tbuckley/cabot-search huggingface dataset:
PP45. GEOGRAPHICAL INEQUALITIES OF ACCESS TO 5-AMINOLEVULINIC ACID IN THE UK – BARRIERS TO IMPLEMENTING RESEARCH FINDINGS INTO CLINICAL PRACTICE.
Authors: Price
Journal: Neuro-Oncology (2017)

AbstractAIMS: Evidence based medicine aims to improve patient care by applying evidence from research studies. This implies that new research findings can be implemented into routine clinical practice. All too often, particularly in the current cash-strapped NHS, it is not possible to implement these research findings. When it is implemented it is often patchy, leaving patients with a ‘post-code lottery’ of whether they will be able to benefit from these findings. To explore this, I have used uptake of 5-aminolevulinc acid (5-ALA) fluorescence guided surgery for glioblastomas as an example of implementing research findings. A multicentre Phase III study was published in 2006 showing improved rate of complete resection of enhancing tumour, improved progression free survival and reduced re-operation rate without impact on neurological function. These findings were confirmed on another prospective cohort study. Subsequent studies have shown improved survival where complete resection of enhancing tumour is achieved. Despite this evidence the uptake in the UK has been patchy. This study aims to identify the geographical distribution of 5-ALA usage in the UK 10 years after publication of this trial. METHODS: A survey of the UK was undertaken by contacting neuro-oncology surgeons at each unit. For each unit the approximate geographical catchment area was estimated from the hospitals that referred tumour patients to these units. Usage of 5-ALA was classified as full use, limited access (including where it is paid for with charity funds) or no access. Where there was no access, the reasons for this were explored. In addition, the training log kept by Medac GmBH was reviewed to identify units without trained surgeons. A map of the uptake of 5-ALA was created from this data. RESULTS: Data was available from 24 of the 30 adult neuroscience units. Full access was available in 8/24 (33%) of the units where data was available, limited access in 7/24 (29%) and no access in 9/24 units (38%). The geographical distribution shows good access in Scotland and the south east of England but limited access in the north of England. There was no access in the south west of England and southern Wales as well as across areas of the midlands and Northern Island. In the units with no access the primary reason is the cost of 5-ALA. Data from the Medac training logs show there are trained surgeons in every neurosurgical unit in the UK. CONCLUSIONS: 10 years after publication of this study there still is limited uptake of 5-ALA in the UK with clear geographical variation. The main reason for this is lack of funding despite favourable published cost-effectiveness data. Further work is needed to explore the decision making process around implementing research findings into clinical practice.
Splicing Factor SLU7 Prevents Oxidative Stress‐Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage
Authors: María Gárate‐Rascón, Miriam Recalde, Maddalen Jimenez, María Elizalde, María Azkona, Iker Uriarte, M. Uxue Latasa, Raquel Urtasun, Idoia Bilbao, Bruno Sangro, Carmen Garcia‐Ruiz, José C. Fernandez‐Checa, Fernando J Corrales, Argitxu Esquivel, Antonio Pineda‐Lucena, Maite G. Fernández‐Barrena, Matías A. Ávila, María Arechederra, Carmen Berasain
Journal: Hepatology (2021)

Background and Aims Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and Results Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α , driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild‐type and Slu7 ‐haploinsufficient/heterozygous ( Slu7+/− ) mice undergoing chronic (CCl 4 ) and acute (acetaminophen) injury. SLU7 expression was restored in CCl 4 ‐injured mice using SLU7‐expressing adeno‐associated viruses (AAV‐SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7+/− mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV‐SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell’s antioxidant machinery. Conclusions Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress‐protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.
Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment
Authors: Ann-Christin Frank, Rebecca Raue, Dominik C. Fuhrmann, Evelyn Sirait-Fischer, Carsten Reuse, Andreas Weigert, Dieter Lütjohann, Karsten Hiller, Shahzad Nawaz Syed, Bernhard Brüne
Journal: Theranostics (2021)

Background: Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy.Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive.Methods: Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model.The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues.Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS.The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging.Results: Macrophage LDHB decreased in murine and human breast carcinoma.LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375.Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages.LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells.Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation.Conclusion: Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions.
A comparative integrated multi-omics analysis identifies CA2 as a novel target for chordoma
Authors: Tong Meng, Runzhi Huang, Jiali Jin, Jianxuan Gao, Fuyan Liu, Ziheng Wei, Xiaowen Xu, Zhengyan Chang, Jun Lin, Na Ta, Zongqiang Huang, Huabin Yin, Wang Zhou, Dianwen Song
Journal: Neuro-Oncology (2021)

