tbuckley/cabot-search huggingface dataset:
Prostate Cancer Risk by BRCA2 Genomic Regions
Authors: Tommy Nyberg, Debra Frost, Daniel Barrowdale, D. Gareth Evans, Elizabeth Bancroft, Julian Adlard, Munaza Ahmed, Julian Barwell, Angela F. Brady, Carole Brewer, Jackie Cook, Rosemarie Davidson, Alan Donaldson, Jacqueline Eason, Helen Gregory, Alex Henderson, Louise Izatt, M. John Kennedy, Claire Miller, Patrick J. Morrison, Alex Murray, Kai-Ren Ong, Mary Porteous, Caroline Pottinger, Mark T. Rogers, Lucy Side, Katie Snape, Vishakha Tripathi, Lisa Walker, Marc Tischkowitz, Rosalind Eeles, Douglas F. Easton, Antonis C. Antoniou
Journal: European Urology (2020)

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.
Microstructure, mechanical property and corrosion behavior of porous Ti–Ta–Nb–Zr
Authors: B.Q. Li, R.Z. Xie, X. Lu
Journal: Bioactive Materials (2020)

In this paper, biomedical porous Ti-Nb-Ta-Zr with 40% porosity and 166 ± 21 μm macro-pore size was successfully fabricated by space holder method. The microstructure, Vickers hardness, compressive and electrochemistry behavior were studied. It results that a few second phases exist in β matrix of the porous Ti-Nb-Ta-Zr. Its Young's modulus is 0.8 GPa, close to 0.01-3 GPa for trabecular bone. The total recovery strain ratio and pseudoelastic strain ratio are 8.8% and 2.7%, respectively. It fails mainly by brittle cleavage with the fan-shaped and smooth cleaved facets. Although, local ductile fracture by a few dimples and a small amount of transcrystalline fracture with the cleavage of similarly oriented laths in a colony are observed on the fracture surface. The impedance spectrum of porous Ti-Nb-Ta-Zr has the characteristics of half capacitive arc resistance, showing good corrosion resistance in SBF solution.
IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN
Authors: Rosalyn S. Yalow, Solomon A. Berson
Journal: Journal of Clinical Investigation (1960)

For years investigators have sought an assay for insulin which would combine virtually absolute specificity with a high degree of sensitivity, sufficiently exquisite for measurement of the minute insulin concentrations usually present in the circulation. Methods in use recently depend on the ability of insulin to exert an effect on the metabolism of glucose in vivo or in excised muscle or adipose tissue. Thus, the insulin concentration in plasma has been estimated: a) from the degree of hypoglycemia produced in hypophysectomized, adrenalectomized, alloxan-diabetic rats (1); b) from the augmentation of glucose uptake by isolated rat hemidiaphragm (2); or c) from the increased oxidation of glucose-1-C14 by the rat epididymal fat pad (3). Since there have been reports indicating the presence, in plasma, of inhibitors of insulin action (4) and of noninsulin substances capable of inducing an insulin-like effect (5,6), these procedures, while yielding interesting information regarding the effects of various plasmas on glucose metabolism in tissues, are of doubtful specificity for the measurement of insulin per se (5).
Serum molecular signatures of weight change during early breast cancer chemotherapy
Authors: J. Stebbing, H. C. Keun, J. Sidhu, M. Patterson, S. R. Bloom, V. Amber, C. Coombes, H. Marconell, D. Pshezhetskiy
Journal: Journal of Clinical Oncology (2009)

