tbuckley/cabot-search huggingface dataset:
Characterization of self-assembled monolayers (SAM) of peptide mimotopes of CD20 antigen and their binding with rituximab (R) using Quartz Crystal Microbalance (QCM) Piezo-Immunosensors: A novel technique to study CD20 antigen interaction.
Authors: Mohammad Muhsin Chisti, Norman Leo, Yuqin Shang, Justin Frank Antoni Klamerus, Ishmael A. Jaiyesimi, Xiangqun Zeng
Journal: Journal of Clinical Oncology (2016)

e14004 Background: CD20 antigen is an established target for antibody therapy like R. Understanding interactions of CD20 antigens is important for developing better agents and overcoming resistance. We have developed a new innovative biosensor based quantitative technique to study real time interaction of CD20 antigens with R using QCM Piezo-immunosensor, which can be used to characterize cell surface antigen, study interactions and understand mechanisms of resistance. Methods: Binding of R with SAM of peptide mimotopes of CD20 antigen was systematically characterized. Four peptide mimotopes of CD 20 antigen were selected from literature and redesigned to allow their SAM immobilizations on gold electrodes through a peptide linker with cysteine. The bindings of these peptides with R and control antibodies (Trastuzumab, Bevacizumab) were characterized by Quartz Crystal Microbalance (QCM). Among the four peptide mimotopes initially selected, the peptide designated as CN-14 was the most selective and sensitive for R binding, which was further characterized by ellipsometry, atomic force microscopy and QCM. Results: We have shown a systematic approach for using QCM technique to quantify the apparent binding of CD20 and R. As the GLU residue pKa of CN-14 increased, the affinity of the SAM to Rituximab increased while the selectivity decreased. This was attributed to the weakening of the salt bridge between the CN-14 ARG-10 and GLU-13 at higher pKa values for GLU-13. Conclusions: Interaction of CD20 antigens with antibodies will help physicians to determine the clinical efficacy and resistance mechanisms to antibodies like R. QCM is low cost, highly sensitive, fast, synthetic, assay which could be used as a basis for developing a new generation of affinity-based Immunosensor assays. Our study shows that peptide mimotopes have potential benefit in sensor applications as the peptide-peptide interactions in the SAM could be manipulated by the addition of functional groups to the peptide to influence binding of the target protein as well as for surface immobilization via SAM.
Case 21-1999
Authors: Simon D. Spivack, Eugene J. Mark
Journal: New England Journal of Medicine (1999)

Presentation of CaseA 69-year-old man was admitted to the hospital because of the radiologic finding of pulmonary nodules.The patient had been well until several weeks earlier, when a cough, fever, and dyspnea developed. A thoracic radiograph obtained at another hospital 11 days before admission (Figure 1) showed an irregular nodule, 2 by 1.5 cm, in the right upper lobe and additional bilateral nodules. There was no hilar or mediastinal lymphadenopathy. A thoracic computed tomographic (CT) scan (Figure 2A and Figure 2B) revealed a spiculated mass in the periphery of the right upper lobe and multiple smaller nodules, 2 to 5 . . .
Curcumin induced toxicity towards human SK-MEL-28 melanoma cells
Authors: Nikhil Vad, Majid Moridani
Journal: Cancer Research (2007)

