tbuckley/cabot-search huggingface dataset:
Prevalence study of carcinoma in situ of testis in oligozoospermic men
Authors: R. Rajentheran, J. Kenworthy, M. Cunnington, A. Giwercman
Journal: BMJ (1998)

Editor—Giwercman et al evaluated the need for screening for carcinoma in situ of the testis in oligozoospermic men from infertile couples.1 They concluded that these men do not have an increased risk of carcinoma in situ, therefore implying that screening is not justified. 

Their study fails to provide the information required to form a proper judgment on the potential benefits of screening. Although no cases of carcinoma in situ of the testis were detected among the 207 men studied, the confidence intervals reported are compatible with a prevalence of almost 18 in every 1000 men and a relative risk 4.6 times that in the general population. This represents a significantly increased risk. To put this in context, the detection rate for breast cancer in the first wave of the NHS breast screening programme was 6.2/1000 women screened.2

No consideration was given to the suitability of testicular biopsy as a screening test. While the uptake rate in the study was 94%, the acceptability of such a highly invasive technique should be addressed. 

The study population comprised men referred to Danish infertility clinics. The authors claim that this population represents the target group for screening. They admit, however, that not all oligozoospermic men are currently referred. If screening were implemented, referral rates would probably change; therefore the study group may not be representative of the target population for screening. 

The basis for evaluating possible screening tests is well established.3 In this instance we believe that the study group was too small for the true prevalence of carcinoma in situ of the testis to be accurately established. Any future evaluation should be carried out in a more representative population and should more fully assess the acceptability of testicular biopsy.
Enhanced in vivo platelet adhesion in vasodilator-stimulated phosphoprotein (VASP)–deficient mice
Authors: Steffen Massberg, Sabine Grüner, Ildiko Konrad, Maisa I. Garcia Arguinzonis, Martin Eigenthaler, Kathrin Hemler, Julia Kersting, Christian Schulz, Iris Müller, Felicitas Besta, Bernhard Nieswandt, Ulrich Heinzmann, Ulrich Walter, Meinrad Gawaz
Journal: Blood (2003)
Validating the Probe-to-Bone Test and Other Tests for Diagnosing Chronic Osteomyelitis in the Diabetic Foot
Authors: Rosario Morales Lozano, Maria L. González Fernández, David Martinez Hernández, Juan V. Beneit Montesinos, Sagrario Guisado Jiménez, Maximo A. Gonzalez Jurado
Journal: Diabetes Care (2010)

To compare the diagnostic characteristics of tests used for a prompt diagnosis of chronic osteomyelitis in the diabetic foot, using bone histology as the criterion standard. The tests assessed were probe-to-bone (PTB), clinical signs of infection, radiography signs of osteomyelitis, and ulcer specimen culture.A prospective study was performed on patients with foot ulcers referred to our diabetic foot clinic. Ulcer infection was diagnosed by recording clinical signs of infection and taking specimens for culture. The presumptive diagnosis of osteomyelitis was based on these results and the findings of a plain X-ray and PTB test. All patients with a clinical suspicion of bone infection were subjected to surgical treatment of the affected bone. During surgery, bone specimens were obtained for a histological diagnosis of osteomyelitis.Over 2.5 years, 210 foot lesions were consecutively examined and 132 of these wounds with clinical suspicion of infection selected as the study sample. Of these, 105 (79.5%) lesions were diagnosed as osteomyelitis. Among the tests compared, the best results were yielded by the PTB test including an efficiency of 94%, sensitivity of 98%, specificity of 78%, positive predictive value of 95%, and negative predictive value of 91% (P < 0.001, κ 0.803); the positive likelihood ratio was 4.41, and the negative likelihood ratio was 0.02 (95% CI).In our outpatient population with a high prevalence of osteomyelitis, the PTB test was of greatest diagnostic value, especially for neuropathic ulcers, and proved to be efficient for detecting osteomyelitis in the diabetic foot.
New genes drive the evolution of gene interaction networks in the human and mouse genomes
Authors: Wenyu Zhang, Patrick Landback, Andrea R. Gschwend, Bairong Shen, Manyuan Long
Journal: Genome biology (2015)

