bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of genetic markers for drug resistance after the introduction of dihydroartemisinin–piperaquine as first-line anti-malarial treatment for uncomplicated falciparum malaria in Indonesia
Authors: Rahmasari Farindira Vesti , Asih Puji Budi Setia , Rozi Ismail Ekoprayitno , Wangsamuda Suradi , Risandi Rifqi , Dewayanti Farahana Kresno , Permana Dendi Hadi , Syahrani Lepa , Prameswari Helen Dewi , Basri Herdiana H. , Bustos Maria Dorina G. , Charunwatthana Prakaykaew , Dondorp Arjen M. , Imwong Mallika , Syafruddin Din 
Published: August 2023

Abstract
Background
Dihydroartemisinin–piperaquine has been Indonesia’s first-line anti-malarial treatment since 2008. Annual therapeutic efficacy studies (TES) done in the last 12 years showed continued high treatment efficacy in uncomplicated Plasmodium falciparum malaria. Although these studies did not show evidence for artemisinin resistance, a slight increase in Late Treatment Failure was observed over time. It is highlight to explore the evolution of genetic markers for ACT partner drug resistance since adopting DHA–PPQ.

Methods
Dry blood spots were identified from a mass blood survey of uncomplicated falciparum malaria patients (N = 50) in Sumba from 2010 to 2018. Analysis of genotypic profile (N = 51) and a Therapeutic Efficacy Study (TES) from Papua (N = 142) from 2020 to 2021, 42-day follow-up. PCR correction using msp1, msp2, and glurp was used to distinguish recrudescence and reinfection. Parasite DNA from DBSs was used for genotyping molecular markers for antimalaria drug resistance, including in Pfk13, pfcrt, and pfmdr1, as well as gene copy number variation in pfpm2/3 and pfmdr1.

Results
The study revealed the absence of SNPs associated with ART resistance and several novel SNPs such as L396F, I526V, M579I and N537S (4.25%). In Sumba, the mutant haplotype SDD of pfmdr1 was found in one-third of the isolates, while only 8.9% in Papua. None of the pfcrt mutations linked to piperaquine resistance were observed, but 71% of isolates had pfcrt I356L. Amplification of the pfpm2/3 genes was in Sumba (17.02%) and Papua (13.7%), while pfmdr1 copy number prevalence was low (3.8%) in both areas. For the TES study, ten recurrences of infection were observed on days 28, 35, and 42. Late parasitological failure (LPF) was observed in 10/117 (8.5%) subjects by microscopy. PCR correction revealed that all nine cases were re-infections and one was confirmed as recrudescence.

Conclusion
This study revealed that DHA–PPQ is still highly effective against P. falciparum. The genetic architecture of the parasite P. falciparum isolates during 2010–2021 revealed single copy of Pfpm2 and pfmdr1 were highly prevalent. The slight increase in DHA–PPQ LTF alerts researchers to start testing other ACTs as alternatives to DHA–PPQ for baseline data in order to get a chance of achieving malaria elimination wants by 2030.

Graphical Abstract
Conductivity reactivity index for monitoring of cerebrovascular autoregulation in early cerebral ischemic rabbits
Authors: Xu Jia , Li Haocheng , Jin Gui , Zhuang Wei , Bai Zelin , Sun Jian , Chen Mingsheng , Wang Feng , Yang Xu , Qin Mingxin 
Published: August 2023

Abstract
Background
Cerebrovascular autoregulation (CVAR) is the mechanism that maintains constant cerebral blood flow by adjusting the caliber of the cerebral vessels. It is important to have an effective, contactless way to monitor and assess CVAR in patients with ischemia.

Methods
The adjustment of cerebral blood flow leads to changes in the conductivity of the whole brain. Here, whole-brain conductivity measured by the magnetic induction phase shift method is a valuable alternative to cerebral blood volume for non-contact assessment of CVAR. Therefore, we proposed the correlation coefficient between spontaneous slow oscillations in arterial blood pressure and the corresponding magnetic induction phase shift as a novel index called the conductivity reactivity index (CRx). In comparison with the intracranial pressure reactivity index (PRx), the feasibility of the conductivity reactivity index to assess CVAR in the early phase of cerebral ischemia has been preliminarily confirmed in animal experiments.

Results
There was a significant difference in the CRx between the cerebral ischemia group and the control group (p = 0.002). At the same time, there was a significant negative correlation between the CRx and the PRx (r = − 0.642, p = 0.002) after 40 min after ischemia. The Bland–Altman consistency analysis showed that the two indices were linearly related, with a minimal difference and high consistency in the early ischemic period. The sensitivity and specificity of CRx for cerebral ischemia identification were 75% and 20%, respectively, and the area under the ROC curve of CRx was 0.835 (SE = 0.084).

