bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Authors: Yi Ming , Zheng Xiaoli , Niu Mengke , Zhu Shuangli , Ge Hong , Wu Kongming 
Published: January 2022

AbstractAntibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.
Betulinic acid self-assembled nanoparticles for effective treatment of glioblastoma
Authors: Li Yong , Wang Yixuan , Gao Lun , Tan Yinqiu , Cai Jiayang , Ye Zhang , Chen Ann T. , Xu Yang , Zhao Linyao , Tong Shiao , Sun Qian , Liu Baohui , Zhang Shenqi , Tian Daofeng , Deng Gang , Zhou Jiangbing , Chen Qianxue 
Published: January 2022

AbstractBackgroundGlioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood–brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment.MethodsBetulinic acid NPs (BA NPs) were synthesized by the standard emulsion approach and characterized by electron microscopy and dynamic light scattering analysis. The resulting NPs were characterized for their anti-tumor effects by cell viability assay, EdU-DNA synthesis assay, cell cycle assay, mitochondrial membrane potential, and PI-FITC apoptosis assay. Further mechanistic studies were carried out through Western Blot and immunostaining analyses. Finally, we evaluated BA NPs in vivo for their pharmacokinetics and antitumor effects in intracranial xenograft GBM mouse models.ResultsBA NPs were successfully prepared and formed into rod shape. BA NPs could significantly suppress glioma cell proliferation, induce apoptosis, and arrest the cell cycle in the G0/G1 phase in vitro. Furthermore, BA NPs downregulated the Akt/NFκB-p65 signaling pathway in a concentration dependent manner. We found that the observed anti-tumor effect of BA NPs was dependent on the function of CB1/CB2 receptors. Moreover, in the intracranial GBM xenograft mouse models, BA NPs could effectively cross the BBB and greatly prolong the survival time of the mice.ConclusionsWe successfully synthesized BA NPs, which could cross the BBB and demonstrated a strong anti-tumor effect. Therefore, BA NPs may potentially be used for effective treatment of GBM.Graphical Abstract
Mitochondria-targeting multifunctional nanoplatform for cascade phototherapy and hypoxia-activated chemotherapy
Authors: Lv Jie , Wang Shuangling , Qiao Duo , Lin Yulong , Hu Shuyang , Li Meng 
Published: January 2022

AbstractDespite considerable progress has been achieved in hypoxia-associated anti-tumor therapy, the efficacy of utilizing hypoxia-activated prodrugs alone is not satisfied owing to the inadequate hypoxia within the tumor regions. In this work, a mitochondrial targeted nanoplatform integrating photodynamic therapy, photothermal therapy and hypoxia-activated chemotherapy has been developed to synergistically treat cancer and maximize the therapeutic window. Polydopamine coated hollow copper sulfide nanoparticles were used as the photothermal nanoagents and thermosensitive drug carriers for loading the hypoxia-activated prodrug, TH302, in our study. Chlorin e6 (Ce6) and triphenyl phosphonium (TPP) were conjugated onto the surface of the nanoplatform. Under the action of TPP, the obtained nanoplatform preferentially accumulated in mitochondria to restore the drug activity and avoid drug resistance. Using 660 nm laser to excite Ce6 can generate ROS and simultaneously exacerbate the cellular hypoxia. While under the irradiation of 808 nm laser, the nanoplatform produced local heat which can increase the release of TH302 in tumor cells, ablate cancer cells as well as intensify the tumor hypoxia levels. The aggravated tumor hypoxia then significantly boosted the anti-tumor efficiency of TH302. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional hypoxia-associated chemotherapy. This work highlights the potential of using a combination of hypoxia-activated prodrugs plus phototherapy for synergistic cancer treatment.
Graphical Abstract
A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy
Authors: Hao Yingchao , Gao Yue , Fan Yu , Zhang Changchang , Zhan Mengsi , Cao Xueyan , Shi Xiangyang , Guo Rui 
Published: January 2022

Abstract
Background
Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy.

Results
In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity.

Conclusions
The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.

Graphical Abstract
Nanocarriers surface engineered with cell membranes for cancer targeted chemotherapy
Authors: Lei Wen , Yang Chen , Wu Yi , Ru Guoqing , He Xianglei , Tong Xiangmin , Wang Shibing 
Published: January 2022

AbstractBackgroundInspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells.Key scientific concepts of reviewNanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems.Aim of reviewThis review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects.Graphical Abstract
Bacteria-engineered porous sponge for hemostasis and vascularization
Authors: Bian Jie , Bao Luhan , Gao Xiaokang , Wen Xiao , Zhang Qiang , Huang Jinhua , Xiong Zhenghui , Hong Feng F. , Ge Zili , Cui Wenguo 
Published: January 2022

Abstract
Background
Hemostasis and repair are two essential processes in wound healing, yet early hemostasis and following vascularization are challenging to address in an integrated manner.

