Miracle-dz/UniFAR-FTUs huggingface dataset:
A mitosis-specific and R loop–driven ATR pathway promotes faithful chromosome segregation

Mitosis-specific role of ATR The ATR (ataxia telangiectasia mutated and Rad3-related) kinase plays important roles in the S phase and during the DNA damage response to safeguard genome integrity. Kabeche et al. identified a distinct ATR activation pathway in mitosis that is also critical for suppressing genome instability (see the Perspective by Saldivar and Cimprich). ATR is recruited by Aurora A and activated by R loops at centromeres of mitotic chromosomes; this leads to Aurora B activation, which is necessary for accurate chromosome segregation. This mitotic, R loop–driven ATR signaling pathway could potentially be exploited in the search for cancer therapeutics. Science, this issue p. 108; see also p. 30 An important kinase is activated by R loops at centromeres to promote accurate chromosome segregation in mitosis. The ataxia telangiectasia mutated and Rad3-related (ATR) kinase is crucial for DNA damage and replication stress responses. Here, we describe an unexpected role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered cyclin-dependent kinase 1 (CDK1) activity, DNA damage responses, or unscheduled DNA synthesis but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A–regulated association with centromere protein F (CENP-F), allowing ATR to engage replication protein A (RPA)–coated centromeric R loops. As ATR is activated at centromeres, it stimulates Aurora B through Chk1, preventing formation of lagging chromosomes. Thus, a mitosis-specific and R loop–driven ATR pathway acts at centromeres to promote faithful chromosome segregation, revealing functions of R loops and ATR in suppressing chromosome instability.
Characteristics of HER-2/neu Oncogene in Korean Women with Early-onset Breast Cancer by Immunohistochemistry and Fluorescence In Situ Hybridization

ligand binding. (7) Over-expression of HER-2 has been shown test may be useful for selecting systemic chemotherapy in Korean patients with early onset breast cancer. And the specific anti-HER-2 therapy will be helpful to a large proportion of Korean patients who have more tumors with HER-2 overexpression than White patients. (Journal of Korean Breast Cancer Society 2003;6:255-262) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ
Dietary Approaches and Alternative Therapies for Polycystic Ovary Syndrome

Abstract: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in reproductive age women. PCOS is characterized by the absence of menstruation or irregular and abnormal menstruation, excessive amounts of body hair, excessive body weight, and infertility. Women with PCOS often have multiple ovarian cysts, high levels of androgen hormones, insulin resistance and metabolic syndrome. This review is focused on the dietary approaches and alternative therapies which have been proved to play major roles in the treatment of PCOS. The ideal diet for PCOS is one that promotes weight loss and then weight maintenance. In addition, some of the essential nutrients may improve associated risk factors of PCOS. Among them are chromium, omega 3 fattyacids, antioxidants, phytosterols, magnesium, calcium, potassium and other essential vitamins and minerals. The most important aspect of treatment is managing cardiovascular risks, such as obesity, high blood cholesterol, diabetes and high blood pressure. Early recognition and aggressive lifestyle interventions are the cornerstones of PCOS treatment. Treating individual risk factors might help to reduce overall risk of PCOS. Some of the PCOS risk factors are modifiable. Aggressive medical nutritional therapy may be appropriate in early conditions than advanced stages.
Relative Toxicity of Three Corneal Anesthetics Measured in Vitro with the Cultured Bovine Lens

