao Xue-Lian , Hu Shang-Ying , Hu Jia-Wei , Wang Hong-Hao , Wen Tian-Meng , Feng Yu-Shu , Qiao You-Lin , Zhao Fang-Hui , Zhang Yong
Published: September 2023

The human papillomavirus (HPV) vaccine is the first vaccine developed specifically targeting the prevention of cervical cancer. For more than 15 years, China has expedited a series of efforts on research and development of the domestically manufactured HPV vaccines, producing local population-based evidence, promoting free HPV vaccination from pilots, and launching action plans to tackle barriers in the scale-up of HPV vaccination. To further roll out the HPV vaccination program in China, several challenges should be addressed to support the steps forward. The availability of more locally manufactured HPV vaccines, pricing negotiation and local evidence supporting the efficacy of one-dose schedule would greatly alleviate the continued supply and financial constraints in China. Meanwhile, more attention should be paid to girls living in low-resource areas and males to ensure equal access to the HPV vaccination. Furthermore, linkage to secondary prevention and further real-world monitoring and evaluation are warranted to inform effective cervical cancer prevention strategies in the post-vaccine era.

Graphical Abstract