snu-aidas/HVMap-dataset huggingface dataset:
New pathologic classification of lung cancer: relevance for clinical practice and clinical trials.

We summarize significant changes in pathologic classification of lung cancer resulting from the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. The classification was developed by an international core panel of experts representing IASLC, ATS, and ERS with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. Because 70% of patients with lung cancer present with advanced stages, a new approach to small biopsies and cytology with specific terminology and criteria focused on the need for distinguishing squamous cell carcinoma from adenocarcinoma and on molecular testing for EGFR mutations and ALK rearrangement. Tumors previously classified as non-small-cell carcinoma, not otherwise specified, because of the lack of clear squamous or adenocarcinoma morphology should be classified further by using a limited immunohistochemical workup to preserve tissue for molecular testing. The terms "bronchioloalveolar carcinoma" and "mixed subtype adenocarcinoma" have been discontinued. For resected adenocarcinomas, new concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma define patients who, if they undergo complete resection, will have 100% disease-free survival. Invasive adenocarcinomas are now classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype with poor prognosis. Former mucinous bronchioloalveolar carcinomas are now called "invasive mucinous adenocarcinoma. " Because the lung cancer field is now rapidly evolving with new advances occurring on a frequent basis, particularly in the molecular arena, this classification provides a much needed standard for pathologic diagnosis not only for patient care but also for clinical trials and TNM classification.
Polymorphisms in EGFR and IL28B are associated with spontaneous clearance in an HCV-infected iranian population

Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim of the present study was to identify genes associated with spontaneous HCV clearance in a population of Iranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59 selected—candidate—genes in a cohort of 107 HCV-infected participants who spontaneously cleared the infection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to be associated with HCV outcome (P-values<0.03). rs11506105 in EGFR (epidermal growth factor receptor gene), and rs11881222 and rs12979860 in IL28B (interferon-λ3 gene). Multivariate logistic regression of the three markers showed that the A/A genotypes in both rs11506105 (EFGR) and rs11881222 (IL28B), and the C/C genotype in rs12979860 (IL28B) are associated with HCV clearance (recessive model: odds ratio (OR)=2.06, 95% confidence interval (95% CI)=1.09–3.88, P=0.025; OR=2.09, 95% CI=1.23–3.60, P=0.007; and OR=1.95, 95% CI=1.15–3.35, P=0.014 for rs11506105, rs12979860 and rs11881222, respectively). In conclusion, EGFR and IL28B SNPs are strong independent predictive markers of spontaneous viral clearance.
Cardiopulmonary exercise testing variables reflect the degree of diastolic dysfunction in patients with heart failure-normal ejection fraction.

PURPOSE Previous investigations have reported a relationship between variables obtained from echocardiography with tissue Doppler imaging (TDI) and cardiopulmonary exercise testing (CPX) in systolic heart failure (HF) cohorts. The purpose of the present investigation was to perform a comparative analysis between echocardiography with TDI and CPX in patients with HF and normal ejection fraction (NEF). METHODS Patients with HF-NEF (N = 32) underwent echocardiography with TDI and CPX to determine the following variables: (1) the ratio between mitral early velocity (E) and mitral annular velocity (E'), (2) ejection fraction, (3) left ventricular (LV) mass, (4) left ventricular end systolic volume, (5) peak oxygen uptake (.VO2), (6) ventilatory efficiency, (7) the partial pressure of end-tidal carbon dioxide (P(ET)CO2) at rest and peak exercise, and (8) heart rate recovery at 1 minute (HRR1). RESULTS Pearson correlation revealed that E/E' was significantly correlated with peak oxygen uptake (r = -0.55, P = .001), the ventilatory efficiency slope (r = 0.60, P < .001), resting P(ET)CO2 (r = -0.39, P = .03), peak P(ET)CO2 (r = -0.50, P = .004), and HRR1 (r = -0.63, P < .001). Left ventricular mass and left ventricular end systolic volume were not correlated with any CPX variable. Ejection fraction was correlated with HRR1 (r = -0.55, P = .001). An HRR1 threshold of less than 16 and/or 16 or more beats per minute (higher value positive) effectively identified subjects with an E/E' > 10 (positive likelihood ratio: 13:2). DISCUSSION E/E' provides an accurate reflection of LV filling pressure and thus, insight into diastolic function. The results of the present investigation indicate CPX provides insight into cardiac dysfunction in patients with HF-NEF and thus, may eventually prove to be a valuable and accepted clinical assessment.
Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: influence of concomitant pathological variables.