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

3966 

Currently, tyrosinase is used as a molecular target for treatment of melanoma in our laboratory. This enzyme is found abundantly in melanoma and can convert phenols to catechols and then o-quinones which are toxic to melanoma cells. Previously, curcumin was investigated and showed toxicity towards various melanoma cell line. Curcumin also demonstrated significant in vivo toxicity. Because curcumin is a phenol we decided to investigate that if o-quinone formation mediated by tyrosinase metabolism of curcumin plays a major role in curcumin induced toxicity in human SK-MEL-28 melanoma cell line. To elucidate the role of quinone induced toxicity a number of modulators were employed to enhance and/or prevent curcumin toxicity. We used ascorbic acid (AA), NADH and GSH depletions as surrogate markers of quinone formation and oxidative stress in tyrosinase mediated curcumin metabolism to delineate their roles in curcumin induced melanoma cell toxicity. Curcumin demonstrated a time dependent and dose dependent anti-proliferative effect against SK-MEL-28 melanoma cells with an IC50 (day 2) of 8 μM. Dicumarol (a quinone:NAD(P)H oxidoreductase inhibitor) and 1-bromoheptane (an intracellular GSH depleting agent) marginally but not significantly increased curcumin toxicity towards SK-MEL-28 melanoma cells. GSH (a thiol containing agent), ascorbic acid (a quinone reducing agent), and trifluperazine (a mitochondrial permeability transition pore inhibitor, MPTP), marginally but not significantly prevented curcumin toxicity. Dicumarol and 1-bromoheptane increased reactive oxygen species (ROS) formation when the melanoma cells were incubated with curcumin. It was found that tyrosinase did not metabolize curcumin. In addition, curcumin did not inhibit tyrosinase activity. The 3 h incubation of cells with 20 μM of curcumin led to a significant intracellular GSH depletion. In summary, we conclude that curcumin was not a substrate for tyrosinase. Neither quinone formation nor mitochondrial toxicity played a major role in curcumin induced toxicity in SK-MEL-28 melanoma cells whereas ROS formation and intracellular GSH depletion contributed significantly in curcumin induced toxicity in SK-MEL-28 melanoma cells.
The role of hemoglobin level in predicting the response to first-line chemotherapy in advanced colorectal cancer (ACC) patients
Authors: M. Tampellini, A. Saini, I. Alabiso, R. Bitossi, M. P. Brizzi, A. Berruti, G. Gorzegno, S. Miraglia, O. Alabiso, L. Dogliotti
Journal: Journal of Clinical Oncology (2004)

3564 Background: Several in vitro studies showed that colorectal cancer cells responding to 5-fluorouracil (5FU) become resistant under hypoxic condition. Moreover, it has been demonstrated that tumoral tissues are hypoxic in anemic pts. We investigated the impact of hemoglobin levels in predicting response to first-line chemotherapy in ACC patients. Methods: We collected data from 394 consecutive patients treated and followed in 2 centers from 1994 to 2003. Two hundred and forty five pts were men and 149 women. Median age: 61 years (29–80); WHO performance status (PS) 0/I/II: 279/90/25 pts; number of organs involved 1/2/3: 267/104/23 pts; metastases (mts) in liver were evident in 71% pts; mts in lung in 28% pts; mts in peritoneum in 19% pts; prior adjuvant chemotherapy was administered in 30% pts. All the pts were submitted to 5-FU-based first-line chemotherapy. 184 pts received 5FU ± folinic acid (FA); 195 pts received 5FU+LOHP±FA; 15 pts received 5FU+CPT-11±FA. Hemoglobin levels were evaluated before chemotherapy start. Pts with hemoglobin < 12 g/dl were considered anemic. Response was evaluated every 3c with CT scan. Results: Clinical response (CR+PR) was recorded in 136 pts (34.6%), stable disease in 155 (39.9%) and progression in 103 (26.5%). At baseline, 170 pts (43.1%) were anemic. 45/170 anemic pts (26.5%) and 91/224 non anemic pts (40.6%) responded to chemotherapy (X2= 8.57; p<0.003). Anemia maintained its predictive role for disease response even adjusting for PS, grading, T, or age in multivariate logistic analysis. Pts with normal hemoglobin level showed a longer time to progression (13.0 mo vs 10.1; p<0.002) and a longer survival (27.6 mo vs 17.8; p<0.0001) than anemic ones. Cox's multivariate survival analysis confirmed hemoglobin level as a independent predictor of time to progression and survival. Conclusions: Anemia is a strong predictive factor of activity and efficacy of 5fluorouracil based chemotherapy in advanced colorectal cancer patients. No significant financial relationships to disclose.
Decreased Expression of Connexin 43 Blunts the Progression of Experimental GN
Authors: Panagiotis Kavvadas, Ahmed Abed, Coralie Poulain, Florence Authier, Lise-Paule Labéjof, Amelie Calmont, Carlo Afieri, Niki Prakoura, Jean-Claude Dussaule, Christos Chatziantoniou, Christos E. Chadjichristos
Journal: Journal of the American Society of Nephrology (2017)

