Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer

The fluoropyrimidine drug fluorouracil (FU) is one of the most frequently prescribed chemotherapeutic drugs for the curative and palliative treatment of various cancer patients. The identification of biological factors associated with tumors either responsiveness or resistance to FU chemotherapy, including FU, is increasingly being recognized as an important field of clinical cancer research. Aim: to analyze the relationship between intra-tumoral dihydropyrimidine dehydrogenase (DPD) level and FU chemosensitivity, as DPD is the initial and rate-limiting enzyme in the catabolism of FU. Materials and Methods: The histoculture drug response assay (HDRA) was performed for 54 patients. DPD expression was examined in 81 tumor samples from breast cancer patients received two cycles of FU-based primary chemotherapy before operation. Results: We found that intra-tumoral DPD enzyme activity was inversely correlated with FU cytotoxicity. We also revealed that low DPD expression was correlated with clinical response to FU-based primary chemotherapy. Conclusions: Our study indicated that DPD is a promising molecular maker for identifying tumor cells sensitivity in breast cancer patients receiving FU-based chemotherapy.Препарат ряда флуоропиримидина, флуороурацил (FU), является одним из наиболее часто используемых химиотерапевтических препаратов паллиативной терапии больных онкологического профиля. Определение биологических факторов, связанных с чувствительностью либо с устойчивостью опухолей к химиотерапевтическим препаратам, в том числе и к FU, является одним из наиболее важных направлений клинических исследований в онкологии. Цель: проанализировать взаимосвязь между внутриопухолевым уровнем дигидропиримидин дегидрогеназы (DPD) и чувствительностью клеток к FU, поскольку DPD является начальным и лимитирующим энзимом в катаболизме FU. Материалы и методы: определяли чувствительность к препаратам в гистокультуре (histoculture drug response assay, HDRA) у 54 пациентов. Экспрессия гена DPD изучена в 81 образце опухолевой ткани больных раком молочной железы, которым провели два цикла неоадъювантной химиотерапии с применением FU. Результаты: показано, что внутриопухолевая активность DPD обратно коррелирует с цитотоксичностью FU. Также выявлено, что сниженная экспрессия гена DPD коррелиирует с высоким клиническим ответом на первичную химиотерапию, основанную на FU. Выводы: результаты исследования дают основание считать DPD потенциальным молекулярным маркером чувствительности клеток злокачественных опухолей молочной железы к FU

TCR Mechanobiology: Torques and Tunable Structures Linked to Early T Cell Signaling

Mechanotransduction is a basis for receptor signaling in many biological systems. Recent data based upon optical tweezer experiments suggest that the TCR is an anisotropic mechanosensor, converting mechanical energy into biochemical signals upon specific peptide-MHC complex (pMHC) ligation. Tangential force applied along the pseudo-twofold symmetry axis of the TCR complex post-ligation results in the αβ heterodimer exerting torque on the CD3 heterodimers as a consequence of molecular movement at the T cell–APC interface. Accompanying TCR quaternary change likely fosters signaling via the lipid bilayer predicated on the magnitude and direction of the TCR–pMHC force. TCR glycans may modulate quaternary change, thereby altering signaling outcome as might the redox state of the CxxC motifs located proximal to the TM segments in the heterodimeric CD3 subunits. Predicted alterations in TCR TM segments and surrounding lipid will convert ectodomain ligation into the earliest intracellular signaling events

HIV-1 Broadly Neutralizing Antibody Extracts Its Epitope from a Kinked gp41 Ectodomain Region on the Viral Membrane

SummaryAlthough rarely elicited during natural human infection, the most broadly neutralizing antibodies (BNAbs) against diverse human immunodeficiency virus (HIV)-1 strains target the membrane-proximal ectodomain region (MPER) of viral gp41. To gain insight into MPER antigenicity, immunogenicity, and viral function, we studied its structure in the lipid environment by a combination of nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and surface plasmon resonance (SPR) techniques. The analyses revealed a tilted N-terminal α helix (aa 664–672) connected via a short hinge to a flat C-terminal helical segment (675–683). This metastable L-shaped structure is immersed in viral membrane and, therefore, less accessible to immune attack. Nonetheless, the 4E10 BNAb extracts buried W672 and F673 after initial encounter with the surface-embedded MPER. The data suggest how BNAbs may perturb tryptophan residue-associated viral fusion involving the mobile N-terminal MPER segment and, given conservation of MPER sequences in HIV-1, HIV-2, and SIV, have important implications for structure-guided vaccine design

The role of 245 phase in alkaline iron selenide superconductors revealed by high pressure studies