The origin of new genes with novel functions creates genetic and phenotypic diversity in organisms. To acquire functional roles, new genes must integrate into ancestral gene-gene interaction (GGI) networks. The mechanisms by which new genes are integrated into ancestral networks, and their evolutionary significance, are yet to be characterized. Herein, we present a study investigating the rates and patterns of new gene-driven evolution of GGI networks in the human and mouse genomes.We examine the network topological and functional evolution of new genes that originated at various stages in the human and mouse lineages by constructing and analyzing three different GGI datasets. We find a large number of new genes integrated into GGI networks throughout vertebrate evolution. These genes experienced a gradual integration process into GGI networks, starting on the network periphery and gradually becoming highly connected hubs, and acquiring pleiotropic and essential functions. We identify a few human lineage-specific hub genes that have evolved brain development-related functions. Finally, we explore the possible underlying mechanisms driving the GGI network evolution and the observed patterns of new gene integration process.Our results unveil a remarkable network topological integration process of new genes: over 5000 new genes were integrated into the ancestral GGI networks of human and mouse; new genes gradually acquire increasing number of gene partners; some human-specific genes evolved into hub structure with critical phenotypic effects. Our data cast new conceptual insights into the evolution of genetic networks.
Pulmonary Hypertension in Transgenic Mice Expressing a Dominant-Negative BMPRII Gene in Smooth Muscle
Authors: James West, Karen Fagan, Wolfgang Steudel, Brian Fouty, Kirk Lane, Julie Harral, Marloes Hoedt-Miller, Yuji Tada, John Ozimek, Rubin Tuder, David M. Rodman
Journal: Circulation Research (2004)

Bone morphogenetic peptides (BMPs), a family of cytokines critical to normal development, were recently implicated in the pathogenesis of familial pulmonary arterial hypertension. The type-II receptor (BMPRII) is required for recognition of all BMPs, and targeted deletion of BMPRII in mice results in fetal lethality before gastrulation. To overcome this limitation and study the role of BMP signaling in postnatal vascular disease, we constructed a smooth muscle-specific transgenic mouse expressing a dominant-negative BMPRII under control of the tetracycline gene switch (SM22-tet-BMPRII(delx4+) mice). When the mutation was activated after birth, mice developed increased pulmonary artery pressure, RV/LV+S ratio, and pulmonary arterial muscularization with no increase in systemic arterial pressure. Studies with SM22-tet-BMPRII(delx4+) mice support the hypothesis that loss of BMPRII signaling in smooth muscle is sufficient to produce the pulmonary hypertensive phenotype.
Deletion of PTEN Promotes Tumorigenic Signaling, Resistance to Anoikis, and Altered Response to Chemotherapeutic Agents in Human Mammary Epithelial Cells
Authors: Michele I. Vitolo, Michele B. Weiss, Marta Szmacinski, Khola Tahir, Todd Waldman, Ben Ho Park, Stuart S. Martin, David J. Weber, Kurtis E. Bachman
Journal: Cancer Research (2009)

Many cancers, including breast cancer, harbor loss-of-function mutations in the catalytic domain of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or have reduced PTEN expression through loss of heterozygosity and/or epigenetic silencing mechanisms. However, specific phenotypic effects of PTEN inactivation in human cancer cells remain poorly defined without a direct causal connection between the loss of PTEN function and the development or progression of cancer. To evaluate the biological and clinical relevance of reduced or deleted PTEN expression, a novel in vitro model system was generated using human somatic cell knockout technologies. Targeted homologous recombination allowed for a single and double allelic deletion, which resulted in reduced and deleted PTEN expression, respectively. We determined that heterozygous loss of PTEN in the nontumorigenic human mammary epithelial cell line MCF-10A was sufficient for activation of the phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase pathways, whereas the homozygous absence of PTEN expression led to a further increased activation of both pathways. The deletion of PTEN was able to confer growth factor-independent proliferation, which was confirmed by the resistance of the PTEN(-/-) MCF-10A cells to small-molecule inhibitors of the epidermal growth factor receptor. However, neither heterozygous nor homozygous loss of PTEN expression was sufficient to promote anchorage-independent growth, but the loss of PTEN did confer apoptotic resistance to cell rounding and matrix detachment. Finally, MCF-10A cells with the reduction or loss of PTEN showed increased susceptibility to the chemotherapeutic drug doxorubicin but not paclitaxel.
PIEPOC: A New Prognostic Index for Advanced Epithelial Ovarian Cancer—Japan Multinational Trial Organization OC01-01
Authors: Satoshi Teramukai, Kazunori Ochiai, Harue Tada, Masanori Fukushima
Journal: Journal of Clinical Oncology (2007)

