Miracle-dz/UniFAR-FTUs huggingface dataset:
The Bruton's tyrosine kinase inhibitor ibrutinib exerts immunomodulatory effects through regulation of tumor-infiltrating macrophages

The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has demonstrated promising efficacy in a variety of hematologic malignancies. However, the precise mechanism of action of the drug remains to be fully elucidated. Tumor-infiltrating macrophages presented in the tumor microenvironment have been shown to promote development and progression of B-cell lymphomas through crosstalk mediated by secreted cytokines and chemokines. Because Btk has been implicated in Toll-like receptor (TLR) signaling pathways that regulate macrophage activation and production of proinflammatory cytokines, we investigated the immunomodulatory effects of Btk inhibitor on macrophages. Our results demonstrate that Btk inhibition efficiently suppresses production of CXCL12, CXCL13, CCL19, and VEGF by macrophages. Furthermore, attenuated secretion of homeostatic chemokines from Btk inhibitor-treated macrophages significantly compromise adhesion, invasion, and migration of lymphoid malignant cells and even those not driven by Btk expression. The supernatants from Btk inhibitor-treated macrophages also impair the ability of endothelial cells to undergo angiogenic tube formation. Mechanistic analysis revealed that Btk inhibitors treatment downregulates secretion of homeostatic chemokines and cytokines through inactivation of Btk signaling and the downstream transcription factors, NF-κB, STAT3, and AP-1. Taken together, these results suggest that the encouraging therapeutic efficacy of Btk inhibitor may be due to both direct cytotoxic effects on malignant B cells and immunomodulatory effects on macrophages present in the tumor microenvironment. This novel mechanism of action suggests that, in addition to B-cell lymphomas, Btk inhibitor may also have therapeutic value in lymphatic malignancies and solid tumors lacking Btk expression.
Morphologic Reappraisal of Serrated Colorectal Polyps

The “hyperplastic polyp” is considered a benign lesion with no malignant potential, whereas “serrated adenoma” is a precursor of adenocarcinoma. The morphologic complexity of the serrated adenoma varies from being clearly adenomatous to being difficult to distinguish from hyperplastic polyp, which creates a need for more detailed morphologic analysis of all serrated polyps. We evaluated 24 morphologic variables in 289 serrated polyps from the colon and rectum. Cluster analysis and discriminant analysis were performed. A subset of polyps was immunostained for hMLH1 and hMSH2. Major differences were found between right-sided and left-sided polyps. A distinct group of serrated polyps with abnormal proliferation was identified throughout the colon and rectum. These polyps demonstrated decreased expression of hMHL1 and hMSH2 compared with polyps with normal proliferation. Left-sided serrated polyps with normal proliferation further clustered into three groups: vesicular cell-type, goblet cell-type, and mucin-poor-type. We recommend evaluation of the localization, size, and morphologic features when serrated polyps are included in colorectal carcinogenesis research. Polyps with abnormal proliferation are similar to the polyps in “hyperplastic polyposis” and, because of their decreased expression of hMLH1 and hMSH2, may be the subset of polyps associated with the development of colorectal carcinoma via the microsatellite instability pathway.
Four CD45/P56lck‐associated phosphorproteins (pp29‐pp32) undergo alterations in human T cell activation

In human T lymphocytes a functional complex is formed between the protein tyrosine phosphatase CD45, the protein tyrosine kinase p56lck and a phospho‐protein, pp32, a possible common substrate. Here we demonstrate that the previously described pp32 protein is composed of two distinct molecules (pp29 and pp32) in both resting human T lymphocytes and continuously proliferating T lymphoma lines. Importantly, T lymphocyte activation employing CD2 monoclonal antibodies (mAb), CD3 mAb or phorbol 12, 13 dibutyrate results in loss of pp29 and pp32 from the CD45/p56lck molecular complex and concomitant association of two distinct phosphoproteins with different molecular weights (pp30 and pp31). These events appear to be unrelated to clonal T cell growth but rather depend on receptor‐mediated differentiation signals. Reprecipitation experiments employing an antiserum directed at a consensus sequence of GTP‐binding proteins suggest that all four pp29‐pp32 molecules might represent proteins with GTP‐binding properties. Biochemical analysis of pp29‐pp32 employing V8‐protease digestion indicates that they differ in low‐molecular weight fragments of 8, 5, 4.5, 4 and 3 kDa, respectively.
SDZ PRI 053, an orally bioavailable human immunodeficiency virus type 1 proteinase inhibitor containing the 2-aminobenzylstatine moiety

