tbuckley/cabot-search huggingface dataset:
Preclinical antitumor activity with MLN8054, a small molecule Aurora A kinase inhibitor
Authors: Jessica Huck, Mengkun Zhang, Olga Burenkova, Kelly Connolly, Mark Manfredi, Kristan Meetze
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4698 

MLN8054 is a selective inhibitor of Aurora A kinase which has demonstrated broad-based efficacy in human xenograft tumor models grown in nude mice. In these studies various schedules were explored in an attempt to identify optimal dosing regimes. MLN8054 dosed orally at 3, 10, and 30 mg/kg once daily (QD) or twice daily (BID) for a period of three weeks resulted in tumor growth inhibition in a dose dependent fashion. The most efficacious dose (30 mg/kg BID) was further explored to determine if efficacy could be retained with non-continuous dosing (addition of dosing holidays). All arms of the study were performed using BID oral dosing over a 20-day period. Schedules included 30 mg/kg dosed continuously; five days on treatment, followed by five days off treatment (5/5), repeated twice; and ten days on, followed by 10 days off treatment (10/10). In addition, a 60 mg/kg BID dosing arm was included on a schedule of 3 days on treatment, followed by 7 days off (3/7), repeated twice. The continuous dosing schedule had the greatest tumor growth inhibition of 103% (p <0.001). Dosing for 5 days followed by 5 days rest (non-dosing), or for 10 days followed by 10 days rest (total dose was equal over 20 days) resulted in similar efficacy (TGI of 77% and 83%, respectively, p <0.001). Dosing at a higher level (60 mg/kg BID) for a shorter duration of time was also efficacious (TGI of 73%, p <0.001). Tumor growth delay was calculated and was greater in the continuous dosing group (TGD = 31 days) than all other groups (10/10 = 15 days, 5/5 = 14 days, 3/7 = 11 days). Similar schedules were explored in additional models including the PC3 prostate and Calu-6 lung human tumor xenografts. Consistent with the HCT-116 results, 30 mg/kg dosed continually was the most efficacious (TGI, PC3 = 119%, Calu-6 84%). These data demonstrate that efficacy in these preclinical models can be achieved with various schedules that allow dose holidays.
Simultaneous Phenotypically Distinct but Clonally Identical Mucosa-Associated Lymphoid Tissue and Follicular Lymphoma in a Patient With Sjögren’s Syndrome
Authors: Antonella Aiello, Ming-Qing Du, Tim C. Diss, Huai-Zheng Peng, Francesco Pezzella, Daniela Papini, Roberto Giardini, Silvana Pilotti, Lang-Xing Pan, Peter G. Isaacson
Journal: Blood (1999)
Some Days Nothing Can Save Us
Authors: Walt McDonald
Journal: JAMA (2001)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 19788: SIRT1 as a Novel Regulator of Cardiac Na+ Channels: A Potential Therapeutic Target for Arrhythmia
Authors: Jin-Young Yoon, Christopher Lewarchik, Shengchuan Dai, Haider Mehdi, Xiaodong Zhu, Gina M Morgan, Young-Rae Kim, Ajit Vikram, Asma Naqvi, Kaikobad Irani, Barry London
Journal: Circulation (2014)

Introduction: Ion channel disorders are responsible for inherited and acquired forms of heart disease. Mutations in the cardiac voltage-gated Na+ channel (Nav1.5) cause inherited long QT and Brugada syndromes, and changes in Nav1.5 expression and function can promote arrhythmia susceptibility. In spite of the critical role of Nav1.5 in cardiac excitation-contraction coupling, the identity and role(s) of Nav1.5 modifying genes in both inherited and acquired arrhythmias are less well established.

Aim of studies: We previously showed in both heterologous expression systems and in rat neonatal cardiac myocytes that SIRTUIN1 (SIRT1), an NAD+-dependent lysine deacetylase, increases Na+ current (INa) by binding to, deacetylating, and promoting membrane localization of Nav1.5. Here, we tested the hypothesis that SIRT1 increases INa in vivo by modifying Nav1.5 acetylation.