The purpose of this study was to construct a simple and powerful prognostic index (PI) of epithelial ovarian cancer, the PIEPOC.In a retrospective review, data from 768 women with stage III or IV epithelial ovarian cancer from 24 institutions in Japan were evaluated for clinical features predictive of overall survival. A PI and risk groups to predict overall survival after initial surgery were developed using the proportional hazards regression model.Of six factors, the four prognostic factors that remained independently significant in the analysis of a training sample (538 randomly selected patients) were age, performance status (PS), histologic cell type, and residual tumor size. From the regression function, we derived a PI = 1 (if age 70 and above) + 1 (if PS 1 or 2) + 2 (if PS 3 or 4) + 1 (if mucinous or clear-cell) + 2 (if residual size 0.1 cm and above). Patients were classified into three risk groups (PIEPOC): low risk (PI 0-2), intermediate risk (PI 3), and high risk (PI 4-6). The PIEPOC was equally predictive in a validation sample (n = 230), identifying three groups (5-year survival: 0.67 in low, 0.43 in intermediate, 0.17 in high risk).Our proposed PI, the PIEPOC, was predictive in our patient population and may have utility in clinical practice. Prospective studies would be needed to confirm the prognostic predictive ability of the PIEPOC for patients with advanced epithelial ovarian cancer.
A Functional Polymorphism in the NAD(P)H Oxidase Subunit <i>CYBA</i> Is Related to Gene Expression, Enzyme Activity, and Outcome in Non–Hodgkin Lymphoma
Authors: Marion Hoffmann, Markus A. Schirmer, Mladen V. Tzvetkov, Markus Kreuz, Marita Ziepert, Leszek Wojnowski, Dieter Kube, Michael Pfreundschuh, Lorenz Trümper, Markus Loeffler, Jürgen Brockmöller
Journal: Cancer Research (2010)

Abstract NAD(P)H oxidase is a major endogenous source of reactive oxygen species (ROS). ROS may not only be involved in carcinogenesis but also in efficacy of chemotherapeutic agents like doxorubicin. By a comprehensive genotyping approach covering 48 genetic polymorphisms (single-nucleotide polymorphisms) in five subunits of phagocytic NAD(P)H oxidase, we asked whether they affect gene expression, enzymatic activity, and outcome of CHO(E)P chemotherapy. A highly consistent effect was observed for the CYBA 640A&amp;gt;G variant. In peripheral blood granulocytes of 125 healthy volunteers, the G allele of 640A&amp;gt;G was associated with lower NAD(P)H oxidase activity (P = 0.006). Moreover, the G allele was associated with lower mRNA and protein expression (both P = 0.02). Of clinical importance, the outcome of patients suffering from non-Hodgkin lymphoma and treated with CHO(E)P regimen was dependent on the CYBA 640A&amp;gt;G polymorphism. In an exploratory study (n = 401), carriers of 640GG had an event-free survival (EFS) risk ratio of 1.95 [95% confidence interval (95% CI), 1.31–2.90; P = 0.001] compared with 640AA. In a confirmatory set (n = 477), the risk ratios were 1.53 (1.04–2.25, P = 0.03). The complete set of 878 patients showed a relative risk of 1.72 (1.30–2.26) and 1.59 (1.14–2.21) for EFS and overall survival, respectively. Further molecular-biological experiments showed lower expression and reduced stability of transcripts with the G allele in lymphoblastoid cell lines. Transfection of allele-specific plasmids into HEK293 cells elicited lower activity for the G allele in a luciferase reporter gene construct. Thus, CYBA 640A&amp;gt;G was shown to be a functional polymorphism with possible consequences for patients receiving CHO(E)P chemotherapy and might have further implications for other ROS-mediated modalities. Cancer Res; 70(6); 2328–38
Detection of Chromosome Abnormalities Pre–High-Dose Treatment in Patients Developing Therapy-Related Myelodysplasia and Secondary Acute Myelogenous Leukemia After Treatment for Non-Hodgkin’s Lymphoma
Authors: Debra M. Lillington, Ivana N.M. Micallef, Emily Carpenter, Michael J. Neat, John A.L. Amess, Janet Matthews, Nicola J. Foot, Bryan D. Young, T. Andrew Lister, Ama Z.S. Rohatiner
Journal: Journal of Clinical Oncology (2001)