A series of inhibitors of human immunodeficiency virus type 1 (HIV-1) proteinase containing the 2-aralkyl-amino-substituted statine moiety as a novel transition-state analog was synthesized, with the aim to obtain compounds which combine anti-HIV potency with oral bioavailability. The reduced-size 2-aminobenzylstatine derivative SDZ PRI 053, which contains 2-(S)-amino-3-(R)-hydroxyindane in place of an amino acid amide, is a potent and orally bioavailable inhibitor of HIV-1 replication. The antiviral activity of SDZ PRI 053 was demonstrated in various cell lines, in primary lymphocytes, and in primary monocytes, against laboratory strains as well as clinical HIV-1 isolates (50% effective dose = 0.028 to 0.15 microM). Cell proliferation was impaired only at 100- to 300-fold-higher concentrations. The mechanism of antiviral action of the proteinase inhibitor SDZ PRI 0.53 was demonstrated to be inhibition of gag precursor protein processing. The finding that the inhibitory potency of SDZ PRI 053 in chronic virus infection, determined by p24 release, was considerably lower than that in de novo infection may be explained by the fact that the virus particles produced in the presence of SDZ PRI 053 are about 50-fold less infectious than those from untreated cultures. Upon intravenous administration, half-lives in blood of 100 and 32 min in mice and rats, respectively, were measured. Oral bioavailability of SDZ PRI 053 in rodents was 20 to 60%, depending on the dose. In mice, rats, and dogs, the inhibitor levels after oral administration remained far above the concentrations needed to efficiently block HIV replication in vitro for a prolonged period. This compound is thus a promising candidate for clinical use in HIV disease.
Gaps in evidence: Management of pediatric obstructive sleep apnea without tonsillar hypertrophy

Persistent obstructive sleep apnea (OSA) is demonstrated in 40% of children after adenotonsillectomy. We previously evaluated the basis of management decisions in children with OSA without tonsillar hypertrophy and found that 61% of decisions were non–evidence based. The aim of this study was to identify gaps in evidence for the management of children with OSA without tonsillar hypertrophy.
SHOPPING EXPERIENCE AND SUBJECTIVE WELL-BEING: AN EMPIRICAL STUDY

While a traditional marketer aims to enhance customer loyalty, a social marketer focuses on the creation of individual well-being. To date, some social marketing programs have been launched to enhance individual well-being. However, only a few studies have been oriented to investigate subjective well-being, in the domain of traditional marketing. Previous studies have indicated that service quality is an important determinant of subjective well-being for a service organization’s customers. However, this notion is not enough as service quality only captures performance of service in the level of attribute. For that reason, this introduces the notion of experience quality as the determinant of subjective well-being. To have a better knowledge about the relationship between these constructs, this study also inserted the notion of customer satisfaction and perceived shopping enjoyment as mediating variables. Two hundred respondents participated in this study. These respondents were recruited at department stores in Malang, a city in the Province of East Java. A self-administered survey was conducted to collect the data. A Covariance Based Structural Equation Model (CBSEM) was employed to analyze the data. The results of a Confirmatory Factor Analysis (CFA) confirmed the model proposed. The structural model showed that the experience of shopping has significant effects on customer satisfaction, perceived shopping enjoyment, and subjective well-being. However, this study failed to prove the mediating effects of customer satisfaction and perceived shopping enjoyment in the relationship between the shopping experience and subjective well-being. Upon the completion of this study, both theoretical and practical contributions were provided.
Hepatitis B virus reactivation in patients with solid tumors receiving systemic anticancer treatment.