Conclusion
The animal experimental results preliminarily demonstrated that the CRx can be used to monitor CVAR and identify CVAR injury in early ischemic conditions. The CRx has the potential to be used for contactless, global, bedside, and real-time assessment of CVAR of patients with ischemic stroke.
REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial
Authors: Martin-Broto Javier , Valverde Claudia , Hindi Nadia , Vincenzi Bruno , Martinez-Trufero Javier , Grignani Giovanni , Italiano Antoine , Lavernia Javier , Vallejo Ana , Tos Paolo Dei , Le Loarer Francois , Gonzalez-Campora Ricardo , Ramos Rafael , Hernández-Jover Diana , Gutierrez Antonio , Serrano Cesar , Monteagudo Maria , Letón Rocio , Robledo Mercedes , Moura David S. , Martin-Ruiz Marta , López-Guerrero Jose A. , Cruz Julia , Fernandez-Serra Antonio , Blay Jean-Yves , Fumagalli Elena , Martinez-Marin Virginia 
Published: August 2023

Abstract
Background
Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST.

Methods
Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment.

Results
From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST.

Conclusions
Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST.

Trial registration
ClinicalTrials.gov Identifier: NCT02638766.
The deubiquitinase EIF3H promotes hepatocellular carcinoma progression by stabilizing OGT and inhibiting ferroptosis
Authors: Tang Jianing , Long Guo , Li Xuanxuan , Zhou Ledu , Zhou Yangying , Wu Zheyu 
Published: August 2023

AbstractHepatocellular carcinoma (HCC) is one of the most prevalent and lethal human malignancies, and with quite limited treatment alternatives. The proteasome is responsible for most of the protein degradation in eukaryotic cells and required for the maintenance of intracellular homeostasis. However, its potential role in HCC is largely unknown. In the current study, we identified eukaryotic translation initiation factor 3 subunit H (EIF3H), belonging to the JAB1/MPN/MOV34 (JAMM) superfamily, as a bona fide deubiquitylase of O-GlcNAc transferase (OGT) in HCC. We explored that EIF3H was positively associated with OGT in HCC and was related to the unfavorable prognosis. EIF3H could interact with, deubiquitylate, and stabilize OGT in a deubiquitylase-dependent manner. Specifically, EIF3H was associated with the GT domain of ERα via its JAB/MP domain, thus inhibiting the K48-linked ubiquitin chain on OGT. Besides, we demonstrated that the knockdown of EIF3H significantly reduced OGT protein expression, cell proliferation and invasion, and caused G1/S arrest of HCC. We also found that the deletion of EIF3H prompted ferroptosis in HCC cells. Finally, the effects of EIF3H depletion could be reversed by further OGT overexpression, implying that the OGT status is indispensable for EIF3H function in HCC carcinogenesis. In summary, our study described the oncogenic function of EIF3H and revealed an interesting post-translational mechanism between EIF3H, OGT, and ferroptosis in HCC. Targeting the EIF3H may be a promising approach in HCC.
Expression of stem cell markers SALL4, LIN28A, and KLF4 in ameloblastoma
Authors: de Albuquerque Dias Rafaela , Balbinot Karolyny Martins , da Silva Kataoka Maria Sueli , de Melo Alves Júnior Sérgio , de Jesus Viana Pinheiro João 
Published: August 2023

Abstract
Background
Ameloblastoma (AME) is a benign odontogenic tumour of epithelial origin characterised by slow but aggressive growth, infiltration, and recurrence; it is capable of reaching large dimensions and invading adjacent structures. Stem cell research has proven to be significant in the sphere of tumour biology through these cells’ possible involvement in the aetiopathogenesis of this tumour.

Methods
Immunohistochemistry was performed on AME, dentigerous cyst (DC), and dental follicle (DF) samples, and indirect immunofluorescence was performed on the AME-hTERT cell line to determine the expression of SALL4, LIN28A, and KLF4.

Results
Expression of proteins related to cellular pluripotency was higher in AME cells than in DC and DF cells. The analysis revealed that the proteins in question were mainly expressed in the parenchyma of AME tissue samples and were detected in the nuclei of AME-hTERT cells.

Conclusions
Stem cells may be related to the origin and progression of AME.
The roles of METTL3 on autophagy and proliferation of vascular smooth muscle cells are mediated by mTOR rather than by CDK1
Authors: Luo Hanshen , Wu Xingliang , Huo Bo , Liu Liyuan , Jiang Ding-Sheng , Yi Xin 
Published: August 2023

Abstract
Background
Aberrant proliferation of vascular smooth muscle cells (VSMCs) is the cause of neointima formation followed by vascular injury. Autophagy is involved in this pathological process, but its function is controversial. Recently, we found that methyltransferase like 3 (METTL3) inhibited VSMC proliferation by activating autophagosome formation. Moreover, we also demonstrated that METTL3 reduced the levels of phosphorylated mammalian target of rapamycin (p-mTOR) and cyclin dependent kinase 1 (p-CDK1/CDC2), which were critical for autophagy and proliferation regulation. However, whether mTOR and CDK1 mediated the function of METTL3 on autophagy and proliferation in VSMCs remains unknown.