Chordoma is a rare mesenchymal malignancy, with a high recurrence rate and unclear tumorigenic mechanism. Genetic alterations, epigenetic regulators, and chromatin spatial organization play crucial roles in the initiation and progression of chordoma. In the current study, we aim to uncover the novel therapeutical targets for chordoma via using integrated multi-omics analysis.The RNA-sequencing (RNA-seq), assay for transposable accessible chromatin by high-throughput sequencing (ATAC-seq), and Hi-C were performed between chordoma and human nucleus pulposus (HNP), along with imageological examination and clinical information. The expressions of identified targets were validated by clinical samples and their functions were further evaluated by cell and animal experiments via gene knockdown and inhibitors.The integrated multi-omics analysis revealed the important roles of bone microenvironment in chordoma tumorigenesis. By comparing the hierarchical structures, CA2 (carbonic anhydrase II) and THNSL2 (threonine synthase-like 2) were identified in the switched compartments, cell-specific boundaries, and loops. Additionally, CA2 was highly expressed in chordoma but barely found in HNP. The cell growth and migration of chordoma cells were dramatically suppressed via inhibition of CA2 either with genetic deletion or pharmaceutical treatment with Dorzolamide HCl. Furthermore, Dorzolamide HCl also regulated the bone microenvironment by blocking the osteoclast differentiation of bone marrow monocytes.This study uncovers the roles of bone microenvironment in the chordoma tumorigenesis and identifies CA2 as a novel therapeutic target for chordoma. Besides, our findings suggest Dorzolamide HCl as a promising therapeutic option for chordoma.
Histopathological differential diagnosis of frontal fibrosing alopecia and fibrosing alopecia in a pattern distribution
Authors: M.S. Teixeira, M.F.R. Gavazzoni Dias, E.A.G. Vilar, L. Pantaleão, R.F.R. Jourdan, C. Ekelem, M.C. Rochael
Journal: British Journal of Dermatology (2021)

Funding sources: none. Conflicts of interest: the authors declare they have no conflicts of interest. Dear Editor, Frontal fibrosing alopecia (FFA) and fibrosing alopecia in a pattern distribution (FAPD) are forms of primary cicatricial alopecia, classified as subtypes of lichen planopilaris.1, 2 FAPD and FFA may present with clinical overlap and similar histopathological and dermoscopic features.1 Parietal scalp involvement with frontal hairline recession can obscure the clinical delineation between FAPD and FFA. The aim of this study was to establish whether FAPD can be differentiated from FFA by histopathological analysis. We conducted a cross‐sectional analysis of biopsies from 43 women, all with a previous classical diagnosis of FAPD or FFA.1–4 All samples had horizontal sections in haematoxylin and eosin stain. Anisotrichia (hair fibre diversity) was present only in patients with FAPD. Twenty‐one histopathological markers were critically compared and contrasted. Analysis of nonparametrically distributed data was performed using the Mann–Whitney U‐test, and Person's χ2‐test was used to measure association. The research complied with Good Clinical Practice guidelines and was approved by an institutional review board.
Abstract 77: Metabolic Reprograming Driven by Interaction AMP-activated Protein Kinase and Coactivator SRC-2 Regulate Cardiac Stress Response
Authors: Deok Hwa Nam, Ji Ho Suh, Erin L Reineke
Journal: Circulation Research (2016)

Flexibility in fuel source for the heart is necessary to meet ATP demands during a high and variable workload such as transaortic constriction (TAC). During such chronic metabolic and hemodynamic stresses, shifts occur in substrate utilization in the heart based on magnitude of the demand, oxygen and nutrient availability. These shifts directly affect the amount of ATP available for other stress responsive pathways and therefore their efficacy. Communication from metabolic changes to these other pathways is crucial. As a result, it is important understand the molecular communication between metabolic and hypertrophic pathways under stress. We have found that chronic loss of cardiomyocyte SRC-2 and transient activation of AMPK both effect metabolic inputs prior to TAC and result in a blunted hypertrophic response. We hypothesized that SRC-2 and AMPK are critical upstream regulators of the cardiac stress response controlling metabolic changes translating into altered hypertrophy. Furthermore, we proposed that they could be regulating each other to control both the temporal changes to the metabolic machinery through AMPK and long-term genetic changes through SRC-2. We identified AMPK as a coregulator of SRC-2 activity and confirmed a direct interaction between them in cardiac cells. We have identified putative AMPK phosphorylation sites on SRC-2 that control SRC-2 stability and activity. Conversely, we found by ChIP that SRC-2 localized to AMPK subunit genes. Additionally, we performed co-immunoprecipitation and luciferase reporters and found that SRC-2 can interact with AMPK subunits and regulate its activity. We believe that disruption of these interactions is a main determinant in efficient hypertrophy in response to metabolic changes. Our results suggest the basis of a mechanism whereby energetic changes are sensed via AMPK and translated to transcriptional machinery of diverse targets via SRC-2 which allows AMPK to effect multiple cardiac transcription pathways. This mechanism provides insights into the role of AMPK-SRC-2 interaction in regulating myocardial function, metabolism, hypertrophy, and the progression to heart failure.
The US biological sciences faculty gap in Asian representation
Authors: James Meixiong, Sherita Hill Golden
Journal: Journal of Clinical Investigation (2021)