e11534 Background: Weight gain in women receiving chemotherapy following breast cancer diagnosis has negative implications on quality of life and those who gain weight during treatment appear to be at higher risk of disease recurrence. The mechanism(s) implicated in chemotherapy associated weight gain are poorly understood. Methods: To investigate this further, we assessed the metabolic, cytokine and appetite related peptide alterations before and during adjuvant FEC chemotherapy for early breast cancer in post-menopausal women, and correlated these with body mass measurements. Specifically, we performed global metabolic profiling (metabonomics/ metabolomics) using 1 H nuclear magnetic resonance spectroscopy of sequential sera, examined ghrelin immunoreactivity, performed radioimmunoassays for glucagon like peptide-1 (GLP-1) and peptide YY (PYY) and electro-chemiluminescent cytokine analyses (tumor necrosis factor-α and interleukin-6; TNF-α, IL-6) on the sequential samples. Results: In those who gained ≥ 1.5kg (on average ∼5% of initial body weight), several metabolite levels were positively associated with weight change, in particular lactate which was 55% greater in patients with increased body weight during chemotherapy compared to those with stable weight during chemotherapy (p&lt;0.01; the pre-specified primary end-point). A significant inverse relationship was also observed between levels of TNF-α and weight change group (ρ 0.476, p&lt;0.05). Baseline lactate, alanine and body fat were all prognostic for weight gain (ROC AUC &gt;0.77, p&lt;0.05). No significant associations were observed between any other parameter and weight gain, nor any parameter and tumor burden, including cytokine and appetite peptide alterations. Conclusions: Metabonomics identifies pathways perturbed during early chemotherapy for breast cancer, and establishes a positive association between serum lactate, body fat, TNF-α and substantive weight changes during chemotherapy. Interventions that target these processes may be clinically useful in breast cancer. No significant financial relationships to disclose.
APSDE-COVID statements: recommendations should be modified according to the prevalence of COVID infection rates
Authors: Pradeep Bhandari, Asma Alkandari
Journal: Gut (2020)

We read the article from Chiu et al 1 and would like to congratulate the authors and Asian Pacific Society for producing APSDE (Asian-Pacific Society for Digestive Endoscopy)-COVID statements. The statements make perfect practical sense in the times where robust evidence is lacking. However, there are some conflicting messages coming out and I would like to draw attention toward it.

Figure 1 is suggesting a very extensive algorithm of clinical and laboratory testing to identify the infective potential of the patient and based on that to decide if urgent or semiurgent or elective endoscopy should be performed and the type of personal protective equipment (PPE) to be used. However, statement 2 clearly indicates and quiet rightly so that in the current pandemic we should only perform endoscopy for urgent indications. I feel that the algorithm in figure 1 is …
Increasing prevalence of asthma, allergic rhinoconjunctivitis and eczema among schoolchildren: Three surveys during the period 1985-2008
Authors: Tonje Hansen, Bjørg Eventh, Jan Holt
Journal: European Respiratory Journal (2013)

Aim: The prevalence of asthma, allergic rhinoconjunctivitis (AR) and eczema among children have increased worldwide in the last decades, but recent studies disagree as to whether the prevalence is continuing to rise, or is leveling off or declining. The aim of this study was to assess time trends in a subarctic population.

Methods: A cross-sectional, questionnaire-based survey was carried out in 2008 among children aged 7-14 years in random selected schools in Nordland County, Norway (n=4150). The results are compared with results from identical studies in 1985 (n=4870) and 1995 (n=4456).

Results: The main findings were an increasing prevalence of asthma ever (7.3% in 1985 to 17.6% in 2008, p for trend < 0.001) and AR ever (15.9% in 1985 to 24.5% in 2008, p for trend < 0.001), while the prevalence of eczema ever, after an increase between 1985 and 1995, remained unchanged in the last time period.

The prevalence of current asthma increased from 4.8% to 9.9%, the prevalence of current AR increased from 6.7% to 21.5% and the prevalence of current eczema increased from 6.4% to 13.5%, all between 1995 and 2008.

Conclusion: A repeated cross-sectional survey between 1985- 2008 documented an increasing prevalence of asthma ever and AR ever among schoolchildren (7-14 years), together with a considerably increase in current asthma, AR and eczema between 1995 and 2008.
The association of clinical outcome to front-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC) patients (Pts).
Authors: M. Y. Al-Marrawi, B. I. Rini, L. C. Harshman, G. A. Bjarnason, L. Wood, U. N. Vaishampayan, M. J. MacKenzie, J. J. Knox, N. Agarwal, C. K. Kollmannsberger, M. Tan, S. Y. Rha, F. Donskov, S. A. North, T. K. Choueiri, D. Y. C. Heng
Journal: Journal of Clinical Oncology (2011)

