Miracle-dz/UniFAR-FTUs huggingface dataset:
Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T‐DM1) vs. treatment of physician's choice in previously treated HER2‐positive advanced breast cancer

In the phase III TH3RESA study (NCT01419197), 602 patients with HER2‐positive advanced breast cancer who received prior taxane therapy and ≥2 HER2‐directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T‐DM1) or treatment of physician's choice (TPC). A statistically significant progression‐free survival (PFS) benefit favoring T‐DM1 was demonstrated. Here, we examine the relationship between HER2‐related biomarkers and PFS in an exploratory analysis. Biomarkers assessed included HER2 (n = 505) and HER3 (n = 505) mRNA expression, PIK3CA mutation status (n = 410) and PTEN protein expression (n = 358). For biomarkers with continuous data (HER2, HER3, PTEN), subgroups were defined using median values (>median and ≤median). For all biomarker subgroups, median PFS was longer with T‐DM1 vs. TPC. The PFS benefit favoring T‐DM1 vs. TPC was numerically greater in the HER2 mRNA >median subgroup (7.2 vs. 3.4 months; unstratified hazard ratio [HR], 0.40; 95% CI, 0.28–0.59; p < 0.0001) vs. ≤median subgroup (5.5 vs. 3.9 months; HR, 0.68; 95% CI, 0.49–0.92; p = 0.0131). The PFS benefit with T‐DM1 was similar among HER3, PIK3CA and PTEN subgroups. Consistent with other reports, benefit was seen with T‐DM1 regardless of PIK3CA mutation status. In a multivariate analysis including an interaction term (treatment group by log2‐transformed HER2 mRNA), patients with higher HER2 mRNA levels benefited more from receiving T‐DM1 (HR, 0.84; 95% CI, 0.75–0.94; interaction p value = 0.0027). In summary, T‐DM1 prolonged median PFS in all biomarker subgroups analyzed, including activating PIK3CA mutations, with numerically greater benefit in patients with tumors expressing HER2 mRNA >median vs. ≤median.
Rationale and Methodological Options for Assessing Infectious Disease and Related Measures in Social Science Surveys

Infectious disease is an important, but often overlooked, component of population health in high-income nations. Common, everyday infections exact significant costs, including school and work absenteeism, reduced productivity, and substantial health care expenditures. Infectious disease also shapes trajectories of biological risk and health and may be causally linked to chronic disease risk later in life. The size, diversity, and representativeness of samples typically employed in survey-based studies of health present exceptional opportunities for advancing scientific knowledge on the social and economic determinants of infectious disease in childhood and adulthood and to investigate the long-term consequences of infectious disease for well-being and attainment across multiple domains. A wide range of interview-based, anthropometric, and biomarker measurement options are currently available for assessing infectious exposures, inflammation, and immune function in nonclinical settings. These methods afford opportunities for innovative, transdisciplinary research on the causes and consequences of infectious disease across the life course that can address questions of interest to social, life, and biomedical scientists.
Heparan sulfate proteoglycans mediate renal carcinoma metastasis

The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive tumor cells with high metastatic potential have enhanced invasion rates in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) in the glycocalyx plays an important role in this flow mediated mechanostransduction and upregulation of invasive and metastatic potential. In this study, highly metastatic renal cell carcinoma cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chamber and microfluidic assays, we show that flow‐enhanced invasion is suppressed in HS deficient cells. To assess the ability of these cells to metastasize in vivo, parental or knockdown cells expressing fluorescence reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from the NDST1 knockdown cells compared to control cells with intact HS. The ability of these cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx in tumor progression.
Genetic Diversity and Differentiation in Urban and Indigenous Populations of Mexico: Patterns of Mitochondrial DNA and Y-Chromosome Lineages

Aside from the admixture between indigenous people and people from overseas, populations in Mexico changed drastically after the Spanish conquest of the sixteenth century, forming an intricate history that has been underutilized in understanding the genetic population structure of Mexicans. To infer historical processes of isolation, dispersal, and assimilation, we examined the phylogeography of mitochondrial (mt) DNA and Y-chromosome lineages in 3,026 individuals from 10 urban and nine indigenous populations by identifying single nucleotide polymorphisms. A geographic array with a predominance of Amerindian lineages was observed for mtDNA, with northern indigenous populations being divergent from the central and southern indigenous populations; urban populations showed low differentiation with isolation by distance. Y-chromosome variation distinguished urban and indigenous populations through the Amerindian haplogroup Q frequency. The MtDNA and the Y-chromosome together primarily distinguished urban and indigenous populations, with different geographic arrays for both. Gene flow across geographical distance and between the urban and indigenous realms appears to have altered the pre-Hispanic phylogeography in central and southern Mexico, mainly by displacement of women, while maintaining the indigenous isolation in the north, southeast, and Zapotec regions. Most Amerindian mtDNA diversity currently occurs in urban populations and appears to be reduced among indigenous people.
Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia.