BACKGROUND Hepatitis B virus (HBV) reactivation is a well-known risk during chemotherapy for hematological malignancies with reported rates ranging between 14% and 72%. However, there is a paucity of data regarding HBV infection management and reactivation risk in patients receiving systemic treatments for solid tumors. DESIGN We conducted a PubMed search for publications from January 1990 until May 2016 related to HBV reactivation. The search terms were 'hepatitis B reactivation', cross-referenced with 'chemotherapy', then 'hepatitis B' cross-referenced with International Non-proprietary Name of each of the most used chemotherapy drugs in solid tumors. RESULTS From these data, a grading of HBV reactivation risk and recommendations for management are given for most frequently used anticancer drugs in solid tumors. CONCLUSION Most drugs used for the treatment of solid tumors can induce hepatitis B reactivation in HBs antigen-positive patients. HBV screening can be recommended before systemic treatment initiation. Pre-emptive antiviral treatment can reduce the risk of HBV reactivation and prevent chemotherapy disruption.
Translesion DNA polymerases in eukaryotes: what makes them tick?

Abstract Life as we know it, simply would not exist without DNA replication. All living organisms utilize a complex machinery to duplicate their genomes and the central role in this machinery belongs to replicative DNA polymerases, enzymes that are specifically designed to copy DNA. “Hassle-free” DNA duplication exists only in an ideal world, while in real life, it is constantly threatened by a myriad of diverse challenges. Among the most pressing obstacles that replicative polymerases often cannot overcome by themselves are lesions that distort the structure of DNA. Despite elaborate systems that cells utilize to cleanse their genomes of damaged DNA, repair is often incomplete. The persistence of DNA lesions obstructing the cellular replicases can have deleterious consequences. One of the mechanisms allowing cells to complete replication is “Translesion DNA Synthesis (TLS)”. TLS is intrinsically error-prone, but apparently, the potential downside of increased mutagenesis is a healthier outcome for the cell than incomplete replication. Although most of the currently identified eukaryotic DNA polymerases have been implicated in TLS, the best characterized are those belonging to the “Y-family” of DNA polymerases (pols η, ι, κ and Rev1), which are thought to play major roles in the TLS of persisting DNA lesions in coordination with the B-family polymerase, pol ζ. In this review, we summarize the unique features of these DNA polymerases by mainly focusing on their biochemical and structural characteristics, as well as potential protein–protein interactions with other critical factors affecting TLS regulation.
Direct observation of Bin/amphiphysin/Rvs (BAR) domain-induced membrane curvature by means of molecular dynamics simulations

The process of membrane curvature generation by BAR (Bin/amphiphysin/Rvs) domains is thought to involve the plastering of the negatively charged cell membrane to the positively charged concave surface of the BAR domain. Recent work [Peter, B. J., et al. (2004) Science, 303,495–499; Masuda, M. , et al. (2006) EMBO J. 25, 2889–2897; and Gallop, J. L. , et al. (2006) EMBO J. 25, 2898–2910] has demonstrated the importance of the charged, crescent-shaped surface and the N-terminal amphipathic helices (present in N-BAR domains) for generating membrane curvature. These experiments suggest that curvature is generated by the synergistic action of the N-terminal helices embedding in the lipid bilayer and the charged crescent-shaped dimer acting to “scaffold” membrane curvature. Here, we present atomistic molecular dynamics simulations that directly show membrane binding to the concave face of N-BAR domains, resulting in the generation of local membrane curvature that matches the curvature presented by the BAR domain. These simulations provide direct molecular-scale evidence that BAR domains create curvature by acting as a scaffold, forcing the membrane to locally adopt the intrinsic shape of the BAR domain. We find that BAR domains bind strongly through the maximum curvature surface and, additionally, at an orientation that presents a lesser degree of curvature, thus enabling N-BAR domains to induce a range of local curvatures. Finally, we find that the N-terminal region may play a role in biasing the orientations of N-BAR domains on the membrane surface to those that favor binding to the concave face and subsequent membrane bending.
Die Rolle der Computerisierung und Digitalisierung für Beschäftigung und Einkommen

