tbuckley/cabot-search huggingface dataset:
NK012, SN-38-incorporating micellar nanoparticle, improves tumor disposition of SN-38 and elicits superior antitumor activity to irinotecan.
Authors: Shin-ichi Matsumoto, Rika Goda, Takeshi Onda, Eiji Ichimura, Iwao Nakamura, Takashi Kawashiro, Kazuya Okamoto, Kiyohiro Nishikawa, Yuh-ichiro Ichikawa
Journal: Cancer Research (2008)

5627  Introduction: NK012 is a novel micelle-forming macromolecular prodrug of SN-38, an active metabolite of irinotecan (CPT-11), which is gradually released from the molecule in an enzyme-independent manner at physiological pH. We previously reported that NK012 continued to circulate in the blood stream and accumulate at high concentration in tumor tissue for more than 7 days after an intravenous injection, and exhibited superior antitumor activity to CPT-11 in a xenograft model subcutaneously transplanted with human colon cancer HT-29 (Koizumi F et al, Cancer Research, 2006; 66: 10048-). Here, we evaluated tumor extracellular fluid (ECF) disposition of released SN-38 in an HT-29 xenograft model, and further we microscopically examined the distribution of NK012 in tumor tissue.  Method: NK012 and CPT-11 were given intravenously to nude mice bearing HT-29. Microdialysis probes were placed in tumors to determine free SN-38 concentration in tumor ECF. NK012 distribution in tumor tissue was also investigated by observing fluorescence of the drug using a fluorescence microscope.  Results: Release of SN-38 in tumor ECF was confirmed after NK012 administration (30mg/kg as SN-38 equivalent) in nude mice bearing HT-29. Free SN-38 in tumor ECF was slowly eliminated with the terminal half-life (T1/2z) of about 90 hours. In contrast, when CPT-11 (66.7 mg/kg, i.e. 39 mg/kg as SN-38 equivalent) was administered, free SN-38 disappeared rapidly from tumor ECF with the T1/2z of about 6 hours. Exposure to free SN-38 released from NK012 in tumor ECF was 3-fold greater than that produced from CPT-11. The IC50 value of SN-38 against HT-29 cells in vitro corrected with protein-unbound ratio of SN-38 (0.65) in medium containing 10% FBS was 1.9 ng/mL. Free SN-38 concentration in tumor ECF sustained over the IC50 value and lasted for 3-7 days after NK012 administration, while free SN-38 level continued less than 2 days after CPT-11 administration. NK012 gradually extravasated from tumor blood vessels to tumor tissue and widely distributed over the tumor tissue and remained until 3rd day. On the contrary, CPT-11 leaked immediately out of capillary, but was not observed on the following day of the administration. Conclusion: These results suggest that the improved antitumor efficacy of NK012 was exerted by the sustained exposure time and concentration of free SN-38 released from the micellar NK012 after specific accumulation in tumor tissue due to leakiness of tumor blood vessel for such nanosize molecules as NK012.
Two decades of experience with sentinel node staging of axilla-is false negative no longera worry?
Authors: T. Arif, M. S. Absar
Journal: Cancer Research (2021)

