Miracle-dz/UniFAR-FTUs huggingface dataset:
DNA Repair Single-Nucleotide Polymorphisms in Colorectal Cancer and their Role as Modifiers of the Effect of Cigarette Smoking and Alcohol in the Singapore Chinese Health Study

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair genes: XRCC1 (Arg194Trp and Arg399Gln), PARP (Val762Ala, Lys940Arg), XPD (Asp312Asn, Lys751Gln), OGG1 (Ser326Cys), and MGMT (Leu84Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P = 0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P = 0.012). The effect of smoking among carriers of the Arg194-Gln399 haplotype was OR = 0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp194-Arg399 haplotype, it was OR = 1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P = 0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.6-1.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2363–72)
Combination chemotherapy as induction therapy for advanced resectable head and neck cancer

Fifty‐four previously untreated patients with locally advanced resectable squamous cell carcinoma of the head and neck (SCCHN) were enrolled into a prospective randomized controlled trial to evaluate whether induction chemotherapy improves the disease‐free survival compared to the standard treatment (surgery + radiation). Thirty patients received chemotherapy, which consisted of cisplatin 20 mg/m2 day 1–5, bleomycin 10 mg/m2, continuous infusion from day 3–7, and methotrexate 40 mg/m2 given on day 15 and day 22. The cycle was repeated on day 29 for two cycles. Twenty patients completed chemotherapy courses. Overall response rate was 77% (23 of 30). No survival improvement was observed. Kaplan‐Meier analysis indicated survival (and 95% confidence interval) at 3 years was 57% (29%‐84%) for the control group and 60% (34%‐87%) for the chemotherapy group, and 57% (29%‐84%) and 45% (12%‐78%) at 4 years (P = 0.736). However, patients who had a complete response were significantly better in terms of long‐term survivors (5 of 7 patients were still alive), in contrast to patients who had partial responses among whom only 4 of 16 were alive. Toxicities of this induction protocol are tolerable; one chemotherapy‐related death occurred from profound thrombocytopenia. If efforts in determining a chemotherapy‐sensitive patient were successfully established, along with a better sequence and the discovery of new and safter drugs, survival of SCCHN should be much improved.
YY1 plays an essential role at all stages of B-cell differentiation

Significance Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor that has been demonstrated to be essential for pro–B-cell development as well as lymphoma. It has recently been proposed that YY1 regulates the germinal center B-cell transcriptional program. We confirm this hypothesis and additionally show that YY1 is equally essential for all stages of B-cell differentiation. Through ChIP-sequencing analysis of YY1 binding, and analysis of differentially expressed genes from RNA-sequencing, our data show that, in addition to the regulation of several B-cell–specific genes, YY1 regulates many genes and pathways important in basic cellular functions, such as mitochondrial bioenergetics, transcription, ribosomal function, and cellular proliferation, thus explaining the requirement for YY1 at all stages of B-cell differentiation. Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor shown to be essential for pro–B-cell development. However, the role of YY1 in other B-cell populations has never been investigated. Recent bioinformatics analysis data have implicated YY1 in the germinal center (GC) B-cell transcriptional program. In accord with this prediction, we demonstrated that deletion of YY1 by Cγ1-Cre completely prevented differentiation of GC B cells and plasma cells. To determine if YY1 was also required for the differentiation of other B-cell populations, we deleted YY1 with CD19-Cre and found that all peripheral B-cell subsets, including B1 B cells, require YY1 for their differentiation. Transitional 1 (T1) B cells were the most dependent upon YY1, being sensitive to even a half-dosage of YY1 and also to short-term YY1 deletion by tamoxifen-induced Cre. We show that YY1 exerts its effects, in part, by promoting B-cell survival and proliferation. ChIP-sequencing shows that YY1 predominantly binds to promoters, and pathway analysis of the genes that bind YY1 show enrichment in ribosomal functions, mitochondrial functions such as bioenergetics, and functions related to transcription such as mRNA splicing. By RNA-sequencing analysis of differentially expressed genes, we demonstrated that YY1 normally activates genes involved in mitochondrial bioenergetics, whereas it normally down-regulates genes involved in transcription, mRNA splicing, NF-κB signaling pathways, the AP-1 transcription factor network, chromatin remodeling, cytokine signaling pathways, cell adhesion, and cell proliferation. Our results show the crucial role that YY1 plays in regulating broad general processes throughout all stages of B-cell differentiation.
Relationship between rates and outcomes of operative treatment for lumbar disc herniation and spinal stenosis.