Die Entwicklung der Computer und die darauf aufbauende Digitalisierung haben technologische Veranderungen ausgelost, die die Anforderungen an und die Nachfrage nach Arbeit, aber auch das Arbeitsangebot in den letzten Dekaden stetig verandert haben. Wie gros die kausalen Effekte dieser Entwicklung auf die Einkommens- und Vermogensverteilung sind, ist in der okonomischen Literatur bisher weder eindeutig, noch abschliesend geklart. Schwierigkeiten in der Bestimmung dieser Effekte haben sich zunachst aus dem unvollstandigen Verstandnis ergeben, wie die Computerisierung und die Digitalisierung die Wertschopfung beeinflusst haben bzw. welchen Beitrag sie leisten. Dies hat zugleich zu der grundsatzlichen Frage gefuhrt, inwiefern der technologische Wandel durch die Computerisierung und Digitalisierung mit traditionellen okonomischen Modellen, die Arbeit, Kapital und technischen Fortschritt in der Regel als trennbare Faktoren unterscheiden und hierbei feste Relationen bzw. proportionale Effekte unterstellen, erfasst werden kann. Das Verstandnis der Bedeutung und Begrundung technischen Fortschritts in seinen Wirkungen fur Wirtschaft und Gesellschaft ist dabei bereits Gegenstand des wirtschaftswissenschaftlichen Denkens in Wealth of Nations von Adam Smith (1776). Die Formulierung des Produktionsprozesses ausgehend von den zu tatigenden Aufgaben, unabhangig ob diese durch menschliche oder maschinelle Arbeit, durch Handel zugekauft oder an einem beliebigen Ort durchgefuhrt werden, ist dabei grundlegend im okonomischen Verstandnis verankert. Trotz dieser bereits recht alten Uberlegungen haben die Computerisierung und die Digitalisierung dazu gefuhrt, dass der durch sie ausgeloste technische Fortschritt sowie insbesondere die implizierten Folgen fur Beschaftigung und Lohne in der aktuellen wirtschaftswissenschaftlichen Literatur nun differenzierter analysiert werden und in den vergangenen zwei Dekaden entsprechende formale Modelle entwickelt worden sind. Mit dem vorliegenden Aufsatz mochte ich eine Einordnung des technischen Fortschritts durch die Computerisierung und Digitalisierung geben. Hierzu will ich kurz auf die Entwicklungsgeschichte des Computerzeitalters eingehen, um Gemeinsamkeiten und Unterschiede zu anderen Entwicklungen zu identifizieren. Im Anschluss gebe ich einen Uberblick uber den Erkenntnisstand zu den Effekten auf Einkommen und Beschaftigung auf Grundlage der verfugbaren Literatur, um die Erklarungen und Begrundungen zu diskutieren.
SPOP mutations in prostate cancer across demographically diverse patient cohorts.

BACKGROUND Recurrent mutations in the Speckle-Type POZ Protein (SPOP) gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unknown. OBJECTIVE To investigate SPOP mutations across diverse cohorts and validate a series of assays employing high-resolution melting (HRM) analysis and Sanger sequencing for mutational analysis of formalin-fixed paraffin-embedded material. DESIGN SETTING AND PARTICIPANTS 720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both prostate-specific antigen-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features (ERG rearrangement, PTEN deletion, and CHD1 deletion) as well as clinical and pathologic features. RESULTS AND LIMITATIONS Overall frequency of SPOP mutations was 8.1% (4.6% to 14.4%), SPOP mutation was inversely associated with ERG rearrangement (P<.01), and SPOP mutant (SPOPmut) cancers had higher rates of CHD1 deletions (P<.01). There were no significant differences in biochemical recurrence in SPOPmut cancers. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes. CONCLUSION SPOP is mutated in 4.6% to 14.4% of patients with prostate cancer across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.
Robotic Task Realizability in Representation Space