Results
In this study, we constructed a hemostatic sponge OBNC-DFO by fermentation of Komagataeibacterxylinus combined with TEMPO oxidation to obtain oxidized bacterial nanocellulose (OBNC). Then angiogenetic drug desferrioxamine (DFO) was grafted through an amide bond, and it promoted clot formation and activated coagulation reaction by rapid blood absorption due to the high total pore area (approximately 42.429 m2/g measured by BET). The further release of DFO stimulated the secretion of HIF-1α and the reconstruction of blood flow, thus achieving rapid hemostasis and vascularization in damaged tissue. This new hemostatic sponge can absorb water at a rate of approximate 1.70 g/s, rapidly enhancing clot formation in the early stage of hemostasis. In vitro and in vivo coagulation experiments (in rat tail amputation model and liver trauma model) demonstrated superior pro-coagulation effects of OBNC and OBNC-DFO to clinically used collagen hemostatic sponges (COL). They promoted aggregation and activation of red blood cells and platelets with shorter whole blood clotting time, more robust activation of endogenous coagulation pathways and less blood loss. In vitro cellular assays showed that OBNC-DFO prevailed over OBNC by promoting the proliferation of human umbilical vein endothelial cells (HUVECs). In addition, the release of DFO enhanced the secretion of HIF-1α, further strengthening vascularization in damaged skin. In the rat skin injury model, 28 days after being treated with OBNC-DFO, skin appendages (e.g., hair follicles) became more intact, indicating the achievement of structural and functional regeneration of the skin.

Conclusion
This hemostatic and vascularization-promoting oxidized bacterial nanocellulose hemostatic sponge, which rapidly activates coagulation pathways and enables skin regeneration, is a highly promising hemostatic and pro-regenerative repair biomaterial.

Graphical Abstract
Qualitative measures that assess functional disability and quality of life in ALS
Authors: Hartmaier Susan L. , Rhodes Thomas , Cook Suzanne F. , Schlusser Courtney , Chen Chao , Han Steve , Zach Neta , Murthy Venkatesha , Davé Shreya 
Published: January 2022

AbstractBackgroundSelection of appropriate trial endpoints and outcome measures is particularly important in rare disease and rapidly progressing disease such as amyotrophic lateral sclerosis (ALS) where the challenges to conducting clinical trials, are substantial: patient and disease heterogeneity, limited understanding of exact disease pathophysiology, and lack of robust and available biomarkers. To address these challenges in ALS, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised version (ALSFRS-R) was developed and has become a key primary endpoint in ALS clinical trials to assess functional disability and disease progression, often replacing survival as a primary outcome. However, increased understanding of the ALS disease journey and improvements in assistive technology for ALS patients have exposed issues with the ALSFRS-R, including non-linearity, multidimensionality and floor and ceiling effects that could challenge its continued utility as a primary outcome measure in ALS clinical trials. Recently, other qualitative scale measures of functioning disability have been developed to help address these issues. With this in mind, we conducted a literature search aimed at identifying both established and promising new measures for potential use in clinical trials.MethodsWe searched PubMed, Google, Google Scholar, and the reference sections of key studies to identify papers that discussed qualitative measures of functional status for potential use in ALS studies. We also searched clinicaltrials.gov to identify functional status and health-related quality of life (HRQoL) measures that have been used in ALS interventional studies.ResultsIn addition to the ALSFRS-R, we identified several newer qualitative scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS. Strengths and limitations of each measure were identified and discussed, along with their potential to act as a primary or secondary outcome to assess patient functional status in ALS clinical trials.ConclusionThis paper serves as a reference guide for researchers deciding which qualitative measures to use as endpoints in their ALS clinical trials to assess functional status. This paper also discusses the importance of including ALS HRQoL and ALS cognitive screens in future clinical trials to assess the value of a new ALS therapy more comprehensively.
First Nations Australians’ self-determination in health and alcohol policy development: a Delphi study
Authors: E. Stearne Annalee , Lee K. S. Kylie , Allsop Steve , Shakeshaft Anthony , Wright Michael 
Published: January 2022

Abstract
Background
Recognition of the role of structural, cultural, political and social determinants of health is increasing. A key principle of each of these is self-determination, and according to the United Nations (2007), this is a right of Indigenous Peoples. For First Nations Australians, opportunities to exercise this right appear to be limited. This paper explores First Nations Australian communities’ responses to reducing alcohol-related harms and improving the health and well-being of their communities, with a focus on understanding perceptions and experiences of their self-determination. It is noted that while including First Nations Australians in policies is not in and of itself self-determination, recognition of this right in the processes of developing health and alcohol policies is a critical element. This study aims to identify expert opinion on what is needed for First Nations Australians’ self-determination in the development of health- and alcohol-related policy.

Methods
This study used the Delphi technique to translate an expert panel’s opinions into group consensus. Perspectives were sought from First Nations Australians (n = 9) and non-Indigenous Peoples (n = 11) with experience in developing, evaluating and/or advocating for alcohol interventions led by First Nations Australians. Using a web-based survey, this study employed three survey rounds to identify and then gain consensus regarding the elements required for First Nations Australians’ self-determination in policy development.

