tbuckley/cabot-search huggingface dataset:
Mass spectrometry of intact complexes of benzyl styryl sulfone ON1910Na with albumin using direct serum injection
Authors: John Roboz, Sool Yeon Cho, Takao Ohnuma, Jian-Dong Jiang, Yanling Wang, Stanley Bell, Premkumar E. Reddy, James F. Holland
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

3099 

The benzyl styryl sulfone analog (ON1910Na, 473.5 Da) is currently in Phase I clinical trials. The objective was to characterize the intact complexes formed between drug and serum albumin in treated mice and in patients. Molecular masses indicated the number of drug molecules in the complex at various dose levels and sampling times. Serum and plasma were obtained from treated mice with various solid tumors and patients. One μL aliquots were injected directly into the mass spectrometer. Positive electrospray mass spectra were obtained with a triple quadrupole instrument. Molecular masses of the intact drug-albumin complexes were obtained from multiple charged ion patterns, based on the interrupted incremental augmentation of albumin masses, using conventional transformation software. Unbound 1910Na was quantified by selected reaction monitoring (m/z 474 to 216 transition). Complex formation between the drug and albumin commenced immediately upon exposure. The smooth lines of the bell-shaped multiply charged ion patterns of serum albumin became ragged. The molecular masses of the intact complexes and the number of bound drug molecules could be determined from the new peaks. Masses were determined to 0.1%. Data from mouse and human samples were comparable but not the same. Up to 21 drug molecules were bound per albumin molecule depending upon drug dose, quantity of unbound drug, and time of sampling. The number of drug molecules added were discontinuous, suggesting conformational changes permitting certain numbers of drug molecules to bind but excluding others. The technique developed demonstrates that free drug concentration and drug-albumin binding data can be measured directly in untreated serum or plasma, thus avoiding iatrogenic artifacts. (Supported by the T. J. Martell Foundation for Leukemia, Cancer and AIDS Research and by Onconova Therapeutics, Inc.).
Mary Tyler Moore (1936–2017): Diabetes Educator and Advocate
Authors: Mark A. Atkinson, Concepcion R. Nierras
Journal: Diabetes Care (2017)

> Having a dream is what keeps you alive. Overcoming the challenges makes life worth living.
> 
> —Mary Tyler Moore

“Who can turn the world on with her smile?” So began the theme song for the popular The Mary Tyler Moore Show , which aired on the CBS television network from 1970 to 1977. With the passing of Mary Tyler Moore, the show’s star, on 25 January 2017, the diabetes community lost an individual who for decades not only brought smiles to her audiences, but also changed the world for people living with diabetes, researchers seeking its cure, and health care providers for those with the disease.



Mary Tyler Moore delivering testimony at a U.S. Senate hearing for JDRF’s Children’s Congress, 2003.



Born in Brooklyn, NY, in 1936, young Mary moved with her family to Los Angeles, CA, when she was 8 years old (1,2). There, she developed a love of show business, and her early efforts as a dancer opened doors into the world of television. Many tributes published since her passing have highlighted Ms. Moore’s creativity and success as a performer; her remarkable talent encompassed dancing, acting, and singing. From 1961 to 1966, she played Laura Petrie, the wife, mother, and homemaker on The Dick Van Dyke Show (3). In the 1970s, on The Mary Tyler Moore Show , she was Mary Richards, the modern, forward-thinking, fearless yet vulnerable producer at a local Minneapolis, MN, television news station who spoke her mind but also fostered teamwork and a sense of camaraderie among her quirky coworkers (4). For her dramatic role as Beth Jarrett in the acclaimed 1980 film Ordinary People , in which she convincingly conveyed a parent’s heart-breaking challenge of surviving a child (5), she was nominated for an Academy Award for Best Actress in a Leading …
Unscheduled screening tests cannot be termed as surveillance
Authors: Xue‐Jun Xu, Huai‐Zhi Wang, Ping Bie
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with great interest the recent article by Atiq et al.1 By assessing benefits and harms from hepatocellular carcinoma (HCC) surveillance, they found that over one‐fourth of patients with cirrhosis experienced physical harm due to false‐positive or indeterminate surveillance tests, which were more often related to ultrasound than alpha‐fetoprotein. They pointed out that high false‐positive or indeterminate results of ultrasound may induce unnecessary computed tomography or magnetic resonance imaging scans, which would cause some degree of physical harm, such as radiation exposure. We have the following concerns. It cannot be neglected that a major limitation of this study was its retrospective nature. All 680 patients with cirrhosis stratified either to the surveillance or nonsurveillance groups were determined by researchers only after review of medical records. As the authors describe, "ultrasounds with indications including 'surveillance,' 'screening,' 'rule out HCC,' and 'cirrhosis' were classified as surveillance exams." However, the authors did not explain whether these patients underwent their regular or scheduled screening tests at every 6‐month interval according to the recommendations from the American Association for the Study of Liver Diseases and the National Comprehensive Cancer Network.2 As a matter of fact, if a rigorous standard is not set for screening interval (for example, undergoing a screening test once a year or more), these tests should not be termed as surveillance. This may explain why the detection rate of early HCC, even in those patients under "surveillance" was far from satisfactory in this study. In a word, the bias caused by stratification error may in all probability lead to an incorrect conclusion, and the reliability of this conclusion warrants careful interpretation and further validation. In summary, clarification regarding the aforementioned omission would greatly solidify the conclusions made by Atiq et al. in their study.
STUDIES IN EDEMA
Authors: Moyer S. Fleisher, Leo Loeb
Journal: The Journal of Experimental Medicine (1909)

