bluuebunny/crossref_metadata_2025_split huggingface dataset:
Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade
Authors: Dixon Michael L. , Luo Lin , Ghosh Sadashib , Grimes Jeffrey M. , Leavenworth Jonathan D. , Leavenworth Jianmei W. 
Published: November 2021

Abstract
Background
Accumulation of Foxp3+ regulatory T (Treg) cells in the tumor often represents an important mechanism for cancer immune evasion and a critical barrier to anti-tumor immunity and immunotherapy. Many tumor-infiltrating Treg cells display an activated phenotype and express the transcription factor Blimp1. However, the specific impact of these Blimp1+ Treg cells and their follicular regulatory T (TFR) cell subset on tumor and the underlying mechanisms of action are not yet well-explored.

Methods
Various transplantable tumor models were established in immunocompetent wild-type mice and mice with a Foxp3-specific ablation of Blimp1. Tumor specimens from patients with metastatic melanoma and TCGA datasets were analyzed to support the potential role of Treg and TFR cells in tumor immunity. In vitro culture assays and in vivo adoptive transfer assays were used to understand how Treg, TFR cells and antibody responses influence tumor control. RNA sequencing and NanoString analysis were performed to reveal the transcriptome of tumor-infiltrating Treg cells and tumor cells, respectively. Finally, the therapeutic effects of anti-PD-1 treatment combined with the disruption of Blimp1+ Treg activity were evaluated.

Results
Blimp1+ Treg and TFR cells were enriched in the tumors, and higher tumoral TFR signatures indicated increased risk of melanoma metastasis. Deletion of Blimp1 in Treg cells resulted in impaired suppressive activity and a reprogramming into effector T-cells, which were largely restricted to the tumor-infiltrating Treg population. This destabilization combined with increased anti-tumor effector cellular responses, follicular helper T-cell expansion, enhanced tumoral IgE deposition and activation of macrophages secondary to dysregulated TFR cells, remodeled the tumor microenvironment and delayed tumor growth. The increased tumor immunogenicity with MHC upregulation improved response to anti-PD-1 blockade. Mechanistically, Blimp1 enforced intratumoral Treg cells with a unique transcriptional program dependent on Eomesodermin (Eomes) expression; deletion of Eomes in Blimp1-deficient Treg cells restored tumor growth and attenuated anti-tumor immunity.

Conclusions
These findings revealed Blimp1 as a new critical regulator of tumor-infiltrating Treg cells and a potential target for modulating Treg activity to treat cancer. Our study has also revealed two FCERIA-containing immune signatures as promising diagnostic or prognostic markers for melanoma patients.
Levels of pretreatment blood lipids are prognostic factors in advanced NSCLC patients treated with anlotinib
Authors: Tang Mengqiu , Song Chao , Zhang Yaowen , Xu Xiaoyu , Wang Chen , Zhang Zhanchun , Chen Tian 
Published: November 2021

Abstract
Background
Anlotinib, a small molecule for multi-target tyrosine kinase inhibition, is the third or further line of defense for treatment of non-small cell lung cancer (NSCLC). Findings from an ALTER0303 phase III trial revealed that this drug confers significant survival benefits in patients. Although numerous inflammatory biomarkers have been shown to play vital roles in treatment, the clinical significance of blood lipid levels before treatment has not been evaluated. Here, this research aims to explore the relationship between blood lipids and efficacy of anlotinib, with a view of generating insights to guide future development of convenient and individualized treatment therapies.

Methods
This study analyzed basal blood lipids levels, including triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL), among other variables before treatment, in 137 patients with advanced NSCLC who received anlotinib as third or further-line treatment at the Ningbo Medical Center Lihuili Hospital, between July 2018 and December 2020. We determined the best cut off value for predicting treatment responses, generated survival curves using the Kaplan–Meier method, then applied univariate and multivariate Cox regression analyses to assess predictors of survival.

Results
The entire study population recorded median progression-free survival (PFS) and overall survival (OS) of 4 (95% CI 3.142–4.858) and 8.3 (95% CI 6.843–9.757) months, respectively. Researchers observed statistically significant differences across subgroups, between blood lipid indexes with different efficacies, except in the HDL subgroup. The low disease control rate (DCR) was associated with significantly elevated TG, TC and LDL levels (P = 0.000). Multivariate analysis demonstrated that elevated TC and LDL levels were independently associated with poor PFS or OS (P ≤ 0.003). Then, we established a prediction model, and set high TC or high LDL as the risk factor, respectively. There were significant differences in PFS (p = 0.000) and OS (p = 0.012) between 0 and ≥ 1 scores.