Methods: We engineered cardiac-specific Sirt1-knockout mice (cSirt1-/-: Sirt1flox/flox x αMHC-Cre), recorded INa from isolated ventricular myocytes by whole cell patch clamp, detected Nav1.5 acetylation by Western blot and immunostaining, and recorded electrocardiograms (ECGs) in anesthetized and telemetry in ambulatory mice.

Results: INa in cSirt1-/- ventricular myocytes was decreased by 39 ± 6 % compared to the littermate controls (n=8 each, p=0.02; Figure). Nav1.5-acetylation was increased in cSirt1-/- mice by Western blot and immunostaining. ECG recordings from 6 month-old cSirt1-/- mice showed QRS prolongation, and ambulatory telemetry showed high degree heart block and runs of ventricular tachycardia. Sudden death was prominent in cSirt1-/- mice despite only mild depression of left ventricular function.

Conclusion: Cardiac-specific disruption of Sirt1 in mice leads to arrhythmias in vivo by decreasing INa, most likely through changes in Nav1.5 trafficking. Increasing SIRT1 expression and/or activity may provide a mechanism for preventing and/or treating arrhythmias.

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Bovine Tuberculosis and Its Control.
Authors: Veranus Alva Moore
Journal: JAMA (1913)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 13782: Tricuspid Regurgitation has Marked Prognostic Impact on Transcatheter Aortic Valve Replacement
Authors: Naohiko Nemoto, Wesley R Pedersen, Paul Sorajja, John R Lesser, Erin M Spinner, Ross F Garberich, Robert S Schwartz
Journal: Circulation (2014)

Introduction: Transcatheter aortic valve replacement (TAVR) is an alternative to surgical valve replacement in severe aortic stenosis. Although tricuspid regurgitation (TR) has prognostic impact in surgical aortic valve replacement, its impact in TAVR procedures is unknown. We examined the effect of TR in TAVR patients.

Methods: TR was examined in 129 patients with prior TAVR. TR was assessed pre- and 30-days post procedure, and classified as none, mild, moderate or severe. Significant TR was defined as greater than mild, and worsened TR (30 days post TAVR) defined as increase of ≥1 grade over baseline. Late TR was > mild at 30 follow-up compared to baseline.

Results: Mean patient age was 84±8 years, and 46% were female, and had severe aortic stenosis (mean gradient 43.7±13.7mmHg, mean valve area 0.7±0.2 cm2). Significant TR occurred in 32 cases (26.4%) at baseline. Cases were divided into 2 TR groups, none (n=89) and significant (n=32). Left ventricular EF did not differ at either timepoint for the no-TR and significant TR groups. All-cause death among no-TR and significant TR patients was 12 (13.5%) and 11 (34.4%), respectively (p<0.005). TR worsened in 17 cases (14.0%) at 30-day follow up. Multivariate analysis showed that predictors of worsening TR were body mass index (OR 0.8, 95% CI 0.71-0.96 p=0.01), paravalvular leak (OR 6.5, 95% CI 1.7-24.4 p=0.0061) and atrial fibrillation (OR 5.4, 95% CI 1.36-21.73, p=0.017). Late TR occurred in 26 cases (23.6%), and predictors were paravalvular leak, BMI, and atrial fibrillation. Kaplan-Meier analysis showed survival was significantly worse both in patients with significant TR and in patients developing late TR (p=0.01).

Conclusions: TR presence and severity, either at baseline or late, is associated with increased mortality/worse survival, independent of baseline left ventricular ejection fraction. Whether this is cause and effect or only a marker for adverse cardiac function should be established. TR status and severity should be included in transcatheter aortic valve replacement risk assessment.
Topical cis-urocanic acid attenuates oedema and erythema in acute and subacute skin inflammation in the mouse
Authors: J.K. Laihia, P. Taimen, H. Kujari, L. Leino
Journal: British Journal of Dermatology (2012)