BACKGROUND Population-based variations in rates of operations for the treatment of lumbar disc herniation and spinal stenosis are well known. This variability may occur in part because of differences in the threshold at which physicians recommend an operation, reflecting uncertainty about the optimum use of an operative procedure. To the best of our knowledge, no previous reports have indicated whether differences in population-based rates of operative treatment are associated with patient outcomes. METHODS The Maine Lumbar Spine Study is an ongoing prospective study of 655 patients who had a herniated lumbar disc or spinal stenosis. The patients were enrolled by their physicians, who provided baseline demographic and treatment-related data. The patients completed baseline and follow-up questionnaires that focused on symptoms, function, satisfaction, and quality of life. Small-area variation analysis was used to develop three distinct so-called spine service areas in Maine. The outcomes (usually at four years; minimum, two years) were compared among these areas, in which a total of 250 patients had been managed operatively and had answered questionnaires. RESULTS Population-based rates of operative treatment derived from statewide data that had been collected over five years in the state of Maine ranged from 38 percent below to 72 percent above the average rate in the state (a greater than fourfold difference). The outcomes for the patients who had been managed by surgeons in the lowest-rate area were superior to those for the patients in the two higher-rate areas. Seventy-nine percent (fifty-seven) of seventy-two patients in the lowest-rate area had marked or complete relief of pain in the lower extremity compared with 60 percent (eighteen) of thirty patients in the highest-rate area. The improvements in the Roland disability score (p < or = 0.01), quality of life (p < or = 0.01), and satisfaction (p < or = 0.05) were significantly greater among the patients in the lowest-rate area. The patients in the higher-rate areas generally had less severe symptoms and findings at baseline than those in the lowest-rate area did. CONCLUSIONS Higher population-based rates of elective spinal operations may be associated with inferior outcomes. This variability is possibly related to differences in physicians' preferences with regard to recommending an operation and in their criteria for the selection of patients. Physicians cannot assume that their outcomes will be the same as those of others, and therefore they need to evaluate their own results.
An Abnormal Right Ventricular Apical Angle is Indicative of Global Right Ventricular Impairment

The presence of right ventricular (RV) dysfunction is an adverse prognostic indicator but current echocardiographic methods have some limitations. RV apical angles in systole and diastole were correlated with known parameters of RV function in patients without pulmonary hypertension (Group 1) and in patients with pulmonary hypertension (Group 2). RV apical angles were significantly smaller in both systole (22 ± 7°) and diastole (33 ± 6°) in Group 1 patients when compared to Group 2 (54 ± 18°, p < 0.0001 and 59 ± 17°, p < 0.0001, respectively). RV apical angles, both in systole and diastole, were strongly correlated with RV end‐systolic area (R = 0.89, p < 0.0001) and end‐diastolic area (R = 0.81, p < 0.0001), respectively. Similarly, the apical systolic and diastolic angle correlated well with decreased tricuspid annular plane systolic excursion (TAPSE, R =−0.76 and R =−0.73, p < 0.001) as well as with decreased RV fractional area change (R =−0.81 and R =−0.77, p < 0.001). Therefore, we conclude that this new measurement of RV apical angle is simple and useful to quantify RV apical structural and functional abnormalities that are well correlated with global RV impairment in patients with chronic pulmonary hypertension.
An association between BPDE-like DNA adduct levels and P53 gene mutation in pterygium.

PURPOSE A previous report of ours noted that not only p53 protein overexpression, but also p53 gene mutation. were indeed detected in pterygium. BaP 7,8-diol 9,10-epoxide (BPDE), an ultimate metabolite of BaP, attacks deoxyguanosine to form a BPDE-N2-dG adduct resulting in p53 mutations. The relationship between BPDE-like DNA adduct levels and abnormal p53 has not been clear in pterygium. Therefore, BPDE-like DNA adduct, p53 protein expression and p53 gene mutation were examined in this study to provide more molecular evidence to understand the cause of p53 gene mutation in pterygium. METHODS In this study, immunohistochemical staining, using a monoclonal antibody (DO7) against p53 and a polyclonal antibody against BPDE-like DNA adducts, was performed on 73 pterygial specimens. DNA samples for p53 mutation analysis were extracted from epithelial cells and then subjected to DNA sequencing for the determination of mutations in exons 4, 5, 6, 7, and 8 of the p53 gene. RESULTS BPDE-like DNA adducts were detected in 36.1% (26/73) pterygium samples. No correlation between adduct levels and p53 protein expression was found in these samples. Additionally, the p53 gene mutation and p53 mutation pattern also did not correlate with BPDE-like DNA adduct levels. CONCLUSIONS Our data provides evidence that BPDE-like DNA adducts are indeed detected in pterygium samples, and they are only minor contributors to the abnormal p53 gene.
Development of flexor tendon surgery: twenty-five years of progress.