Conclusions
Prior to anlotinib therapy, TC and LDL levels, are independent prognostic indicators for patients with advanced NSCLC treated with this drug as a third or further-line treatment option. In addition, a risk score of 0 was attributed to a combination of low TC and low LDL, and these patients were exhibited excellent efficacies and survival rates.
Hybrid membrane-coated nanosuspensions for multi-modal anti-glioma therapy via drug and antigen delivery
Authors: Hao Wenyan , Cui Yuexin , Fan Yueyue , Chen Mengyu , Yang Guobao , Wang Yuli , Yang Meiyan , Li Zhiping , Gong Wei , Yang Yang , Gao Chunsheng 
Published: November 2021

Abstract
Background
Glioma is one of the deadliest human cancers. Although many therapeutic strategies for glioma have been explored, these strategies are seldom used in the clinic. The challenges facing the treatment of glioma not only involve the development of chemotherapeutic drugs and immunotherapeutic agents, but also the lack of a powerful platform that could deliver these two moieties to the targeted sites. Herein, we developed chemoimmunotherapy delivery vehicles based on C6 cell membranes and DC membranes to create hybrid membrane-coated DTX nanosuspensions (DNS-[C6&DC]m).

Results
Results demonstrated successful hybrid membrane fusion and nanosuspension functionalization, and DNS-[C6&DC]m could be used for different modes of anti-glioma therapy. For drug delivery, membrane coating could be applied to target the source cancer cells via a homotypic-targeting mechanism of the C6 cell membrane. For cancer immunotherapy, biomimetic nanosuspension enabled an immune response based on the professional antigen-presenting characteristic of the dendritic cell membrane (DCm), which carry the full array of cancer cell membrane antigens and facilitate the uptake of membrane-bound tumor antigens for efficient presentation and downstream immune n.

Conclusion
DNS-[C6&DC]m is a multifunctional biomimetic nano-drug delivery system with the potential to treat gliomas through tumor-targeted drug delivery combined with immunotherapy, thereby presenting a promising approach that may be utilized for multiple modes of cancer therapy.

Graphical Abstract
The impact and cost-effectiveness of 9-valent human papillomavirus vaccine in adolescent females in Hong Kong
Authors: Cheung Tak Hong , Cheng Sally Shuk Yee , Hsu Danny C. , Wong Queenie Wing-Lei , Pavelyev Andrew , Walia Anuj , Saxena Kunal , Prabhu Vimalanand S. 
Published: November 2021

Abstract
Introduction
In Hong Kong (HK), a single-cohort vaccination program for 10–12-year-old girls with the 9-valent human papillomavirus (HPV) vaccine (9vHPV; types 6/11/16/18/31/33/45/52/58) has been launched. This study assessed the public health impact and cost-effectiveness of implementing routine 9vHPV vaccination (12-year-olds) with or without catch-up 9vHPV vaccination (13–18-year-olds) in HK.

Methods
The health impact and costs of implementing routine 9vHPV vaccination with or without catch-up vaccination over a 100-year time horizon were evaluated using a validated HPV-type transmission dynamic model adapted to the HK population; analyses were performed from a healthcare payer perspective. Routine vaccination (12-year-old girls) and catch-up vaccination (13–18 years) assumed vaccine coverage rates of 70% (base case) and 30%, respectively. The model also assumed herd immunity, lifelong vaccine protection, a discount rate of 3%, and a cost per dose of HK dollars (HKD) 858 [United States dollars (USD) 110] and HKD 1390 (USD 179) for the 2-valent HPV (2vHPV) and 9vHPV vaccines, respectively. HPV disease-related incidence and the incremental cost-effectiveness ratio (ICER) per quality-adjusted-life-year (QALY) were estimated. Cost-effectiveness was determined at a ceiling threshold of HK dollars (HKD) 382,046 (USD 49,142) or 1.0 times the gross domestic product per capita of HK.

Results
Compared with routine 9vHPV alone, routine plus catch-up 9vHPV is projected to reduce cervical cancer incidence by 3.4%. Routine plus catch-up 9vHPV will also reduce genital warts incident cases for males/females by 2.6%/5.4%. The incremental cost-effectiveness ratios were HKD 29,911 (USD 3847)/quality-adjusted life-year (QALY) for routine plus catch-up 9vHPV versus routine 9vHPV alone and HKD 25,524 (USD 3283)/QALY for routine 9vHPV alone versus screening only. Sensitivity analyses indicated that routine plus catch-up 9vHPV compared with routine 9vHPV alone remained cost-effective at coverage rates of 30% and 90%.

