bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Progress in Inoperable or Recurrent Advanced Gastric Cancer Treatment from 1004 Single Institute Experiences Between 2007 and 2018
Authors: Nakayama Izuma , Takahari Daisuke , Shimozaki Keitaro , Chin Keisho , Wakatsuki Takeru , Ogura Mariko , Ooki Akira , Kamiimabeppu Daisaku , Osumi Hiroki , Shinozaki Eiji , Yamaguchi Kensei 
Published: January 2022

Abstract

Background
In the past decade, several successful clinical trials provided new therapeutic agents approved for advanced gastric cancer (AGC). This study evaluated whether these practice-changing results actually altered the clinical practice.

Patients and Methods
We retrospectively reviewed medical records of treatment-naive AGC patients who received combination chemotherapy of fluoropyrimidine and platinum between 2007 and 2018 and divided them into three groups: Groups A (2007-10), B (2011-14), and C (2015-2018), respectively. We compared the clinicopathological features, treatment details, and clinical outcomes among the three groups.

Results
In total, 1004 consecutive patients were enrolled (A; n = 254, B; n = 300, and C; n = 450). The number of patients with poor performance status, older age, esophagogastric junction adenocarcinoma, and primary tumor increased during the study period. All groups had similar median overall survival (OS); ~16 months) without any statistical difference but steady prolongation of survival was observed in the adjusted with imbalance prognostic factors among groups (B/A; hazard ratio, HR 0.82, 95% C.I 0.68-0.98, C/A; HR 0.72, 95% CI 0.60-0.86); OS of HER2-positive AGC patients was clearly improved (HER2-positive vs HER2-negative in Group B, HR 0.80, 95% CI 0.60-1.06; Group C, HR 0.68, 95% CI 0.51-0.90) but that of diffuse-type AGC patients remained dismal.

Conclusions
The increasing availability of chemotherapy options potentially contributed to improved survival of AGC patients, but expanded chemotherapeutic indications made the survival benefit inconspicuous in the whole population. Future therapeutic development for the AGC subset not adequately receiving benefit from previous clinical trials is warranted.
Photochemical Internalization of Gemcitabine Is Safe and Effective in Locally Advanced Inoperable Cholangiocarcinoma
Authors: Trojan Jörg , Hoffmeister Albrecht , Neu Bruno , Kasper Stefan , Dechêne Alexander , Jürgensen Christian , Schirra Jörg , Jakobs Ralf , Palmer Dan , Selbo Pål k. , Olivecrona Hans , Finnesand Lena , Høgset Anders , Walday Per , Sturgess Richard 
Published: January 2022

Abstract

Background
Photochemical internalization (PCI) is a novel technology for light-induced enhancement of the local therapeutic effect of cancer drugs, utilizing a specially designed photosensitizing molecule (fimaporfin). The photosensitizing molecules are trapped in endosomes along with macromolecules or drugs. Photoactivation of fimaporfin disrupts the endosomal membranes so that drug molecules are released from endosomes inside cells and can reach their therapeutic target in the cell cytosol or nucleus. Compared with photodynamic therapy, the main cytotoxic effect with PCI is disruption of the endosomal membrane resulting in delivery of chemotherapy drug, and not to the photochemical reactions per se. In this study we investigated the effect of PCI with gemcitabine in patients with inoperable perihilar cholangiocarcinoma (CCA).

Methods
The in vitro cytotoxic effect of PCI with gemcitabine was studied on two CCA-derived cell lines. In a fimaporfin dose-escalation phase I clinical study, we administered PCI with gemcitabine in patients with perihilar CCA (n = 16) to establish a safe and tolerable fimaporfin dose and to get early signals of efficacy. The patients enrolled in the study had tumors in which the whole length of the tumor could be illuminated from the inside of the bile duct, using an optical fiber inserted via an endoscope (Fig. 1). Fimaporfin was administered intravenously at day 0; gemcitabine (i.v.) and intraluminal biliary endoscopic laser light application on day 4; followed by standard gemcitabine/cisplatin chemotherapy.

Results
Preclinical experiments showed that PCI enhanced the effect of gemcitabine. In patients with CCA, PCI with gemcitabine was well tolerated with no dose-limiting toxicities, and no unexpected safety signals. Disease control was achieved in 10 of 11 evaluable patients, with a clearly superior effect in the two highest dose groups. The objective response rate (ORR) was 42%, including two complete responses, while ORR at the highest dose was 60%. Progression-free survival at 6 months was 75%, and median overall survival (mOS) was 15.4 months, with 22.8 months at the highest fimaporfin dose.

