Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting DNA damage response in head and neck cancers through abrogation of cell cycle checkpoints

Abstract Purpose Head and neck cancers (HNSCC) are routinely treated with radiotherapy; however, normal tissue toxicity remains a concern. Therefore, it is important to validate treatment modalities combining molecularly targeted agents with radiotherapy to improve the therapeutic ratio. The aim of this study was to assess the ability of the PARP inhibitor niraparib (MK-4827) alone, or in combination with cell cycle checkpoint abrogating drugs targeting Chk1 (MK-8776) or Wee1 (MK-1775), to radiosensitize HNSCCs in the context of HPV status. Materials and methods PARP1, PARP2, Chk1 or Wee1 shRNA constructs were analyzed from an in vivo shRNA screen of HNSCC xenografts comparing radiosensitization differences between HPV(+) and HPV(−) tumors. Radiosensitization by niraparib alone or in combination with MK-8776 or MK-1775 was assessed by clonogenic survival in HPV(−) and HPV(+) cells; and the role of p16 in determining response was explored. Relative expressions of DNA repair genes were compared by PCR array in HPV(+) and HPV(−) cells, and following siRNA-mediated knockdown of TRIP12 in HPV(−) cells. Results In vivo shRNA screening showed a modest preferential radiosensitization by Wee1 and PARP2 in HPV(−) and Chk1 in HPV(+) tumor models. Niraparib alone enhanced the radiosensitivity of all HNSCC cell lines tested. However, HPV(−) cells were sensitized to a greater degree, as suggested by the shRNA screen. When combined with MK-8776 or MK-1775, radiosensitization was further enhanced in an HPV dependent manner with HPV(+) cells enhanced by MK-8776 and HPV(−) cells enhanced by MK-1775. A PCR array for DNA repair genes showed PARP and HR proteins BRCA1 and RAD51 were much lower in HPV(+) cells than in HPV(−). Similarly, directly knocking down p16-dependent TRIP12 decreased expression of these same genes. Overexpressing p16 decreased TRIP12 expression and increased radiosensitivity in HPV(−) HN5. However, while PARP inhibition led to significant radiosensitization in the control, it led to no further significant radiosensitization in p16 overexpressing cells. Forced p16 expression in HPV(−) HN5 increased accumulation in G1 and subG1 and limited progression to S phase, thus reducing effectiveness of PARP inhibition. Conclusions Niraparib effectively radiosensitizes HNSCCs with a greater benefit seen in HPV(−). HPV status also plays a role in response to MK-8776 or MK-1775 when combined with niraparib due to differences in DNA repair mechanisms. This study suggests that using cell cycle abrogators in combination with PARP inhibitors may be a beneficial treatment option in HNSCC, but also emphasizes the importance of HPV status when considering effective treatment strategies.
Top-cited articles versus top Altmetric articles in nuclear medicine: a comparative bibliometric analysis

Background The impact of any scientific article has traditionally been measured by the number of citations received. More recently, alternative metrics (altmetrics) reflect the digital dissemination of knowledge across the online mediasphere. Purpose To evaluate and compare the characteristics of top-cited articles with those of top Altmetric articles related to nuclear medicine (NM). Material and Methods We performed a search of the Web of Science and Altmetric databases using 114 search terms to identify the 50 top-cited and 50 top Altmetric articles, respectively, in the field of NM. We then compared the following characteristics of the selected articles: publication type; journal category; country of origin; year of publication; topic; imaging modality; and accessibility. Chi-square tests were performed for statistical analysis. Results There were no overlaps between the 50 top-cited and 50 top Altmetric articles. In general, compared to the leading Altmetric articles in this field, the cited articles were: more frequently review works published in NM and radiology journals (76% vs. 13%, P = 0.000); published in or before 2005 (84% vs. 0%, P = 0.000); the majority were related to oncology (56% vs. 44%, P = 0.000); and originated from the Netherlands (12% vs. 0%, P = 0.000). Compared to the top-cited articles, the leading Altmetric articles were: more frequently original articles published in other clinical field journals (54% vs. 0%, P = 0.000); primarily published between 2016 and 2018 (70% vs. 0%, P = 0.000); focused on neurology (50% vs. 22%, P = 0.000); and originated from the UK (18% vs. 2%, P = 0.000). Conclusion Citation counts and Altmetric scores represent unique perspectives for evaluating the impact of NM research.
Metal Oxide Nanosheets as 2D Building Blocks for the Design of Novel Materials