PURPOSE We evaluated the long-term outcome of radical prostatectomy for pathological Gleason score 8 or greater prostate cancer and characterized the prognostic significance of other pathological variables. MATERIALS AND METHODS A total of 6,419 patients underwent radical prostatectomy between 1987 and 1996. There were 407 patients classified as having pathological Gleason 8 or greater, including 8 in 48%, 9 in 49% and 10 in 3%. Adjuvant treatment was used in 45% of patients and adjuvant hormonal therapy was administered to 155 (38%). Progression-free, including local or systemic, and/or prostate specific antigen (PSA) 0.4 ng./ml. or greater, and cancer specific survival were determined by the Kaplan-Meier method. The effect of pathological grade and stage, preoperative PSA, DNA ploidy, margin status, tumor dimension, seminal vesicle invasion, and adjuvant treatment was assessed with the univariate and multivariate analyses. RESULTS Pathological stage distribution was pT2 in 26% of patients, pT3 48% and pTxN+ 27%. Overall and progression-free survival at 10 years was 67% and 36%, respectively, compared to cancer specific survival 85%. Adjuvant treatment, pathological stage, preoperative PSA and pathological grade were significant (less than 0.05) univariate predictors of progression-free survival. Pathological stage, margin status and ploidy were univariately associated with cancer specific survival. Progression-free survival at 10 years of those patients who did and did not receive adjuvant treatment was 52% and 23%, respectively. In the multivariate analysis pathological grade (p=0.02), preoperative PSA (p <0.0001), adjuvant therapy (p <0.0001) and pathological stage (p=0.036) were significant independent predictors of progression-free survival. CONCLUSIONS High grade prostate cancer can be controlled with radical prostatectomy in some patients with disease confined pathologically, and 10-year cause specific survival is 96%. Predictors of outcome in patients with Gleason 8 disease or greater are similar to established predictors derived by using all grades. Although adjuvant hormonal therapy appears to improve disease progression rates after radical prostatectomy on the basis of this nonrandomized study, it may not affect prostate cancer death rates within 10 years in patients with high grade cancer.
[Acupuncture combined with auricular point sticking therapy for post stroke depression:a randomized controlled trial].

OBJECTIVE To observe the clinical effects of acupuncture combined with auricular point sticking based on the western medication for post stroke depression (PSD). METHODS Sixty patients with PSD were randomly assigned into an acupuncture plus auricular application group (a combination group) and a medication group, 30 cases in each one. 20 mg paroxetine hydrochloride was prescribed orally in the medication group, once a day for continuous 8 weeks. Based on the above treatment, 30-minute acupuncture was used in the combination group for 8 weeks at Baihui (GV 20), Sishencong (EX-HN 1), Shenting (GV 24), Yintang (GV 29), Shenmen (HT 7), Neiguan (PC 6), Taichong (LR 3), Hegu (LI 4), Zusanli (ST 36), Sanyinjiao (SP 6) and Fenglong (ST 40), once the other day and three times a week. Auricular point sticking therapy for 8 weeks was applied at shenmen (TF4), pizhixia (AT4), xin (CO15), and gan (CO12), with pressing 3 times a day and once 3-5 days. The total score and each factor scores of Hamilton's depression scale (HAMD) were observed in the two groups before and after treatment, and Asberg's antidepressant side-effect rating scale (SERS) and clinical effect were evaluated. RESULTS After treatment, the total HAMD scores of the two groups decreased compared with those before treatment (both P<0.05), with better effect in the combination group (P<0.05). The scores of the combination group after treatment were lower than those in the medication group, including the anxiety/somatization factor, sleep disturbance factor, hopelessness factor (all P<0.05). The total effective rate of the combination group was 86.7% (26/30), which was better than 66.7% (20/30) of the medication group (P<0.05). The SERS score of the combination group was lower than that of the medication group (P<0.05). CONCLUSIONS Acupuncture combined with auricular point sticking can improve the clinical symptoms and are effective and safe for PSD.
Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension

Genetic evidence implicates the loss of bone morphogenetic protein type II receptor (BMPR-II) signaling in the endothelium as an initiating factor in pulmonary arterial hypertension (PAH). However, selective targeting of this signaling pathway using BMP ligands has not yet been explored as a therapeutic strategy. Here, we identify BMP9 as the preferred ligand for preventing apoptosis and enhancing monolayer integrity in both pulmonary arterial endothelial cells and blood outgrowth endothelial cells from subjects with PAH who bear mutations in the gene encoding BMPR-II, BMPR2. Mice bearing a heterozygous knock-in allele of a human BMPR2 mutation, R899X, which we generated as an animal model of PAH caused by BMPR-II deficiency, spontaneously developed PAH. Administration of BMP9 reversed established PAH in these mice, as well as in two other experimental PAH models, in which PAH develops in response to either monocrotaline or VEGF receptor inhibition combined with chronic hypoxia. These results demonstrate the promise of direct enhancement of endothelial BMP signaling as a new therapeutic strategy for PAH.
Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells.