Aim: To review current literature and standard practices in various techniques of sentinel node biopsy for staging theaxilla for treating early breast cancer  The purpose is to provide evidence based recommendation as guidanceplatform for optimal true sentinel node retrieval irrespective of surgeon expertise  Background: Axillary conservationis the way forward after game changing trials like ACOSOG Z0011, surrogate trials like IBCSG,AMAROS,ALMANAC, ongoing POSNOC, and newbie ATNEC have progressively or plan to decrease the need tounnecessarily fiddle with the axilla thereby increasing the chances of arm related and other morbidities  Axillarysentinel node biopsy entails retrieval of first draining lymph node in the breast-axilla pathway to plan treatment inbreast cancer by appropriate staging of axilla  Current standard is the utilisation of double agent technique withradioactive isotope and blue dye injection to decrease false negative rates for true sentinel node retrieval  Noveltechniques like magnetic and infrared tracing are still being investigated for validation  Method: PMC, Medline,EMBASE, PubMed and Cochrane library searched for clinical trials, randomised trials, systematic reviews and meta-analysis on techniques of axillary sentinel node biopsy in early breast cancer  This covered the last 25 yearsliterature on the topic  Results: The search yielded 197 publications which were subjected to a meticulous reviewand narrowed to a select pertinent body of evidence to extrapolate suggested guidance rationally, the bibliography of which is provided at the end  Conclusion: Single agent preferably radioisotope for lymphatic mapping isrecommended in palpable and good biology tumours  Use of single agent blue dye can be standardised in axillary tail tumours  It is also recommended as being effective when isotope mapping is logistically not feasible or duringpandemics like COVID 19 where looming infrastructure challenges are prevalent  Dual agent technique should beconsidered in previously treated breast and axilla, neoadjuvant chemotherapy cohort, bad tumour biology, high BMIand macromastia groups for true nodal retrieval  Optimal number of nodes taken out should not be more than three(n=3)  Lower axillary sampling of not more than 3 nodes is recommended for troubleshooting with any localisingagent technique  Triple site injection at peri-tumoural, subcutaneous and sub areolar regions and larger volume ofblue dye agent injection of up to 8mls increases the localisation success in the dual technique group for lymphaticmapping  Magnetic tracing can be used as an adjunct to either single agent radioactive isotope or blue dye (RI/BD)technique when there is failure to localise the sentinel node
Rammya Mathew: Women in leadership—not just an unattainable ideal
Authors: Rammya Mathew
Journal: BMJ (2021)

Last month, as part of International Women's Day celebrations, the BMA hosted a webinar with an impressive line-up of eminent female GPs, who spoke openly and passionately about their individual leadership careers.I was on the edge of my seat, refuelling on their energy and soaking up their words of wisdom.At the end of the 90 minutes, however, I was still waiting to hear the secret to maintaining a fast paced leadership career while also managing the demands of home and family life.
Sixty seconds on . . . a covid-19 inquiry
Authors: Richard Hurley
Journal: BMJ (2021)

Surely it's not the right time?That's what Prime Minister Boris Johnson said when he committed last July to an independent inquiry. 1 Such a thing would be "an irresponsible diversion" while the pandemic continues, he recently reiterated. 2 But the public want answersSo polling suggests, 3 but formal inquiries take years.Calls for a quick review, from medical journals, 4 the BMA and royal colleges, 5 and bereaved families, have gone unheeded, however. So why are we waiting?I don't know.Norway and Sweden have started inquiries. 6Scotland may begin one by the end of the year. 7 What about learning lessons to save lives now?Quite.The informal People's Covid Inquiry (www.peoplescovidinquiry.com), convened by the Keep Our NHS Public campaign, is filling the gap, receiving testimony from experts, key workers, and the public at fortnightly hearings. 8The inquiry's panellist Neena Modi, professor of neonatal medicine, told The BMJ, "If ever there was a time to ask questions, it has got to be now."7
Geoffrey Norman Marsh
Authors: Chris Marsh, David White
Journal: BMJ (2021)

Geoffrey Norman Marsh, a GP in Norton, Stockton on Tees, helped to transform general practice from its 1950s pattern of doctors working independently to its current pattern of multidisciplinary teams and targeted preventive work. In over 30 papers in The BMJ and three books he contributed to many developments including the adoption of remunerated cytology and immunisation targets in the 1990 GP contract as a means of raising the standard …
Helen Salisbury: Does it matter who owns general practice?
Authors: Helen Salisbury
Journal: BMJ (2021)

Alarm has been voiced about Operose Health purchasing 37 general practices in London across 49 sites and whether this represents further “privatisation of the NHS by stealth.”12 Operose is the UK subsidiary of Centene, a multi-billion dollar US corporation whose main business is health insurance. However, some suggest that there’s no need for concern, as GP surgeries are already privately owned.