1. Animals in which experimental myocarditis has been produced and winch are infused with sodium chloride solutions show a marked decrease in the amount of the secretion of urine. This decrease is even more pronounced than that produced when calcium chloride is added to sodium chloride solution. The intestinal fluid which is markedly decreased, and the peritoneal transudate which is increased by calcium chloride are, on the other hand, not markedly influenced by myocarditic lesions. We may, therefore, conclude that calcium chloride does not exert its specific effect on the quantity of peritoneal fluid through a lowering of blood pressure. 2. Each of the three factors, namely, calcium chloride, adrenalin and myocarditic lesions affects the elimination of fluid through the kidneys, through the mucosa of the small intestine and through the endothelial lining of the peritoneal cavity in a specific way. The conditions influencing the elimination of fluids through these three surfaces seem, therefore, to be different in each case and characteristic for the cells lining these surfaces.
Activity of MK1775, a selective Wee1 inhibitor, alone or in combination with gemcitabine, in sarcomas.
Authors: Jenny Kreahling, Damon R. Reed, Parastou Foroutan, Gary Martinez, Robert Gillies, Soner Altiok
Journal: Journal of Clinical Oncology (2012)

10084 Background: Sarcomas consist of more than 50 subtypes of mesenchymal tumors. Doxorubicin alone or in combination has been the primary therapy for treatment of sarcomas; however, the response rates are suboptimal in many of the more common adult subtypes of soft tissue sarcoma. Accordingly, new agents are needed for the treatment of this heterogeneous group of diseases. Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Methods: MK1775 treatment of multiple sarcoma preclinical models at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death. In our current study we have investigated the therapeutic efficacy of MK1775 in sarcoma cell lines, patient-derived tumor explants ex vivo and in vivo in a xenograft model of osteosarcoma both alone and in combination with gemcitabine. Results: In patient-derived bone and soft tissue sarcoma samples ex vivo treatments show MK1775 in combination with gemcitabine causes significant apoptotic cell death suggesting that this treatment may represent a novel approach in the treatment of sarcomas. The cytotoxic effect of Wee1 inhibition on sarcoma cells appears to be independent of p53 mutational status. Furthermore, in a patient-derived osteosarcoma xenograft mouse model we show the therapeutic efficacy of MK1775 in vivo by utilizing magnetic resonance imaging (MRI) and diffusion MRI methods. Our data shows MK1775 in combination with gemcitabine dramatically slows tumor growth, increases apoptotic cell death and increases CDC2 activity. Cell viability, a clinically established prognostic indicator of survival, was lowest with the combination and very low in animals treated with MK1775 alone. This was mainly due to increased mineralization of the tumors. Caspase-3 was increased in MK1775 treated animals by immunohistochemistry as well. Conclusions: These results together with the promising safety profile of MK1775 strongly suggest that this drug can be used as a potential therapeutic agent alone or in combination with gemcitabine in the treatment of both adult as well as pediatric sarcoma patients.
Abstract 151: MCL-1 Promotes Mitochondrial Fusion and Survival in Cardiac Myocytes
Authors: Robert L Thomas, Jennifer Kuo, Åsa B Gustafsson
Journal: Circulation Research (2014)

Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 protein that is highly expressed in myocardium, but little is known about its function in myocytes. Recently, we reported that MCL-1 is essential for myocardial homeostasis and autophagy. Cardiac-specific deletion of MCL-1 in mice led to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Despite extensive mitochondrial damage, MCL-1 deficient hearts failed to activate mitochondrial autophagy. Parkin, an E3 ubiquitin ligase, normally translocates to damaged mitochondria to promote mitochondrial autophagy, but loss of MCL-1 resulted in cytosolic accumulation of Parkin. However, we found no evidence that MCL-1 functions as a mitochondrial Parkin receptor or substrate. Instead, loss of MCL-1 reduced mitochondrial accumulation of PINK1, which is involved in Parkin recruitment. Additionally, we identified mitochondrial outer membrane (OM) and matrix isoforms of MCL-1 in mouse hearts and found that the two forms respond differently to ischemic injury. Four hours after myocardial infarction, MCL-1 OM levels were reduced by 40% in border zone tissue. After 24 hours, MCL-1 OM levels returned to baseline. Meanwhile, MCL-1 Matrix levels were preserved at four hours, and increased significantly compared to control 24 hours after infarction. These changes correlated with increased expression of HSP70, a chaperone protein that stabilizes MCL-1 and participates in import of mitochondrial proteins. Overexpression of MCL-1 Matrix promoted mitochondrial fusion in fibroblasts under baseline conditions and protected cells against FCCP-mediated mitochondrial fission. While 94.1% (1269 of 1349) of control cells exhibited fragmented mitochondria after two hours of FCCP treatment, mitochondria were only fragmented in 41.3% (391 of 947) of cells overexpressing MCL-1 Matrix . These data suggest MCL-1 isoforms play different roles in the cellular stress response. MCL-1 OM protects against apoptosis, whereas MCL-1 Matrix protects mitochondria by promoting fusion. In addition, upregulation of HSP70 may preserve mitochondrial function and cell viability in damaged cardiac myocytes by increasing the stability and mitochondrial import of MCL-1.
Accuracy of pedicle screw placement in posterior lumbosacral instrumentation by computer tomography evaluation: A multi-centric retrospective clinical study
Authors: Tianming Yu, Shuang Mi, Yuansong He, Zhenwu Zhang, Wenjie Dai, Jiqing Tian, Zhenghua Hong, Shunwu Fan, Fengdong Zhao
Journal: International Journal of Surgery (2017)
Abstract 164: Microdomain Specific Effects of Transient Receptor Potential Channels on Pathological Cardiac Hypertrophy and Myocyte Contractility
Authors: Catherine A Makarewich, Hongyu Zhang, Hui Gao, Robert N Correll, Jason M Duran, Jeffery D Molkentin, Steven R Houser
Journal: Circulation Research (2013)

Hypothesis: Ca2+ influx through transient receptor potential canonical (TRPC) channels and L-type Ca2+ channels (LTCCs) within caveolin-3 (Cav3) stabilized signaling microdomains provide a unique source of Ca2+ to activate pathologic cardiac hypertrophy through calcineurin (Cn)-mediated nuclear factor of activated T-cells (NFAT) signaling. We suggest that a distinct and separate population of TRPC channels localized in excitation-contraction (EC) coupling microdomains may have potent effects on myocyte contractility independent of Cav3 signaling domains. Methods and Results: Membrane localization studies and immunohistochemistry show that TRPC channels and LTCCs co-localize to Cav3 signaling microdomains. To explore a role for these caveolae based Ca2+ channels in the initiation of Cn-NFAT signaling we used an adenoviral NFAT-GFP reporter in cultured adult feline myocytes (AFMs). Infecting AFMs with ad-TRPC3 dramatically increased NFAT translocation, which was inhibited with dominant negative ad-dnTRPC6. Expression of a Cav3 targeted LTCC blocker (ad-Cav-Rem) reduced NFAT translocation while a targeted LTCC activator (ad-Cav-β2a) significantly increased NFAT activation. Neither LTCC modulator had significant effects on Ca2+ current or contractility in AFMs but we found that the expression of TRPC3 reduced myocyte contractility and induced spontaneous Ca2+ spark activity that was exacerbated by the DAG activator OAG. Moreover, dnTRPC6 blocked spontaneous Ca2+ sparks even in the presence of OAG. Immunohistochemistry analysis revealed the presence of TRPC channels in transverse tubules, consistent with the idea that they could have direct effects on EC coupling microdomains. Conclusions: Our data show that TRPC channels and LTCCs co-localize to Cav3 signaling domains where they generate a unique Ca2+ microenvironment that directly regulates Cn-NFAT signaling. Our findings also suggest that a separate and distinct population of TRPC channels within EC coupling microdomains cause reduced myocyte contractility by inducing SR Ca2+ leak and Ca2+ spark activity.
A phase I/II study (TaxXel) on the treatment with docetaxel in combination with capecitabin in patients with metastatic esophageal cancer or cancer in the cardia region.
Authors: Signe Friesland, Gun Wickart-Johansson, Lianna Kadar, Charlotte Bratthall, Henry Letocha, Lars Franzen, Anne-Birgitte Jacobsen, Petra Weber Hauge, Gunnar Wagenius, Ingunn Hatlevoll, Nils Glenjen
Journal: Journal of Clinical Oncology (2012)