PURPOSE To compare the efficacy and safety of pravastatin, gemfibrozil, combined therapy, and placebo in the treatment of hypercholesterolemia. PATIENTS AND METHODS At 5 centers in Sweden and 2 in Finland, 290 ambulatory patients were randomized to active treatment or placebo for 12 weeks following a single-blind placebo lead-in period. The study was double-blind and placebo-controlled. Patients has plasma total cholesterol levels of at least 6.0 mmol/L or in the 90th percentile by age and sex and triglycerides less than 4.0 mmol/L. Concentrations of lipids, lipoproteins, and apolipoproteins were measured, and clinical laboratory tests included liver function and creatine kinase determinations. RESULTS Pravastatin reduced total cholesterol (26.3% versus 15.2%, p < or = 0.01), low-density lipoprotein cholesterol (LDL-C) (33.5% versus 16.8%, p < or = 0.01), and apolipoprotein B (28.8% versus 15.3%, p < or = 0.01) more than gemfibrozil. Gemfibrozil reduced very-low-density lipoprotein cholesterol (VLDL-C) (49.1% versus 21.9%, p < or = 0.01) and triglycerides (42.2% versus 14.2%, p < or = 0.01) and increased high-density lipoprotein cholesterol (HDL-C) (15.2% versus 5.9%, p < or = 0.01) more than pravastatin. Pravastatin and gemfibrozil increased apolipoprotein A-I comparably (3.3% versus 5.0%, p = NS). The combination significantly (p < or = 0.01) reduced total cholesterol (29.0%), LDL-C (37.1%), VLDL-C (49.4%), and apolipoprotein B (31.6%), and increased HDL-C (16.8%). The combination reduced the total cholesterol/HDL-C (39.3%) and LDL-C/HDL-C (45.8%) ratios significantly (p < 0.01). Adverse events and clinical laboratory abnormalities were generally mild and transient in all groups, although creatine kinase tended to be higher with combination therapy. Study drugs were withdrawn from two patients with asymptomatic creatine kinase elevations. Severe myopathy was not observed; however, the presence of subclinical musculoskeletal effects cannot be excluded. CONCLUSIONS Co-administration of pravastatin and gemfibrozil combined the specific effects of the two drugs on lipoprotein concentrations and ratios. The incidence of side effects was low; severe myopathy did not occur. The combination may be useful in selected cases of combined hyperlipidemia; however, since myopathy at a low incidence or after long-term therapy cannot be excluded, the routine use of combination therapy is not advisable.
Sex-Based Differences in the Determinants of Old Age Life Expectancy: The Influence of Perimenopause

ABSTRACT Studies using the sensitive periods framework typically examine the effects of early life exposures on later life health, due to the significant growth and development occurring during the first few years of life. The menopausal transition (i.e., perimenopause) is similarly characterized by rapid physiological change, yet rarely has been tested as a sensitive window in adulthood. Cohort mortality data drawn from three historic populations, Sweden (1751–1919), France (1816–1919), and England and Wales (1841–1919), were analyzed using time series methods to assess whether conditions at midlife significantly influenced or “programmed” later life longevity. Results indicated a significant inverse association between mortality at ages 45–49, the average age range in which perimenopause occurred, and life expectancy at age 60 among females in all three countries. Study findings suggest a degree of plasticity associated with women’s aging and, in particular, the age group correlated with perimenopause.
Endometrial cancer risk prediction including serum‐based biomarkers: results from the EPIC cohort

Endometrial cancer risk prediction models including lifestyle, anthropometric and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines and cytokines were evaluated in a step‐wise backward selection process; biomarkers were retained at p < 0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C‐statistic for all biomarkers alone, and change in C‐statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000‐fold) to adjust for over‐fitting. Adiponectin, estrone, interleukin‐1 receptor antagonist, tumor necrosis factor‐alpha and triglycerides were selected into the model. After accounting for over‐fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination.
Simuliidae (Diptera: Culicomorpha) no Brasil: X - Descrição de Simulium (Psaroniocompsa) guaporense sp.n