Regaining satisfactory digital function after flexor tendon laceration and repair within the digit has long been one of the most difficult problems in hand surgery. Until the 1960s it was universally recommended that tendons divided in the digit (then referred to as “no man’s land”) should not be repaired. Bunnell taught that “it is better to remove the tendons entirely from the finger and graft in new tendons smooth throughout its length. ” That dictum remained sacrosanct until the 1960s when reports by Verdan, Kleinert et al, and Kessler and Nissim challenged the concept that flexor tendons should not be repaired primarily. These investigators noted that when done correctly, immediate tendon suture would outperform secondary free tendon grafting. Armed by those encouraging reports, there was a gradual and cautious development of the concept and practice of primary flexor tendon repair. Initially, primary tendon repair was often combined with anecdotal protocols by Duran et al, Lister et al, and Strickland and Glogovac for applying varying amounts of early post-repair motion to the repaired tendons. As often happens with advances in medicine, the efforts to improve the performance of flexor tendon repairs were based almost entirely on individual experience and clinical experimentation with little or no scientific support. The last 25 years, however, have heralded an enormous amount of basic research designed to improve our knowledge of the structure of tendons, including the kinesiology, the biomechanics of their action on the joints they move, their biologic response to injury and repair, the mechanical characteristics of various tendon suture constructs, and the effect of post-repair motion stress on tendon strength and healing. These investigative efforts have given rise to improved methods of tendon repair, a greater emphasis on flexor sheath preservation and restoration, and protocols for the early application of passive and active wrist and digital motion as a means to more rapidly increase the strength and gliding of repaired tendons. The following sections will provide a concise review of some of the most important of these reports.
Multivariate analysis of 9 disease-associated variables for outcome prediction in patients with sepsis.

OBJECTIVE To assess the ability of 9 clinical or biological variables to predict outcome (survival or nonsurvival) using multiple regression and classification analyses. DESIGN Prospective, descriptive cohort study with no interventions. SETTING Surgical intensive care unit of a tertiary care hospital and a medical school research laboratory. PATIENTS Eighteen patients with a documented source of infection who met currently accepted criteria for sepsis syndrome or septic shock. MAIN OUTCOME MEASURES Prediction of survival or nonsurvival based on analysis of clinical (Multiple Organ Dysfunction score, Acute Physiology and Chronic Health Evaluation III scores) and biological (plasma levels of cortisol, interleukin 6, interleukin 10, phospholipase A2, soluble tumor necrosis factor receptor p75, and monocyte membrane tumor necrosis factor receptor levels) variables, with comparison of predicted and actual outcomes. RESULTS Plasma interleukin 6, interleukin 10, and phospholipase A2 concentrations were not significantly (P>.05) different between survivors and nonsurvivors. By standard, forward stepwise, and backward stepwise multiple regression analyses, only monocyte membrane tumor necrosis factor receptor levels measured at the onset of sepsis significantly predicted outcome in all 3 analyses. However, by both standard and backward stepwise analyses, Multiple Organ Dysfunction scores based on evaluation at the onset of sepsis and 24 hours later were also significant predictors of outcome. Classification analysis showed that assignment to outcome group was statistically significant when based on monocyte membrane tumor necrosis factor receptor levels determined at the onset of sepsis or on Multiple Organ Dysfunction scores assessed 24 hours after sepsis was diagnosed. CONCLUSION Although these findings were based on a relatively small cohort, both multiple regression and classification analyses indicated that only monocyte membrane tumor necrosis factor receptor levels are able to discriminate survivors from nonsurvivors at the onset of sepsis.
Primary progressive aphasia: Diagnosis, varieties, evolution

A referred cohort of 67 clinically defined PPA patients were compared to 99 AD patients with formal language and nonverbal cognitive tests in a case control design. Language fluency was determined at the first and last follow up visits. Quantitation of sulcal and ventricular atrophy on MRI was carried out in 46 PPA and 53 AD patients. Most PPA patients (57%) are relatively fluent when first examined. Visuospatial and memory functions are initially preserved. Aphemic, stuttering, “pure motor” presentation, or agrammatic aphasia are seen less frequently. Later most PPAs become logopenic and nonfluent, even those with semantic aphasia (dementia). In contrast, AD patients were more fluent and had relatively lower comprehension, but better overall language performance. MRI showed significant left sided atrophy in most PPA patients. Subsequent to PPA, 25 patients developed behavioral manifestations of frontotemporal dementia and 15 the corticobasal degeneration syndrome, indicating the substantial clinical overlap of these conditions. Language testing, particularly fluency scores supported by neuroimaging are helpful differentiating PPA from AD. The fluent–nonfluent dichotomy in PPA is mostly stage related. The aphemic-logopenic-agrammatic and semantic distinction is useful, but the outcomes converge. (JINS, 2003, 9, 710–719.)
Identification of MEK‐ and phosphoinositide 3‐kinase‐dependent signalling as essential events during Chlamydia pneumoniae invasion of HEp2 cells