e14531 Background: This is an open label, non-randomized, multicenter phase I-II study with Docetaxel (Doc) given in combination with capecitabine (Cap) in patients (pts) with metastatic oesophageal cancer (mEC) or cancer in the cardia region (mCCR). Methods: In phase I, pts were treated with Cap day 1-14, 22-36 and Doc day 1, 8, 15, 22, 29. Cap was dose escalated from 1300 mg up to 1650mg/m2 per day according to modified Fibonacci design. The dose of Doc was fixed to 30mg/m2 in both Phase I-II. In Phase II 1650mg/m 2 Cap was given. The primary objective in phase I was to define a dose of Cap recommended for the Phase II and to determine the feasibility and safety of this treatment. The primary objective in the phase II was to determine the response rate (RR), safety profile, quality of life and survival.The median age was 64.8 years, PS was 0 in 23 pts, I in 57 and II in 13 pts. The histology was as follows: 58 adenoca, 33 squamous cell ca and 2 poorly diff ca. Forty-three pts had previously been treated with chemotherapy, 41 with radiotherapy, 50 were chemotherapy-naive and 31 had underwent surgery. Results: From March 2006 to Oct 2010, 93 eligible pts with measurable disease were enrolled in the study. Fourteen were treated in phase I and 79 in phase II. Four pts (1 in ph I and 3 in ph II) did not receive any study treatment. Twenty-seven pts of 93 (29%) were not evaluable according to study protocol which included CT after 6 w of treatment due to rapid tumour progression and deterioration of general condition. RR was 29%, 2 CR and 25 PR, 15 pts (16%) had SD and 24 pts (26%) had PD. Median OS was 7.3 months (5.76-8.9) and median PFS was 4.2 months (2.3-4.7 months).Treatment related grad 3 or 4 toxicity was as follows: 60% of pts experienced any grade 3 or 4 toxicity, 30% related to infections, 24% had nausea, diarrhea, vomiting, mucositis, &lt;10% had cardiac related symptoms, &lt;1% had an allergic reaction to Doc. Conclusions: Cap together with Doc appears tolerable and has a RR of 29% in selected group of patients with mET and mCCR. Majority of treatment courses were given on out-patient bases. However, there is un urgent need to define an optimal therapy regime and further studies are warranted.
Efficacy of self-expandable metal stents in management of benign biliary strictures and comparison with multiple plastic stents: a meta-analysis
Authors: Muhammad Khan, Todd Baron, Faisal Kamal, Bilal Ali, Richard Nollan, Mohammad Ismail, Claudio Tombazzi, Everson Artifon, Alessandro Repici, Mouen Khashab
Journal: Endoscopy (2017)

Abstract Background and study aims There is burgeoning interest in the utilization of covered self-expandable metal stents (CSEMSs) for managing benign biliary stricture (BBS). This systematic review and meta-analysis evaluated cumulative stricture resolution and recurrence rates using CSEMSs and compared performance of CSEMSs and multiple plastic stents (MPS) in BBS management. Method Searches in several databases identified studies including ≥ 10 patients that utilized CSEMSs for BBS treatment. Weighted pooled rates were calculated for stricture resolution and recurrence. Pooled risk ratios (RRs) comparing CSEMSs with MPS were calculated for stricture resolution, stricture recurrence, and adverse events. Pooled difference in means was calculated to compare number of endoscopic retrograde cholangiopancreatographies (ERCPs) in each group. Results The meta-analysis included 22 studies with 1298 patients. Weighted pooled rate for BBS resolution with CSEMS was 83 % (95 % confidence limits [95 %CLs] 78 %, 87 %; I 2 = 72 %). On meta-regression analysis, resolution in chronic pancreatitis patients and post-orthotopic liver transplant patients were significant predictors of heterogeneity. Weighted pooled rate for stricture recurrence with CSEMSs was 16 % (11 %, 22 %). Overall rate of adverse events requiring intervention and/or hospitalization was 15 %. Four randomized controlled trials with 213 patients compared CSEMSs with MPS: the pooled RRs for stricture resolution, recurrence, and adverse events were 1.07 (0.97, 1.18), 0.88 (0.48, 1.63), and 1.16 (0.71, 1.88), respectively with no heterogeneity. Pooled difference in means for number of ERCPs was – 1.71 ( – 2.33, – 1.09) in favor of CSEMS. Conclusions CSEMSs appear to have excellent efficacy in BBS management. They are as effective as MPS but require fewer ERCPs to achieve clinical success.
King-devick (kd) test as a rinkside tool for concussion assessment
Authors: DJ Rhine, T Lamvohee, BD Rhine
Journal: British Journal of Sports Medicine (2017)