Conclusions
This analysis predicts that the current HK vaccination strategy can be considered cost-effective and will provide maximum health benefit. These results support addition of the routine 9vHPV vaccine with or without catch-up 9vHPV vaccination to the regional vaccination program in HK.
Multiomic analysis on human cell model of wolfram syndrome reveals changes in mitochondrial morphology and function
Authors: Zmyslowska Agnieszka , Kuljanin Miljan , Malachowska Beata , Stanczak Marcin , Michalek Dominika , Wlodarczyk Aneta , Grot Dagmara , Taha Joanna , Pawlik Bartłomiej , Lebiedzińska-Arciszewska Magdalena , Nieznanska Hanna , Wieckowski Mariusz R. , Rieske Piotr , Mancias Joseph D. , Borowiec Maciej , Mlynarski Wojciech , Fendler Wojciech 
Published: November 2021

Abstract
Background
Wolfram syndrome (WFS) is a rare autosomal recessive syndrome in which diabetes mellitus and neurodegenerative disorders occur as a result of Wolframin deficiency and increased ER stress. In addition, WFS1 deficiency leads to calcium homeostasis disturbances and can change mitochondrial dynamics. The aim of this study was to evaluate protein levels and changes in gene transcription on human WFS cell model under experimental ER stress.

Methods
We performed transcriptomic and proteomic analysis on WFS human cell model—skin fibroblasts reprogrammed into induced pluripotent stem (iPS) cells and then into neural stem cells (NSC) with subsequent ER stress induction using tunicamycin (TM). Results were cross-referenced with publicly available RNA sequencing data in hippocampi and hypothalami of mice with WFS1 deficiency.

Results
Proteomic analysis identified specific signal pathways that differ in NSC WFS cells from healthy ones. Next, detailed analysis of the proteins involved in the mitochondrial function showed the down-regulation of subunits of the respiratory chain complexes in NSC WFS cells, as well as the up-regulation of proteins involved in Krebs cycle and glycolysis when compared to the control cells. Based on pathway enrichment analysis we concluded that in samples from mice hippocampi the mitochondrial protein import machinery and OXPHOS were significantly down-regulated.

Conclusions
Our results show the functional and morphological secondary mitochondrial damage in patients with WFS.

Graphical Abstract
Development of a real-time RT-PCR assay for the detection of pan-human parechoviruses
Authors: Lu Huanhuan , Xiao Jinbo , Zhang Keyi , Han Zhenzhi , Song Yang , Wang Dongyan , Ji Tianjiao , Yan Dongmei , Zhu Shuangli , Xu Wenbo , Zhang Yong 
Published: November 2021

Abstract
Background
Parechoviruses (PeV-As), which constitute a new genus within the family Picornaviridae, have been associated with numerous localized outbreaks of serious diseases, such as coryza, pneumonia, maculopapular exanthem, and conjunctivitis. However, to the best of our knowledge, only a few laboratories worldwide conduct tests for the identification of this group of viruses. Therefore, in this study, we aimed to develop and validate a real-time RT-PCR assay for the identification of PeV-As.

Methods
To design and validate a real-time PCR primer–probe targeting the 5′-UTR region of PeV-As, the 5′-UTR sequences of PeV-As available in GenBank were aligned using the MUSCLE algorithm in MEGA v7.0. Thereafter, the highly conserved 5′-UTR region was selected, and its primer–probe sequence was designed using Primer Premier v5.0. This primer–probe sequence was then evaluated for specificity, sensitivity, and repeatability, and for its validation, it was tested using fecal samples from 728 healthy children living in Beijing (China).

Results
The PeV-A real-time RT-PCR assay detected only the RNA-positive standards of PeV-A genotypes (1–8, 14, 17, and 18), whereas 72 serotypes of non-PeV-A EV viruses were undetected. In addition, the VP1 region of these 11 PeV-A genotypes that tested positive were amplified using the primers designed in this study. Typing results indicated that eight, one, and two strains of the 11 were PeV-A1, PeV-A4, and PeV-A6, respectively. We also determined and presented the genetic characterization and phylogenetic analyses results corresponding to these 11 VP1 region sequences. Furthermore, real-time RT-PCR assay showed good sensitivity with LOD of 102 copies/μL. Positive results in eight parallel experiments at each concentration gradient from 107 copies/μL to 102 copies/μL, indicating good repeatability.

