bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of patients at risk for biochemical recurrence after radical prostatectomy with intra‐operative frozen section
Authors: Tully Karl H. , Schulmeyer Max , Hanske Julian , Reike Moritz J. , Brock Marko , Moritz Rudolf , Jütte Hendrik , Tannapfel Andrea , von Bodman Christian , Noldus Joachim , Palisaar Rein‐Jüri , Roghmann Florian 
Published: May 2021

ObjectiveTo identify patients at risk for biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) with intra‐operative whole‐mount frozen section (FS) of the prostate.Material and MethodsWe examined differences in BCR between patients with initial negative surgical margins at FS, patients with final negative surgical margins with initial positive margins at FS without residual PCa after secondary tumour resection, and patients with final negative surgical margins with initially positive margins at FS with residual PCa in the secondary tumour resection specimen. Institutional data of 883 consecutive patients undergoing RP were collected. Intra‐operative whole‐mount FS was routinely used to check for margin status and, if necessary, to resect more periprostatic tissue in order to achieve negative margins. Patients with lymph node‐positive disease or final positive surgical margins were excluded from the analysis. Kaplan−Meier curves and multivariable Cox proportional hazards regression analyses adjusting for clinical covariates were employed to examine differences in biochemical recurrence‐free survival (BRFS) according to the resection status mentioned above.ResultsThe median follow‐up was 22.4 months. The 1‐ and 2‐year BRFS rates in patients with (81.0% and 72.9%, respectively; P = 0.001) and without residual PCa (90.3% and 82.3%, respectively; P = 0.033) after secondary tumour resection were significantly lower compared to patients with initial R0 status (93.4% and 90.9%, respectively). On multivariable Cox regression only residual PCa in the secondary tumour resection was associated with a higher risk of BCR compared to initial R0 status (hazard ratio 1.99, 95% confidence interval 1.01–3.92; P = 0.046).ConclusionDespite being classified as having a negative surgical margin, patients with residual PCa in the secondary tumour resection specimen face a high risk of BCR. These findings warrant closer post‐RP surveillance of this particular subgroup. Further research of this high‐risk subset of patients should focus on examining whether these patients benefit from early salvage therapy and how resection status impacts oncological outcomes in the changing landscape of PCa treatment.
The effects of cocaine exposure in adolescence: Behavioural effects and neuroplastic mechanisms in experimental models
Authors: Caffino Lucia , Mottarlini Francesca , Zita Gianmaria , Gawliński Dawid , Gawlińska Kinga , Wydra Karolina , Przegaliński Edmund , Fumagalli Fabio 
Published: May 2021

Drug addiction is a devastating disorder with a huge economic and social burden for modern society. Although an individual may slip into drug abuse throughout his/her life, adolescents are at higher risk, but, so far, only a few studies have attempted to elucidate the underlying cellular and molecular bases of such vulnerability. Indeed, preclinical evidence indicates that psychostimulants and adolescence interact and contribute to promoting a dysfunctional brain. In this review, we have focused our attention primarily on changes in neuroplasticity brought about by cocaine, taking into account that there is much less evidence from exposure to cocaine in adolescence, compared with that from adults. This review clearly shows that exposure to cocaine during adolescence, acute or chronic, as well as contingent or non‐contingent, confers a vulnerable endophenotype, primarily, by causing changes in neuroplasticity. Given the close relationship between drug abuse and psychiatric disorders, we also discuss the translational implications providing an interpretative framework for clinical studies involving addictive as well as affective or psychotic behaviours.LINKED ARTICLESThis article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc
Establishment and characterization of a novel treatment‐related neuroendocrine prostate cancer cell line KUCaP13
Authors: Okasho Kosuke , Mizuno Kei , Fukui Tomohiro , Lin Yen‐Yi , Kamiyama Yuki , Sunada Takuro , Li Xin , Kimura Hiroko , Sumiyoshi Takayuki , Goto Takayuki , Kobayashi Takashi , Lin Dong , Wang Yuzhuo , Collins Colin C. , Inoue Takahiro , Ogawa Osamu , Akamatsu Shusuke 
Published: May 2021

AbstractThe prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC‐associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient‐derived, treatment‐related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.
Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma
Authors: Inoue Jun , Kishikawa Masahiro , Tsuda Hitoshi , Nakajima Yasuaki , Asakage Takahiro , Inazawa Johji 
Published: May 2021