The ability of Chlamydia pneumoniae to survive and cause disease is predicated on efficient invasion of cellular hosts. While it is recognized that chlamydial determinants are important for mediating attachment and uptake into non‐phagocytic cells, little is known about the bacterial ligands and cellular receptors that facilitate invasion or host cell signal transduction pathways implicated in this process. We used transmission and scanning electron microscopy to demonstrate that attachment of bacteria to host cells induced the appearance of microvilli on host cell membranes. Invasion occurred 30–120 min after cell contact with the subsequent loss of membrane microvilli. Using an epithelial cell infection model, C. pneumoniae invasion caused a rapid and sustained increase in MEK‐dependent phosphorylation and activation of ERK1/2, followed by PI 3‐kinase‐dependent phosphorylation and activation of Akt. Tyrosine phosphorylation of focal adhesion kinase (FAK) preceded its appearance in a complex with the p85 subunit of PI 3‐kinase during chlamydial invasion and isoform‐specific tyrosine phosphorylation of the docking protein Shc also occurred at the time of attachment and entry of bacteria. Chlamydia entry but not attachment could be abrogated with specific inhibitors of MEK, PI 3‐kinase and actin polymerization, demonstrating the importance of these signalling pathways and an intact actin cytoskeleton for C. pneumoniae invasion. These results suggest that activation of spe‐cific cell signalling pathways is an essential strategy used by C. pneumoniae to invade epithelial cells.
Lipin Expression Preceding Peroxisome Proliferator-activated Receptor-γ Is Critical for Adipogenesis in Vivo and in Vitro*

We recently identified mutations in the lipin gene, Lpin1, as the cause of lipodystrophy in the fatty liver dystrophy (fld) mouse. Here we identify impaired adipocyte differentiation as the basis for lipodystrophy in lipin-deficient mice and demonstrate that lipin is required for normal induction of the adipogenic gene transcription program. We found that the reduced adiposity in chow fed fld mice and resistance to obesity in fld mice fed a high-fat diet is associated with reduced adipogenic gene expression. Using primary mouse embryonic fibroblasts isolated from fld mice, we confirmed that lipin deficiency prevents normal lipid accumulation and induction of key adipogenic genes, including peroxisome proliferator-activated receptor (PPAR)γ and CCAAT enhancer-binding protein (C/EBP)α. However, our previous studies of daily gene expression in differentiating 3T3-L1 preadipocytes indicated that lipin expression is undetectable until about day 3 of differentiation, at a point after PPARγ and C/EBPα gene expression is established. This paradox was resolved by examining gene expression at 10-h intervals during 3T3-L1 cell differentiation, leading to detection of transient lipin expression at 10 h into the differentiation program, prior to the induction of PPARγ and C/EBPα. Consistent with a requirement for lipin expression upstream of PPARγ, differentiation of lipin-deficient mouse embryonic fibroblasts could be rescued by ectopic expression of PPARγ. Thus, we conclude that lipin expression is required prior to PPARγ during adipocyte differentiation.
Good Timing in the Cell Cycle for Precise DNA Repair by BRCA1

It is now clear that large DNA-binding proteins have evolved in mammals to orchestrate the relatively ancient processes of DNA recombinational repair. These proteins are recruited to accurately repair DNA double-strand breaks (DSBs) - the frequent, potentially lethal and mutagenic lesions in the genomes of all organisms. An essential mammalian regulator of DSB repair is BRCA1. Heterozygous BRCA1 mutations predispose individuals to breast, ovarian and other secondary cancers. BRCA1-defective cells exhibit reduced DSB repair, sensitivity to a wide range of DNA damaging agents, genomic instability and defects in the S-phase checkpoint, transcription and chromatin remodelling. DSBs can be repaired by Rad51/RPA-dependent homologous recombination (HR) or DNA-PK-dependent non-homologous end-joining (NHEJ). Both of these pathways can be imprecise and mutagenic. BRCA1 plays a central role in promoting accurate repair by both HR and NHEJ. Consistent with recent evidence, we have assembled a novel cell-cycle-dependent model in which DNA-PK inhibits RPA in S-phase of the cell cycle, while BRCA1 inhibits the exonuclease processivity of the MRE11/RAD50/NBS1 (MRN) complex and facilitates the removal of RPA in S and G2 phase. This model provides an explanation for how BRCA1 promotes accurate DSB repair during various phases of the cell cycle and also accounts for the dual effects that BRCA1 and MRN activity have upon DNA repair and S-phase arrest.