Conclusion
Our findings suggested that the real-time RT-PCR assay developed in this study can be applied for routine PeV-A identification. We detected PeV-A1, 4 and 6 genotypes in the 728 faecal samples using this method. Additionally, we believe that our results will serve as a foundation for further studies on PeV-As and facilitate the expansion of the gene sequence information available in GenBank.
Association between maternal hepatitis B virus carrier and gestational diabetes mellitus: a retrospective cohort analysis
Authors: Yin Wanchang , Chen Bingjun , Yang Yilin , Li Xiuzi , Li Ruirui , Xie Jiangnan , Chen Guixian , He Fang , Chen Dunjin 
Published: November 2021

Abstract
Introduction
Given that many pregnant women have chronic hepatitis B virus (HBV) infection and that gestational diabetes mellitus (GDM) is linked to poor maternal and neonatal outcomes, we looked into the relationship between the hepatitis B surface antigen (HBsAg) and GDM to see if a high HBV DNA load is linked to a higher risk of GDM in chronic maternal HBsAg carriers.

Materials and methods
Our study included 39,539 pregnant women who gave birth at the Third Affiliated Hospital of Guangzhou Medical University in Guangzhou, China, between January 1, 2009, and December 31, 2019. The patients were divided into two groups: HBsAg negative (36,500) and positive (3039). The viral load levels of 1250 HBsAg-positive women who had tested their HBV DNA load during pregnancy were separated into three groups. We utilized univariate and multivariable logistical regression analysis to determine the relationship between maternal chronic HBsAg carrier and GDM.

Results
Being HBsAg positive was discovered to be an independent risk factor for GDM.Pre-pregnancy Obesity and advanced age were linked to an increased incidence of GDM. Those with a high HBV DNA load (> 106 IU/mL) had a higher risk of GDM than HBsAg-positive women with a low viral load (< 103 IU/mL). Pre-eclampsia and intrahepatic cholestasis of pregnancy (ICP) appeared to be more common in HBsAg-positive women than in uninfected women.

Conclusions
Being HBsAg positive, advanced age, and pre-pregnancy obesity were all revealed to be independent risk factors for GDM in our study. In HBsAg carrier, pregnant women, a high HBV DNA burden was linked to a greater risk of GDM. Furthermore, being an HBsAg carrier during pregnancy raised the risk of ICP and pre-eclampsia.
Case report: composite pancreatic intraductal papillary mucinous neoplasm and neuroendocrine tumor: a new mixed neuroendocrine-non-neuroendocrine neoplasm?
Authors: Chen Jingci , Wang Pengyan , Lv Ke , Zhou Weixun 
Published: November 2021

AbstractBackgroundMixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) of the pancreas are extremely rare. Their pathogenesis and molecular landscape are largely unknown. Here, we report a case of mixed pancreatic intraductal papillary mucinous neoplasm (IPMN) and well-differentiated neuroendocrine tumor (NET) and identify its genetic alterations by next-generation sequencing (NGS).Case presentationA fifty-year-old male was admitted into the hospital for evaluation of a pancreatic lesion detected during a routine examination. Abdominal ultrasound indicated a hypoechoic mass of 2.6 cm at the head of the pancreas. Malignancy was suspected and partial pancreatectomy was performed. Thorough histopathological examination revealed a mixed IPMN-NET. In some areas, the two components were relatively separated, whereas in other areas IPMN and NET grew in a composite pattern: The papillae were lined with epithelial cells of IPMN, and there were clusters of NET nests in the stroma of papillary axis. NGS revealed shared somatic mutations (KRAS,PCK1,MLL3) in both components. The patient has been uneventful 21 months after the surgery.ConclusionsOur case provides evidence of a common origin for mixed IPMN-NET with composite growth features. Our result and literature review indicate thatKRASmutation might be a driver event underlying the occurrence of MiNEN. We also recommend the inclusion of mixed non-invasive exocrine neoplasms and neuroendocrine neoplasms into MiNEN.
Morphological predictors for microsatellite instability in urothelial carcinoma
Authors: Sobrino-Reig Eduardo , Meizoso Telma , García Jesús , Varillas-Delgado David , Martin Yasmina B. 
Published: November 2021

Abstract
Introduction
Microsatellite instability occurs due to a series of mutations in the DNA pairing error repair (Mismatch repair; MMR) genes, which can affect germ cells as occurs in Lynch syndrome, whose patients are at high risk of developing multiple cancers. The loss of MMR protein is commonly determined by immunohistochemical studies. Although the relation between microsatellite instability and urothelial carcinomas has been widely studied, its evaluation is not currently performed in the analysis of urothelial carcinomas.