Simulium (Psaroniocompsa) guaporense, found in the Hydrogeological Province of the Central Shield, is described. S. (P.) guaporense belongs to the "siolii" group (S.siolii, S.lourencoi, S.damascenoi) described by Py-Daniel (1988).
Multimodal lung cancer screening using the ITALUNG biomarker panel and low dose computed tomography. Results of the ITALUNG biomarker study

Asymptomatic high‐risk subjects, randomized in the intervention arm of the ITALUNG trial (1,406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1,356), in which samples of blood and sputum were analyzed for plasma DNA quantification (cut off 5 ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen‐detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2‐years) and biomarker tests after a suspect Non Calcific Nodule follow‐up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen‐detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71 and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%.
The Human Central Nervous System: A Synopsis and Atlas

The Human Central Nervous System is an excellently diagrammed atlas and brief synopsis of neuroanatomy, extending to and from the cortices, depicting and defining functions of the afferent and efferent tracts. The descriptive material is at times distant from the diagrams, necessitating some shifting back and forth but preserving the continuity of the graphic and descriptive material. The drawings are well numbered and labeled, but the labels are in Latin and are abbreviated. Three-dimensional diagramming permits the viewer to follow tracts at various levels of the spinal cord or brain. The use of color at least to differentiate some of the nervus tracts would have further enhanced the book. Likewise the anatomy might have been more easily ingested and related had some effort been made to make clinical or physiological correlations. However, whatever deficiencies exist, they are more than compensated for by the beauty and clarity of the drawings. Medical
Dietary intake of selected nutrients and persistence of HPV infection in men

Human papillomavirus (HPV) infection is a common sexually transmitted disease. Although often transitory, persistent oncogenic HPV infection may progress to a precursor lesion and, if not treated, can further increase the risk of cancer. The purpose of this study was to investigate the relation between dietary intake and HPV persistent infection in men of a Brazilian cohort. The study population consisted of 1,248 men from the Brazilian cohort of the HIM (HPV in Men) Study, ages 18 to 70 years, who completed a quantitative food frequency questionnaire. U Mann‐Whitney test was used to assess differences in median nutrient intake of selected nutrients. The association of dietary intake and persistent HPV infection was assessed in multivariate logistic models. The prevalence of any HPV infection at baseline was 66.6%. Of 1,248 participants analyzed, 1,211 (97.0%) were HPV positive at one or more times during the 4 years of follow‐up and 781 (62.6%) were persistently HPV positive. Men with nonpersistent oncogenic HPV infections had higher median intake of retinol (p = 0.008), vitamin A (p < 0.001) and folate (DFE; p = 0.003) and lower median intake of energy (p = 0.005) and lycopene (p = 0.008) in comparison to men with persistent oncogenic infections. No significant association was found between selected nutrients and persistent oncogenic HPV infection. For nononcogenic persistent infections, only vitamin B12 intake was significantly associated (p = 0.003, test for trend). No association was observed between dietary intake and persistent oncogenic‐type HPV infection; however, vitamin B12 intake was inversely associated with nononcogenic HPV persistence.
Genome‐wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. It is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS‐specific characteristics in localization and frequencies of chromosomal breakages strongly implicate a specific set of responsible driver genes or a specific mechanism of fragility induction. In this study, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples using whole‐genome CytoScan High Density arrays (Affymetrix, Santa Clara, CA). Genes or regions frequently targeted by SCNAs were identified. Breakage analysis revealed OS specific unstable regions in which well‐known OS tumor suppressor genes, including TP53, RB1, WWOX, DLG2 and LSAMP are located. Certain genomic features, such as transposable elements and non‐B DNA‐forming motifs were found to be significantly enriched in the vicinity of chromosomal breakage sites. A complex breakage pattern—chromothripsis—has been suggested as a widespread phenomenon in OS. It was further demonstrated that hyperploidy and in particular chromothripsis were strongly correlated with OS patient clinical outcome. The revealed OS‐specific fragility pattern provides novel clues for understanding the biology of OS.
Sequencing on the SOLiD 5500xl System – in-depth characterization of the GC bias