AbstractThe relative ocular toxicity (damage and recovery) of three corneal anesthetics was determined by measuring changes in focal length variability (i.e., sharpness of focus) in the cultured bovine lens. The optical quality of cultured lenses was measured using a scanning laser system consisting of a low-power scanning helium-neon laser, video cameras, and a video-frame digitizer. Lenses were exposed to three common corneal anesthetics: Fluress, Fluoracaine, and Alcaine. The results indicate that lenses treated with Alcaine surpassed a 100% increase in focal length variability (FLV) in the least amount of time, but did demonstrate recovery. Lenses treated with Fluoracaine showed a 100% increase in FLV after Alcaine, but recovered more slowly. The Fluress-treated lenses did not experience a 100% increase in FLV and did not differ significantly (p<0.05) from the controls at any point in the 48 h study. The results indicate that Fluress exhibits the lowest level of ocular toxicity compared to Alcaine and.
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Predicting responses to immunotherapy Colon cancers with loss-of-function mutations in the mismatch repair (MMR) pathway have favorable responses to PD-1 blockade immunotherapy. In a phase 2 clinical trial, Le et al. showed that treatment success is not just limited to colon cancer (see the Perspective by Goswami and Sharma). They found that a wide range of different cancer types with MMR deficiency also responded to PD-1 blockade. The trial included some patients with pancreatic cancer, which is one of the deadliest forms of cancer. The clinical trial is still ongoing, and around 20% of patients have so far achieved a complete response. MMR deficiency appears to be a biomarker for predicting successful treatment outcomes for several solid tumors and indicates a new therapeutic option for patients harboring MMR-deficient cancers. Science, this issue p. 409; see also p. 358 A pan-cancer biomarker is identified that can predict successful response to cancer immunotherapy in human patients. The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.
Strengthening acute inpatient mental health care for Indigenous clients

Abstract Indigenous people are over-represented in inpatient mental health care in Australia. Evidence suggests client-orientated care planning increase client engagement, reduce substance dependence and improve self-management among Indigenous people. The successful uptake and implementation of interventions, however, which promote access and cultural security in primary care practice, remains challenging. The Aboriginal and Islander Mental Health initiative introduced a multi-faceted approach to client-oriented care planning, as part of routine care to the Royal Darwin Hospital inpatient psychiatric unit, to determine whether there was change in the quality of care to Indigenous clients over time. The study used a mixed methods design. It was underpinned by an action-oriented research approach and incorporated stakeholder engagement, interactive training in strengths based recovery approach and psycho-education and a quantitative audit of inpatient files. The results suggest some improvements in quality of care for clients in the inpatient unit with increased attention to social and family history, involvement of translators, and allocation of case managers. Cross-cultural training and tools promoted change in some aspects of clinical practice. Some changes, however, were often not sustained and it did not necessarily promote engagement of AMHWs in routine care. Greater emphases on follow up training and provision of clinician feedback, in conjunction with high-level system change and commitment to introduction of culturally adapted recovery principles, is required for more sustained changes to clinician care and implementation success.
Fast and Robust Spatially Constrained Gaussian Mixture Model for Image Segmentation

In this paper, a new mixture model for image segmentation is presented. We propose a new way to incorporate spatial information between neighboring pixels into the Gaussian mixture model based on Markov random field (MRF). In comparison to other mixture models that are complex and computationally expensive, the proposed method is fast and easy to implement. In mixture models based on MRF, the M-step of the expectation-maximization (EM) algorithm cannot be directly applied to the prior distribution ${\pi_{ij}}$ for maximization of the log-likelihood with respect to the corresponding parameters. Compared with these models, our proposed method directly applies the EM algorithm to optimize the parameters, which makes it much simpler. Experimental results obtained by employing the proposed method on many synthetic and real-world grayscale and colored images demonstrate its robustness, accuracy, and effectiveness, compared with other mixture models.
Impact of Zoledronic Acid in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole: Z-FAST, ZO-FAST, and E-ZO-FAST.