cis-Urocanic acid (cis-UCA) is an endogenous immunosuppressive molecule of the epidermis. We investigated the effects of topical cis-UCA creams (2·5% and 5%) in acute and subacute mouse models of skin inflammation.Acute skin irritation was induced by applying dimethyl sulphoxide (DMSO) on the earlobe of CD-1 mice. Topical cis-UCA, hydrocortisone (1%) or tacrolimus (0·1%) were applied 10 min later. In another model, subacute inflammation was provoked and maintained by three applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the ears of NMRI mice on days 1, 2 and 4. The test products were applied topically twice a day during 6 days.In the acute DMSO model, cis-UCA creams suppressed ear swelling at 1 h significantly more efficiently than hydrocortisone (P < 0·01) and tacrolimus (P < 0·001). Ear swelling was significantly inhibited by cis-UCA (P < 0·001) in the subacute TPA model as well. The 5% cream also decreased erythema, whereas tacrolimus enhanced skin reddening. Treatments with cis-UCA did not affect TPA-induced infiltration of neutrophils to the skin. In contrast to hydrocortisone, cis-UCA did not reduce epidermal thickness.The results suggest that cis-UCA - unlike hydrocortisone and tacrolimus - is efficient in both acute and subacute skin inflammation, attenuating skin oedema and erythema. Topical drug therapy with cis-UCA may provide a safe and effective drug treatment modality in inflammatory skin disorders.
Abstract 754: Selective ALK inhibitor alectinib (CH5424802/RO5424802) with potent antitumor activity in models of crizotinib resistance, including intracranial metastases
Authors: Tatsushi Kodama, Toshiyuki Tsukaguchi, Masami Hasegawa, Miyuki Yoshida, Kenji Takanashi, Osamu Kondoh, Hiroshi Sakamoto
Journal: Cancer Research (2014)

Abstract Purpose: EML4-ALK has been implicated as a driver oncogene and a therapeutic target in non-small cell lung cancer (NSCLC). The clinical efficacy of the ALK inhibitor crizotinib has been demonstrated in ALK fusion-positive NSCLC; however, resistance to crizotinib certainly occurs through ALK secondary mutations in clinical use. In addition, brain metastases are frequent sites of initial failure in patients because crizotinib has poor penetration of the central nervous system. This study aimed to clarify the efficacy of ALK inhibitor alectinib (CH5424802/RO5424802) in models of crizotinib-resistant ALK mutant tumors and intracranial tumors. Experimental Design: The antitumor activity of alectinib was evaluated in subcutaneous xenograft tumor models of Ba/F3 cells expressing mutated EML4-ALK, and in intracranial tumor implantation models of EML4-ALK-positive NSCLC NCI-H2228. Results: Alectinib had kinase inhibitory activity against some ALK mutations, including G1269A, and blocked tumor growth driven by a mutant of EML4-ALK in vitro and in vivo. In intracranial tumor implantation mouse models, alectinib resulted in regression of NCI-H2228 tumor in brain and provided a survival benefit. Alectinib is not a substrate for P-glycoprotein efflux transporter in vitro and showed a high brain-to-plasma ratio in rat. Additionally, alectinib led to tumor size reduction in the subcutaneous NCI-H2228 xenograft tumor that had failed to regress fully during treatment with crizotinib. Conclusions: Alectinib was effective against most EML4-ALK mutations and showed potent efficacy against intracranial ALK-positive tumor. Thus, alectinib might provide therapeutic opportunities for crizotinib-treated patients with ALK secondary mutations and brain metastases. Citation Format: Tatsushi Kodama, Toshiyuki Tsukaguchi, Masami Hasegawa, Miyuki Yoshida, Kenji Takanashi, Osamu Kondoh, Hiroshi Sakamoto. Selective ALK inhibitor alectinib (CH5424802/RO5424802) with potent antitumor activity in models of crizotinib resistance, including intracranial metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 754. doi:10.1158/1538-7445.AM2014-754
Differential regulation of PML function by PML-RAR
Authors: Fong Jek Howe, Matiullah Khan
Journal: Clinical Cancer Research (2007)