Conclusion
Photochemical internalization with gemcitabine was found to be safe and resulted in encouraging response and survival rates in patients with unresectable perihilar CCA.
Rh-Endostatin Plus Irinotecan/Cisplatin as Second-Line Therapy for Advanced Esophageal Squamous Cell Carcinoma: An Open-Label, Phase II Study
Authors: Hu Zhihuang , Sun Si , Zhao Xinmin , Yu Hui , Wu Xianghua , Wang Jialei , Chang Jianhua , Wang Huijie 
Published: January 2022

Abstract

Background
This open-label, phase II study aimed to investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) plus irinotecan/cisplatin as second-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC).

Methods
Eligible patients received 15mg/m2 Rh-endostatin as a continuous intravenous pump infusion (7 continuous days), 60mg/m2 irinotecan (days 1 and 8), and 60mg/m2 cisplatin (day 1) every 3 weeks. The primary endpoint was progression-free survival (PFS).

Results
A total of 50 patients were assessable for efficacy and safety analysis. The median follow-up was 10.97 months (95%CI: 7.03-19.42) as the data cutoff. Median PFS was 4.01 months (95% CI: 3.19-5.49), and median overall survival (OS) was 12.32 months (95% CI: 8.21-17.45); 13 (26%; 95% CI: 15.87-39.55) of 50 patients had an objective response, and 31 (62%; 95% CI: 48.15-74.14) had disease control. Grade 3 or greater treatment-related adverse events (AEs) occurred in 12 (24.0%) patients, and no deaths were reported. The common grade 3 or greater AEs were leucopenia (18.0%) and neutropenia (16.0%). Five (10%) patients discontinued treatment because of AEs.

Conclusion
Rh-endostatin plus irinotecan/cisplatin showed promising anti-tumor activity in advanced ESCC patients with a good safety profile in the second-line setting, which warrants further study in this population. (ClinicalTrials.gov identifier: NCT03797625).
Phytochrome interacting factor MdPIF7 modulates anthocyanin biosynthesis and hypocotyl growth in apple
Authors: Liu Yankai , Zhang Xiao-Wei , Liu Xin , Zheng Peng-Fei , Su Ling , Wang Gui-Luan , Wang Xiao-Fei , Li Yuan-Yuan , You Chun-Xiang , An Jian-Ping 
Published: January 2022

Abstract
Light affects many physiological and developmental processes of plants by regulating the expression and activity of light-responsive proteins. Among them, phytochrome interacting factors (PIFs) play pivotal roles in the regulation of anthocyanin accumulation and hypocotyl growth. However, the molecular mechanism is not well understood, especially in woody plants, such as apple (Malus × domestica). In this study, we identified a light-responsive PIF protein, MdPIF7, in apple and investigated the molecular mechanism of its regulation of anthocyanin biosynthesis and hypocotyl growth. We found that overexpression of MdPIF7 decreased anthocyanin accumulation in transgenic apple materials and promoted hypocotyl elongation in ectopically expressed Arabidopsis (Arabidopsis thaliana). Further investigation showed that MdPIF7 functioned by interacting with B-box 23 (MdBBX23), a positive regulator of anthocyanin biosynthesis in apple and hypocotyl growth inhibition in ectopically expressed Arabidopsis, and attenuating the transcriptional activation of MdBBX23 on LONG HYPOCOTYL 5 (MdHY5). In addition, MdPIF7 interacted with basic region leucine zipper 44 (MdbZIP44) and ethylene response factor 38 (MdERF38), two positive regulators of anthocyanin biosynthesis, and it negatively regulated MdbZIP44- and MdERF38-promoted anthocyanin accumulation by interfering with the interaction between MdbZIP44/MdERF38 and MdMYB1. Taken together, our results reveal that MdPIF7 regulates anthocyanin biosynthesis in apple and hypocotyl growth in ectopically expressed Arabidopsis through MdPIF7–MdBBX23–MdHY5 and MdPIF7–MdbZIP44/MdERF38–MdMYB1 modules. Our findings enrich the functional studies of PIF proteins and provide insights into the molecular mechanism of PIF-mediated anthocyanin biosynthesis and hypocotyl growth.
Yeast surface display-based identification of ACE2 mutations that modulate SARS-CoV-2 spike binding across multiple mammalian species
Authors: Heinzelman Pete , Greenhalgh Jonathan C , Romero Philip A 
Published: January 2022