Background : Aromatase inhibitors (AI) are accepted as adjuvant endocrine therapy for hormone receptor-positive (HR+) postmenopausal early breast cancer (EBC) with superior efficacy to tamoxifen. However, because of the increased bone loss associated with the use of AI, three international randomised studies Z-FAST, ZO-FAST and E-ZO-FAST were performed to evaluate the bone protective effects of zoledronic acid (ZOL). These studies showed that the bone mineral density (BMD) loss associated with AI therapy can effectively be prevented by ZOL. In addition, these studies included disease-free survival (DFS) as a secondary endpoint, although the studies were not powered to detect a difference between treatment arms. Following the results from ABCSG 12 indicating a powerful effect of ZOL in premenopausal women receiving endocrine therapy, exploratory analyses of the individual trials have been done. However, this is the first report of DFS outcome for all three studies. Materials and Methods : Across the three studies 2194 patients(pts) with HR+ EBC were randomised to either immediate ZOL 4mg every 6 months or delayed ZOL where bone protection was started if either the BMD T-score fell below Results : Median follow up times for this analysis are 54, 48 and 36 months respectively for Z-FAST, ZO-FAST and E-ZO-FAST. The proportion of pts with a follow-up lag time of ≥ 6 months was 29.7% Z-FAST, 8.3% ZO-FAST and 8.7% E-ZO-FAST. The pt-years of time on study for both arms combined were calculated; Z-FAST 2709; ZO-FAST 4260 and E-ZO-FAST 1580. The percent of pts starting ZOL in the delayed ZOL arm was: Z-FAST 26%, ZO-FAST 25%, and E-ZO-FAST 17%. The Gail-Simon test was statistically significant for a quantitative interaction between studies (p-value 0.047). Therefore, combining the results was not considered statistically appropriate. Numbers of recurrences and individual trial hazard ratios are shown below. Conclusion : This exploratory analysis of DFS has several limitations: a small number of pt events, differences between trials in the method of collecting pt follow up data on DFS and length of median follow-up times, a wide range of pt-years on study, and a statistically significant interaction between studies, reflecting the heterogeneity of results. Also, the use of a ZOL delayed arm as active control limits a direct assessment to that of no ZOL. Additional analyses are planned when the studies are completed. Results from ongoing appropriately powered randomised studies are awaited to determine the true role of adjuvant ZOL in EBC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4082.
Relation of Soluble Endothelial Protein C Receptor and Cytokines After Allogeneic Hematopoietic Stem Cell Transplantation

Aim: The objective of this study was to elucidate the effects of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 2 (IL-2), interleukin 6 (IL-6), and interleukin 8 (IL-8) on the expression of soluble endothelial protein C receptor (sEPCR) in the pathogenesis of thrombotic complications after hematopoietic stem cell transplantation (HSCT). Methods: The relationship between plasma concentrations of proinflammatory cytokines (TNF-α, IL-1β, IL-2, IL-6, and IL-8) and sEPCR was evaluated in 32 consecutive allogeneic hematopoietic stem cell—transplanted patients prior to conditioning regimen and randomly once between +5 and +30 days after transplantation and compared these results with 20 healthy controls. Results: Soluble endothelial protein C receptor levels did not indicate any significant difference between pre- and posttransplantation period, and sEPCR levels showed a significantly negative correlation between IL-6 and IL-8 (sEPCR and IL-6, r = —.43, P < .01; sEPCR and IL-8, r = —.57, P < .01). There was no correlation between sEPCR levels and TNF-α, IL-1β, or IL-2 (sEPCR and TNF-α, r = —.13, P > .05; sEPCR and IL-1β, r = —.1, P ≥ .05; sEPCR and IL-2, r = —.07, P > .05). Conclusions: Our results suggest that the production of sEPCR was not affected by allogeneic HSCT. Soluble endothelial protein C receptor did not show any positive correlation between these proinflammatory cytokines (TNF-α, IL-1β, IL-2, IL-6, and IL-8), on the contrary a significantly negative correlation was determined between sEPCR and either IL-6 or IL-8. This negative correlation may be a protective mechanism in the pathway of protein C activation.
Impact of Thrombogenic Mutations on Clinical Phenotypes of von Willebrand Disease