Holliday junctions (HJs) are four-way DNA intermediates that form during homologous recombination, and their efficient resolution is essential for chromosome segregation. Here, we show that three structure-selective endonucleases, namely SLX1-SLX4, MUS81-EME1, and GEN1, define two pathways of HJ resolution in human cells. One pathway is mediated by GEN1, whereas SLX1-SLX4 and MUS81-EME1 provide a second and genetically distinct pathway (SLX-MUS). Cells depleted for SLX-MUS or GEN1 pathway proteins exhibit severe defects in chromosome segregation and reduced survival. In response to CDK-mediated phosphorylation, SLX1-SLX4 and MUS81-EME1 associate at the G2/M transition to form a stable SLX-MUS holoenzyme, which can be reconstituted in vitro. Biochemical studies show that SLX-MUS is a HJ resolvase that coordinates the active sites of two distinct endonucleases during HJ resolution. This cleavage reaction is more efficient and orchestrated than that mediated by SLX1-SLX4 alone, which exhibits a potent nickase activity that acts promiscuously upon DNA secondary structures.
Prevalence of frequent headache in a population sample.

PURPOSE Patients with daily or near-daily headaches are commonly seen in neurology practices and in headache subspecialty centers, but there is little information on the prevalence of this condition in the general population. We present the first US-based study describing the prevalence and characteristics of frequent headache in the general population. METHODS In Baltimore County, Maryland, 13 343 individuals 18 to 65 years of age were selected by random-digit dialing and interviewed by telephone about their headaches. Subjects reporting 180 or more headaches per year were classified as having frequent headache. Three mutually exclusive subtypes of frequent headache were identified: frequent headache with migrainous features, chronic tension-type headache, and unclassified frequent headache. RESULTS The overall prevalence of frequent headache was 4.1% (5.0% female, 2.8% male; 1.8:1 female to male ratio). Frequent headache was 33% more common in Caucasians (4.4%) than in African Americans (3.3%). In both males and females, prevalence was highest in the lowest educational category. Among frequent headache sufferers, more than half (52% female, 56% male) met criteria for chronic tension-type headache, almost one third (33% female, 25% male) met criteria for frequent headache with migrainous features, and the remainder (15% female, 19% male) were unclassified. Overall, 30% of female and 25% of male frequent headache sufferers met International Headache Society (IHS) criteria for migraine (with or without aura). CONCLUSIONS Frequent headache is common in the general population and is more prevalent in Caucasians and in those with less than a high school education. Chronic tension-type headache is more common than frequent headache with migrainous features, though the latter is more disabling. Although more common in females than males, the female preponderance of frequent headache is less marked than in migraine. The sex ratio varies by frequent headache subtype.
HTLV-I/II associated disease in England and Wales, 1993-7: retrospective review of serology requests.

Apart from HIV two exogenous retroviruses (human T cell leukaemia viruses type I (HTLV-I) and type II (HTLV-II)) infect humans. HTLV-I infection is endemic in Japan, the Caribbean, Africa, and Melanesia and is found among immigrants from these regions in Europe. HTLV-I infection is associated with a 1-5% lifetime risk of adult T cell leukaemia/lymphoma, 1 a 0.25% lifetime risk of HTLV-I associated myelopathy, 2 and other inflammatory conditions (uveitis, alveolitis, and arthritis).1 HTLV-II infection is endemic in some native American and African peoples and among injecting drug users and has been associated with neurological disease.1 Between 1986 and 1992, 100 cases of HTLV-I associated myelopathy and 44 cases of adult T cell leukaemia/lymphoma were diagnosed in the United Kingdom.3 Adult T cell leukaemia/lymphoma was first described in 1977 and patients with it have a mean life expectancy of only six months, so most of the 44 cases were probably incident cases. …
EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome

Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic and renal dysfunction, mental retardation and cardiovascular abnormalities. On the basis of two consanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval of approximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3) resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3 that segregated with the disorder in each of the families. The first mutation produces a truncated protein in which the entire catalytic domain is missing. The other changes an amino acid, located in the catalytic domain of the protein, that is highly conserved among kinases from the same subfamily. Our results provide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight into the understanding of the more common forms of diabetes and other pathologic manifestations of WRS.
Aging, frailty and age-related diseases

