tbuckley/cabot-search huggingface dataset:
External validation of prognostic models for overall survival (OS) in patients (pts) with advanced cancer (UC) treated with cisplatin-based chemotherapy.
Authors: Andrea Borghese Apolo, George Philips, Irina Ostrovnaya, Jonathan E. Rosenberg, Matthew I. Milowsky, Eric Jay Small, Dean F. Bajorin, Susan Halabi
Journal: Journal of Clinical Oncology (2012)

4592 Background: The most commonly used model predicting OS for UC pts treated with cisplatin-based chemotherapy is based on 2-variables (visceral metastases and performance status), developed at MSKCC in 1999, and validated in a phase III study (DeSantis JCO 2011). A prognostic model of OS for advanced UC pts based on 4 variables (visceral metastases, albumin, performance status, and hemoglobin) was developed using 308 pts from MSKCC (ASCO 2007 abstr 5055). We report the discriminative ability of the 4- and 2- variable models for advanced UC pts using an independent dataset from CALGB 90102. Methods: The analysis was performed using an external multi-institutional dataset from CALGB 90102. The primary measurement of predictive discrimination was Harrell’s c-index which was computed with 95% confidence interval (CI). To assess whether there was a statistically significant difference in discrimination between the two models, the U statistic was used to test whether the predictions of the 4-variable model in all possible pairs were more concordant with actual observations than the 2-variable model in the same pairs. Results: CALGB 90102 included 74 UC pts (58 males, 16 females), median age 64 years, treated with cisplatin, gemcitabine and gefitinib, enrolled from 7/02 to 4/05 with a median follow-up of 72.5 months. Visceral metastases were present in 64% (bone, 18%, liver, 31%, lung, 43%), median KPS 90%. The MSKCC 2-variable risk group distribution was 30% =0, 65%= 1 and 5%=2. The median OS =12.7 months (95% CI=10.4-20.5) with 68 deaths observed. When applied to the CALGB cohort, the predictive accuracy for the 4- and 2-variable models were 0.63 (95 CI= 0.56- 0.69) and 0.58 (95% CI= 0.52-0.65), respectively. There was a statistically significant difference in discrimination between the two models (p =0.019), with superiority of the 4-variable model compared to the 2-variable model. Conclusions: A 4-variable prognostic nomogram for survival in pts with advanced UC was superior to a 2-variable risk-group model. The 4-variable prognostic model may replace the widely used 2-variable model and can be used in the design and conduct of future phase II and III trials in advanced UC.
Biomechanical loads in running-based sports: estimating ground reaction forces from segmental accelerations (PhD Academy Award)
Authors: Jasper Verheul
Journal: British Journal of Sports Medicine (2019)

The overall aim of this thesis was to investigate whether ground reaction forces (GRFs) can be estimated from segmental accelerations, to provide further insight in the feasibility of using body-worn accelerometers to monitor whole-body biomechanical loading during running-based (team-) sports.

Although the physiological demands of training have been investigated extensively, biomechanical loads and consequent responses are still poorly quantified and, therefore, not well understood.1 GRF is a well-established measure of external biomechanical loading which drives and is affected by muscular actions, and at the same time contributes to internal loads acting on individual structures (eg, muscles, tendons and bones). GRF thus forms an overall measure of the biomechanical loads experienced by the body as a whole and might be used to investigate the relation between whole-body loading and musculoskeletal responses. However, valid …
Fluid assessment in dialysis patients by point-of-care magnetic relaxometry
Authors: Lina A. Colucci, Kristin M. Corapi, Matthew Li, Xavier Vela Parada, Andrew S. Allegretti, Herbert Y. Lin, Dennis A. Ausiello, Matthew S. Rosen, Michael J. Cima
Journal: Science Translational Medicine (2019)