Abstract
Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with different mammalian angiotensin-converting enzyme II (ACE2) cell entry receptors elucidates determinants of virus transmission and facilitates development of vaccines for humans and animals. Yeast display-based directed evolution identified conserved ACE2 mutations that increase spike binding across multiple species. Gln42Leu increased ACE2-spike binding for human and four of four other mammalian ACE2s; Leu79Ile had an effect for human and three of three mammalian ACE2s. These residues are highly represented, 83% for Gln42 and 56% for Leu79, among mammalian ACE2s. The above findings can be important in protecting humans and animals from existing and future SARS-CoV-2 variants.
Discourses of Social Inclusion in Chilean Sexual and Reproductive Health Policy
Authors: Cubillos-Almendra Javiera 
Published: January 2022

AbstractSexual and reproductive health (SRH) policy raises important normative questions. Accordingly, this article—inspired by a discursive approach to public policy—uses social inclusion approach to analyze Chilean SRH policy (2000–2018). It argues that despite long decades of capitalist neoliberal modernization and four consecutive center/left-wing governments, Chilean SRH policy remains as conservative as under right-wing dictatorship, and focused mainly on fertile women. The proposed conceptual model that informs this analysis considers three features of the public policy: the normative referent that guides it, the vision of society that underlies its discourse, and the presupposed concept of subject. The methodology includes tracing Chile’s SRH policy, critical frame analysis of relevant political texts, and interviews with governmental and nongovernmental political stakeholders.
Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws—What, When, Where, and Why
Authors: Li Xiaofei , Sundström Erik 
Published: January 2022

Abstract
Traumatic injury of the central nervous system (CNS) is a worldwide health problem affecting millions of people. Trauma of the CNS, that is, traumatic brain injury (TBI) and spinal cord injury (SCI), lead to massive and progressive cell loss and axonal degeneration, usually with very limited regeneration. At present, there are no treatments to protect injured CNS tissue or to replace the lost tissue. Stem cells are a cell type that by definition can self-renew and give rise to multiple cell lineages. In recent years, therapies using stem and progenitor cells have shown promising effects in experimental CNS trauma, particularly in the acute-subacute stage, but also in chronic injuries. However, the therapeutic mechanisms by which transplanted cells achieve the structural and/or functional improvements are often not clear. Stem cell therapies for CNS trauma can be categorized into 2 main concepts, transplantation of exogenous neural stem cells and neural progenitor cells and recruitment of endogenous stem and progenitor cells. In this review, focusing on the advances during the last decade, we will discuss the major cell therapies, the pros and cons of these 2 concepts for TBI and SCI, and the treatment strategies we believe will be successful.
Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell
Authors: Romecín Paola Alejandra , Vinyoles Meritxell , López-Millán Belén , de la Guardia Rafael Diaz , Atucha Noemi M , Querol Sergi , Bueno Clara , Benitez Raquel , Gonzalez-Rey Elena , Delgado Mario , Menéndez Pablo 
Published: January 2022

Abstract
Mesenchymal stromal stem/cells (MSC) therapies are clinically used in a wide range of disorders based on their robust HLA-independent immunosuppressive and anti-inflammatory properties. However, the mechanisms underlying MSC therapeutic activity remain elusive as demonstrated by the unpredictable therapeutic efficacy of MSC infusions reported in multiple clinical trials. A seminal recent study showed that infused MSCs are actively induced to undergo apoptosis by recipient cytotoxic T cells, a mechanism that triggers in vivo recipient-induced immunomodulation by such apoptotic MSCs, and the need for such recipient cytotoxic cell activity could be replaced by the administration of ex vivo-generated apoptotic MSCs. Moreover, the use of MSC-derived extracellular vesicles (MSC-EVs) is being actively explored as a cell-free therapeutic alternative over the parental MSCs. We hypothesized that the introduction of a “suicide gene” switch into MSCs may offer on-demand in vivo apoptosis of transplanted MSCs. Here, we prompted to investigate the utility of the iCasp9/AP1903 suicide gene system in inducing apoptosis of MSCs. iCasp9/AP1903-induced apoptotic MSCs (MSCiCasp9+) were tested in vitro and in in vivo models of acute colitis. Our data show a very similar and robust immunosuppressive and anti-inflammatory properties of both “parental” alive MSCGFP+ cells and apoptotic MSCiCasp9+ cells in vitro and in vivo regardless of whether apoptosis was induced in vivo or in vitro before administering MSCiCasp9+ lysates. This development of an efficient iCasp9 switch may potentiate the safety of MSC-based therapies in the case of an adverse event and, will also circumvent current logistic technical limitations and biological uncertainties associated to MSC-EVs.
Rejuvenation of Tissue Stem Cells by Intrinsic and Extrinsic Factors
Authors: Cai Yusheng , Wang Si , Qu Jing , Belmonte Juan Carlos Izpisua , Liu Guang-Hui 
Published: January 2022