4555 Background: In mRCC pts who fail first-line VEGF-targeted therapy, there are no available randomized data comparing active drugs. Currently, many clinicians choose a second-line VEGF-targeted therapy based on the type of response to first-line VEGF therapy, although no data exists to support this practice. Methods: Pts treated with targeted therapy in the International mRCC Database Consortium were examined to identify pts who received a second-line VEGF-targeted therapy after failure of a different first-line VEGF-targeted therapy. Response rates and progression-free survival (PFS) were compared in the first- and second-line settings. Results: Of 1,602 total database pts, 464 pts received second-line VEGF-targeted therapy (sunitinib 37%, sorafenib 51%, axitinib 2%, bevacizumab 7%, pazopanib 3%) after failure of first-line VEGF-targeted therapy (sunitinib 54%, sorafenib 33%, bevacizumab 13%). The median overall survival from initiation of first-line therapy for pts who received second-line therapy was 26.5 months. The median first-line and second-line PFS were 7.5 months and 3.9 months (95% CI 3.6-4.5), respectively. There was no correlation between first-line and second-line PFS (Pearson correlation coefficient 0.025; p=0.59). RECIST-defined objective response rate (ORR) was available for both first- and second-line therapy in 323 pts. The ORR in first- and second-line therapy was 22% and 11%, respectively. There was no significant association between first-line objective response and second-line objective response (chi squared trend test p=0.17; Table). Conclusions: There is no association between first-line and second-line objective response or PFS to VEGF-targeted therapy in mRCC. Response to second-line based on first-line VEGF-targeted therapy response. OR to 1st line VEGF-targeted therapy OR to 2nd line VEGF-targeted therapy CR PR SD PD CR/PR (n=72) 1% 13% 36% 50% SD (n=175) 1% 9% 50% 40% PD (n=76) 0% 11% 34% 55%
Characteristics of oral methicillin-resistant Staphylococcus epidermidis isolated from dental plaque
Authors: Boyu Tang, Tao Gong, Yujia Cui, Lingyun Wang, Chao He, Miao Lu, Jiamin Chen, Meiling Jing, Anqi Zhang, Yuqing Li
Journal: International Journal of Oral Science (2020)

The oral microbial community is widely regarded as a latent reservoir of antibiotic resistance genes. This study assessed the molecular epidemiology, susceptibility profile, and resistance mechanisms of 35 methicillin-resistant Staphylococcus epidermidis (MRSE) strains isolated from the dental plaque of a healthy human population. Broth microdilution minimum inhibitory concentrations (MICs) revealed that all the isolates were nonsusceptible to oxacillin and penicillin G. Most of them were also resistant to trimethoprim (65.7%) and erythromycin (54.3%). The resistance to multiple antibiotics was found to be largely due to the acquisition of plasmid-borne genes. The mecA and dfrA genes were found in all the isolates, mostly dfrG (80%), aacA-aphD (20%), aadD (28.6%), aphA3 (22.9%), msrA (5.7%), and the ermC gene (14.3%). Classical mutational mechanisms found in these isolates were mainly efflux pumps such as qacA (31.4%), qacC (25.7%), tetK (17.1%), and norA (8.6%). Multilocus sequence type analysis revealed that sequence type 59 (ST59) strains comprised 71.43% of the typed isolates, and the eBURST algorithm clustered STs into the clonal complex 2-II(CC2-II). The staphyloccoccal cassette chromosome mec (SCCmec) type results showed that 25 (71.43%) were assigned to type IV. Moreover, 88.66% of the isolates were found to harbor six or more biofilm-associated genes. The aap, atlE, embp, sdrF, and IS256 genes were detected in all 35 isolates. This research demonstrates that biofilm-positive multiple-antibiotic-resistant ST59-SCCmec IV S. epidermidis strains exist in the dental plaque of healthy people and may be a potential risk for the transmission of antibiotic resistance.
True Mediterranean Fever in England
Authors: E. F. Hunt
Journal: BMJ (1946)