In the past year, the COVID-19 pandemic has inflicted untold human suffering, remade the global economy, and highlighted numerous weaknesses in political, health, and social systems. In the US, Asian Americans and immigrants have faced increased xenophobia, as evident by exponential increases in reported hate crimes and the horrific massage parlor shootings in Atlanta. This tragic spate of violence has renewed conversation on America's long history of anti-Asian discrimination, from prior racist immigration policy like the Chinese Exclusion Act of 1882, to the more recent model-minority myth of Asian attainment. Here, Meixiong and Golden discuss the impact of this history, including in the biomedical sciences.
Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes
Authors: Hertzel C. Gerstein, Naveed Sattar, Julio Rosenstock, Chinthanie Ramasundarahettige, Richard Pratley, Renato D. Lopes, Carolyn S.P. Lam, Nardev S. Khurmi, Laura Heenan, Stefano Del Prato, Leanne Dyal, Kelley Branch
Journal: New England Journal of Medicine (2021)

Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain.
Silencing of METTL3 effectively hinders invasion and metastasis of prostate cancer cells
Authors: Yabing Chen, Chun Pan, Xiaotong Wang, Dihui Xu, Yuhan Ma, Jianhang Hu, Peilin Chen, Zou Xiang, Qiu Rao, Xiaodong Han
Journal: Theranostics (2021)

Background: Since primary prostate cancer (PCa) can advance to the life-threatening metastatic PCa, exploring the molecular mechanisms underlying PCa metastasis is crucial for developing the novel targeted preventive strategies for decreasing the mortality of PCa.RNA N 6 -methyladenosine (m 6 A) is an emerging regulatory mechanism for gene expression and its specific roles in PCa progression remains elusive.Methods: Western blotting, quantitative real-time PCR and immunohistochemical analyses were used to detect target gene expression in PCa cells in vitro and prostate tissues from patients.RNA immunoprecipitation was conducted to analyze the specific binding of mRNA to the target protein.Migration and invasion assays were used to assess the migratory capacities of cancer cells.The correlation between target gene expression and survival rate of PCa patients was analyzed based the TCGA database.Results: We found that total RNA N 6 -methyladenosine (m 6 A) modification levels were markedly upregulated in human PCa tissues due to increased expression of methyltransferase like 3 (METTL3).Further studies revealed that the migratory and invasive capacities of PCa cells were markedly suppressed upon METTL3 knockdown.Mechanistically, METTL3 mediates m 6 A modification of USP4 mRNA at A2696, and m 6 A reader protein YTHDF2 binds to and induces degradation of USP4 mRNA by recruiting RNA-binding protein HNRNPD to the mRNA.Decrease of USP4 fails to remove the ubiquitin group from ELAVL1 protein, resulting in a reduction of ELAVL1 protein.Lastly, downregulation of ELAVL1 in turn increases ARHGDIA expression, promoting migration and invasion of PCa cells.Conclusions: Our findings highlight the role of METTL3 in modulating invasion and metastasis of PCa cells, providing insight into promising therapeutic strategies for hindering PCa progressing to deadly metastases.
Corrigendum to Berchtold L, Letouzé E, Alexander MP, et al. HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients. Kidney Int. 2021;99:671–685
Authors: Lena Berchtold, Eric Letouzé, Mariam Priya Alexander, Guillaume Canaud, Anne-Els van de Logt, Patrick Hamilton, Christiane Mousson, Vincent Vuiblet, Ann M. Moyer, Sylvain Guibert, Petra Mrázová, Charlène Levi, Valérie Dubois, Josep Maria Cruzado, Armando Torres, Manish J. Gandhi, Nadhir Yousfi, Vladimir Tesar, Ondřej Viklický, Maryvonne Hourmant, Bruno Moulin, Philippe Rieu, Gabriel Choukroun, Christophe Legendre, Jack Wetzels, Paul Brenchley, José Aurelio Ballarín Castan, Hanna Debiec, Pierre Ronco
Journal: Kidney International (2021)
Tapentadol Versus Tramadol: A Narrative and Comparative Review of Their Pharmacological, Efficacy and Safety Profiles in Adult Patients
Authors: Lucien Roulet, Victoria Rollason, Jules Desmeules, Valérie Piguet
Journal: Drugs (2021)