Abstract
Stem cell therapies, including stem cell transplantation and rejuvenation of stem cells in situ, are promising avenues for tackling a broad range of diseases. Stem cells can both self-renew and differentiate into other cell types, and play a significant role in the regulation of tissue homeostasis and regeneration after cell degeneration or injury. However, stem cell exhaustion or dysfunction increases with age and impedes the normal function of multiple tissues and systems. Thus, stem cell therapies could provide a solution to aging and age-associated diseases. Here, we discuss recent advances in understanding the mechanisms that regulate stem cell regeneration. We also summarize potential strategies for rejuvenating stem cells that leverage intrinsic and extrinsic factors. These approaches may pave the way toward therapeutic interventions aiming at extending both health and life span.
Umbilical Cord Blood and Cord Tissue-Derived Cell Therapies for Neonatal Morbidities: Current Status and Future Challenges
Authors: Zhou Lindsay , McDonald Courtney , Yawno Tamara , Jenkin Graham , Miller Suzanne , Malhotra Atul 
Published: January 2022

AbstractCell therapies are an emerging focus for neonatal research, with benefits documented for neonatal respiratory, neurological, and cardiac conditions in pre-clinical studies. Umbilical cord blood (UCB) and umbilical cord (UC) tissue-derived cell therapy is particularly appealing for preventative or regenerative treatment of neonatal morbidities; they are a resource that can be collected at birth and used as an autologous or allogeneic therapy. Moreover, UCB contains a diverse mix of stem and progenitor cells that demonstrate paracrine actions to mitigate damaging inflammatory, immune, oxidative stress, and cell death pathways in several organ systems. In the past decade, published results from early-phase clinical studies have explored the use of these cells as a therapeutic intervention in neonates. We present a systematic review of published and registered clinical trials of UCB and cord tissue-derived cell therapies for neonatal morbidities. This search yielded 12 completed clinical studies: 7 were open-label phase I and II safety and feasibility trials, 3 were open-label dose-escalation trials, 1 was a open-label placebo-controlled trial, and 1 was a phase II randomized controlled trial. Participants totaled 206 infants worldwide; 123 (60%) were full-term infants and 83 (40%) were preterm. A majority (64.5%) received cells via an intravenous route; however, 54 (26.2%) received cells via intratracheal administration, 10 (4.8%) intraoperative cardiac injection, and 9 (4.3%) by direct intraventricular (brain) injection. Assessment of efficacy to date is limited given completed studies have principally been phase I and II safety studies. A further 24 trials investigating UCB and UC-derived cell therapies in neonates are currently registered.
Gadd45g, A Novel Antidepressant Target, Mediates Metformin-Induced Neuronal Differentiation of Neural Stem Cells Via DNA Demethylation
Authors: Zhang Le , Li Qingfeng , Wang Huan , Wu Yuanfei , Ye Xiujuan , Gong Zhuo , Li Qingqing , Xuan Aiguo 
Published: January 2022

Abstract
Increased neurogenesis elicits antidepressive-like effects. The antidiabetic drug metformin (Met) reportedly promotes hippocampal neurogenesis, which ameliorates spatial memory deficits and depression-like behaviors. However, the precise molecular mechanisms underpinning Met-induced neuronal differentiation of neural stem cells (NSCs) remain unclear. We showed that Met enhanced neuronal differentiation of NSCs via Gadd45g but not Gadd45a and Gadd45b. We further found that Gadd45g increased demethylation of neurogenic differentiation 1 promoter by regulating the activity of passive and active DNA demethylation enzymes through an adenylate-activated protein kinase -independent mechanism in Met-treated NSCs. Importantly, genetic deficiency of Gadd45g decreased hippocampal neurogenesis, which could contribute to spatial memory decline, and depression-like behaviors in the adult mice, whereas forced expression of Gadd45g alleviated the depressive-like behaviors. Our findings provide a model that Gadd45g-mediated DNA demethylation contributes to Met-induced neuronal genesis and its antidepressant-like effects and propose the concept that targeting Gadd45g regulation of neurogenesis might serve as a novel antidepressant strategy.
DDX04+ Stem Cells in the Ovaries of Postmenopausal Women: Existence and Differentiation Potential
Authors: Wu Meng , Lu Zhiyong , Zhu Qingqing , Ma Lingwei , Xue Liru , Li Yan , Zhou Su , Yan Wei , Ye Wenlei , Zhang Jinjin , Luo Aiyue , Wang Shixuan 
Published: January 2022