Results
Twenty panellists (n = 9 First Nations Australian) participated in at least one of the three surveys. Following the qualitative round 1 survey, six main themes, 60 subthemes and six examples of policy were identified for ranking in round 2. In round 2, consensus was reached with 67% of elements (n = 40/60). Elements that did not reach consensus were repeated in round 3, with additional elements (n = 5). Overall, consensus was reached on two thirds of elements (66%, n = 43/65).

Conclusions
Self-determination is complex, with different meaning in each context. Despite some evidence of self-determination, systemic change in many areas is needed, including in government. This study has identified a starting point, with the identification of elements and structural changes necessary to facilitate First Nations Australian community-led policy development approaches, which are vital to ensuring self-determination.
Associations of lipoprotein particle profile and objectively measured physical activity and sedentary time in schoolchildren: a prospective cohort study
Authors: Jones Paul Remy , Rajalahti Tarja , Resaland Geir Kåre , Aadland Eivind , Steene-Johannessen Jostein , Anderssen Sigmund Alfred , Bathen Tone Frost , Andreassen Trygve , Kvalheim Olav Martin , Ekelund Ulf 
Published: January 2022

Abstract
Background
Our understanding of the mechanisms through which physical activity might benefit lipoprotein metabolism is inadequate. Here we characterise the continuous associations between physical activity of different intensities, sedentary time, and a comprehensive lipoprotein particle profile.

Methods
Our cohort included 762 fifth grade (mean [SD] age = 10.0 [0.3] y) Norwegian schoolchildren (49.6% girls) measured on two separate occasions across one school year. We used targeted proton nuclear magnetic resonance (1H NMR) spectroscopy to produce 57 lipoprotein measures from fasted blood serum samples. The children wore accelerometers for seven consecutive days to record time spent in light-, moderate-, and vigorous-intensity physical activity, and sedentary time. We used separate multivariable linear regression models to analyse associations between the device-measured activity variables—modelled both prospectively (baseline value) and as change scores (follow-up minus baseline value)—and each lipoprotein measure at follow-up.

Results
Higher baseline levels of moderate-intensity and vigorous-intensity physical activity were associated with a favourable lipoprotein particle profile at follow-up. The strongest associations were with the larger subclasses of triglyceride-rich lipoproteins. Sedentary time was associated with an unfavourable lipoprotein particle profile, the pattern of associations being the inverse of those in the moderate-intensity and vigorous-intensity physical activity analyses. The associations with light-intensity physical activity were more modest; those of the change models were weak.

Conclusion
We provide evidence of a prospective association between time spent active or sedentary and lipoprotein metabolism in schoolchildren. Change in activity levels across the school year is of limited influence in our young, healthy cohort.

Trial registration
ClinicalTrials.gov, #NCT02132494. Registered 7th April 2014
Heart-specific DNA methylation analysis in plasma for the investigation of myocardial damage
Authors: Ren Jie , Jiang Lin , Liu Xiaomeng , Liao Yuhan , Zhao Xueyan , Tang Fuchou , Yu Huimin , Shao Yibing , Wang Jizheng , Wen Lu , Song Lei 
Published: January 2022

Abstract
Background
Circulating cell-free DNA (cfDNA) can be released when myocardial damage occurs.

Methods
Here, we used the methylated CpG tandem amplification and sequencing (MCTA-seq) method for analyzing dynamic changes in heart-derived DNA in plasma samples from myocardial infarction (MI) patients.

Results
We identified six CGCGCGG loci showing heart-specific hypermethylation patterns. MCTA-seq deconvolution analysis combining these loci detected heart-released cfDNA in MI patients at hospital admission, and showed that the prominently elevated total cfDNA level after percutaneous coronary intervention (PCI) was derived from both the heart and white blood cells. Furthermore, for the top marker CORO6, we developed a digital droplet PCR (ddPCR) assay that clearly detected heart damage signals in cfDNA of MI patients at hospital admission.

Conclusions
Our study provides insights into MI pathologies and developed a new ddPCR assay for detecting myocardial damage in clinical applications.
RNA-binding proteins in ovarian cancer: a novel avenue of their roles in diagnosis and treatment
Authors: Wu Jiangchun , Wu Yong , Guo Qinhao , Wang Simin , Wu Xiaohua 
Published: January 2022

AbstractOvarian cancer (OC), an important cause of cancer-related death in women worldwide, is one of the most malignant cancers and is characterized by a poor prognosis. RNA-binding proteins (RBPs), a class of endogenous proteins that can bind to mRNAs and modify (or even determine) the amount of protein they can generate, have attracted great attention in the context of various diseases, especially cancers. Compelling studies have suggested that RBPs are aberrantly expressed in different cancer tissues and cell types, including OC tissues and cells. More specifically, RBPs can regulate proliferation, apoptosis, invasion, metastasis, tumorigenesis and chemosensitivity and serve as potential therapeutic targets in OC. Herein, we summarize what is currently known about the biogenesis, molecular functions and potential roles of human RBPs in OC and their prospects for application in the clinical treatment of OC.