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

B76 

PML, the fusion partner of RAR in PML-RARα oncoprotein which causes acute promyelocytic leukemia (APL), is involved in many growth suppressive pathways such as apoptosis, cell cycle arrest and senescence. We have demonstrated that PML is essential for the growth suppressive functions of tumour suppressors Mad and Rb. Although most of these growth suppressive functions of PML are attributed to its localization to specific nuclear domains known as PML oncogenic domains (PODs), recent findings suggest that a certain cytoplasmic pool of PML is equally involved in critical tumor suppressive pathways. We, therefore, investigated whether nuclear and cytoplasmic PML are differentially regulated by oncoprotein PML-RAR. Here we report that PML-RAR promotes selective endoplasmic reticulum associated degradation (ERAD) of cytoplasmic PML, while, at the same time, decreasing the turnover of nuclear PML protein. PML-RAR targets ubiquitinated PML protein to endoplasmic reticulum where it co-localizes with ER resident proteins ATF6, GRP78 and PDI. The PML-RAR-induced degradation of PML protein could be abrogated by proteasome inhibitor MG132, which interestingly, also promoted apoptosis of APL cells and reorganized the microspeckled like PODs to normal dot like pattern. PML-RAR expression leads to accumulation of protease resistance PML protein bands, suggesting that PML-RAR may induce mis-folding in PML protein. The PML-RAR-induced mis-folding of PML protein depends on the integrity of coiled-coil domain of PML-RAR, as a coiled-coil domain deletion mutant of PML-RAR had no effect on the conformation of PML protein. These finding identifies differential spatial regulation of PML function by PML-RAR protein.
Incidence of bovine spongiform encephalopathy is higher in cows born after feed ban
Authors: M Bennett
Journal: BMJ (1996)

EDITOR,—R W Lacey could have made more of the data on the ages of cattle with bovine spongiform encephalopathy that he discusses.1 The ban on the inclusion of recycled animal remains in agricultural feeds came into force in July 1988. Many calves born before this date might be expected eventually to develop the disease; those born later should have a greatly reduced, and diminishing, incidence of the disease. In his table …
Oxford Textbook of Medicine.
Authors: D. J. Weatherall, J. G. G. Ledingham, D. A. Warrell
Journal: Annals of Internal Medicine (1988)

The <italic>Oxford Textbook of Medicine</italic> is published online and has been regularly updated for many years, but the production of a new and very substantially updated edition provides a moment when it is natural and proper to reflect on what has changed in Medicine—and what has not—in recent years. The sixth edition of the textbook considers exactly what modern medicine has to offer patients and their doctors. Advances in biomedical sciences, the broader context of health and disease, patients and their expectations, and access to medical knowledge are some of the key areas examined in detail among the 30 sections of the book. Sections include introductory sections on patients and their treatment, background to medicine, cell biology, and immunological mechanisms, as well as more subject-specific sections such as infectious diseases, neurological disorders, cardiovascular disorders, rheumatology, and the kidney, as well as many more.
Abstract P161: Peripheral Arterial Disease in Hispanic Communities: Results from the Hispanic Community Health Study/Study of Latinos
Authors: Matthew A Allison, Franklyn Gonzales, Leopoldo Raij, Robert Kaplan, Robert Ostfeld, Maria Pattany, Gerardo Heiss, Michael Criqui
Journal: Circulation (2015)

Background: Compared to non-Hispanic Whites, Hispanic Americans have a significantly lower prevalence of peripheral arterial disease (PAD). Since Hispanic ethnicity in the United States is heterogeneous, the purpose of this study was to determine the differential odds for PAD by Hispanic/Latino subgroup. Methods: Subjects were 9,648 men and women over the age of 45 years enrolled in the Hispanic Community Health Study - Study of Latinos (HCHS-SOL) who were evaluated by extensive survey information, relevant physical measurements and fasting blood assays. The ankle brachial index (ABI) was computed as the higher of the posterior tibial and dorsalis pedis systolic blood pressures (SBP) for each leg divided by the higher brachial artery SBP. The index ABI was the lower of the two. An ABI ≤ 0.90 was criterion for the presence of PAD. Results: The mean age was 56 years and 62% were female. Thirty percent were Mexican American, while 27% were Cuban American, 19% Puerto Rican American, 9% Dominican American, 7% Central American, 5% South American and 3% Mixed or Other Hispanic ethnicities. Overall, the prevalence of an ABI ≤ 0.90 (PAD), 0.90 to 0.99 (borderline), 1.0 to 1.39 (normal) and ≥ 1.40 (high) was 5.7, 19.3, 72.5 and 2.6%, respectively. Cuban Americans had the highest prevalence of PAD (9.1%), followed by Puerto Rican (5.9%), Central American (5.3%), Mixed/Other (5.0%), Dominican (4.7%), South American (4.6%) and Mexican Americans (3.2%). The prevalence of an ABI ≥ 1.40 ranged from 3.1% (South Americans) to 0.6% (Mixed/Other). After multivariable adjustment, and compared to Mexican Americans, Cuban Americans had nearly a 3-fold higher odds for PAD (OR = 2.85). The odds of PAD for the other Hispanic/Latino groups ranged from 1.23 to 1.82. Although males had over a 3-fold higher odds of an ABI ≥ 1.40 (OR = 3.55), the odds did not differ significantly by Hispanic/Latino ethnicity. Conclusions: Compared to Mexican Americans, all other Hispanic/Latino ethnic groups have a significantly higher odds of having PAD, with the odds being nearly 3-fold higher among Cuban Americans.
Locums in Wales are poorly managed, says Audit Commission
Authors: Roger Dobson
Journal: BMJ (2001)