von Willebrand disease (VWD) is a most common inherited bleeding disorder. von Willebrand factor (VWF) exists as an extracellular adaptor molecule and generally involves in the hemostasis mechanism through binding with GP (Glycoprotein) Ib-IX-V platelet receptor. Clinical phenotype of bleeding disorders modulated to a decrease in bleeding symptoms by thrombogenic mutations. We made an attempt to investigate the impact of thrombogenic mutations/polymorphisms on the clinical phenotype of 114 different types of patients with VWD, and 120 healthy controls were screened for methylenetetrahydrofolate reductase (MTHFR) 677C/T, factor V (FV) Leiden (1691G/A), β3 integrin (HPA-I) (Human platelets antigen-I) gene (1565T/C), and prothrombin 20210G/A mutations. Genotypic analysis was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism. Forty-five patients (39.5%) were found to be positive for at least one of the prothrombotic risk factors screened. Prothrombin 20210G/A was not found in any patient with VWD as well as healthy control. Eight patients with VWD were carrying the defective alleles of different thrombogenic markers, showing milder phenotypes than expected. A high prevalence was observed for MTHFR 677C/T (677C/C 73.6%, 677C/T 24.6%, 677T/T 1.8%) and PLA1/A2 (1565T/T 88.6%, 1565T/C 10.5%, 1565C/C 0.87%) polymorphism followed by FV Leiden (1691G/G 97.4%, 1691G/ A 2.6%, 1691A/A 0.00%) in patients with VWD with allelic frequencies 11.4% (677T), 5% (1565C), and 1.3% (1691A). Hence, we concluded that thrombophilic markers were seen to be influencing the clinical phenotypes of patients with VWD.
Nontraditional Risk Factors in Carotid Artery Disease

Carotid atherosclerosis (AS) is one of the main risk factors for ischemic stroke. Our aim is to evaluate the nontraditional biochemical markers in asymptomatic and symptomatic patients with carotid artery plaque. This study was conducted on 55 patients: 43 with symptomatic and 12 with asymptomatic carotid artery disease. Lipoprotein (a) (Lp(a)), homocysteine, adiponectin, nitric oxide (NO), and tumor necrosis factor α (TNF-α) levels were measured in the plasma. The mean of total cholesterol, triglyceride, and homocysteine levels was significantly elevated in the symptomatic group as compared with the asymptomatic group (P = .03). In the asymptomatic group, adiponectin and NO levels showed elevations as compared with the symptomatic group but this increase was not significant (P > .05). Lipoprotein (a) and TNF-α levels acted inversely with adiponectin and NO. There was an insignificant decline in Lp(a) and TNF-α levels in the asymptomatic group as compared with the symptomatic group (P > .05).
Prophylactic Fibrinogen Infusion in Cardiac Surgery Patients: Effects on Biomarkers of Coagulation, Fibrinolysis, and Platelet Function

Objective: We have recently reported that prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass grafting (CABG) surgery. Because fibrinogen for the first time was administered to patients without hereditary fibrinogen deficiency or ongoing bleeding, a detailed analysis of the effects of fibrinogen concentrate on biomarkers of coagulation, fibrinolysis, and platelet function was performed. Methods: Twenty CABG patients with preoperative plasma fibrinogen levels <3.8 g/L were included in a prospective study. Patients were randomized to preoperative infusion of 2 g fibrinogen concentrate (fibrinogen group) or no infusion (control group). Activated partial thromboplastin time (aPTT), prothrombin time, activated clotting time, and plasma concentrations of fibrinogen, antithrombin, thrombin-antithrombin complex, prothrombin fragment 1.2, and D-dimer, thromboelastometry, platelet count, and platelet aggregometry were analyzed before and 15 minutes after infusion, and 2 and 24 hours after surgery. Results: Fifteen minutes after infusion of fibrinogen concentrate, fibrinogen plasma levels increased by 0.6 ± 0.2 g/L (P < .001 between groups), and induced minimal changes in aPTT and plasma levels of antithrombin, while remaining variables remained unchanged. After surgery, fibrinogen levels no longer differed between groups. D-dimer was significantly higher after surgery in the fibrinogen group (P = .03), while none of the other markers were statistically different between groups. Conclusions: Infusion of 2 g fibrinogen to cardiac surgery patients, without hereditary or acquired fibrinogen deficiency or ongoing bleeding, results in no or minimal changes in biomarkers reflecting coagulation and platelet function. An increased release of fibrin degradation products was detected after surgery in fibrinogen-treated patients.
Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism

Two-step role for mutant TERT promoters Telomeres preserve genomic stability by preventing chromosomal fusions. The recent discovery that human tumors harbor mutations in the promoter region of the telomerase gene (TERT) produced a flurry of research aimed at elucidating the role of these mutations in cancer development. Chiba et al. present data that reconcile many of the conflicting results reported to date (see the Perspective by Shay). In human melanoma samples and a fibroblast model, TERT promoter mutations acted in two steps. First, the mutations allowed cells to proliferate with short telomeres. This fueled genomic instability and up-regulation of telomerase expression, leading to uncontrolled cell proliferation. Science, this issue p. 1416; see also p. 1358 Mutations in the telomerase gene promoter allow cancer cells to grow with short telomeres, fueling genome instability. TERT promoter mutations (TPMs) are the most common noncoding mutations in cancer. The timing and consequences of TPMs have not been fully established. Here, we show that TPMs acquired at the transition from benign nevus to malignant melanoma do not support telomere maintenance. In vitro experiments revealed that TPMs do not prevent telomere attrition, resulting in cells with critically short and unprotected telomeres. Immortalization by TPMs requires a gradual up-regulation of telomerase, coinciding with telomere fusions. These data suggest that TPMs contribute to tumorigenesis by promoting immortalization and genomic instability in two phases. In an initial phase, TPMs do not prevent bulk telomere shortening but extend cellular life span by healing the shortest telomeres. In the second phase, the critically short telomeres lead to genome instability and telomerase is further up-regulated to sustain cell proliferation.
Hippocampal ripples down-regulate synapses

Rebalancing mechanisms during sleep Synapses are often strengthened during wake periods and thus need to be homeostatically readjusted during sleep. During slow-wave sleep, synaptic depression is dominant. Sharp wave and ripple events are transient high-frequency field oscillations that occur spontaneously during slow-wave sleep in the brain. Norimoto et al. found that these events induced long-term depression of hippocampal synapses and may thus help to refine recently acquired memories (see the Perspective by Draguhn). Science, this issue p. 1524; see also p. 1461 Sharp-wave ripple events in slow-wave sleep induce long-term depression at hippocampal synapses in sleeping mice. The specific effects of sleep on synaptic plasticity remain unclear. We report that mouse hippocampal sharp-wave ripple oscillations serve as intrinsic events that trigger long-lasting synaptic depression. Silencing of sharp-wave ripples during slow-wave states prevented the spontaneous down-regulation of net synaptic weights and impaired the learning of new memories. The synaptic down-regulation was dependent on the N-methyl-d-aspartate receptor and selective for a specific input pathway. Thus, our findings are consistent with the role of slow-wave states in refining memory engrams by reducing recent memory-irrelevant neuronal activity and suggest a previously unrecognized function for sharp-wave ripples.
Spectroscopic signatures of localization with interacting photons in superconducting qubits

Putting photons to work Interacting quantum particles can behave in peculiar ways. To understand that behavior, physicists have turned to quantum simulation, in which a tunable and clean system can be monitored as it evolves under the influence of interactions. Roushan et al. used a chain of nine superconducting qubits to create effective interactions between normally noninteracting photons and directly measured the energy levels of their system. The interplay of interactions and disorder gave rise to a transition to a localized state. With an increase in the number of qubits, the technique should be able to tackle problems that are inaccessible to classical computers. Science, this issue p. 1175 A many-body spectroscopy technique based on a chain of superconducting qubits gives insight into the localization transition. Quantized eigenenergies and their associated wave functions provide extensive information for predicting the physics of quantum many-body systems. Using a chain of nine superconducting qubits, we implement a technique for resolving the energy levels of interacting photons. We benchmark this method by capturing the main features of the intricate energy spectrum predicted for two-dimensional electrons in a magnetic field—the Hofstadter butterfly. We introduce disorder to study the statistics of the energy levels of the system as it undergoes the transition from a thermalized to a localized phase. Our work introduces a many-body spectroscopy technique to study quantum phases of matter.