Abstract Research into 2‐dimensional materials has soared during the last couple of years. Next to van der Waals type 2D materials such as graphene and h‐BN, less well‐known oxidic 2D equivalents also exist. Most 2D oxide nanosheets are derived from layered metal oxide phases, although few 2D oxide phases can be also made by bottom‐up solution syntheses. Owing to the strong electrostatic interactions within layered metal oxide crystals, a chemical process is usually needed to delaminate them into their 2D constituents. This Review article provides an overview of the synthesis of oxide nanosheets, and methods to assemble them into nanocomposites, mono‐ or multilayer films. In particular, the use of Langmuir–Blodgett methods to form monolayer films over large surface areas, and the emerging use of ink jet printing to form patterned functional films is emphasized. The utilization of nanosheets in various areas of technology, for example, electronics, energy storage and tribology, is illustrated, with special focus on their use as seed layers for epitaxial growth of thin films, and as electrochemically active electrodes for supercapacitors and Li ion batteries.
Pyrolysis of polystyrene waste for recovery of combustible hydrocarbons using copper oxide as catalyst

The present work is focused on pyrolysis of polystyrene waste for production of combustible hydrocarbons. The experiments were performed in an indigenously made furnace in the presence of a laboratory synthesised copper oxide. The pyrolysis products were collected and characterised. The Fourier transform infrared spectra showed that the liquid fraction contains C–H, C–O, C–C, C=C and O–H bonds, which correspond to various aliphatic and aromatic compounds. Gas chromatography–mass spectrometry traced compounds ranging from C1 to C4 in the gaseous fraction, whereas in the liquid fraction 15 components ranging from C3 to C24 were detected. From the results it has been concluded that CuO as a catalyst not only increased the liquid yield but also reduced the degradation temperature to great extent. Fuel properties of the pyrolysis oil were determined and compared with standard values of commercial fuel oil. The comparison suggested potential application of pyrolysis oil for domestic and commercial use.
Three‐month efficacy of three knee braces in the treatment of medial knee osteoarthritis in a randomized crossover trial

Immediate biomechanical and functional effects of knee braces are often reported, however, the duration and type of knee brace treatment for knee osteoarthritis (KOA) remain unclear. The objective was to evaluate usage, comfort, pain, and knee adduction moment (KAM) of three knee braces each worn 3 months by patients. Twenty‐four patients with KOA were assigned in a randomized crossover trial a valgus three‐point bending system brace (V3P‐brace), an unloader brace with valgus and external rotation functions (VER‐brace) and a stabilizing brace used after ligament injuries (ACL‐brace). Functional questionnaires and gait assessment were carried out before and after each brace wear period of 3 months. A Friedman test was applied between brace wear diary recordings. Repeated measures analyses of variance contrasted the factors brace type (ACL, V3P, and VER), time (pre and post) and wear (without and with) on comfort, pain, function, and KAM. Brace usage was similar, but the V3P‐brace was slightly less worn. Discomfort was significantly lowered with the VER‐brace. All knee braces relieved pain and symptoms from 10% to 40%. KAM angular impulse was reduced with the three braces, but the VER‐brace obtained the lowest relative reduction of 9%. The interaction between time and wear indicated that part of the KAM reduction with brace wear was maintained post treatment. All three knee braces have great benefits for pain and function among the medial KOA population. The VER‐brace offers additional advantages on daily use, comfort and KAM, which could improve compliance to brace treatment.
Socioeconomic Cost of Obesity in Korea

With dramatic transitions from a traditionally food-insecure to a food-sufficient society, over weight and/or obesity are an increasing health concern in Korea. In 2000, of Korean adults were over weight (BMI>25) with increasing trends. It is well known that obesity is highly correlated with chronic diseases, such as diabetes, hypertension, cardiovascular disease, cancer and high cholesterol. In 2003, the social cost of obesity is estimated at billion won (direct cost) and at billion won (including indirect cost). The share of the direct cost is estimated at of total medical bill 20,742 billion won. These costs are underestimated and would surely be higher if the expenditures outside of the official medical insurance system of Korea were included. Based on the rapid increase of obesity rate among the Korean youth, it is crucial to develop and implement appropriate policies to curb the obesity epidemic.
Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression

Gastric cancer (GC) is the second main cause of cancer‐related mortality worldwide. The poor prognosis and survival of GC are due to diagnosis in an advanced, noncurable stage and with a restricted response to chemotherapy. GC is usually monitored in an advanced stage; therefore, the poor prognosis and lower level of survival rate with a restricted response to chemotherapy can be detected. Valuable and sensible biomarkers are urgently needed to display screen patients with a high risk of GC that can complement endoscopic diagnosis. Such biomarkers will enable the efficient prediction of the therapeutic response and prognosis of GC patients and prefer the establishment of an advantageous treatment method for each and every patient. Noninvasive diagnostic biomarkers may additionally make a contribution to the early identification of GC and enhance medical management. MicroRNAs (miRNAs) are a group of small noncoding RNAs that have displayed a strong association with GC. Accumulating evidence indicates that miRNAs are potential biomarkers with more than one diagnostic function for GC. Actually, miRNAs regulate cell proliferation, apoptosis, migration, invasion, and metastasis via many biological pathways through the repression of target mRNAs. The current review is accordingly to spotlight the multifaceted roles of miRNAs in GC, which would provide indications for future research. Therefore, we review right here the aberrant expression of miRNAs and underlying mechanisms, consequent effects due to miRNAs dysregulation, and accountable target genes in GC. Besides, potential clinical applications are also highlighted.
Addition of Partial Envelope Domain II into Envelope Domain III of Dengue Virus Antigen Potentiates the Induction of Virus-Neutralizing Antibodies and Induces Protective Immunity

Dengue virus (DENV) comprises four serotypes in the family Flaviviridae and is a causative agent of dengue-related diseases, including dengue fever. Dengue fever is generally a self-limited febrile illness. However, secondary infection of patients with a suboptimal antibody (Ab) response provokes life-threatening severe dengue hemorrhagic fever or dengue shock syndrome. To develop a potent candidate subunit vaccine against DENV infection, we developed the EDII-cEDIII antigen, which contains partial envelope domain II (EDII) including the fusion loop and BC loop epitopes together with consensus envelope domain III (cEDIII) of all four serotypes of DENV. We purified Ab from mice after immunization with EDII-cEDIII or cEDIII and compared their virus neutralization and Ab-dependent enhancement of DENV infection. Anti-EDII-cEDIII Ab showed stronger neutralizing activity and lower Ab-dependent peak enhancement of DENV infection compared with anti-cEDIII Ab. Following injection of Ab-treated DENV into AG129 mice, anti-EDII-cEDIII Ab ameliorated DENV infection in tissues with primary and secondary infection more effectively than anti-cEDIII Ab. In addition, anti-EDII-cEDIII Ab protected against DENV1, 2, and 4 challenge. We conclude that EDII-cEDIII induces neutralizing and protective Abs, and thus, shows promise as a candidate subunit vaccine for DENV infection.
The transpeptidase PBP2 governs initial localization and activity of the major cell-wall synthesis machinery in E. coli

Bacterial shape is physically determined by the peptidoglycan cell wall. The cell-wall-synthesis machinery responsible for rod shape in Escherichia coli is the processive 'Rod complex'. Previously, cytoplasmic MreB filaments were thought to govern formation and localization of Rod complexes based on local cell-envelope curvature. Using single-particle tracking of the transpeptidase and Rod-complex component PBP2, we found that PBP2 binds to a substrate different from MreB. Depletion and localization experiments of other putative Rod-complex components provide evidence that none of those provide the sole rate-limiting substrate for PBP2 binding. Consistently, we found only weak correlations between MreB and envelope curvature in the cylindrical part of cells. Residual correlations do not require curvature-based Rod-complex initiation but can be attributed to persistent rotational motion. We therefore speculate that the local cell-wall architecture provides the cue for Rod-complex initiation, either through direct binding by PBP2 or through an unknown intermediate.
De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients’ families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS.
Inhibition of urinary bladder cancer cell proliferation by silibinin

Silibinin, a natural compound extracted from milk thistle, has demonstrated antitumor properties in urinary bladder cancer cells; however, the role of TP53 gene in these effects is unclear. In order to better understand the molecular and antiproliferative mechanisms of this compound, urinary bladder cancer cells with different TP53 gene status, RT4 (low‐grade tumor, wild TP53 gene), 5637 (high‐grade tumor, Grade 2, mutated TP53 gene), and T24 (high‐grade tumor, Grade 3, mutated TP53 gene) were treated with several concentrations of silibinin (1, 5, 10, 50, 100, and 150 μM). Cytotoxicity, prooxidant effect, morphological changes, cell migration, cell cycle progression, global methylation profile, and relative expression of HOXB3, c‐MYC, PLK1, SMAD4, SRC, HAT, HDAC, and RASSF1A genes were evaluated. The silibinin presented cytotoxic and prooxidant effects in the three cell lines. In mutated TP53 cells, significant interference in cell migration and cell cycle arrest at the G2/M phase was observed. Additionally, silibinin induced global DNA hypomethylation in the highest grade tumor cells. For wild‐type TP53 cells, a sub‐G1 apoptotic population was present. Furthermore, there was modulation of gene expression responsible for cell growth (SMAD and c‐MYC), migration (SRC), cell cycle kinetics (PLK1), angiogenesis (HOXB3), and of genes associated with epigenetic events such as DNA acetylation (HAT) and deacetylation (HDAC). In conclusion, the silibinin inhibited the urinary bladder tumor cell proliferation independently of TP53 status; however, cell cycle effects, gene expression changes, and alteration of cell migration are dependent on TP53 status. © 2020 Wiley Periodicals, Inc.
Insights Obtained by Culturing Saccharibacteria With Their Bacterial Hosts