Results
We showed that the activator of mTOR, MHY1485 largely reversed the effects of METTL3 overexpression on VSMC autophagy and proliferation. Rapamycin, the inhibitor of mTOR, obviously nullified the pro-proliferation effects of METTL3 knockdown by activating autophagy in VSMCs. Unexpectedly, mTOR did not contribute to the impacts of METTL3 on migration and phenotypic switching of VSMCs. On the other hand, by knockdown of CDK1 in VSMC with METTL3 deficiency, we demonstrated that CDK1 was involved in METTL3-regulated proliferation of VSMCs, but this effect was not mediated by autophagy.

Conclusions
We concluded that mTOR but not CDK1 mediated the role of METTL3 on VSMC proliferation and autophagy.
Postoperative complications analysis of circular stapled versus linear stapled anastomosis for patients undergoing esophagectomy: a systematic review and meta-analysis
Authors: Gu Hao-Yu , Luo Jing , Qiang Yong 
Published: August 2023

Abstract
Background
The choice of anastomosis technique after esophagectomy is closely associated with the postoperative complications. Whether circular stapled or linear stapled anastomosis is the optimal technique has not been established. Therefore, we conducted this meta-analysis to show the latest and most comprehensive published assessment of circular stapled anastomosis in comparison with linear stapled anastomosis in postoperative complications.

Methods
Databases (PubMed, Embase, Web of science, Cochrane Library) were searched for all randomized controlled trials and comparative studies comparing circular stapled anastomosis with linear stapled anastomosis after esophagectomy. The odd ratio and mean difference with 95% confidence interval were calculated. We used the Higgins I² statistics to assess the statistical heterogeneity between studies. Review manager (version 5.4) software was used in this analysis.

Results
Sixteen studies with 2322 patients were included in our study. The study demonstrated that the use of linear stapled technique after esophagectomy could reduce the risk of both anastomotic leakage (P = 0.0003) and stricture (P < 0.00001) compared with circular stapled technique. Stratification by anastomotic site showed that no matter what kind of anastomotic site (cervical or thoracic anastomosis) was used, linear stapled anastomosis could effectively reduce the anastomotic stricture in comparison with circular stapled anastomosis. Moreover, linear stapled anastomosis could decrease the risk of thoracic anastomotic leakage. There were no significant differences between circle stapled anastomosis and linear stapled anastomosis in reflux esophagitis (P = 0.17), pneumonia (P = 0.91), operation time (P = 0.41) and hospital stay (P = 0.38).

Conclusions
The study suggested that linear stapled anastomosis could be considered to be an optimal treatment associated with a reduced risk of anastomotic leakage and stricture in comparison with circular stapled anastomosis.
The association of feeding difficulties and generic health-related quality of life among children born with esophageal atresia
Authors: Örnö Ax Sofie , Dellenmark-Blom Michaela , Abrahamsson Kate , Jönsson Linus , Gatzinsky Vladimir 
Published: August 2023

Abstract
Background
Children born with esophageal atresia experience feeding difficulties. This study investigates the association of feeding difficulties and generic health-related quality of life among children aged 2–7 and 8–17 years, born with esophageal atresia.

Methods
108 families (n = 36 aged 2–7 years; n = 72 aged 8–17) answered a survey regarding difficulties in their child’s mealtimes and a validated generic health-related quality of life instrument(PedsQL 4.0). Clinical data was collected from hospital records. The association of feeding difficulties and health-related quality of life was analysed trough Mann-Whitney U-test. Linear regression determined whether the number of concurrent feeding difficulties in the child decreased the health-related quality of life scores. P < 0.05 was considered significant.

Results
In children aged 2–7 and 8–17 years, to have a gastrostomy, to use a food infusion pump, need for energy-enriched food and eating small portions were respectively significantly associated with lower total health-related quality of life scores in the parent-reports (p < 0.05). Most of the feeding difficulties had a negative significant relationship with the domains of physical and social functioning. Additionally, in the older age group, long mealtimes and adult mealtime supervision were associated with lower scores in both child and parent reports. In both age groups, an increased number of feeding difficulties in the child decreased the total generic health-related quality of life scores (p < 0.01).