Portable nuclear magnetic resonance (NMR) sensors enable quantitative diagnostic measurements of fluid status in patients with end-stage renal disease.
Individual PK-guided sunitinib dosing: A feasibility study in patients with advanced solid tumors.
Authors: Nienke A.G. Lankheet, Jacqueline S.L. Kloth, Christa G.M. Gadellaa-van Hooijdonk, Geert A. Cirkel, Ron H.J. Mathijssen, Martijn P.J.K. Lolkema, Jan H. M. Schellens, Emile E. Voest, Stefan Sleijfer, Jos H. Beijnen, Alwin D.R. Huitema, Neeltje Steeghs
Journal: Journal of Clinical Oncology (2012)

2596 Background: Sunitinib treatment shows a clear dose-efficacy relationship. However, due to large inter-individual variations in plasma exposure, target total trough levels (&gt; 50 ng/mL) are frequently not reached with the current dosing schedule. Therefore, a prospective Phase I study was performed to determine the safety and feasibility of PK-guided dosing of sunitinib. Methods: Thirty patients with solid tumors with a potential benefit from sunitinib treatment were included. Patients were treated continuously with sunitinib 37.5 mg once daily. At day 15 and 29 of sunitinib treatment, plasma trough levels of sunitinib and its active metabolite (N-desethyl sunitinib) were measured. If the total trough level (TTL) was &lt; 50 ng/mL and the patient did not show any ≥ grade 3 toxicity (CTCAE 4.02), the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from ≥ grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg. After 8 weeks a final TTL evaluation was performed. Results: All 30 patients started treatment and in 18 patients all 3 TTLs were measured at the time of this analysis. Given TTL &lt; 50 ng/mL and &lt; grade 3 toxicity, a first sunitinib dose increase could be applied in 10 patients and a second dose increase in 2 patients at day 15 and 29, respectively. At day 15, day 29 and 8 weeks of treatment, mean TTLs were 49.7 ng/mL (coefficient of variation (CV) 27.7%), 62.4 ng/mL (CV 35.5%) and 56.7 ng/mL (CV 47.8%), respectively. At day 15, using the sunitinib standard dose of 37.5 mg, target TTLs were reached in 8 patients (44%). At 8 weeks, the mean sunitinib daily dose intensity was increased to 40.3 mg (standard deviation (SD) ± 11.0). At the end of the 8 week study period, 5 out of 18 patients (28%) were still at an increased sunitinib dose level without additional side effects. In these patients the mean daily sunitinib dose was 55.0 mg (SD ± 6.8) and their final TTLs were all &gt; 50 ng/mL (mean: 70.8 ng/mL (CV 29.8%)). Using PK-guided sunitinib dosing, target TTLs were reached in 10 out of 18 patients (56%) at the final TTL evaluation, compared to 44% at day 15 before any dose adjustment. Conclusions: Individual PK guided dosing is feasible and enables a significant increase in sunitinib dose intensity without causing additional toxicity.
Abstract 15877: CMR Effects on Pacemaker/ICD Parameters; An in vivo Reproducibility Study Pre and Post MRI Exam; Should We be Concerned?
Authors: Loretta Gevenosky, Ronald Williams, Richard Lombardi, Christopher Bonnet, Moneal Shah, Mark Doyle, Robert W Biederman
Journal: Circulation (2017)

Introduction: The evolution of pacemaker/ICD safety in the MRI field has triggered considerable interest in the possibility of more routine use. However, several limitations to widespread adoption ...
US Pentagon is told to investigate claims that Lyme disease is escaped bioweapon from cold war
Authors: Owen Dyer
Journal: BMJ (2019)

The US House of Representatives has ordered the Pentagon’s inspector general to conduct a review of whether the defence department “experimented with ticks and other insects regarding use as biological weapons between 1950 and 1975.”1

The demand for a review, proposed by Chris Smith, a New Jersey Republican, passed easily among a raft of other late amendments to a House bill on defence spending. It must still be “reconciled” with the Senate’s version of the spending bill, but Smith said that he was confident of Senate support.

He told the House that his amendment had been “inspired by a number of books and articles suggesting that significant research had been done at US government facilities including Fort Detrick, Maryland, and Plum Island, New York, to turn ticks and other insects into bioweapons.”

