tbuckley/cabot-search huggingface dataset:
Clinical significance and therapeutic potential of PD-L/PD-1 pathway in human pancreatic cancer
Authors: Takeo Nomi, Masayuki Sho, Takahiro Akahori, Kaoru Hamada, Hiromichi Kanehiro, Michiyoshi Hisanaga, Naoya Ikeda, Miyuki Azuma, Yoshiyuki Nakajima
Journal: Cancer Research (2006)

413  PD-L/PD-1 pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. However, the clinical relevance of PD-L/PD-1 pathway on prognosis and characteristics of cancer patients has not been fully determined yet. In this study, we tried to reveal the clinical importance and therapeutic potential of PD-L/PD-1 pathway in pancreatic cancer that is one of most aggressive and intractable tumors. To this end, we examined PD-L1 and PD-L2 expression by RT-PCR in four human pancreatic cancer cell lines including PK-8, MiaPaca-2, Panc-1 and Capan-2. Both PD-L1 and PD-L2 were expressed in all cell lines. By immunohistochemical analysis using anti-human PD-L1 (MIH1) and anti-human PD-L2 (MIH18) mAb, we examined the expressions in 51 patients with pancreatic cancer who underwent surgery. PD-L1 and PD-L2 were stained mainly in the cytoplasm of pancreatic cancer cells. PD-L1 positive patients (n=20) had a significantly poorer prognosis than the negative patients (n=31) (P=0.023) (1-year survival rate, 35.6% vs 60.3%, 2-year survival 10.7% vs 32.8%, 3-year survival 10.7% vs 23.4%, respectively). There were no significant differences in prognosis between PD-L2 positive (n=14) and negative patients (n=37). In subgroup analysis, significant differences were noted in survival rate between positive and negative patients of PD-L1 when categorized by the following variables: T3 status (P=0.032, 1-year survival 44.9% vs 62.9%), N0 status (P=0.033, 1-year survival 25.0% vs 87.5%) and pathologic stage of IIA (P=0.010, 1-year survival 25% vs 100%). Furthermore, immunohistochemical analysis revealed that PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, more profoundly CD8+ T cells (CD4+ T cell P=0.026, CD8+ T cell P
Waiting for the working draft from the human genome project
Authors: L. R Cardon
Journal: BMJ (2000)

See also p 1257

Hyped as biology's holy grail, the generation of a consensus sequence of the entire human genome is the flagship endeavour of the human genome project.1 2 About 1.7 billion base pairs have been sequenced so far in publicly funded projects, representing just over 50% of the genome and including the complete sequence of one full chromosome.3 By June 2000, another one billion base pairs are expected to be sequenced, completing 90% of the genome at what is called fivefold sequencing coverage (this being the number of times each part of the sequence is read in order to eliminate errors).5

The aim of the project, 99% completion of the genome at tenfold coverage, seems on track for its deadline of 2003.4 By any standards, an effectively complete sequence will be a remarkable achievement.6 However, the hyperbole that surrounds it may reflect the scale of the undertaking rather than its immediate impact. A consensus sequence will make it possible to carry out a wide variety of studies involving gene content (even the number of genes remains contentious), comprehensively classify gene or …
An antibody-FRET conjugate that sheds light on intracellular antibody-drug conjugate activation.
Authors: Damon Meyer, Patrick Burke, Angelyn Larkin, Roger Zabinski, Ruth Moser, Timothy Lewis, Leia Smith, Ivan Stone, Dennis Benjamin
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4086 

Antibody-drug conjugates (ADCs) incorporating protease sensitive linkages release drugs through the action of proteases after being taken into cells. In target cells ADC uptake is antigen mediated, and drug release occurs in lysosomes. To help define the time and location of drug release a FRET reagent was designed and synthesized. The FRET reagent comprises a fluorophore (Alexa Fluor 488) and a quencher (DABMI) connected through the same linkage by which drugs are attached to antibodies in ADCs. When the antibody-FRET conjugate (AFC) encounters proteolytic activity capable of releasing drug from an ADC, the linkage between fluorophore and quencher is broken revealing a fluorescent signal. Characterization of AFCs prepared with the FRET reagent indicates that the fluorescence is very efficiently quenched in the native form, as the fluorescent signal increases approximately 250 fold when the attachment to the quencher is ruptured. Tumor cells treated with suitable AFCs in vitro , and examined live by fluorescence microscopy, show the appearance of punctate fluorescence characteristic of lysosomes, starting about two hours after exposure of the cells to the AFC. Other studies have shown that the rate of quencher release in antigen positive tumor cells is comparable to the rate of drug release from ADCs. Pharmacokinetic and biodistribution studies of AFCs in tumor bearing mice have been used to identify sites of linker hydrolysis and provide insight into the activities of ADCs in preclinical models.
Abstract 5657: Esophageal Temperature Monitoring during Balloon Cryoablation of the Pulmonary Veins
Authors: Humera Ahmed, Petr Neuzil, Andre d’Avila, Margaret Laragy, Karel Mares, William R Brugge, David G Forcione, Jeremy N Ruskin, Vivek Y Reddy
Journal: Circulation (2008)