It’s true that general practices are run as businesses. This is because, at the founding of the NHS, most GPs worked as individuals from their own homes, and it …
Predictive Models of Genetic Redundancy in <i>Arabidopsis thaliana</i>
Authors: Siobhan A Cusack, Peipei Wang, Serena G Lotreck, Bethany M Moore, Fanrui Meng, Jeffrey K Conner, Patrick J Krysan, Melissa D Lehti-Shiu, Shin-Han Shiu
Journal: Molecular Biology and Evolution (2021)

Genetic redundancy refers to a situation where an individual with a loss-of-function mutation in one gene (single mutant) does not show an apparent phenotype until one or more paralogs are also knocked out (double/higher-order mutant). Previous studies have identified some characteristics common among redundant gene pairs, but a predictive model of genetic redundancy incorporating a wide variety of features derived from accumulating omics and mutant phenotype data is yet to be established. In addition, the relative importance of these features for genetic redundancy remains largely unclear. Here, we establish machine learning models for predicting whether a gene pair is likely redundant or not in the model plant Arabidopsis thaliana based on six feature categories: functional annotations, evolutionary conservation including duplication patterns and mechanisms, epigenetic marks, protein properties including posttranslational modifications, gene expression, and gene network properties. The definition of redundancy, data transformations, feature subsets, and machine learning algorithms used significantly affected model performance based on holdout, testing phenotype data. Among the most important features in predicting gene pairs as redundant were having a paralog(s) from recent duplication events, annotation as a transcription factor, downregulation during stress conditions, and having similar expression patterns under stress conditions. We also explored the potential reasons underlying mispredictions and limitations of our studies. This genetic redundancy model sheds light on characteristics that may contribute to long-term maintenance of paralogs, and will ultimately allow for more targeted generation of functionally informative double mutants, advancing functional genomic studies.
Radiation-Induced Toxicity in the Era of Stereotactic Body Radiation Therapy—Lessons From NRG-BR001
Authors: Charles R. Thomas
Journal: JAMA Oncology (2021)