Plum Island, a secure government biological research site since 1945, lies directly across a narrow stretch of water from Lyme, …
Neoadjuvant chemotherapy with metronomic doxorubicin, cyclophosphamide, and capecitabine in patients with locally advanced (LA) triple-negative breast cancer (TNBC).
Authors: Mona Frolova, Marina Skrypnikova, Ekaterina Ignatova, Alexander Petrovsky, Marina Stenina, Oxana Ivankina, Yana Vishnevskaja, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2013)

e12027 Background: TNBC is associated with aggressive behavior and poor prognosis. It has been shown that patients (pts) with TNBC with pathological complete regression (pCR) after neoadjuvant chemotherapy have a higher survival. Rates of pCR with standard antracycline- and taxanebased chemotherapy regimens don’t exceed 20-27%. Dose-dense and metronomic schedules may be more effective in these highly proliferative tumors. We performed a prospective pilot trial to evaluate efficacy of metronomic schedule of doxorubicin, cyclophosphamide and capecitabine in pts with LA TNBC. Methods: Pts with LA TNBC (cT2-4N1-3M0) were treated with doxorubicin 25 mg/m2 iv weekly, cyclophosphamide 50 mg po daily and capecitabine 1500 mg po daily for planned 16-19 weeks followed by surgery. Pathological response was evaluated according to the Chevallier classification. Results: Twenty pts was included in the study in 2009-2010. Median agewas 47 years (33-70), 63% of pts had tumor grade 3, Ki67 was &gt;20% in all cases. Nineteen pts completed chemotherapy (median treatment duration 17.1 weeks) and underwent surgery. One pt had a disease progression during chemotherapy and was switched to 2nd-line chemotherapy. Seven pts (36,8%) achieved a pCR (6 pts class 1 and 1 pt class 2). With median follow-up of 33 months, 3-year DFS and OS were 60%. All but one pt with pCR, who developed brain mts shortly after surgery, are currently alive without relapse. In contrast 50% of pts with residual tumor relapsed. Pts with pCR had significantly higher median cumulative dose of doxorubicin (420 mg/m2) than pts with residual disease (300 mg/m2, p=0.046). The dose-limiting toxicities were hand-foot syndrome (26.3% grade 3), mucositis (31.6% grade 3), and neutropenia (31.6% grade 3-4), which resulted in permanent discontinuation of doxorubicin in 4 pts. Conclusions: Despiterelatively hightoxicity metronomic doxorubicin, cyclophosphamide and capecitabine regimen shows promising activity as neoadjuvant treatment of LA TNBC. Achievement of pCR and higher cumulative dose of doxorubicin were strongly associated with improvement of survival.
Sex modulates the ApoE ε4 effect on brain tau deposition measured by <sup>18</sup>F-AV-1451 PET in individuals with mild cognitive impairment
Authors: Min Liu, Manish D Paranjpe, Xin Zhou, Phan Q. Duy, Manu S Goyal, Tammie L.S. Benzinger, Jie Lu, Rongfu Wang, Yun Zhou
Journal: Theranostics (2019)