Oral microbiome research has moved from asking “Who’s there? ” to “What are they doing? ” Understanding what microbes “do” involves multiple approaches, including obtaining genomic information and examining the interspecies interactions. Recently we isolated a human oral Saccharibacteria (TM7) bacterium, HMT-952, strain TM7x, which is an ultrasmall parasite of the oral bacterium Actinomyces odontolyticus. The host-parasite interactions, such as phage-bacterium or Saccharibacteria–host bacterium, are understudied areas with large potential for insight. The Saccharibacteria phylum is a member of Candidate Phyla Radiation, a large lineage previously devoid of cultivated members. However, expanding our understanding of Saccharibacteria-host interactions requires examining multiple phylogenetically distinct Saccharibacteria-host pairs. Here we report the isolation of 3 additional Saccharibacteria species from the human oral cavity in binary coculture with their bacterial hosts. They were obtained by filtering ultrasmall Saccharibacteria cells free of other larger bacteria and inoculating them into cultures of potential host bacteria. The binary cocultures obtained could be stably passaged and studied. Complete closed genomes were obtained and allowed full genome analyses. All have small genomes (<1 Mb) characteristic of parasitic species and dramatically limited de novo synthetic pathway capabilities but include either restriction modification or CRISPR-Cas systems as part of an innate defense against foreign DNA. High levels of gene synteny exist among Saccharibacteria species. Having isolates growing in coculture with their hosts allowed time course studies of growth and parasite-host interactions by phase contrast, fluorescence in situ hybridization, and scanning electron microscopy. The cells of the 4 oral Saccharibacteria species are ultrasmall and could be seen attached to their larger Actinobacteria hosts. Parasite attachment appears to lead to host cell death and lysis. The successful cultivation of Saccharibacteria species has significantly expanded our understanding of these ultrasmall Candidate Phyla Radiation bacteria.
Remodeling Translation Primes CD8+ T-cell Antitumor Immunity

Altering protein translation in T cells can affect their antitumor function. IL15-conditioned T cells have diminished protein translation in vitro but reinvigorate translation in tumors, a property that is attributed to T cells that produce superior tumor control. The requisites for protein translation in T cells are poorly understood and how translation shapes the antitumor efficacy of T cells is unknown. Here we demonstrated that IL15-conditioned T cells were primed by the metabolic energy sensor AMP-activated protein kinase to undergo diminished translation relative to effector T cells. However, we showed that IL15-conditioned T cells exhibited a remarkable capacity to enhance their protein translation in tumors, which effector T cells were unable to duplicate. Studying the modulation of translation for applications in cancer immunotherapy revealed that direct ex vivo pharmacologic inhibition of translation elongation primed robust T-cell antitumor immunity. Our work elucidates that altering protein translation in CD8+ T cells can shape their antitumor capability.
Beneficial Effects of Dark Chocolate for Episodic Memory in Healthy Young Adults: A Parallel-Groups Acute Intervention with a White Chocolate Control

There is good evidence that cocoa flavonoids can acutely improve cognitive function in humans, possibly via mechanisms such as increased cerebral blood flow. To date, much of the evidence is based on measures of executive function with extracts and cocoa-based interventions with a high flavonoid content. The aim of the present study was to explore whether benefits to episodic verbal memory and mood are observed two hours post consumption of a commercially available dark chocolate (DC) bar relative to a 35 g white chocolate bar (WC). Ninety-eight healthy young adults (n = 57 females) aged 18–24 years consumed either a 35 g DC bar or a calorie-matched low flavonoid WC bar. Verbal episodic memory and mood were assessed pre consumption and 2 h post consumption. An ANOVA analysis showed that the DC was associated with better verbal memory performance for several outcome measures of the Rey Auditory Verbal Learning Test relative to the WC, however, there were no effects on mood. These findings lend support to the notion that everyday available portions of dark chocolate can confer benefits to the brain in healthy consumers.
PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.