ABSTRACT Different types of sequencing biases have been described and subsequently improved for a variety of sequencing systems, mostly focusing on the widely used Illumina systems. Similar studies are missing for the SOLiD 5500xl system, a sequencer which produced many data sets available to researchers today. Describing and understanding the bias is important to accurately interpret and integrate these published data in various ongoing research projects. We report a particularly strong GC bias for this sequencing system when analyzing a defined gDNA mix of 5 microbes with a wide range of different GC contents (20–72%) when comparing to the expected distribution and Illumina MiSeq data from the same DNA pool. Since we observed this bias already under PCR-free conditions, changing the PCR conditions during library preparation – a common strategy to handle bias in the Illumina system - was not relevant. Source of the bias appeared to be an uneven heat distribution during the SOLiD emulsion PCR (ePCR) - for enrichment of libraries prior loading – since ePCR in either small pouches or in 96-well plates improved the GC bias. Sequencing of chromatin immunoprecipitated DNA (ChIP-seq) is a common approach in epigenetics. ChIP-seq of the mixed source histone mark H3K9ac (acetyl Histone H3 lysine 9), typically found on promoter regions and on gene bodies, including CpG islands, performed on a SOLiD 5500xl machine, resulted in major loss of reads at GC rich loci (GC content ≥ 62%), not explained by low sequencing depth. This was improved with adaptations of the ePCR.
Identification of novel RNA isoforms of LMNA

ABSTRACT The nuclear lamina is a proteinaceous meshwork situated underneath the inner nuclear membrane and is composed of nuclear lamin proteins, which are type-V intermediate filaments. The LMNA gene gives rise to lamin A and lamin C through alternative splicing. Mutations in LMNA cause multiple diseases known as laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disorder caused by a point mutation that activates a cryptic 5′ splice site in exon 11, resulting in a 150 bp deletion in the LMNA mRNA and the production of the dominant lamin A isoform progerin. During RNA sequencing analysis of wild type and HGPS patient skin fibroblasts, we discovered two novel LMNA isoforms. LMNAΔ447 and LMNAΔ297 use an alternative 3′ splice acceptor site in the 3′ untranslated region, and either the HGPS cryptic 5′ splice site in exon 11 or the wild type 5′ splice site. Both isoforms are present at low levels in HGPS patient and wild type cells in multiple cell types. We validate and quantify the expression levels of these novel isoforms in HGPS and wild type fibroblasts. Overexpression of either LMNAΔ447 or LMNAΔ297 is not sufficient to induce the typical HGPS cellular disease phenotypes and no significant difference in the two isoforms were found between young and old fibroblasts. These results identify and characterize two novel RNA isoforms of LMNA produced through alternative splicing.
The student case presentation: An integral component of the undergraduate curriculum

Concern among our medical students and faculty about a lack of teaching in the art of case presentation led us to modify the curriculum of our junior clerkship in Internal Medicine to introduce formal teaching of this skill. We used a modified Delphi expert‐opinion technique to develop a standardized case report format that was distributed to students and tutors at the beginning of the 10‐week course. Each student was required to present two cases to his or her tutor and clinical group. The presentations were evaluated, discussed, and marked by the entire group. Evaluation of the success of the innovation 1 year later revealed enthusiastic acceptance by tutors and students. Students’ marks for the case presentations were similar to those obtained on written case reports—indicating concurrent validity of the evaluations done by the entire tutorial group.
Gynecomastia: glandular-liposculpture through a single transaxillary one hole incision

Abstract Gynecomastia is characterized by the benign proliferation of breast tissue in men. Herein, we present a new method for the treatment of gynecomastia, using ultrasound-assisted liposuction with both conventional and reverse-cutting edge tip cannulas in combination with a pull-through lipectomy technique with pituitary forceps through a single transaxillary incision. Thirty patients were treated with this technique at the author’s institution from January 2010 to January 2015. Ten patients were treated with conventional surgical excision of the glandular/fibrous breast tissue combined with liposuction through a periareolar incision before January 2010. Medical records, clinical photographs and linear analog scale scores were analyzed to compare the surgical results and complications. The patients were required to rate their cosmetic outcomes based on the linear analog scale with which they rated their own surgical results; the mean overall average score indicated a good or high level of satisfaction. There were no incidences of skin necrosis, hematoma, infection and scar contracture; however, one case each of seroma and nipple inversion did occur. Operative time was reduced overall using the new technique since it is relatively simple and straightforward. According to the evaluation by the four independent researchers, the patients treated with this new technique showed statistically significant improvements in scar and nipple-areolar complex (NAC) deformity compared to those who were treated using the conventional method. Glandular liposculpture through a single transaxillary incision is an efficient and safe technique that can provide aesthetically satisfying and consistent results.