Bone marrow stromal Ag 2 (BST2) is a transmembrane protein that prevents virus release from infected cells. It was also reported that BST2 inhibits type I IFN production by plasmacytoid dendritic cells. To determine BST2 impact on antiviral responses in vivo, we generated BST2<sup>−/−</sup> mice. Following infection with a murine retrovirus, BST2<sup>−/−</sup> mice had slightly elevated viral loads; however, infection with other enveloped viruses revealed unexpected roles of BST2. BST2<sup>−/−</sup> mice showed reduced type I IFN production by plasmacytoid dendritic cells. Moreover, BST2<sup>−/−</sup> mice had lower viral titers in lungs following intranasal infection with vesicular stomatitis virus expressing OVA and influenza B and increased numbers of virus-specific CD8 T cells in the lungs, suggesting that BST2 may facilitate entry and/or replication of enveloped viruses and modulate priming of CD8 T cells. These findings suggest complex roles of BST2 beyond retroviral control in vivo, possibly reflecting the involvement of BST2 in endocytosis and intracellular trafficking of viruses, viral nucleic acids, and Ags.
PTH-061 Missed oesophagogastric cancer correlates with higher list intensity but not rates of sedation
Authors: David FW Tai, Andrew Hopper, Mark McAlindon
Journal: Endoscopy (2018)

<h3>Introduction</h3> Oesophagogastric (OG) cancers diagnosed within three years of an unremarkable oesophagogastroduodenoscopy (OGD) can be considered a failure to earlier diagnose the OG cancer, or post-OGD upper GI cancer (POUGIC). Retrospective studies suggest that they comprise up to 11% of OG cancer diagnosis [Menon, Endosc Int Open 2014] and auditing rates of POUGIC is a recent quality standard for endoscopy units [Beg, Gut 2017]. We examined whether patient sedation or procedural burden affects the rate of POUGIC. <h3>Methods</h3> Cases of OG cancer diagnosed at OGD between Jan 2013 and Dec 2016 at Sheffield Teaching Hospitals were identified from our upper GI cancer database. OGD performed up to three years prior to diagnostic OGD were reviewed to identify cases of POUGIC. Rates of sedation and number of procedural points (one for OGD; two for colonoscopy; plus one for therapeutics) on lists were compared in three groups: a) the index procedures, b) the diagnostic procedures and c) age, sex and endoscopist matched patient control procedures in which focal (mucosal or vascular) lesions (FL) were identified. FL were approximated in size and location (oesophageal or gastric) as a surrogate for an early neoplastic lesion. <h3>Results</h3> A total of 553 patients (64.2% male, mean age 72±1, 50.4% gastric) were diagnosed with OG cancer. Forty (7.2%, mean age 74±2, 55% male, 55% gastric,) patients had 47 non-diagnostic procedures up to three years prior to diagnosis. Mean time from index to diagnostic OGD was 486±55 days. In 42.5% OGD was performed within one year of diagnosis. There was no difference in the age, gender and rates of sedation (25 vs 28.5%) between patients at index and diagnostic procedures. At index OGD the sedation rates were higher (44.7 vs 26.3% p=0.049) than at diagnostic OGD but there was a greater number of procedural points on the list (7.9 vs 9.3 p=0.007). Control patients (n=38, mean age 72±2 p=0.64 compared to POUGIC patients) with FL had OGD done a median of 33 days (−357 to 728 days) from the index OGD. No suitable controls were identified in 2 patients. There was no difference in the sedation rates (25.0 vs 26.3% p=0.89) but there was a trend towards a higher number of procedural points (9.3 vs 8.7 p=0.057) between the index OGD for POUGIC patients and their controls. <h3>Conclusions</h3> The local POUGIC rate is 7.2%. No differences in sedation rate between index, diagnostic or control procedures with representative FL suggest use of sedation may not help detection of early neoplastic lesions. However, endoscopy lists with OGDs which miss OG cancer seem to have a heavier burden than ones that diagnosed cancer and other FL suggesting that reduced list intensity may reduce the likelihood of missed pathology.
Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System
Authors: Vikas Mehta, Sanjay Goel, Rafi Kabarriti, Daniel Cole, Mendel Goldfinger, Ana Acuna-Villaorduna, Kith Pradhan, Raja Thota, Stan Reissman, Joseph A. Sparano, Benjamin A. Gartrell, Richard V. Smith, Nitin Ohri, Madhur Garg, Andrew D. Racine, Shalom Kalnicki, Roman Perez-Soler, Balazs Halmos, Amit Verma
Journal: Cancer Discovery (2020)