To assess whether pre-high-dose therapy (HDT)-related factors play a critical role in the development of therapy-related myelodysplasia (tMDS) or secondary acute myelogenous leukemia (sAML).Twenty-nine of 230 patients with a primary diagnosis of non-Hodgkin's lymphoma (NHL) developed tMDS/sAML after HDT comprising cyclophosphamide and total-body irradiation (TBI) supported by autologous hematopoietic progenitor cells. G-banding and fluorescence in-situ hybridization (FISH) were used to detect clonal cytogenetic abnormalities.The majority of patients showed complex karyotypes at diagnosis of tMDS/sAML containing, in particular, complete or partial loss of chromosomes 5 and/or 7. Using single locus-specific FISH probes, significant levels of clonally abnormal cells were found before HDT in 20 of 20 tMDS/sAML patients screened, compared with three of 24 patients screened who currently have not developed tMDS/sAML, at a median follow-up of 5.9 years after HDT.Prior cytotoxic therapy may play an important etiologic role and may predispose to the development of tMDS/sAML. Using a triple FISH assay designed to detect loss of chromosomal material from 5q31, 7q22, or 13q14, significant levels of abnormal cells can be detected before HDT and may predict which patients are at increased risk of developing secondary disease. Further prospective evaluation of this FISH assay is warranted to determine its predictive power in this setting.
Increased serum procollagen III aminoterminal peptide in myelofibrosis
Authors: S. Hochweiss, S. Fruchtman, E. G. Hahn, H. Gilbert, P. B. Donovan, J. Johnson, J. D. Goldberg, P. D. Berk
Journal: American Journal of Hematology (1983)

Abstract Myelofibrosis has been shown to involve an increase in type III collagen in the marrow. The aminoterminal procollagen III (PC III) peptide fragment is released during the production of PC III by fibroblasts and its serum level is therefore a marker for type III collagen synthesis. Using a recently developed sensitive radioimmunoassay, serum levels of PC III peptide were measured in 30 patients with myeloproliferative disease and 23 normal volunteers. Levels were found to be elevated above normal values in patients with polycythemia vera, even more elevated in patients with polycythemia and evidence of secondary myelofibrosis with mycloid metaplasia, and most strikingly elevated in patients with agnogenic myeloid metaplasia and severe marrow fibrosis. There was a significant association between serum levels of PC III peptide and the extent of reticulin fibrosis in bone marrow biopsies. Serum PC III level appears to be a quantitative marker for myelofibrosis.
Varicocele and male infertility: Part II: The pathophysiology of varicoceles in the light of current molecular and genetic information
Authors: J. L. Marmar
Journal: Human Reproduction Update (2001)