AbstractThe metabolism in tumors is reprogrammed to meet its energetic and substrate demands. However, this metabolic reprogramming creates metabolic vulnerabilities, providing new opportunities for cancer therapy. Metabolic vulnerability as a therapeutic target in esophageal squamous cell carcinoma (ESCC) has not been adequately clarified. Here, we identified pyruvate dehydrogenase (PDH) component X (PDHX) as a metabolically essential gene for the cell growth of ESCC. PDHX expression was required for the maintenance of PDH activity and the production of ATP, and its knockdown inhibited the proliferation of cancer stem cells (CSCs) and in vivo tumor growth. PDHX was concurrently upregulated with the CD44 gene, a marker of CSCs, by co‐amplification at 11p13 in ESCC tumors and these genes coordinately functioned in cancer stemness. Furthermore, CPI‐613, a PDH inhibitor, inhibited the proliferation of CSCs in vitro and the growth of ESCC xenograft tumors in vivo. Thus, our study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex‐associated metabolic vulnerability.
Role of tumor‐associated macrophages at the invasive front in human colorectal cancer progression
Authors: Inagaki Katsuaki , Kunisho Shoma , Takigawa Hidehiko , Yuge Ryo , Oka Shiro , Tanaka Shinji , Shimamoto Fumio , Chayama Kazuaki , Kitadai Yasuhiko 
Published: May 2021

AbstractMacrophages are an essential component of antitumor activity; however, the role of tumor‐associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM‐CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM‐CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM‐CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan‐, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.
Regulation of vascular permeability in cancer metastasis
Authors: Tomita Takeshi , Kato Masayoshi , Hiratsuka Sachie 
Published: May 2021

AbstractEnhancement of vascular permeability is indispensable for cancer metastasis. Weakened endothelial barrier function enhances vascular permeability. Circulating tumor cells moving in the microvasculature tend to invade into stromal tissue at the location where vascular permeability is enhanced. Many basic studies have identified permeability factors by using gene‐modified animals and cells. These factors directly/indirectly interact with endothelial cells. Here, we review vascular permeability factors and their molecular mechanisms. Interactions between tumor cells and endothelial cells are also discussed in the process of extravasation, one of the most critical steps in tumor metastasis. In some cases, primary tumors can manipulate permeability in a remote organ by secreting permeability factors. In addition, the importance of glycocalyx, which covers the endothelial cell surface, in controlling vascular permeability and tumor metastasis is also described. Furthermore, analysis of the hyperpermeable region found in a mouse model study is introduced. It clearly showed that tumor‐bearing mouse lungs had a hyperpermeable region due to the influence of a remote primary tumor, and fibrinogen deposition was observed in that region. Given that fibrinogen was reported to be a permeability factor and a key regulator of inflammation, eliminating fibrinogen deposition may prevent future metastasis.
Discovery of novel SecA inhibitors against “Candidatus Liberibacter asiaticus” through virtual screening and biological evaluation
Authors: Zhang Zhengfang , Han Quan , Mao Xiongxing , Liu Jinhua , Wang Wei , Li Dong , Zhou Feng , Ke Yang , Xu Lei , Hu Liu 
Published: May 2021

Abstract“Candidatus Liberibacter asiaticus” (Ca. L. asiaticus) is the causal agent of Huanglongbing disease of citrus and current study focuses on the discovery of novel small‐molecule inhibitors against SecA protein of Ca. L. asiaticus. In this study, homologous modeling was used to construct the three‐dimensional structure of SecA. Then, molecular docking‐based virtual screening and two rounds of in vitro bacteriostatic experiments were utilized to identify novel small‐molecule inhibitors of SecA. Encouragingly, 93 compounds were obtained and two of them (P684‐2850, P684‐3808) showed strong antimicrobial activities against Liberibacter crescens BT‐1 in bacteriostatic experiments. Finally, molecular dynamics simulations were employed to explore the binding modes of the receptor–ligand complexes. Results in MD simulations showed that compound P684‐3808 was relatively stable during simulation, while compound P684‐2850 left the binding pocket. Compound P684‐3808 might be suitable as a lead compound for further development of antimicrobial compounds against SecA of Ca. L. asiaticus.
Design, synthesis and antifungal evaluation of novel mandelic acid derivatives containing a 1,3,4‐oxadiazothioether moiety
Authors: Hou Shuaitao , Xie Dewen , Yang Jingxin , Niu Xue , Hu Deyu , Wu Zhibing 
Published: May 2021