Abstract Patients with cancer are presumed to be at increased risk from COVID-19 infection–related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19–positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six of 11 (55%) patients with lung cancer died from COVID-19 disease. Increased mortality was significantly associated with older age, multiple comorbidities, need for ICU support, and elevated levels of D-dimer, lactate dehydrogenase, and lactate in multivariate analysis. Age-adjusted CFRs in patients with cancer compared with noncancer patients at our institution and New York City reported a significant increase in case fatality for patients with cancer. These data suggest the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population. Significance: COVID-19 in patients with cancer is associated with a significantly increased risk of case fatality, suggesting the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population. This article is highlighted in the In This Issue feature, p. 890
Phase I and pharmacokinetic (PK) study of IHL-305 (pegylated liposomal irinotecan) in patients with advanced solid tumors
Authors: S. F. Jones, W. C. Zamboni, H. A. Burris, E. Chan, J. R. Infante, V. Keedy, J. C. Bendell, W. Lee, S. Ikeda, M. Rothenberg
Journal: Journal of Clinical Oncology (2009)

2547 Background: Irinotecan (CPT-11) is a prodrug of SN-38 that has antitumor activity in a wide range of solid tumors. IHL- 305 is a PEGylated-liposomal formulation of irinotecan designed to increase the therapeutic index by prolonging the duration of exposure in both plasma and tumors. IHL-305 demonstrates superior anti-tumor activity in preclinical models. Methods: Eligible patients (pts) had advanced solid tumors, ECOG ≤2, adequate organ function and no prior exposure to CPT-11. In a standard 3+3 escalation, IHL-305 was infused over 60 minutes q 28 days. UGT1A1*28 genotyping was performed with the homozygous (*28/*28) variants treated at 50% of current dose (subsequent escalation allowed). The area under the plasma concentration- time curve (AUC) of sum total (encapsulated + released) CPT-11, released CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was calculated. The % CPT-11 released was calculated as the ratio of released CPT-11 AUC to sum total CPT-11 AUC x 100. The primary objectives were to determine the dose limiting toxicities (DLTs), phase II recommended dose (P2RD), and clinical pharmacology of IHL- 305. Results: 42 pts treated; homozygous wild-type (wt/wt; n=23), heterozygous (wt/*28; n=13) and homozygous variants (*28/*28; n= 6). 10 dose levels explored; 7, 14, 28, 37, 50, 67, 88, 120, 160 and 210 mg/m 2 . DLTs included: 1 Gr 3 acute nausea/vomiting at 67 mg/ m 2 (subsequent pts received premedication), 1 Gr 3 delayed-onset diarrhea at 160 mg/m 2 , and 1 Gr 3 delayed nausea/vomiting and one Gr 3 febrile neutropenia at 210mg/m 2 . Pts received repeated courses of IHL-305 with no delays for myelosuppression or diarrhea. 7 pts had stable disease ≥ 6 cycles. The mean ± SD PK parameters are summarized in the table below. Conclusions: The MTD and P2RD of IHL-305 is 160 mg/m2 IV q 28 days. IHL-305 shows a high and prolonged exposure of sum total and released CPT-11 and SN-38. [Table: see text] [Table: see text]
Will helminth co-infection modulate COVID-19 severity in endemic regions?
Authors: Richard S. Bradbury, David Piedrafita, Andrew Greenhill, Siddhartha Mahanty
Journal: Nature reviews. Immunology (2020)

As COVID-19 spreads through the world, most cases to date are in middle- and high-income nations. The impact on resource-poor nations remains unknown. Amongst many factors likely to affect the impact of COVID-19 in these areas, co-infections need to be considered. Here, we discuss whether the immunomodulatory effects of helminth infections may affect COVID-19 severity. Helminth co-infections can skew systemic immunity towards type 2 responses. Here, Bradbury and colleagues consider how this may impact the severity of COVID-19 in helminth-endemic regions.
NARASIMHA: Novel Assay based on Targeted RNA Sequencing to Identify ChiMeric Gene Fusions in Hematological Malignancies
Authors: Nikhil Patkar, Prasanna Bhanshe, Sweta Rajpal, Swapnali Joshi, Shruti Chaudhary, Gaurav Chatterjee, Prashant Tembhare, Chetan Dhamne, Maya Prasad, Nirmalya Roy Moulik, Dhanalaxmi Shetty, Anant Gokarn, Avinash Bonda, Lingaraj Nayak, Sachin Punatkar, Bhausaheb Bagal, Manju Sengar, Gaurav Narula, Navin Khattry, Shripad Banavali, P. G. Subramanian, Sumeet Gujral
Journal: Blood Cancer Journal (2020)