GN refers to a variety of renal pathologies that often progress to ESRD, but the molecular mechanisms underlying this progression remain incompletely characterized. Here, we determined whether dysregulated expression of the gap junction protein connexin 43, which has been observed in the progression of renal disease, contributes to GN progression. Immunostaining revealed de novo expression of connexin 43 in damaged glomeruli in patients with glomerular diseases as well as in mice after induction of experimental GN. Notably, 2 weeks after the induction of GN with nephrotoxic serum, mice with a heterozygous deletion of the connexin 43 gene (connexin 43+/-) had proteinuria, BUN, and serum creatinine levels significantly lower than those of wild-type animals. Additionally, the connexin 43+/- mice showed less crescent formation, tubular dilation, monocyte infiltration, and interstitial renal fibrosis. Treatment of cultured podocytes with connexin 43-specific blocking peptides attenuated TGF-β-induced cytoskeletal and morphologic changes and apoptosis as did treatment with the purinergic blocker suramin. Finally, therapeutic treatment of GN mice with connexin 43-specific antisense oligodeoxynucleotide improved functional and structural renal parameters. These findings suggest that crosstalk between connexin 43 and purinergic signaling contributes to podocyte damage in GN. Given that this protein is highly induced in individuals with glomerular diseases, connexin 43 may be a novel target for therapeutic treatment of GN.
The short-term outcome and quality of life after isoperistaltic jejunum-later-cut overlap method ——A new esophagojejunostomy anastomosis after totally laparoscopic total gastrectomy: A Propensity Score-Matched Analysis
Authors: Changming Huang, Chao-Hui Zheng, Ping Li, Jian-Wei Xie, Jun Lu
Journal: Annals of Oncology (2017)
Monitoring of Minimal Residual Disease before and after Allogeneic Stem Cell Transplantation Childhood ALL - a Retrospective Assessment on Behalf of the PDWP of the EBMT, the COG, PBMTC, the I-BFM and the Westhafen-Intercontinental-Group
Authors: Peter Bader, Emilia Salzmann-Manrique, Adriana Balduzzi, Jean-Hugues Dalle, Ann E Woolfrey, Merav Bar, Michael R Verneris, Michael J. Borowitz, Nirali N Shah, Nathan Gossai, Peter J Shaw, Allen R. Chen, Hermann Kreyenberg, Sophia L. Yohe, Lucia Di Maio, Cornelia Eckert, Vincent H.J. van der Velden, Arjan C Lankester, Thomas Klingebiel, Christina Peters, Stephan A Grupp, Michael A Pulsipher
Journal: Blood (2016)
‘Caution, this treatment is a placebo. It might work, but it might not’: why emerging mechanistic evidence for placebo effects does not legitimise complementary and alternative medicines in sport
Authors: Chris Beedie, Greg Whyte, Andrew M Lane, Emma Cohen, John Raglin, Phil Hurst, Damian Coleman, Abby Foad
Journal: British Journal of Sports Medicine (2017)

Complementary and alternative medicines (CAM) are treatments for which either evidence is lacking, or for which evidence suggests no effect over a placebo treatment. When a non-evidence-based treatment is used alongside conventional medicine, it is considered ‘complementary’. When a non- evidence-based treatment is used instead of conventional medicine, it is considered ‘alternative’. Many forms of CAM have origins and/or a history of use beyond evidence-based medicine. Further, many CAM treatments are based on principles and/or evidence that are not recognised by the majority of independent scientists. When a person uses CAM and experiences an improvement in symptoms, this may be due to the placebo effect.1 

CAM is widely used in sport, often by elite athletes. One example is Michael Phelps’ use of ‘cupping’ during the 2016 Olympics. Evidence for the effectiveness of CAM in sport has been reported in some work, but more studies have reported CAM outcomes as no better than placebo. The link between CAM and the placebo effect has been made explicit by health agencies1 and scientists.2 As a consequence, where credible causal mechanisms for apparent therapeutic effects are absent, placebo effects are often assumed.