The strongest genetic risk factor for Alzheimer's disease (AD) is the Apolipoprotein E type 4 allele (ApoE ε4). The interaction between sex and ApoE ε4 carrier status on AD risk remains an area of intense investigation. We hypothesized that sex modulates the relationship between ApoE ε4 carrier status and brain tau deposition (a quantitative endophenotype in AD) in individuals with mild cognitive impairment (MCI). Methods: Preprocessed 18F-AV-1451 tau and 18F-AV-45 amyloid PET images, T1-weighted structural magnetic resonance imaging (MRI) scans, demographic information, and cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) measurements from 108 MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included. After downloading pre-processed images from ADNI, an iterative reblurred Van Cittertiteration partial volume correction (PVC) method was applied to all PET images. MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to cerebellum were computed. ApoE ε4 by sex interaction analyses on 18F-AV-1451 and CSF tau (t-tau, p-tau) were assessed using generalized linear models. The association between 18F-AV-1451 SUVR and CSF tau (t-tau, p-tau) was assessed. Results: After applying PVC and controlling for age, education level and global cortical 18F-AV-45 SUVR, we found that the entorhinal cortex, amygdala, parahippocampal gyrus, posterior cingulate, and occipital ROIs exhibited a significant ApoE ε4 by sex interaction effect (false discovery rate P < 0.1) among MCI individuals. We also found a significant ApoE ε4 by sex interaction effect on CSF t-tau and p-tau. 18F-AV-1451 SUVR in the 5 ROIs with ApoE ε4 by sex interaction was significantly correlated with CSF p-tau and t-tau. Conclusions: Our findings suggest that women are more susceptible to ApoE ε4-associated accumulation of neurofibrillary tangles in MCI compared to males. Both CSF tau (p-tau, t-tau) and brain tau PET are robust quantitative biomarkers for studying ApoE ε4 by sex effects on brain tau deposition in MCI participants.
Sotatercept (ACE-011) Alone and in Combination with Ruxolitinib in Patients (pts) with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Anemia
Authors: Prithviraj Bose, Naval Daver, Naveen Pemmaraju, Elias J. Jabbour, Zeev Estrov, Allison Pike, Julie Huynh-Lu, Madeleine Nguyen-Cao, Xuemei Wang, Lingsha Zhou, Sherry Pierce, Hagop M. Kantarjian, Srdan Verstovsek
Journal: Blood (2017)
Interpretation of Vitamin B<sub>12</sub>Status After a Roux-en-Y Gastric Bypass
Authors: Sameer B. Murali, MD MSHS
Journal: JAMA (2019)

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Molecular Engineering of Near-Infrared Light-Responsive BODIPY-Based Nanoparticles with Enhanced Photothermal and Photoacoustic Efficiencies for Cancer Theranostics
Authors: Duyang Gao, Boyu Zhang, Yubin Liu, Dehong Hu, Zonghai Sheng, Xuanjun Zhang, Zhen Yuan
Journal: Theranostics (2019)

Background: Engineering a single organic-molecule-based nanoparticle integrating precise diagnosis and effective therapy is of great significance for cancer treatment and future clinical applications but remains a great challenge. The goal of this study is to explore small organic molecule-based nanoparticles with high photothermal conversion efficiency for photoacoustic imaging-guided therapy. Methods: Heptacyclic B, O-chelated BODIPY structure (namely Boca-BODIPY) with strong near-infrared (NIR) absorption was designed as a theranostic agent through simply molecular engineering, in which heavy atoms and alkyl chains were introduced to promote its application for tumor theranostics. The Boca-BODIPY molecules are further encapsulated in reduced bovine serum albumin (BSA) through self-assembly. Results: The BSA-Boca-BODIPY exhibited excellent biocompatibility, extraordinary stability and high photothermal conversion efficiency up to 58.7%. The nanoparticles could dramatically enhance photoacoustic contrast of the tumor region, and the signal-to-noise ratio was increased about 14 times at 10 h post intravenous injection in 4T1 tumor-bearing mice. In addition, the nanoassemblies can efficiently convert laser energy (808 nm, 0.75 w cm-2, 5min) into hyperthermia for tumor ablation. Under the photoacoustic imaging-guided photothermal therapy (PTT), the 4T1 cancer cells were efficiently killed, no tumor recurrence and PTT-induced toxicity is observed. Conclusions: Molecular engineering is a promising way to design organic-molecule-based nanoparticles for cancer theranostics. Other organic-molecule-based nanoparticles which show great promise for imaging-guided cancer precision therapy can be engineered through this method.
John Ernest Bowerman
Authors: John Bradley
Journal: BMJ (2019)

John Ernest Bowerman was born on 13 March and brought up in Torquay. His father was an eminent pharmacist and president of the Pharmaceutical Society.

John went to Bristol to study dentistry in 1949. He won all the gold medals in the dental school and qualified BDS in 1955. He met Hilary in that year, and they were married in 1956. John then did national service in the Royal Army Dental Corps for the following two years. However, his uncle, a general dental practitioner in Honiton, had become seriously ill and John was released to be able to run the practice for the next two years.