Objective King-Devick test as a rinkside tool for concussion diagnosis. Design KD was administered to hockey players immediately after removal from the game with a suspected concussion. Results were compared to baseline. Concussion was suspected with slowing by &gt;5.2 sec. 1 Setting Hockey games. Participants Hockey players (male/female) – school-based hockey academy and a Canadian junior hockey team Interventions Athletic trainers were trained in the use of KD and obtained baseline KD times for players. AT’s administered the KD test to hockey players immediately after removal from the game with a suspected concussion. Main outcome measures KD time post-injury was compared to the KD time baseline. Results During the 2015–16 season, KD testing was collected on players with suspected concussion (42 concussions identified out of 148 players). Of the 42 concussions, 13 had KD sideline testing done immediately post-injury; 8/13 demonstrated &gt;5.2 sec slowing in their KD baseline scores. All were further evaluated with a comprehensive concussion assessment protocol that included symptom scoring-balance assessments-cognitive testing. Concussion was confirmed with this diagnostic approach in 8/8 players with KD times slowed by more than 5.2 sec. Abstarct 212 Table 1 King-Devick Sideline Assessment for Concussion: Diagnostic Difference &gt;5.2 sec from Baseline AGE GENDER SPORT Baseline Sideline ΔKD 14yr Male Hockey 53.08 61.08 8.0 sec 14yr Male Hockey 30.09 42.81 12.72 15yr Female Hockey 42.5 53.5 11.0 15yr Female Hockey 37.0 54.0 23.0 17yr Female Hockey 46.5 54.05 7.55 18yr Male Hockey 36.88 43.35 6.97 19yr Male Hockey 36.01 61.0 24.99 20yr Male Hockey 39.02 47.08 8.06 Conclusions An ideal concussion sideline diagnostic tool should be inexpensive, portable, reproducible, fatigue-tolerant, resistant to test-retest learning and suitable for non-medical personnel. 2 3 The King-Devick test, that assesses saccadic eye movements, has these characteristics. It can be administered in less than 2-minutes. It has been reported that a post-injury slowing of KD times &gt;5.2 seconds is diagnostic of concussion. 4 Sideline/rinkside KD testing with &gt; 5.2 sec slowing compared to baseline results accurately identified concussion with 100% accuracy.
Genetic evidence for tumor-hematopoietic cell hybrids in a human renal cell carcinoma metastasis
Authors: Ashok Chakraborty, Rossitza Lazova, Stella Davies, Helena Bäckvall, Fredrik Ponten, Douglas Brash, John Pawelek
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1768 

Previous studies using experimental animal tumor models have identified tumor-host hybrid cells through the use of heterologous genetic markers. Here we analyzed human tumor DNA for evidence of hybrid cells in a child who developed metastatic renal cell carcinoma subsequent to an allogeneic (sibling, child) bone marrow transplant. We searched for the donor’s A blood group allele within the O/O recipient’s tumor cells. Clusters of metastatic cells were laser microdissected from deparaffinized tissue sections. DNA was analyzed for restriction fragments specific for A and O alleles. Of the 21 tumor cell DNA samples tested, 16 yielded PCR products, and all 16 contained the donor A allele, while 14 of 16 also contained the O allele. The samples were isolated from diverse areas of the metastasis, and donor DNA was observed throughout. Since it was highly unlikely that renal cell carcinoma cells were transferred via the BMT, the most probable explanation is that the metastasis contained donor-recipient hybrids. Tumor cells also stained strongly for beta 1,6-branched oligosaccharides, a myeloid trait that is upregulated in experimental macrophage-tuymor fusion hybrids. The prevalence of hybrids throughout the metastasis would suggest hybridization as a potential source of metastatic cells in this patient.