Here we show that a pressure of about 8 GPa suppresses both the vacancy order and the insulating phase, and a further increase of the pressure to about 18 GPa induces a second transition or crossover. No superconductivity has been found in compressed insulating 245 phase. The metallic phase in the intermediate pressure range has a distinct behavior in the transport property, which is also observed in the superconducting sample. We interpret this intermediate metal as an orbital selective Mott phase (OSMP). Our results suggest that the OSMP provides the physical pathway connecting the insulating and superconducting phases of these iron selenide materials.Comment: 32 pages, 4 figure

The human amygdala parametrically encodes the intensity of specific facial emotions and their categorical ambiguity

The human amygdala is a key structure for processing emotional facial expressions, but it remains unclear what aspects of emotion are processed. We investigated this question with three different approaches: behavioural analysis of 3 amygdala lesion patients, neuroimaging of 19 healthy adults, and single-neuron recordings in 9 neurosurgical patients. The lesion patients showed a shift in behavioural sensitivity to fear, and amygdala BOLD responses were modulated by both fear and emotion ambiguity (the uncertainty that a facial expression is categorized as fearful or happy). We found two populations of neurons, one whose response correlated with increasing degree of fear, or happiness, and a second whose response primarily decreased as a linear function of emotion ambiguity. Together, our results indicate that the human amygdala processes both the degree of emotion in facial expressions and the categorical ambiguity of the emotion shown and that these two aspects of amygdala processing can be most clearly distinguished at the level of single neurons

Efficient Luminescence from CsPbBr₃ Nanoparticles Embedded in Cs₄PbBr₆

This work was financially supported by the “Advanced Research Center of Green Materials Science and Technology” from The Featured Area Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (107L9006) and the Ministry of Science and Technology in Taiwan (MOST 107-2113-M-002-008-MY3, MOST 107-2923-M-002-004-MY3, and MOST 107-3017-F-002-001), the National Centre for Research and Development Poland Grant (No. PL-TW/V/1/2018), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000), the CAS/SAFEA International Partnership Program for Creative Research Teams, and the NSFC (Nos. U1805252 and 11774345). J.P.A. acknowledges financial support from EPSRC, U.K.Cs4PbBr6 is regarded as an outstanding luminescent material with good thermal stability and optical performance. However, the mechanism of green emission from Cs4PbBr6 has been controversial. Here we show that isolated CsPbBr3 nanoparticles embedded within a Cs4PbBr6 matrix give rise to a “normal” green luminescence while superfluorescence at longer wavelengths is suppressed. High-resolution transmission electron microscopy shows that the embedded CsPbBr3 nanoparticles are around 3.8 nm in diameter and are well-separated from each other, perhaps by a strain-driven mechanism. This mechanism may enable other efficient luminescent composites to be developed by embedding optically active nanoparticles epitaxially within inert host lattices.PostprintPeer reviewe

Assessing the Quality of Reports about Randomized Controlled Trials of Acupuncture Treatment on Diabetic Peripheral Neuropathy

BACKGROUND: To evaluate the reports' qualities which are about randomized controlled trials (RCTs) of acupuncture treatment on Diabetic Peripheral Neuropathy (DPN). METHODOLOGY/PRINCIPAL FINDINGS: Eight databases including The Cochrane Library(1993-Sept.,2011), PubMed (1980-Sept., 2011), EMbase (1980-Sept.,2011), SCI Expanded (1998-Sept.,2011), China Biomedicine Database Disc (CBMdisc, 1978-Sept., 2011), China National Knowledge Infrastructure (CNKI, 1979-Sept., 2011 ), VIP (a full text issues database of China, 1989-Sept., 2011), Wan Fang (another full text issues database of China 1998-Sept., 2011) were searched systematically. Hand search for further references was conducted. Language was limited to Chinese and English. We identified 75 RCTs that used acupuncture as an intervention and assessed the quality of these reports with the Consolidated Standards for Reporting of Trials statement 2010 (CONSORT2010) and Standards for Reporting Interventions Controlled Trials of Acupuncture 2010(STRICTA2010). 24 articles (32%) applied the method of random allocation of sequences. No article gave the description of the mechanism of allocation concealment, no experiment applied the method of blinding. Only one article (1.47%) could be identified directly from its title as about the Randomized Controlled Trials, and only 4 articles gave description of the experimental design. No article mentioned the number of cases lost or eliminated. During one experiment, acupuncture syncope led to temporal interruption of the therapy. Two articles (2.94%) recorded the number of needles, and 8 articles (11.76%) mentioned the depth of needle insertion. None of articles reported the base of calculation of sample size, or has any analysis about the metaphase of an experiment or an explanation of its interruption. One (1.47%) mentioned intentional analysis (ITT). CONCLUSIONS/SIGNIFICANCE: The quality of the reports on RCTs of acupuncture for Diabetic Peripheral Neuropathy is moderate to low. The CONSORT2010 and STRICTA2010 should be used to standardize the reporting of RCTs of acupuncture in future