The representation space (R-Space) is proposed and constructed for a robot system to evaluate its feasibility to a prescribed task. The process of a task realization is transformed to be a process that the system representations transit in its Rspace. All factors affecting the task realization, including system configurations and physical and environmental constraints, are denoted as unreachable areas in the R-space, indicating the limitation for the system to accomplish the task. Reachable area in the R-space formalizes the criteria for task realizability. And the optimal strategy to fulfil a realizable task can further be identified. Otherwise, causes for unrealizability are clarified to transform the task to be realizable. The proposed framework is applied to different robotic tasks to show the validity as well as its performance.
The Effects of Different Substrates on the Growth, Yield, and Nutritional Composition of Two Oyster Mushrooms (Pleurotus ostreatus and Pleurotus cystidiosus)

Abstract The study was conducted to compare the effects of different agro-wastes on the growth, yield, and nutritional composition of oyster mushrooms Pleurotus ostreatus (PO) and Pleurotus cystidiosus (PC). Seven substrate formulas including sawdust (SD), corncob (CC), sugarcane bagasse (SB) alone and in combination of 80 : 20, 50 : 50 ratio between SD and CC, SD and SB were investigated. The results indicated that different substrate formulas gave a significant difference in total colonization period, characteristics of fruiting bodies, yield, biological efficiency (BE), nutritional composition and mineral contents of two oyster mushrooms PO and PC. The results showed that increasing CC and SB reduced C/N ratio, and enhanced some mineral contents (Ca, P, and Mg) of substrate formulas. The increased amount of CC and SB of substrate formulas enhanced protein, ash, mineral contents (Ca, K, Mg, Mn, and Zn) of fruiting bodies of both mushrooms. Substrates with 100% CC and 100% SB were the most suitable substrate formulas for cultivation of oyster mushrooms PO and PC in which they gave the highest values of cap diameter, stipe thickness, mushroom weight, yield, BE, protein, fiber, ash, mineral content (Ca, K, and Mg) and short stipe length. However, substrate formula 100% CC gave the slowest time for the first harvest of both mushrooms PO and PC (46.02 days and 64.24 days, respectively). It is also found that the C/N ratio of substrate formulas has close correlation with total colonization period, mushroom weight, yield, BE and protein content of mushroom PO and PC.
Cell kinetic indicators of premalignant stages of colorectal cancer

Using an in vitro double labeling technique with two different levels of 3H‐thymidine, the duration of the phase of DNA synthesis (S) and the labeling index (LI) were measured in the colorectal mucosa of three groups of patients: patients with colorectal neoplasms (adenomas and/or adenocarcinomas), patients with inflammatory bowel disease, and a control group of patients without gastrointestinal pathology. In those patients with colorectal neoplasms, samples were obtained from both the neoplastic mucosa and from the normal appearing mucosa at various distances from the lesions. One‐way analyses of variance were used to test the equality of mean S‐phase duration and LI in the various types of tissues. S‐phase duration was significantly longer in the tumor than in the unaffected mucosa of patients with adenocarcinoma (18.65 hours ± 2.3 versus 10.13 hours ± 1.26 P < 0.0001). However, S‐phase duration was significantly longer in the unaffected mucosa of cancer patients than in the mucosa of patients without gastrointestinal pathology (10.58 hours ± 1.84 versus 7.91 hours ± 0.46, P = 0.013). Similarly, LI was significantly higher in the unaffected mucosa of patients with adenoma and adenocarcinoma than in the mucosa of patients without gastrointestinal pathology (19.1% ± 3.0 versus 9.5% ± 2.2, P < 0.0001). There was a highly significant trend to a progressive increase of LI from flat histologically normal appearing mucosas to inflammatory mucosas, adenomas, and adenocarcinomas (P < 0.0001). These results suggest that increased S‐phase duration is specifically related to cancer. In mucosa without histologic sign of malignancy, an increased S‐phase duration would indicate that the malignant process has started. An increased LI would appear to relate to the selective advantage that rapidly proliferating cells hold over less proliferating ones.