Methods
In this study, the microsatellite status of 139 urothelial carcinomas was analyzed and their clinicopathological characteristics were evaluated. We identified that 10.3% (13 patients) of urothelial carcinomas had loss of MMR protein expression (9 MLH1; 5 MSH2; 2 PMS2; 2 PSH6; n = 139).

Results
Results suggest that these tumors occur more frequently in males, are more frequently located in the bladder or ureters, and present a high tumor grade with a papillary histological pattern that does not infiltrate the lamina propria or, in the case of infiltrating tumors, that grows into perivesical tissues.

Conclusions
We identified patients with the aforementioned tumor characteristics as patients with a high probability of presenting loss of MMR protein expression, and consider that only these patients should undergo further immunohistochemical and molecular techniques for proper diagnosis. Therefore, we propose that the clinicopathological characteristics found in the present study could become possible markers to determine which cases should undergo additional tests.
Local control of bone metastases treated with external beam radiotherapy in recent years: a multicenter retrospective study
Authors: Makita Kenji , Hamamoto Yasushi , Kanzaki Hiromitsu , Kataoka Masaaki , Yamamoto Shuhei , Nagasaki Kei , Ishikawa Hirofumi , Takata Noriko , Tsuruoka Shintaro , Uwatsu Kotaro , Kido Teruhito 
Published: November 2021

Abstract
Background
Over the past decades, remarkable advancements in systemic drug therapy have improved the prognosis of patients with bone metastases. Individualization is required in external beam radiotherapy (EBRT) for bone metastases according to the patient’s prognosis. To establish individualized EBRT for bone metastases, we investigated factors that affect the local control (LC) of bone metastases.

Methods
Between January 2010 and December 2019, 536 patients received EBRT for 751 predominantly osteolytic bone metastases. LC at EBRT sites was evaluated with a follow-up computed tomography. The median EBRT dose was biologically effective dose (BED10) (39.0) (range of BED10: 14.4–71.7 Gy).

Results
The median follow-up time and median time of computed tomography follow-up were 11 (range 1–123) months and 6 (range 1–119) months, respectively. The 0.5- and 1-year overall survival rates were 73% and 54%, respectively. The 0.5- and 1-year LC rates were 83% and 79%, respectively. In multivariate analysis, higher age (≥ 70 years), non-vertebral bone metastases, unfavorable primary tumor sites (esophageal cancer, colorectal cancer, hepatobiliary/pancreatic cancer, renal/ureter cancer, sarcoma, melanoma, and mesothelioma), lower EBRT dose (BED10 < 39.0 Gy), and non-administration of bone-modifying agents (BMAs)/antineoplastic agents after EBRT were significantly unfavorable factors for LC of bone metastases. There was no statistically significant difference in the LC between BED10 = 39.0 and BED10 > 39.0 Gy.

Conclusions
Regarding tumor-related factors, primary tumor sites and the sites of bone metastases were significant for the LC. As for treatment-related factors, lower EBRT doses (BED10 < 39.0 Gy) and non-administration of BMAs/antineoplastic agents after EBRT were associated with poor LC. Dose escalation from BED10 = 39.0 Gy did not necessarily improve LC.
Music therapy and Sanfilippo syndrome: an analysis of psychological and physiological variables of three case studies
Authors: Pérez-Núñez P. , Lázaro E. , Amayra I. , López-Paz J. F. , Caballero P. , Martínez O. , Pérez M. , Berrocoso S. , Al-Rashaida M. , García M. , Rodríguez A. A. , Luna P. M. 
Published: November 2021

Abstract
Introduction
Mucopolysaccharidosis type III (MPS III) or Sanfilippo syndrome is a neurodegenerative disease caused by the accumulation of mucopolysaccharides in the body. As the symptoms are wide ranging, it is a challenge to provide a diagnosis and psychological treatment for affected children.

Method
The main objective of this study was to describe a form of music therapy treatment applied to three children diagnosed with MPS III. The psychological variables were evaluated by an ad hoc observation recording template, and the physiological variables were measured with a digital meter before and after each session. The perception of the parents was also considered through a semi-structured interview.

Results
An improvement in the psychological variables was shown in all cases. Changes in the physiological variables were also noted, although they varied according to each child. The parents report some benefit of music therapy and they share difficulty in assessing the extent of benefits of the music therapy.

Discussion
Findings indicate that music therapy can be a useful form of treatment with multiple benefits for children with conditions such as MPS III or similar conditions. However, further research is needed in this area and in the development of specific ways of evaluating music therapy.