The Tumor-Log Odds of Positive Lymph Nodes-Metastasis Staging System, a Promising New Staging System for Gastric Cancer after D2 Resection in China

BACKGROUND: In this study, we established a hypothetical tumor-lodds-metastasis (TLM) and tumor-ratio-metastasis (TRM) staging system. Moreover, we compared them with the 7(th) edition of American Joint Committee on Cancer tumor-nodes-metastasis (AJCC TNM) staging system in gastric cancer patients after D2 resection. METHODS: A total of 1000 gastric carcinoma patients receiving treatment in our center were selected for the analysis. Finally, 730 patients who received D2 resection were retrospectively studied. Patients were staged using the TLM, TRM and the 7(th) edition AJCC TNM system. Survival analysis was performed with a Cox regression model. We used two parameters to compare the TNM, TRM and TLM staging system, the -2log likelihood and the hazard ratio. RESULTS: The cut points of lymph node ratio (LNR) were set as 0, 0-0.3, 0.3-0.6, 0.6-1.0. And for the log odds of positive lymph nodes (LODDS), the cut points were established as≤-0.5, -0.5-0, 0-0.5, >0.5. There were significant differences in survival among patients in different LODDS classifications for each pN or LNR groups. When stratified by the LODDS classifications, the prognosis was highly homologous between those in the according pN or LNR classifications. Multivariate analysis showed that TLM staging system was better than the TRM or TNM system for the prognostic evaluation. CONCLUSIONS: The TLM system was superior to the TRM or TNM system for prognostic assessment of gastric adenocarcinoma patients after D2 resection

Arp2/3 Complex Regulates Asymmetric Division and Cytokinesis in Mouse Oocytes

Mammalian oocyte meiotic maturation involves oocyte polarization and a unique asymmetric division, but until now, the underlying mechanisms have been poorly understood. Arp2/3 complex has been shown to regulate actin nucleation and is widely involved in a diverse range of processes such as cell locomotion, phagocytosis and the establishment of cell polarity. Whether Arp2/3 complex participates in oocyte polarization and asymmetric division is unknown. The present study investigated the expression and functions of Arp2/3 complex during mouse oocyte meiotic maturation. Immunofluorescent staining showed that the Arp2/3 complex was restricted to the cortex, with a thickened cap above the meiotic apparatus, and that this localization pattern was depended on actin. Disruption of Arp2/3 complex by a newly-found specific inhibitor CK666, as well as by Arpc2 and Arpc3 RNAi, resulted in a range of effects. These included the failure of asymmetric division, spindle migration, and the formation and completion of oocyte cytokinesis. The formation of the actin cap and cortical granule-free domain (CGFD) was also disrupted, which further confirmed the disruption of spindle migration. Our data suggest that the Arp2/3 complex probably regulates oocyte polarization through its effect on spindle migration, asymmetric division and cytokinesis during mouse oocyte meiotic maturation

The Threonine Protease Activity of Testes-Specific Protease 50 (TSP50) Is Essential for Its Function in Cell Proliferation

Background: Testes-specific protease 50 (TSP50), a newly discovered threonine enzyme, has similar amino acid sequences and enzymatic structures to those of many serine proteases. It may be an oncogene. TSP50 is up-regulated in breast cancer epithelial cells, and ectopic expression of TSP50 in TSP50-deficient Chinese hamster ovary (CHO) cells has been found to promote cell proliferation. However, the mechanisms by which TSP50 exerts its growth-promoting effects are not yet fully understood. Methodology/Principal Findings: To delineate whether the threonine protease activity of TSP50 is essential to its function in cell proliferation, we constructed and characterized a mutant TSP50, called TSP50 T310A, which was identified as a protease-dead mutant of TSP50. By a series of proliferation analyses, colony formation assays and apoptosis analyses, we showed that T310A mutation significantly depresses TSP50-induced cell proliferation in vitro. Next, the CHO stable cell line expressing either wild-type or T310A mutant TSP50 was injected subcutaneously into nude mice. We found that the T310A mutation could abolish the tumorigenicity of TSP50 in vivo. A mechanism investigation revealed that the T310A mutation prevented interaction between TSP50 and the NF-kBIkBa complex, which is necessary for TSP50 to perform its function in cell proliferation. Conclusion: Our data highlight the importance of threonine 310, the most critical protease catalytic site in TSP50, to TSP50induce