Introduction: Atrial-esophageal fistula is a feared complication of atrial fibrillation (AF) ablation. There have been no reported instances after ablation with the Cryoballoon catheter, which is believed to be associated with a relatively low risk of thromboembolism and PV stenosis, and no risk of atrial perforation. Yet, given the high frequency of subclinical esophageal ulceration reported with radiofrequency energy, we sought to determine the effect of cryoenergy on the esophagus. Methods: Catheter ablation was performed using the cryoballoon in 50 pts with paroxysmal AF (Age: 56±10 years, 29 male/21 female, LVEF: 67±6%, LA size 40±5mm). A temperature probe was used to monitor LET; however, LET changes did not guide therapy . Post-procedural endoscopy was systematically performed on the last 25 consecutive pts. Results: Significant (&gt;1°C) LET drops were observed in 48 (96%) patients (5±3 per patient). The greatest mean LET drop was observed in the LIPV (3.5°C), followed by the RIPV (2.7°C), LSPV (2.1°C) and RSPV (0.9°C). The LET nadir (13.8°C) was observed in the RIPV. Esophageal ulceration was observed in 4/25 (16%) pts; all were asymptomatic and prescribed proton pump inhibitors. Follow-up EGDs at one month revealed complete resolution of ulceration. No patient or procedural characteristics (age, history of GERD, LA size, LVEF, pre-procedural TEE) predicted ulceration. A significant correlation was found between the incidence of esophageal ulceration and LET nadir, number of LETs &lt;30°C, and cumulative LET drop ( Figure ). Conclusion: Esophageal ulceration can occur after balloon cryoablation; however, in no instances did this progress to fistula formation.
Severe hospitalised 2009 pandemic influenza A(H1N1) cases in France, 1 July-15 November 2009
Authors: C Fuhrman, I Bonmarin, A C Paty, N Duport, E Chiron, E Lucas, D Bitar, A Mailles, M Herida, S Vaux, D Lévy-Bruhl
Journal: Eurosurveillance (2010)

From 1 July 2009 to 15 November 2009, 244 patients with 2009 pandemic influenza A(H1N1) were admitted to intensive care unit (ICU) and were compared with 514 cases hospitalised in medical wards in France until 2 November 2009. Detailed case-based epidemiological information and outcomes were gathered for all hospitalised cases. Infants and pregnant women are overrepresented among cases admitted to ICU with seven per cent for both groups respectively, and twenty per cent of ICU cases did not belong to a risk group. Chronic respiratory disease was the most common risk factor among cases but obesity (body mass index >or= 30 Kg/m(2)), chronic cardiac disease and immunosuppression were risk factors associated with severe illness after adjustment for age and for other co-morbidities.
Working ability and educational level among long-term survivors of testicular cancer (TCSS) compared to a general population (GenPop)
Authors: L. Balteskard, R. M. Bremnes, O. Dahl, O. Klepp, E. Wist, S. D. Fossa
Journal: Journal of Clinical Oncology (2004)