Conclusion
Specific feeding difficulties are associated with low health-related quality of life among children with esophageal atresia. An increasing number of feeding difficulties is associated to decreasing health-related quality of life-scores. Further research is needed to understand these associations.
Epidemiological research on rare diseases using large-scale online search queries and reported case data
Authors: Zhang Lei , Jin Ye , Li Jiayu , He Zhiyu , Zhang Dingding , Zhang Min , Zhang Shuyang 
Published: August 2023

Abstract
Background
Rare diseases have become a major public health concern worldwide. However, detailed epidemiological data are lacking. With the development of the Internet, search queries have played an important role in disease surveillance. In this study, we explored a new method for the epidemiological research on rare diseases, using large-scale online search queries and reported case data. We distilled search logs related to rare diseases nationwide from 2016 to 2019. The case data were obtained from China’s national database of rare diseases during the same period.

Results
A total of 120 rare diseases were included in this study. From 2016 to 2019, the number of patients with rare diseases estimated using search data and those obtained from the case database showed an increasing trend. Rare diseases can be ranked by the number of search estimated patients and reported patients, and the rankings of each disease in both search and reported case data were generally stable. Furthermore, the disease rankings in the search data were relatively consistent with the reported case data in each year, with more than 50% of rare diseases having a ranking difference of -20 to 20 between the two systems. In addition, the relationship between the disease rankings in the two systems was generally stable over time. Based on the relationship between the disease rankings in the search and reported case data, rare diseases can be classified into two categories.

Conclusion
Online search queries may provide an important new resource for detecting rare diseases. Rare diseases can be classified into two categories to guide different epidemiological research strategies.
Trends in the effect of COVID-19 on consultations for persons with clinical and subclinical eating disorders
Authors: Kawai Keisuke , Tachimori Hisateru , Yamamoto Yurie , Nakatani Yuki , Iwasaki Shinmi , Sekiguchi Atsushi , Kim Yoshiharu , Tamura Naho 
Published: August 2023

Abstract
Background
The coronavirus disease 2019 (COVID-19) pandemic has increased the risk of individuals developing eating disorders and has exacerbated existing eating disorders. This observational study investigated the impact of the COVID-19 pandemic on patients with clinical and subclinical eating disorders.

Methods
This study was conducted over a period of four years: two years before and after the onset of the COVID-19 pandemic in Japan. We recorded the number and types of consultations provided by the Eating Disorder Treatment and Support Center coordinator. For subgroup analysis, data were classified by age, body mass index, and source of consultation, including patients, families, and personnel. The Seasonal Decomposition of Time Series by Loess was used for time series analysis.

Results
The total number of consultations increased after the start of the pandemic and peaked around the beginning of 2022, before subsequently falling despite the increase in the number of COVID-19 infections. A similar trend was observed in patients aged 10–29 years. The study period coincided with social isolation and school/college/university closures.

Conclusions
The number of eating disorder consultations increased after the start of the pandemic. Although COVID-19 infections persisted, the pandemic’s impact was transient.
An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
Authors: Montero Juan Carlos , del Carmen Sofía , Abad Mar , Sayagués José M. , Barbáchano Antonio , Fernández-Barral Asunción , Muñoz Alberto , Pandiella Atanasio 
Published: August 2023

Abstract
Background
Advanced colorectal cancer (CRC) is difficult to treat. For that reason, the development of novel therapeutics is necessary. Here we describe a potentially actionable plasma membrane target, the amino acid transporter protein subunit CD98hc.

Methods
Western blot and immunohistochemical analyses of CD98hc protein expression were carried out on paired normal and tumoral tissues from patients with CRC. Immunofluorescence and western studies were used to characterize the action of a DM1-based CD98hc-directed antibody–drug conjugate (ADC). MTT and Annexin V studies were performed to evaluate the effect of the anti-CD98hc-ADC on cell proliferation and apoptosis. CRISPR/Cas9 and shRNA were used to explore the specificity of the ADC. In vitro analyses of the antitumoral activity of the anti-CD98hc-ADC on 3D patient-derived normal as well as tumoral organoids were also carried out. Xenografted CRC cells and a PDX were used to analyze the antitumoral properties of the anti-CD98hc-ADC.

Results
Genomic as well proteomic analyses of paired normal and tumoral samples showed that CD98hc expression was significantly higher in tumoral tissues as compared to levels of CD98hc present in the normal colonic tissue. In human CRC cell lines, an ADC that recognized the CD98hc ectodomain, reached the lysosomes and exerted potent antitumoral activity. The specificity of the CD98hc-directed ADC was demonstrated using CRC cells in which CD98hc was decreased by shRNA or deleted using CRISPR/Cas9. Studies in patient-derived organoids verified the antitumoral action of the anti-CD98hc-ADC, which largely spared normal tissue-derived colon organoids. In vivo studies using xenografted CRC cells or patient-derived xenografts confirmed the antitumoral activity of the anti-CD98hc-ADC.

Conclusions
The studies herewith reported indicate that CD98hc may represent a novel ADC target that, upon well-designed clinical trials, could be used to increase the therapeutic armamentarium against CRC.