AbstractA series of novel mandelic acid derivatives containing a 1,3,4‐oxadiazothioether moiety were designed and synthesized. Bioassay results showed that some target compounds exhibited certain antifungal activity against six kinds of pathogenic fungi in vitro. Among the compounds, the EC50 values of T41 against Gibberella saubinetii, Verticillium dahlia and Sclerotinia sclerotiorum were 31.0, 27.0 and 32.1 μg/ml, respectively, and the EC50 value of T14 against S. sclerotiorum was 14.7 μg/ml. The antifungal activity against the resistant fungus S. sclerotiorum indicated that this series of target compounds may have the similar action modes or sites as the commercialized succinate dehydrogenase inhibitor carboxin. A morphological study with fluorescence microscope demonstrated that T41 can significantly destroy the membrane integrity of G. saubinetii.
Bone turnover markers are associated with the PTH levels in different subtypes of pseudohypoparathyroidism type 1 patients
Authors: Duan Xiaoye , Yang Yi , Wang Ou , Nie Min , Chu Xueying , Quan Tingting , Guan Wenmin , Jiang Yan , Li Mei , Xia Weibo , Xing Xiaoping 
Published: May 2021

AbstractObjectiveBone responsiveness to parathyroid hormone (PTH) in different subtypes of pseudohypoparathyroidism type 1 (PHP1) remains controversial. We aimed to investigate this phenomenon using bone turnover markers (BTMs) in a large cohort of PHP1 patients.DesignRetrospective study.PatientsSixty‐three PHP1 patients diagnosed by molecular analysis were used as subjects, and 48 sex‐ and age‐matched patients with nonsurgical hypoparathyroidism (NS‐HP) were used for comparison.MeasurementsBone turnover markers, alkaline phosphatase (ALP), C‐terminal telopeptide of type I collagen (β‐CTX) and related parameters in PHP1 were compared among different subtypes and with NS‐HP.ResultsAmong all the PHP1 patients (15 PHP1A, 14 familial 1B and 34 sporadic 1B), 23.8% had elevated baseline BTM levels. No significant difference was found in the β‐CTX levels among different subtypes. The β‐CTX level was positively correlated with the PTH level for all PHP1, PHP1B and PHP1A patients (B = 0.001, 0.001 and 0.004, respectively; all p < .05). The BTM levels of PHP1 patients were significantly higher than those of NS‐HP patients (β‐CTX: 0.56 ng/ml vs. 0.20 ng/ml, p = .001; ALP: 105 U/L vs. 72 U/L, p = .001). The serum β‐CTX levels in different PHP1 subtypes were all significantly higher than those in NS‐HP patients in adults. Among the 22 followed up patients, changes in BTMs were associated with changes in PTH (β‐CTX: r = .507, p = .023; ALP: r = .475, p = .034).ConclusionsBone tissues respond to PTH in different PHP1 subtypes, and it is reasonable to monitor and normalize PTH and BTMs in addition to the serum and urinary calcium levels in the follow‐up of PHP1 patients.
COG1‐congenital disorders of glycosylation: Milder presentation and review
Authors: Salazar Marne , Miyake Noriko , Silva Sebastián , Solar Benjamín , Papazoglu Gabriela M. , Asteggiano Carla G. , Matsumoto Naomichi 
Published: May 2021

AbstractCongenital disorders of glycosylation (CDG) are a heterogeneous group of genetic defects in glycoprotein and glycolipid glycan synthesis and attachment. A CDG subgroup are defects in the conserved oligomeric Golgi complex encoded by eight genes, COG1–COG8. Pathogenic variants in all genes except the COG3 gene have been reported. COG1‐CDG has been reported in five patients. We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing. Exome sequencing identified a homozygous COG1 variant (NM_018714.3: c.2665dup: p.[Arg889Profs*12]), which has been reported previously in one patient. We review the reported patients.
A homozygous missense mutation in TBPL2 is associated with oocyte maturation arrest and degeneration
Authors: Wang Yu , Xiang Mingfei , Yu Zhaojuan , Hao Yan , Xu Qianhua , Kong Shuai , Wang Fengsong , Shi Xuanming , Song Gaojie , Cao Yunxia , Huang Lingli , Zhu Fuxi 
Published: May 2021