4640 Background: The working ability and educational level in long-term TCSs may be negatively influenced by the experience of cancer and its treatment during young adulthood. Methods: Sociodemographic data and data on working ability were obtained by a postal questionnairy national multicenter survey in1383 TCSs aged 23–66 years (mean: 44 years) treated between 1980 and 1994 (12 years mean follow up). Working ability was defined as “employed/self-employed” and “not working, but seeking work”. Five groups were constructed based on the overall treatment: surveillance only, SURV (n=116); retroperitonal lymph node dissection, RPLND (n=152); radiation only, RAD (n=574); cisplatin-based chemotherapy: cisplatin <850mg, CHEM-1 (n=439); cisplatin >850mg, CHEM-2 (n=102). Data from the GenPop were obtained from a health status study within a Norwegian county (HUNT-2) comprising 23 844 aged matched men. Results: There was no difference in working ability between the TCSs and the GenPop (89% and 88%). However, 6% of the GenPop received unemployment benefits compared to only 2.6% of the TCSs (p<0.0001). There were no differences between the groups regarding economical compensation for absences due to disease, rehabilitation or invalidity. Among side effects due to treatment, persisting peripheral neuropathy and Reynauds phenomena did significantly affect the working ability. The working disability risk was 3-fold higher in CHEM-2 compared to SURV. Such difference was not seen for any of the other subgroups. A significantly larger proportion of the TCSs (19%) obtained a higher university education compared to the GenPop, (9%, p<0.0001). Conclusions: The working ability of long-term TCSs is similar to the GenPop, and TSCs are employed/self-employed at a larger extent than the GenPop, possibly due to a higher educational level. TSCs receiving more than 4 courses with cisplatin have the highest risk of disability. No significant financial relationships to disclose.
Replication of mutant strains of oncolytic reovirus in different cell lines
Authors: Guy Lemay
Journal: Cancer Research (2008)

906   Murine NIH-3T3 cells are poorly infected by mammalian reovirus but support productive infection upon cell transformation by H-Ras(G12V), leading to the idea that reovirus could be used as an “oncolytic” virus. It was initially believed that the inhibition of cellular interferon-inducible RNA-dependent protein kinase, PKR, was responsible for increased permissivity of Ras-transformed cells to reovirus. Other data later suggested an enhanced uncoating of the virions, due to increased levels of lysosomal proteases in transformed cells. Literature data also indicate that Ras activation is neither sufficient nor necessary for productive reovirus infection, depending on the cell types. --- Additional studies are thus needed to better comprehend the cellular and viral factors that ultimately determine the ability of reovirus to productively infect “normal” and/or “transformed” cells. --- A mutant reovirus (P4L-12) was previously isolated in our laboratory, based on increased sensitivity of this virus to interferon and on its better ability to discriminate between parental and Ras-transformed NIH-3T3 cells. Another mutant (SC1-PV) was obtained from persistently-infected murine fibroblasts; this virus requires only low levels of proteases to be uncoated, compared to the wild type virus. Our recent sequencing data revealed that both mutant viruses exhibit amino acid substitutions in their σ3 protein. This is consistent with the known importance of σ3 in the virus’ ability to be uncoated, as well as accumulating evidence suggesting the central role of σ3 in determining reovirus’ susceptibility to PKR. Mutant and wild-type viruses were used to infect a panel of murine and human cell lines; viral titers were then determined by TCID50 and plaque assays. Interestingly, both mutant viruses can infect cell lines that are relatively resistant to the wild type virus due to inefficient uncoating in these cells. Furthermore, the infectivity of P4L-12 was either unaffected or even slightly decreased by prior chymotrypsin treatment, while infectivity of wild type and SC1-PV was increased, as judged by virus titer and viral plaque size. However, P4L-12 was strongly restricted in cells that produce and respond to interferon, and thus this virus does not form plaques on these cells. We also observed a correlation between the ability of a given cell line to form colonies in soft agar and its ability to support reovirus replication, rather than a correlation with the Ras activation status of the cells. --- Altogether, our data thus support the idea that cellular factors affecting reovirus replication are complex and linked to pathways leading to cellular transformation. We further suggest that viral strains should be chosen or manipulated to optimize their oncolytic potential. The σ3 protein appears as the most likely viral factor to be involved in modulating the virus’ ability to replicate in different normal or transformed cell types.
Evaluation of hyperglycosylated erythropoiesis stimulating proteins developed using glycoengineering
Authors: Steven Elliott, Kenneth Aoki, Balaji Agoram, David Brankow, Sameer Doshi, Graham Molineux
Journal: Cancer Research (2006)