The placebo effect was historically considered a non-specific phenomenon, …
Abstract 287: Identification of a Novel PKCα Isoform in Heart Transcriptome via RNA Deep Sequencing
Authors: Chen Gao, Jae-Hyung Lee, Grace (Xinshu) Xiao, Yibin Wang
Journal: Circulation Research (2012)

The Protein kinase C (PKC) family of Ca2+ and /or lipid-activated AGC kinases are important regulators of multiple cellular responses including cell growth and programmed cell death. Among these, PKCα is the predominant conventional PKC isoform in heart and has been implicated to have a major impact on cardiac function, hypertrophic response and heart failure. Earlier studies have revealed that the conserved AGC-C-terminal tail containing active site cleft is responsible for regulating AGC kinase activity. The phosphorylation events in AGC-C-terminal tail mediate the activity of kinase by regulating kinase maturation, translocation and substrate interaction. In a genome-wide RNA-Seq analysis in mouse heart, we have identified a novel isoform of PKCα-- due to the insertion of a novel exon in its C-terminal tail. This novel exon has a highly conserved sequence from mouse to human, suggesting a conserved role in PKCα regulation. Tissue analysis showed that this PKCα isoform with Novel Exon (PKCαNE) has enriched expression in heart and skeletal muscle, indicating the involvement of a muscle specific alternative splicing event. The insertion of this novel exon lies between the kinase C-Lobe Tether and Active Site Tether. Biochemistry study in cells showed that both PKCα and PKCαNE were activated and translocated from cytosol to membrane and nucleus in response to PMA. However, upon IGF-1 treatment, PKCαNE showed no activation and could not translocate to either membrane or nucleus in contrast to PKCα. To further explore the mechanism for PKCαNE activation, we have determined the phosphorylation events of this novel isoform. Interestingly, the PKCαNE showed a decreased phosphorylation level at the Turn Motif , which could directly impact its activation and maturation. In summary, we have identified a novel isoform of PKCα that is enriched in heart and skeletal muscle. The PKCαNE isoform has different activation profile and its biological significance in cell signaling in physiology and diseases remains to be further explored.
Feeding the microbiota: transducer of nutrient signals for the host
Authors: Fergus Shanahan, Douwe van Sinderen, Paul W O’Toole, Catherine Stanton
Journal: Gut (2017)

Advances in microbiome science cast light on traditional concepts on nutritional science, and are poised for clinical translation. Epidemiologic observations which linked lifestyle factors to risk of disease are being re-interpreted with mechanistic insight based on improved understanding of the microbiota. Examples include the role of dietary fibre in disease prevention, the deleterious effects of highly restricted diets, and the contribution of the microbiota to over- and undernutrition. While the microbiota transduces nutrient signals for the host, food and habitual diet shape the composition of the gut microbiota at every stage of life. The composition and diversity of food intake determines which microbes will colonise, flourish, persist, or become extinct. Disruption of the developing microbiota in infancy contributes to the risk of immune and metabolic disease in later life, whereas loss of microbes in the elderly due to monotonous diets has been linked with unhealthy ageing and frailty. This should influence modern dietary advice regarding prevention and management of chronic non-communicable inflammatory and metabolic disorders, and will inform the design of infant and future food formula. The microbiota profile is also emerging as a biomarker to predict responsiveness to dietary interventions and promises to make personalised nutrition a reality.
TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss
Authors: Rosa C. Paolicelli, Ali Jawaid, Christopher M. Henstridge, Andrea Valeri, Mario Merlini, John L. Robinson, Edward B. Lee, Jamie Rose, Stanley Appel, Virginia M.-Y. Lee, John Q. Trojanowski, Tara Spires-Jones, Paul E. Schulz, Lawrence Rajendran
Journal: Neuron (2017)

Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.
The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial
Authors: Nadine G Rouphael, Michele Paine, Regina Mosley, Sebastien Henry, Devin V McAllister, Haripriya Kalluri, Winston Pewin, Paula M Frew, Tianwei Yu, Natalie J Thornburg, Sarah Kabbani, Lilin Lai, Elena V Vassilieva, Ioanna Skountzou, Richard W Compans, Mark J Mulligan, Mark R Prausnitz, Allison Beck, Srilatha Edupuganti, Sheila Heeke, Colleen Kelley, Wendy Nesheim
Journal: The Lancet (2017)
Final results of a randomized phase 2 study showing the clinical benefit of quizartinib (AC220) in patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia.
Authors: Gary J. Schiller, Martin S. Tallman, Stuart L. Goldberg, Alexander E. Perl, Jean-Pierre Marie, Giovanni Martinelli, Richard A. Larson, Nigel Russell, Denise Trone, Guy Gammon, Mark J. Levis, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2014)