AbstractThe genetic causes in most of patients with oocyte maturation arrest remain largely unknown. In this study, we identified a homozygous missense mutation (c.895T>C; p.C299R) in TBPL2 (TATA box binding protein like 2) in two infertile sisters with oocyte maturation arrest and degeneration from a consanguineous family by whole‐exome sequencing. The TBPL2 mutation is rare and pathogenic, and impaired the transcription initiation function of the protein. Our results showed that TBPL2 mutation might be associated with female infertility due to oocyte maturation arrest and degeneration.
Carbon monoxide alleviates senescence in diabetic nephropathy by improving autophagy
Authors: Chen Li , Mei Guibin , Jiang Chunjie , Cheng Xueer , Li Dan , Zhao Ying , Chen Huimin , Wan Cheng , Yao Ping , Gao Chao , Tang Yuhan 
Published: May 2021

AbstractObjectivesSenescence, characterized by permanent cycle arrest, plays an important role in diabetic nephropathy (DN). However, the mechanism of renal senescence is still unclear, and the treatment targeting it remains to be further explored.Materials and MethodsThe DN mice were induced by HFD and STZ, and 3 types of renal cells were treated with high glucose (HG) to establish in vitro model. Senescence‐related and autophagy‐related markers were detected by qRT‐PCR and Western blot. Further, autophagy inhibitors and co‐immunoprecipitation were used to clarify the mechanism of CO. Additionally, the specific relationship between autophagy and senescence was explored by immunofluorescence triple co‐localization and ELISA.ResultsWe unravelled that senescence occurred in vivo and in vitro, which could be reversed by CO. Mechanistically, we demonstrated that CO inhibited the dysfunction of autophagy in DN mice partly through dissociating Beclin‐1‐Bcl‐2 complex. Further results showed that autophagy inhibitors blocked the improvement of CO on senescence. In addition, the data revealed that autophagy regulated the degradation of senescence‐related secretory phenotype (SASP) including Il‐1β, Il‐6, Tgf‐β and Vegf.ConclusionsThese results suggested that CO protects DN mice from renal senescence and function loss via improving autophagy partly mediated by dissociating Beclin‐1‐Bcl‐2 complex, which is possibly ascribed to the degradation of SASP. These findings bring new ideas for the prevention and treatment of DN and the regulation of senescence.
Magnetic resonance imaging‐derived proton density fat fraction (MRI‐PDFF) is a viable alternative to liver biopsy for steatosis quantification in living liver donor transplantation
Authors: Qi Qiaochu , Weinstock Allison K. , Chupetlovska Kalina , Borhani Amir A. , Jorgensen Dana R. , Furlan Alessandro , Behari Jaideep , Molinari Michele , Ganesh Swaytha , Humar Abhinav , Duarte‐Rojo Andres 
Published: May 2021

AbstractThis study aimed to investigate whether magnetic resonance imaging‐derived proton density fat fraction (MRI‐PDFF) can be a viable noninvasive alternative to liver biopsy for the quantification of living liver donor steatosis. Hepatic steatosis for 143 donors was graded by MRI‐PDFF. Study endpoints included liver volume regeneration in donors, recipient outcomes including length of hospital stay, deaths, primary non‐function (PNF), early allograft dysfunction (EAD), and small for size syndrome (SFSS). Correlation between MRI‐PDFF determined donor steatosis and endpoints were analyzed. Donors had lower steatosis grade than non‐donors. Donor remnant liver regenerated to an average of 82% of pre‐donation volume by 101 ± 24 days with no complications. There was no correlation between percent liver regeneration and steatosis severity. Among recipients, 4 underwent redo‐transplantation and 6 died, with no association with degree of steatosis. 52 recipients (36%) fulfilled criteria for EAD (driven by INR), with no difference in hepatic steatosis between groups. MRI‐PDFF reliably predicted donor outcomes. Living donors with no or mild steatosis based on MRI‐PDFF (ie, <20%) and meeting other criteria for donation can expect favorable post‐surgical outcomes, including liver regeneration. Recipients had a low rate of death or retransplantation with no association between mild hepatic steatosis and EAD.
Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis
Authors: Stodtmann Sven , Nader Ahmed , Polepally Akshanth R. , Suleiman Ahmed A. , Winzenborg Insa , Noertersheuser Peter , Ng Juki , Mostafa Nael M. , Shebley Mohamad 
Published: May 2021

AbstractElagolix is a novel, oral gonadotropin‐releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose‐dependent suppression of estradiol (E2) in clinical studies. A dose‐response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross‐linked telopeptide of type 1 collagen [CTX]), formation (N‐terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in −0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.