2176   Background: Candidate protein therapeutics may exhibit high clearance (low serum half-life), limiting their usefulness. The addition of new sialic acid-containing carbohydrates through glycoengineering has been shown to reduce clearance of protein therapeutics. Darbepoetin alfa (DA), a glycoengineered recombinant human erythropoietin (Epo) analog, exhibits an approximately 3-fold longer serum half-life than epoetin alfa (EA) in humans. DA has also been shown to be well tolerated and efficacious in treating anemia in oncology and nephrology settings at extended dosing intervals. Methods: We developed methods to evaluate Epo analogs with increased numbers of carbohydrate chains that met bioactivity, clearance, and stability requirements. We created multiple Epo analogs by introducing N-linked carbohydrate consensus sequences into different positions. The analogs were expressed in COS-1 cells and evaluated for the extent of N-linked glycosylation using Western blotting. In vitro and in vivo assays were used to assess bioactivity. Using the anti-human EPO monoclonal antibody 9G8a, we examined conformational and structural changes. We evaluated O-linked glycosylation using immunoblots after treatment of the analogs with N-glycanase. Pharmacokinetics of promising analogues were evaluated after single intravenous and subcutaneous doses in animals. Results: 62 analogs with N-linked consensus sequences introduced into 48 different positions were examined. Analog size increased with the addition of functional N-linked consensus sequences. Combinations of analogs were constructed and tested to identify multiple glycosylated molecules. AMG205, an analog with 4 additional carbohydrates compared to EA, had low 9G8a immunoreactivity, indicating intact conformation. However, AMG205 had an O-linked glycosylation deficit. Another candidate, AMG114, was identified that had an amino acid substitution that exhibited improved O-linked glycosylation as well as comparable folding and in vitro activity compared with AMG205. Compared to DA, AMG114 demonstrated increased potency in mouse in vivo experiments and the half-life was nearly 2-fold longer in mice and 2-3-fold longer in dogs. Conclusions: Application of design strategies and technologies used to create DA enabled the development of new ESP candidates. These new ESPs had longer serum half-lives in animals with increased in vivo potency in mice. While exhibiting promising qualities in animal models, the actual clinical benefit of AMG114 in humans needs to be examined in clinical studies.
Abacterial Cystitis
Authors: J. W. Czekalowski, G. O. Horne
Journal: BMJ (1951)

ACROSCLEROSISMEDICBAONA 879thick necrotic tissue from the edges of which pus constantly oozed.There was an odour of gangrene, and the nails were extremely painful to touch.Circular scars covered the ends of the fingers.The body skin was slightly pigmented, the abdomen flabby and prominent; axillary hair was absent, and pubic hair scanty.Mitral stenosis with regurgitation was present.Discussion Others (Harbinson, 1904; Johnson and Hedges, 1935) have'reported cases in which rheumatoid arthritis pre- ceded the onset of acrosclerosis, but few cases in the literature are described fully enough to show whether or not arthritis is a frequent forerunner of the disease.As the arthritis has involved many joints other than the hands it is unlikely that the pains and stiffness are actually the onset of acrosclerosis.Hunt (1936) described a "rheumatic " arteritis in which sore throats, arthritis, carditis, or chorea may rapidly be followed by a typical Raynaud's phenomenon, and in severe cases " nutritional changes such as super- ficial sores at the finger-tips and whitlows may appear," but such cases usually improve rapidly.Hunt also thought that " the vascular symptoms and the rheumatic manifestations suggest a common aetiological factor."Littler and Canter (1951) are of the opinion that dys- function of the suprarenal glands is the chief aetiological factor in the pathogenesis of acrosclerosis.They quote Winfield (1904) as obtaining much improvement in a case given suprarenal extract and Schwartz (1917) as improving six cases with pituitary extract.Two of my cases have had rheumatoid arthritis and two had rheumatic endocarditis.It is suggested that acrosclerosis is a disease of adaptation and would pro- bably respond to cortisone treatment. SummaryThe clinical picture of acrosclerosis is reviewed and three cases are described in detail.It is suggested that it is a disease of adaptation and would respond to cortisone therapy.
The Effect of Donor Age on Penetrating Keratoplasty for Endothelial Disease
Authors: Mark J. Mannis, Edward J. Holland, Robin L. Gal, Mariya Dontchev, Craig Kollman, Dan Raghinaru, Steven P. Dunn, Robert L. Schultze, David D. Verdier, Jonathan H. Lass, Irving M. Raber, Joel Sugar, Mark S. Gorovoy, Alan Sugar, R. Doyle Stulting, Monty M. Montoya, Jeffrey G. Penta, Beth Ann Benetz, Roy W. Beck
Journal: Ophthalmology (2013)
Abstract 044: Trends in Race/Ethnic Disparities in Ideal Cardiovascular Health: NHANES 1999-2006
Authors: Norrina B Allen, Hongyan Ning, Donald Lloyd-Jones
Journal: Circulation (2012)