Steve Chmura, MD, PhD; Kathryn A. Winter, MS; Clifford Robinson, MD; Thomas M. Pisansky, MD; Virginia Borges, MD; Hania Al-Hallaq, PhD; Martha Matuszak, PhD; Sean S. Park, MD; Sun Yi, MD; Yasmin Hasan, MD; Jose Bazan, MD; Philip Wong, MD; Harold A. Yoon, MD; Janet Horton, MD; Gregory Gan, MD; Michael T. Milano, MD, PhD; Elin Ruth Sigurdson, MD; Jennifer Moughan, MS; Joseph K. Salama, MD; Julia White, MD
Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies
Authors: Sigrid P Dubois, Milos D Miljkovic, Thomas A Fleisher, Stefania Pittaluga, Jennifer Hsu-Albert, Bonita R Bryant, Michael N Petrus, Liyanage P Perera, Jürgen R Müller, Joanna H Shih, Thomas A Waldmann, Kevin C Conlon
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Full application of cytokines as oncoimmunotherapeutics requires identification of optimal regimens. Our initial effort with intravenous bolus recombinant human interleukin-15 (rhIL-15) was limited by postinfusional reactions. Subcutaneous injection and continuous intravenous infusion for 10 days (CIV-10) provided rhIL-15 with less toxicity with CIV-10 giving the best increases in CD8 + lymphocytes and natural killer (NK) cells. To ease rhIL-15 administration, we shortened time of infusion. Treatment with rhIL-15 at a dose of 3–5 µg/kg as a 5-day continuous intravenous infusion (CIV-5) had no dose-limiting toxicities while effector cell stimulation was comparable to the CIV-10 regimen. Methods Eleven patients with metastatic cancers were treated with rhIL-15 CIV-5, 3 µg (n=4), 4 µg (n=3), and 5 µg/kg/day (n=4) in a phase I dose-escalation study (April 6, 2012). Results Impressive expansions of NK cells were seen at all dose levels (mean 34-fold), including CD56 bright NK cells (mean 144-fold for 4 µg/kg), as well as an increase in CD8 + T cells (mean 3.38-fold). At 5 µg/kg/day, there were no dose-limiting toxicities but pulmonary capillary leak and slower patient recovery. This led to our choice of the 4 µg/kg as CIV-5 dose for further testing. Cytolytic capacity of CD56 bright and CD56 dim NK cells was increased by interleukin-15 assayed by antibody-dependent cellular cytotoxicity (ADCC), natural cytotoxicity and natural killer group 2D-mediated cytotoxicity. The best response was stable disease. Conclusions IL-15 administered as CIV-5 substantially expanded NK cells with increased cytotoxic functions. Tumor-targeting monoclonal antibodies dependent on ADCC as their mechanism of action including alemtuzumab, obinutuzumab, avelumab, and mogamulizumab could benefit from those NK cell expansions and provide a promising therapeutic strategy. Trial registration numbers NCT01572493 , NCT03759184 , NCT03905135 , NCT04185220 and NCT02689453 .
Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis
Authors: Roya Babaei-Jadidi, Arundhati Dongre, Suzanne Miller, Marcos Castellanos Uribe, Ian D. Stewart, Zoe M. Thompson, Abdolrahman S. Nateri, Peter Bradding, Sean T. May, Debbie Clements, Simon R. Johnson
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Lymphangioleiomyomatosis (LAM) is a multisystem disease that causes lung cysts and respiratory failure. Loss of TSC (tuberous sclerosis complex) gene function results in a clone of "LAM cells" with dysregulated mTOR (mechanistic target of rapamycin) activity. LAM cells and fibroblasts form lung nodules that also contain mast cells, although their significance is unknown. Objectives: To understand the mechanism of mast-cell accumulation and the role of mast cells in the pathogenesis of LAM. Methods: Gene expression was examined using transcriptional profiling and qRT-PCR. Mast cell/LAM nodule interactions were examined in vitro using spheroid TSC2-null cell/fibroblast cocultures and in vivo using an immunocompetent Tsc2-null murine homograft model. Measurements and Main Results: LAM-derived cell/fibroblast cocultures induced multiple CXC chemokines in fibroblasts. LAM lungs had increased tryptase-positive mast cells expressing CXCRs (CXC chemokine receptors) (P < 0.05). Mast cells located around the periphery of LAM nodules were positively associated with the rate of lung function loss (P = 0.016). LAM spheroids attracted mast cells, and this process was inhibited by pharmacologic and CRISPR/cas9 inhibition of CXCR1 and CXCR2. LAM spheroids caused mast-cell tryptase release, which induced fibroblast proliferation and increased LAM-spheroid size (1.36 ± 0.24-fold; P = 0.0019). The tryptase inhibitor APC366 and sodium cromoglycate (SCG) inhibited mast cell-induced spheroid growth. In vivo, SCG reduced mast-cell activation and Tsc2-null lung tumor burden (vehicle: 32.5.3% ± 23.6%; SCG: 5.5% ± 4.3%; P = 0.0035). Conclusions: LAM-cell/fibroblast interactions attract mast cells where tryptase release contributes to disease progression. Repurposing SCG for use in LAM should be studied as an alternative or adjunct to mTOR inhibitor therapy.
Preventable Vision Loss Affects Millions Globally
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

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 IA-003: Oxygen dependent resistance to PARP inhibitors
Authors: Manal Mehibel, Jimmy Xu, Grace Li, Jung Moon, Kaushik Thakkar, Anh Diep, Ryan Kim, Joshua Bloomstein, Siren Xiao, Julien Bacal, Joshua Saldivar, Quynh Le, Karlene Cimprich, Erinn Rankin, Amato Giaccia
Journal: Clinical Cancer Research (2021)