The concept of frailty as a medically distinct syndrome has evolved based on the clinical experience of geriatricians and is clinically well recognizable. Frailty is a nonspecific state of vulnerability, which reflects multisystem physiological change. These changes underlying frailty do not always achieve disease status, so some people, usually very elderly, are frail without a specific life threatening illness. Current thinking is that not only physical but also psychological, cognitive and social factors contribute to this syndrome and need to be taken into account in its definition and treatment. Together, these signs and symptoms seem to reflect a reduced functional reserve and consequent decrease in adaptation (resilience) to any sort of stressor and perhaps even in the absence of extrinsic stressors. The overall consequence is that frail elderly are at higher risk for accelerated physical and cognitive decline, disability and death. All these characteristics associated with frailty can easily be applied to the definition and characterization of the aging process per se and there is little consensus in the literature concerning the physiological/biological pathways associated with or determining frailty. It is probably true to say that a consensus view would implicate heightened chronic systemic inflammation as a major contributor to frailty. This review will focus on the relationship between aging, frailty and age-related diseases, and will highlight possible interventions to reduce the occurrence and effects of frailty in elderly people.
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

The gene encoding apolipoprotein E (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. To identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APOE with suggestive evidence of association (P < 10−5) were examined in collections from Belgium, Finland, Italy and Spain totaling 3,978 Alzheimer's disease cases and 3,297 controls. Two loci gave replicated evidence of association: one within CLU (also called APOJ), encoding clusterin or apolipoprotein J, on chromosome 8 (rs11136000, OR = 0.86, 95% CI 0.81–0.90, P = 7.5 × 10−9 for combined data) and the other within CR1, encoding the complement component (3b/4b) receptor 1, on chromosome 1 (rs6656401, OR = 1.21, 95% CI 1.14–1.29, P = 3.7 × 10−9 for combined data). Previous biological studies support roles of CLU and CR1 in the clearance of β amyloid (Aβ) peptide, the principal constituent of amyloid plaques, which are one of the major brain lesions of individuals with Alzheimer's disease.
Cytochemistry and C-values: the less-well-known world of nuclear DNA amounts.

BACKGROUND In the plant sciences there are two widely applied technologies for measuring nuclear DNA content: Feulgen absorbance cytophotometry and flow cytometry (FCM). While FCM is, with good reasons, increasingly popular among plant scientists, absorbance-cytophotometric techniques lose ground. This results in a narrowing of the methodological repertoire, which is neither desirable nor beneficial. Both approaches have their advantages, but static cytophotometry seems to pose more instrumental difficulties and material-based problems than FCM, so that Feulgen-based data in the literature are often less reliable than one would expect. SCOPE The purpose of this article is to present a selective overview of the field of nuclear DNA content measurement, and C-values in particular, with a focus on the technical difficulties imposed by the characteristics of the biological material and with some comments on the photometrical aspects of the work. For over 20 years it has been known that plant polyphenols cause problems in Feulgen DNA cytophotometry, since they act as major staining inhibitors leading to unreliable results. However, little information is available about the chemical classes of plant metabolites capable of DNA staining interference and the mechanisms of their inhibition. Plant slimes are another source of concern. CONCLUSIONS In FCM research to uncover the effects of secondary metabolites on measurement results has begun only recently. In particular, the analysis of intraspecific genome size variation demands a stringent methodology which accounts for inhibitors. FCM tests for inhibitory effects of endogenous metabolites should become obligatory. The use of dry seeds for harvesting embryo and endosperm nuclei for FCM and Feulgen densitometry may often provide a means of circumventing staining inhibitors. The importance of internal standardization is highlighted. Our goal is a better understanding of phytochemical/cytochemical interactions in plant DNA photometry for the benefit of an ever-growing list of plant genome sizes.
Interplay between microtubule bundling and sorting factors ensures acentriolar spindle stability during C. elegans oocyte meiosis

In many species, oocyte meiosis is carried out in the absence of centrioles. As a result, microtubule organization, spindle assembly, and chromosome segregation proceed by unique mechanisms. Here, we report insights into the principles underlying this specialized form of cell division, through studies of C. elegans KLP-15 and KLP-16, two highly homologous members of the kinesin-14 family of minus-end-directed kinesins. These proteins localize to the acentriolar oocyte spindle and promote microtubule bundling during spindle assembly; following KLP-15/16 depletion, microtubule bundles form but then collapse into a disorganized array. Surprisingly, despite this defect we found that during anaphase, microtubules are able to reorganize into a bundled array that facilitates chromosome segregation. This phenotype therefore enabled us to identify factors promoting microtubule organization during anaphase, whose contributions are normally undetectable in wild-type worms; we found that SPD-1 (PRC1) bundles microtubules and KLP-18 (kinesin-12) likely sorts those bundles into a functional orientation capable of mediating chromosome segregation. Therefore, our studies have revealed an interplay between distinct mechanisms that together promote spindle formation and chromosome segregation in the absence of structural cues such as centrioles.