NHS trusts in Wales and the National Assembly have been told that they need to improve controls over locum doctors, including an accreditation scheme. An Audit Commission review has found that management monitoring of the use of locums was poor and that data on the costs and reasons for the use of individual locums were generally missing.

Lack of formal contact with locum agencies also meant that it was not clear whose job it was to carry out each appointment check, resulting in omissions and duplications.

Performance review …
US judges rule against medical use of marijuana
Authors: Deborah Josefson
Journal: BMJ (2001)

The US Supreme Court has ruled unanimously against the medical use of marijuana, finding, by eight to nil, that because it is an illegal substance in federal law, no exceptions can be made, even for its medicinal use.

The court rejected the arguments brought by the Oakland Cannabis Buyers' Cooperative, which argued for compassionate exceptions in medical cases.

Justice Clarence Thomas wrote that “the Federal Controlled Substances Act, while authorising the medical use of some drugs that generally cannot be bought and sold, makes no exception whatever for marijuana.”

He added that marijuana had no currently accepted medical use according to the Controlled Substances Act.

The Supreme Court's decision deals a serious blow to the medical marijuana movement and pits federal against state laws. It comes at a time when marijuana is gaining broad acceptance as a medicinal substance.

The drive to legalise marijuana for medicinal purposes …
1018. Immune-Competent Cotton Rat Animal Model for Evaluation of Oncolytic Adenoviruses
Authors: Samuel K. Campos, M. Brandon Parrott, Michael March, Wah Chiu, Michael A. Barry
Journal: Molecular Therapy (2004)

While genetic modification of adenoviral vectors can produce vectors with modified tropism, incorporation of targeting peptides/proteins into the structural context of the virion can also result in destruction of ligand targeting or virion integrity. To combat this problem, we have developed a versatile targeting system using metabolically biotinylated adenoviral vectors bearing biotinylated fiber proteins. These vectors have demonstrated utility as a platform for avidin-based ligand screening and vector targeting by conjugating biotinylated ligands to the virus using high affinity tetrameric avidin (Kd = 10-15 M). The biotinylated vector could also be purified by biotin-reversible binding on monomeric avidin (Kd = 10-7 M). In this report, a second metabolically-biotinylated adenovirus vector, Ad-IX-BAP, has been engineered by fusing a biotin acceptor peptide (BAP) to the C-terminus of the adenovirus pIX protein. This biotinylated vector displays twice as many biotins and was markedly superior for single-step affinity purification on monomeric avidin resin. However, unlike the fiber-biotinylated vector, Ad-IX-BAP failed to retarget to cells with biotinylated antibodies including anti-CD71 against the transferrin receptor. In contrast, Ad-IX-BAP was retargeted if transferrin, the cognate ligand for CD71, was used as a ligand rather than the anti-CD71. This work demonstrates the utility of metabolic biotinylation as a molecular screening tool to assess the utility of different viral capsid proteins for ligand display and the biology and compatibility of different ligands and receptors for vector targeting applications. These results also demonstrate the utility of the pIX-biotinylated vector as a platform for gentle single-step affinity purification of adenoviral vectors. Finally, we have recently used pIX-BAP as a structural tag to image the location of pIX on adenoviral virions by cryo-EM. By this approach, we demonstrate that previous reports of pIX's capsid localization were incorrect and that tis has implications for the use of pIX for vector targeting. Therefore, metabolic biotinylation has utility for vector targeting, purification, ligand-receptor screening, and capsid characterization.