7100 Background: The presence of FLT3-internal tandem duplication (ITD) in patients (pts) with acute myeloid leukemia (AML) is associated with early relapse and poor survival. Quizartinib (AC220) is an orally active inhibitor of the FLT3 receptor tyrosine kinase being developed for the treatment of pts with FLT3-ITD(+) AML. This randomized, open-label, study was conducted to assess the effect of two different dosages of quizartinib in FLT3-ITD+ pts, aged 18 years or older, with relapsed or refractory AML after either one-second line therapy or HSCT. Methods: Pts were randomized to quizartinib 30 mg/day (Group A) or 60 mg/day (Group B) given orally during 28-day continuous treatment cycles, until relapse, intolerance or proceeding to HSCT. Primary endpoint was the rate of CRc (CR+CRp+CRi). Results: Seventy six pts were randomized equally to the two arms. Demographics and baseline characteristics were balanced between the two arms except for age over 60 years (42% Group A, 26% Group B) and the percentage with secondary AML (8% Group A, 18% Group B). The analysis included a minimum of 8 weeks of follow-up. The median duration of treatment in Group A was 10.9 weeks (range 2.1 to 24.9+ weeks) and 11.0 weeks (range 2.6 to 26 weeks) in Group B. The CRc rate in both groups was 47% and the overall response rate (CRc + partial response (PR)) was 61% in Group A and 71% in Group B. 32% of pts in Group A and 42% in Group B were able to receive a HSCT, mostly after achieving CRc or PR. The median overall survival was 20.7 weeks in Group A; and 25.4 weeks in Group B with 35 of the 76 patients alive at last follow-up (range: 7.4 – 40.4+ weeks). Grade 2 or greater QTcF prolongation occurred in 11% Group A pts and in 17% Group B pts. The most common treatment related adverse events occurring in 15% or more pts were diarrhea (18%), febrile neutropenia (16%), and QT prolongation (15%). Conclusions: Quizartinib in second salvage or post HSCT FLT3-ITD+ AML demonstrated a high degree of efficacy (CRc 47%) with an acceptable safety profile, specifically decreased QTcF prolongation rates compared to higher doses used previously. Further analysis with additional follow-up will be available for presentation. Clinical trial information: NCT01565668.
A genome-wide association study suggests that<i>MAPK14</i>is associated with diabetic foot ulcers
Authors: W. Meng, A. Veluchamy, H.L. Hébert, A. Campbell, H.M. Colhoun, C.N.A. Palmer
Journal: British Journal of Dermatology (2017)

Background Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. Objectives To identify genetic contributors to the development of DFUs in the presence of peripheral neuropathy in a Scottish cohort with diabetes using a genome‐wide association study. Methods A genome‐wide association approach was applied. A case was defined as a person with diabetes (type 1 or type 2) who had ever had a foot ulcer (current or previous) in at least one foot, as well as a positive monofilament test result (i.e. evidence of peripheral neuropathy) recorded in their longitudinal e‐health records. A control was defined as an individual with diabetes (type 1 or type 2) who has never been recorded as having a foot ulcer in either foot but who had a positive monofilament test result recorded in either foot in their longitudinal e‐health records. Results There were 699 DFU cases and 2695 controls in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. The single‐nucleotide polymorphism rs80028505 (Chr6p21·31) in MAPK14 reached genome‐wide significance with a lowest P‐value of 2·45 × 10−8. The narrow‐sense heritability of this phenotype is 0·06. Conclusions We suggest that MAPK14 is associated with DFUs.
Functional analysis of deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14)
Authors: Domenica Ronchetti, Silvana Compasso, Luigia Lombardi, Silvia Bogni, Palma Finelli, Angela Greco, Takemi Otsuki, Anna Teresa Maiolo, Antonino Neri
Journal: Blood (2000)