We conducted a narrative review of the literature to compare the pharmacological, efficacy and safety profiles of tapentadol and tramadol, and to assess the clinical interest of tapentadol in adult patients. Tapentadol and tramadol share a mixed mechanism of action, including both mu-agonist and monoaminergic properties. Tapentadol is approximately two to three times more potent than tramadol and two to three times less potent than morphine. It has no identified analgesically active metabolite and is not significantly metabolised by cytochrome P450 enzymes, thus overcoming some limitations of tramadol, including the potential for pharmacokinetic drug-drug interactions and interindividual variability due to genetic polymorphisms of cytochrome P450 enzymes. The toxicity profiles of tramadol and tapentadol are similar; however tapentadol is likely to result in less exposure to serotoninergic adverse effects (nausea, vomiting, hypoglycaemia) but cause more opioid adverse effects (constipation, respiratory depression, abuse) than tramadol. The safety of tapentadol in real-world conditions remains poorly documented, particularly in at-risk patient subgroups and also in the ability to assess the risk associated with its residual serotonergic activity (serotonin syndrome, seizures). Because of an earlier market introduction, more real-world safety data are available for tramadol, including data from at-risk patient subgroups. The level of evidence on the efficacy of both tramadol and tapentadol for the treatment of chronic pain is globally low. The trials published to date show overall that tapentadol does not provide a clinically significant analgesic improvement compared to existing treatments, for which the safety profile is much better known. In conclusion, tapentadol is not a first-line opioid but represents an additional analgesic in the therapeutic choices, which some patients may benefit from after careful examination of their clinical situation, co-morbidities and co-medications.
Prevalence of Voluntary Medical Male Circumcision for HIV Infection Prevention — Chókwè District, Mozambique, 2014–2019
Authors: Jonas Z. Hines, Ricardo Thompson, Carlos Toledo, Robert Nelson, Isabelle Casavant, Sherri Pals, Marcos Canda, Juvencio Bonzela, Alicia Jaramillo, Judite Cardoso, Dawud Ujamaa, Stelio Tamele, Victor Chivurre, Inacio Malimane, Ishani Pathmanathan, Kristen Heitzinger, Stanley Wei, Aleny Couto, Jotamo Come, Alfredo Vergara, Duncan MacKellar
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Male circumcision is an important preventive strategy in lifelong partial protection against heterosexually acquired HIV infection among males. This report describes how the prevalence of male circumcision increased in Chókwè District in southern Mozambique.
Identification of a novel PHGDH covalent inhibitor by chemical proteomics and phenotypic profiling
Authors: Chen Chen, Tianyu Zhu, Xiaoqin Liu, Dongrong Zhu, Yi Zhang, Sifang Wu, Chao Han, Hao Zhang, Jianguang Luo, Lingyi Kong
Journal: Acta Pharmaceutica Sinica B (2021)

The first rate-limiting enzyme of the serine synthesis pathway (SSP), phosphoglycerate dehydrogenase (PHGDH), is hyperactive in multiple tumors, which leads to the activation of SSP and promotes tumorigenesis. However, only a few inhibitors of PHGDH have been discovered to date, especially the covalent inhibitors of PHGDH. Here, we identified withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PHGDH. Affinity-based protein profiling identified that WA could directly bind to PHGDH and inactivate the enzyme activity of PHGDH. Biolayer interferometry and LC-MS/MS analysis further demonstrated the selective covalent binding of WA to the cysteine 295 residue (Cys295) of PHGDH. With the covalent modification of Cys295, WA blocked the substrate-binding domain (SBD) of PHGDH and exerted an allosteric effect to induce PHGDH inactivation. Further studies revealed that with the inhibition of PHGDH mediated by WA, the glutathione synthesis was decreased and intracellular levels of reactive oxygen species (ROS) were elevated, leading to the inhibition of tumor proliferation. This study indicates WA as a novel PHGDH covalent inhibitor, which identifies Cys295 as a novel allosteric regulatory site of PHGDH and holds great potential in developing anti-tumor agents for targeting PHGDH.
プライバシー保護連合学習とドメイン適応を用いたマルチサイトfMRI解析:ABIDE結果【JST・京大機械翻訳】
Authors: Li Xiaoxiao, Gu Yufeng, Dvornek Nicha, H Staib Lawrence, Ventola Pamela, S Duncan James
Journal: Medical Image Analysis (2020)