In 1960 he returned to Bristol to study medicine. To help pay for the tuition fees he carried out general dental practice in the evenings, with Hilary as the chairside assistant and secretary. He won all the gold medals in the medical school as well and at the same time he sat the primary dental fellowship exam and won the triennial prize for the best set of papers over a three …
APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target
Authors: Huarong Chen, Chi-Chun Wong, Dabin Liu, Minnie Y Y Go, Bin Wu, Sui Peng, Ming Kuang, Nathalie Wong, Jun Yu
Journal: Theranostics (2019)

Background: The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process contributed by the accumulation of molecular alterations. We identified Apelin (APLN) as an outlier gene up-regulated in hepatocellular carcinoma (HCC) through RNA-Seq and microarray analysis. We aimed to investigate its function, mechanism of action and clinical implication in HCC. Methods: Gene expression and clinical implication of APLN were assessed in multiple human HCC cohorts. Ectopic expression and silencing of APLN were performed to determine its function. The therapeutic potential of APLN and its downstream pathway was investigated using in vitro and in vivo models. Results: APLN overexpression was commonly observed in more than 80% of HCCs and independently predicted poorer survival of patients in three independent HCC cohorts. Apelin up-regulation was mediated by active β-catenin, which binds to the APLN promoter to induce transcription. Ectopic APLN expression in HCC cells promoted cell proliferation, accelerated G1/S progression and inhibited apoptosis, whilst APLN knockdown exerted opposite effects in vitro and inhibited HCC xenograft growth in mice. Mechanistically, APLN activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway via APLN receptor, leading to increased expression of phospho-glycogen synthase kinase 3β (p-GSK3β) and cyclin D1. Pharmacological targeting of APLN by ML221 was safe and effective in inhibiting APLN-PI3K/Akt cascade and HCC growth in vitro and in vivo. Conclusions: Our findings unraveled an oncogenic role of APLN in HCC, and that targeting of APLN might be a promising for HCC treatment. APLN may serve as an independent prognostic factor for HCC patients.
Accelerated wound healing in diabetes by reprogramming the macrophages with particle-induced clustering of the mannose receptors
Authors: Jingjing Gan, Chunyan Liu, Huanling Li, Shaocong Wang, Zhenzhen Wang, Zhiqian Kang, Zhen Huang, Junfeng Zhang, Chunming Wang, Dalun Lv, Lei Dong
Journal: Biomaterials (2019)
Patient selection for anti-EGFViii therapies in glioblastoma multiforme (GBM): Use of circulating tumor DNA.
Authors: El Mustapha Bahassi, Mohamad Adham Salkeni, Christopher McPherson, Ronald Warnick, Olivier Rixe
Journal: Journal of Clinical Oncology (2013)

e13023 Background: Several strategies have been recently developed to target EGFRvIII in Glioblastoma Multiforme (GBM), including vaccines (CDX-110) and antibody-drug conjugates (AMG595) and represents a new challenging therapeutic avenue with potential great clinical benefits. EGFRvIII is a truncated extracellular mutant of the EGF receptor (EGFR) found in about a third of GBMs, confers enhanced tumorigenic behavior and is associated with chemo- and radio-resistance. GBM patients testing positive for EGFRvIII have a bleaker prognosis than those who do not. Methods: We developed a strategy to detect EGFRvIII deletion in the circulating tumor DNA. The purpose of this study is to identify a simple and robust biomarker from the peripheral of patients diagnosed with GBM in order to screen patients for the EGFRvIII deletion. 11 patients have been included in this study. Results: The circulating DNA status for EGFvIII correlates with the analysis performed on the respective tumors samples, and its level seems to be correlated with the extend of the tumor resection. Conclusions: This semi-quantitative blood biomarker may represents a strategy to 1) screen patients for anti-EGFRvIII therapy 2) monitor the therapeutic response to specific targeted therapies.