Abstract
Ovarian aging is a pacemaker with multiple organ dysfunction. Recently, stem cells with the ability to generate new oocytes have been identified, which provides the possibility of stem cell therapy for ovarian aging. Several studies have revealed the existence of stem cells in the human postmenopausal ovary. In this study, we describe a new method using magnetic-activated cell sorting combined with differential adhesion to isolate DDX4+ stem cells from ovaries of postmenopausal women and show that the cells exhibit similar gene expression profiles and growth characteristics with primitive germ cells. Furthermore, the DDX4+ stem cells could enter the meiosis stage and differentiation into oocytes. The RNA-seq data of the differentiated oocytes shows that mitochondrial metabolism may play an important role in the oogenesis process of the DDX4+ stem cells. Through using the human ovarian cortical fragments transplantation model, we indicated that the GFP-DDX4+ stem cells differentiated into some GFP positive oocyte-like structure in vivo. Our study provided a new method for the isolation of DDX4+ stem cells from the ovaries of postmenopausal women and confirmed the ability of these stem cells to differentiate into oocytes.
Linc1548 Promotes the Transition of Epiblast Stem Cells Into Neural Progenitors by Engaging OCT6 and SOX2
Authors: Bai Mingliang , Li Guoping , Jiapaer Zeyidan , Guo Xudong , Xi Jiajie , Wang Guiying , Ye Dan , Chen Wen , Duan Baoyu , Kang Jiuhong 
Published: January 2022

Abstract
The transition of embryonic stem cells from the epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs), called the neural induction process, is crucial for cell fate determination of neural differentiation. However, the mechanism of this transition is unclear. Here, we identified a long non-coding RNA (linc1548) as a critical regulator of neural differentiation of mouse embryonic stem cells (mESCs). Knockout of linc1548 did not affect the conversion of mESCs to EpiSCs, but delayed the transition from EpiSCs to NPCs. Moreover, linc1548 interacts with the transcription factors OCT6 and SOX2 forming an RNA-protein complex to regulate the transition from EpiSCs to NPCs. Finally, we showed that Zfp521 is an important target gene of this RNA-protein complex regulating neural differentiation. Our findings prove how the intrinsic transcription complex is mediated by a lncRNA linc1548 and can better understand the intrinsic mechanism of neural fate determination.
Histone Variant macroH2A1.1 Enhances Nonhomologous End Joining-dependent DNA Double-strand-break Repair and Reprogramming Efficiency of Human iPSCs
Authors: Giallongo Sebastiano , Řeháková Daniela , Biagini Tommaso , Lo Re Oriana , Raina Priyanka , Lochmanová Gabriela , Zdráhal Zbyněk , Resnick Igor , Pata Pille , Pata Illar , Mistrík Martin , de Magalhães João Pedro , Mazza Tommaso , Koutná Irena , Vinciguerra Manlio 
Published: January 2022

Abstract
DNA damage repair (DDR) is a safeguard for genome integrity maintenance. Increasing DDR efficiency could increase the yield of induced pluripotent stem cells (iPSC) upon reprogramming from somatic cells. The epigenetic mechanisms governing DDR during iPSC reprogramming are not completely understood. Our goal was to evaluate the splicing isoforms of histone variant macroH2A1, macroH2A1.1, and macroH2A1.2, as potential regulators of DDR during iPSC reprogramming. GFP-Trap one-step isolation of mtagGFP-macroH2A1.1 or mtagGFP-macroH2A1.2 fusion proteins from overexpressing human cell lines, followed by liquid chromatography-tandem mass spectrometry analysis, uncovered macroH2A1.1 exclusive interaction with Poly-ADP Ribose Polymerase 1 (PARP1) and X-ray cross-complementing protein 1 (XRCC1). MacroH2A1.1 overexpression in U2OS-GFP reporter cells enhanced specifically nonhomologous end joining (NHEJ) repair pathway, while macroH2A1.1 knock-out (KO) mice showed an impaired DDR capacity. The exclusive interaction of macroH2A1.1, but not macroH2A1.2, with PARP1/XRCC1, was confirmed in human umbilical vein endothelial cells (HUVEC) undergoing reprogramming into iPSC through episomal vectors. In HUVEC, macroH2A1.1 overexpression activated transcriptional programs that enhanced DDR and reprogramming. Consistently, macroH2A1.1 but not macroH2A1.2 overexpression improved iPSC reprogramming. We propose the macroH2A1 splicing isoform macroH2A1.1 as a promising epigenetic target to improve iPSC genome stability and therapeutic potential.