Background: Significant racial/ethnic disparities exist in the cardiovascular health of the nation. Prior studies have identified differences between groups, but have not summarized trends in these disparities across multiple race/ethnic subgroups, which could allow us to assess the extent to which we are achieving disparity-related goals. Methods: We used NHANES Surveys from cycles 1999–2000, 2001–2002, 2003–2004, and 2005–2006 to examine the age-adjusted prevalence of ideal levels of CV health factors by race/ethnicity. Ideal levels of BMI, cholesterol, glucose, blood pressure, diet, physical activity and smoking were defined according to the AHA 2020 strategic goals. Racial/ethnic groups were categorized as Hispanic, Non-Hispanic White, Non-Hispanic Black and other. Both absolute (Between Group Variance- BGV) and relative measures (Theil Index -T) of disparities were calculated, calculations were weighted by population share. The percentage change in disparities relative to 1999–2000 was examined. Results: Age-adjusted rates of ideal CV health components and the percentage change from 1999–2006 varied by race/ethnicity (see Table). Disparities in the prevalence rates of ideal levels of blood pressure, cholesterol and physical activity have increased dramatically between race/ethnic groups in both men and women (see Table). Disparities in smoking and diet have increased in men but decreased in women. Disparities in BMI have changed little in men (BGV= 0.5%, T=−37.8%), but increased dramatically in women (BGV= 894%, T=280%). Findings were generally similar for both absolute and relative measures of disparities. Conclusions: Representative national data on these summary measures of disparities suggest that disparities between race/ethnic groups have increased for many cardiovascular health factors over the past decade. Understanding the issues underlying these increasing disparities and addressing them will be critical to improving the cardiovascular health of all Americans by 2020 and beyond.
Case 28-2015
Authors: Paul D. Biddinger, David C. Hooper, Erica S. Shenoy, Ednan K. Bajwa, Gregory K. Robbins, John A. Branda
Journal: New England Journal of Medicine (2015)

A public health authority contacted the hospital about a 32-year-old man with fever, headache, and myalgias that had developed 8 days after he had traveled from Liberia during an epidemic of Ebola virus disease. Management decisions were made.
European Risk Assessment Guidance for Infectious Diseases transmitted on Aircraft – the RAGIDA project
Authors: K Leitmeyer
Journal: Eurosurveillance (2011)

In order to assist national public health authorities in the European Union to assess the risks associated with the transmission of infectious agents on board aircrafts, the European Centre for Disease Prevention and Control initiated in 2007 the RAGIDA project (Risk Assessment Guidance for Infectious Diseases transmitted on Aircraft). RAGIDA consists of two parts: the production of a systematic review and a series of disease-specific guidance documents. The systematic review covered over 3,700 peer-reviewed articles and grey literature for the following diseases: tuberculosis, influenza, severe acute respiratory syndrome (SARS), invasive meningococcal disease, measles, rubella, diphtheria, Ebola and Marburg haemorrhagic fevers, Lassa fever, smallpox and anthrax. In addition, general guidelines on risk assessment and management from international aviation boards and national and international public health agencies were systematically searched. Experts were interviewed on case-based events by standardised questionnaires. Disease-specific guidance documents on tuberculosis, SARS, meningococcal infections, measles, rubella, Ebola and Marburg haemorrhagic fevers, Lassa fever, smallpox and anthrax were the result of consultations of disease-specific expert panels. Factors that influence the risk assessment of infectious disease transmission on board aircrafts and decision making for contact tracing are outlined.
Susan Greenfield replies to Vaughan Bell and colleagues
Authors: Susan Greenfield
Journal: BMJ (2015)

A year after I wrote Mind Change , Vaughan Bell and colleagues claim I’m scaremongering about potentially adverse effects of internet and computer use.1 They assert there’s no evidence that “typical internet use harms the adolescent brain.” Tellingly, they don’t define “typical use” or reflect on the escalating use preoccupying children—crucial omissions given reports from Ofcom,2 3 the House of Commons Health Committee,4 and Public Health England.5

Recent research shows teens using screens for an average of 10.75 aggregated hours daily.6 Such findings raise the all important question: where should we draw the boundaries between harmless use and misuse? Change in brain structure and function in response to experience is a well-established phenomenon. High levels of multi-tasking,7 internet use,8 or playing video games9 are associated with significant differences in the anterior …