Varicoceles are a common cause of male infertility, but despite data being obtained from animal models and human studies the pathophysiology remains unclear. Recently, molecular and genetic information has been reported on men with varicoceles which may shed new light onto the causes of decreased semen parameters and poor sperm function. Here, a number of studies are reviewed in an attempt to develop a working hypothesis for the relationship of varicoceles and infertility. New studies on testicular tissue of men with varicoceles have demonstrated increased apoptosis among developing germ cells, which may be the cause of oligospermia. Other studies with semen have shown increased levels of reactive oxygen species (ROS) in association with poor sperm motility. Recent studies of morphologically abnormal spermatozoa have demonstrated disruption of the sperm head actin by cadmium, a cation reported to be present in high concentrations among some men with varicoceles. Finally, microdeletions of the alpha-1 subunit of the sperm calcium channels in a proportion of men with varicoceles suggests a genetic defect leading to abnormal acrosomal function. The intent of this review was to explain the pathophysiology of varicoceles, and the findings seem to support a 'co-factor' hypothesis. In order for varicoceles to be associated with infertility, they exist as 'co-factors' along with other molecular/genetic problems.
Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype
Authors: Elena Bresin, Erica Rurali, Jessica Caprioli, Pilar Sanchez-Corral, Veronique Fremeaux-Bacchi, Santiago Rodriguez de Cordoba, Sheila Pinto, Timothy H.J. Goodship, Marta Alberti, David Ribes, Elisabetta Valoti, Giuseppe Remuzzi, Marina Noris
Journal: Journal of the American Society of Nephrology (2013)

Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype–phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%–10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation.
A cyclosporin A/maltosyl- -cyclodextrin complex for inhalation therapy of asthma
Authors: H. Fukaya, A. Iimura, K. Hoshiko, T. Fuyumuro, S. Noji, T. Nabeshima
Journal: European Respiratory Journal (2003)

The inhalation of cyclosporin (Cs)A to the lung is limited by its hydrophobic properties. In order to improve the poor solubility of CsA, cyclodextrin (CD) was evaluated for its suitability for dry powder inhaler formation, and the benefit of an inhaled CsA/CD complex in vivo was demonstrated. The solubilising effect of CDs on CsA was measured by high-performance liquid chromatography. Ciliostatic activity and haemolysis were determined to assess some safety profiles of CDs. The efficacy of an inhaled CsA/CD complex was evaluated by eosinophil infiltration into the bronchoalveolar lavage fluid in actively sensitised mice. CDs markedly improved the poor solubility of CsA. The ciliostatic and haemolytic activities of maltosyl‐α‐CD were the weakest of all the tested CDs. CsA inhaled alone showed inhibitory effects on allergen-induced eosinophilia. Inhalation of the complex of CsA with maltosyl‐α‐CD, where the dose of CsA was approximately nine-times less than that of CsA inhaled alone, also inhibited eosinophil accumulation significantly, with a longer duration of action in comparison with the response to CsA alone. Thus the effective dose of cyclosporin A could be reduced by formation of a complex with maltosyl‐α‐cyclodextrin, and a wider therapeutic safety margin by inhalation of cyclosporin A as a complex with maltosyl‐α‐cyclodextrin could be expected.
Skin Eruptions Occurring in Patients already Suffering from Infected Wounds
Authors: G. G. S. Taylor
Journal: BMJ (1897)

wall, pendulous parts of the genitalia, seem to be invariably affected.The abdominal viscera and intestinal canal also are prone to attack.Internal pain is followed by indigestion, sometimes by vomiting, and diarrhcea is frequent.This latter, indeed, seems generally to act as a curative agency, and to occur at a period of crisis.In one case that came under my notice there was deep perineal effusion into the perirectal tissue, which was followed by sharp dysentery.
PREOPERATIVE PARTITIONING OF PULMONARY VASCULAR IMPEDANCE: A NOVEL HEMODYNAMIC INDEX FOR OPERABLE AND INOPERABLE CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION
Authors: Maria J. Ruiz-Cano, Juan C. Grignola, Pilar Escribano, José Cortina, Teresa Velázquez, Miguel A. Gómez Sánchez, Juan F. Delgado, Carlos Sáenz de la Calzada
Journal: Journal of the American College of Cardiology (2010)
Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG)
Authors: D. Mavroudis, E. Saloustros, N. Malamos, S. Kakolyris, I. Boukovinas, P. Papakotoulas, N. Kentepozidis, N. Ziras, V. Georgoulias
Journal: Annals of Oncology (2015)