Abstract Severe hypoxia causes resistance to conventional chemotherapy and has been reported to synergize with PARP inhibitors (PARPi) through suppression of homologous recombination (HR). While this synergistic killing is true at oxygen levels less than 0.5%, our study shows that less severe hypoxia (e.g. 2% oxygen) is instead associated with resistance to PARPi in HR proficient cells. Interestingly, we demonstrate that HR deficient hypoxic tumors are significantly less responsive to PARPi, due to limited ROS-induced intrinsic DNA damage. To determine the contribution of hypoxic cells to PARPi, we used the hypoxic cytotoxin Tirapazamine to target hypoxic tumor cells. We found that the elimination of hypoxic tumor cells by Tirapazamine led to a substantial antitumor response with PARPi compared to PARPi treated tumors alone, without enhancing normal tissue toxicity. These studies indicate that tumor hypoxia reduces the efficacy of PARPi to tumor cells and that eliminating hypoxic tumor cells will enhance the efficacy of PARPi therapy. Citation Format: Manal Mehibel, Jimmy Xu, Grace Li, Jung Moon, Kaushik Thakkar, Anh Diep, Ryan Kim, Joshua Bloomstein, Siren Xiao, Julien Bacal, Joshua Saldivar, Quynh Le, Karlene Cimprich, Erinn Rankin, Amato Giaccia. Oxygen dependent resistance to PARP inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-003.
Birmingham council sets up task force to tackle high rate of infant mortality
Authors: Gareth Iacobucci
Journal: BMJ (2021)

A task force has been set up to tackle the high rate of neonatal mortality in Birmingham, which experts believe is linked to ethnicity and deprivation.

The move by Birmingham City Council follows a report1 showing that infant mortality rates in Birmingham are nearly twice the national average, with the Pakistani population overrepresented in these figures.

Councillor Rob Pocock, chair of Birmingham’s health and social care scrutiny committee, which produced the report, said, “Something is going wrong. We need to act to put it right. This is a tragedy that can and must be reduced.”

The task force will include representatives from the NHS, local government, community and voluntary sector organisations, and faith groups, and …
Abstract 15021: Modern Prevalence of Fredrickson-Levy-Lees Type III Hyperlipoproteinemia: Findings From the Very Large Database of Lipids and National Health and Nutrition Examination Survey
Authors: Vincent A Pallazola, Vasanth Sathiyakumar, Jihwan Park, Rachit Vakil, Peter P Toth, Mariana Lazo-Elizondo, Emily Brown, Renato Quispe, Eliseo Guallar, Roger S Blumenthal, Steven R Jones, David Marais, Daniel Soffer, Allan D Sniderman, Seth S Martin
Journal: Circulation (2019)

Introduction: Dysbetalipoproteinaemia (HLP3) is a genetic disorder of excess lipoprotein remnants that powerfully promotes premature atherogenic cardiovascular disease. Prior smaller studies using ...
Questions on <i>NOTCH2NLC</i> Repeat Expansions in Parkinson Disease—Reply
Authors: Dongrui Ma, Yi Jayne Tan, Eng-King Tan
Journal: JAMA Neurology (2021)

In Reply We appreciate the interest shown by Yau and colleagues for our recent article.1 They have previously highlighted an absence of abnormal NOTCH2NLC GGC repeat expansions in a sample of White patients with PD.2
Scholarly communications harmed by covid-19 (vol 372, n742, 2021)
Authors: R. Bhopal, A. P. S. Munro
Journal: BMJ (2021)

researchers and clinicians 1 -4 Such division is especially evident in non-academic routes of communication such as declarations, letters, petitions, and personal views  Many of the worst examples are occurring in public forums  This is potentially harmful to public trust in scientists and healthcareprofessionals  It suppresses dispassionate and constructive academic exchange, which undermines the academic freedom so vital to higher education 5 The concept of academic freedom is contested,5 but in 2009 a leading UK university defined some important principles6 including the freedom of individuals to express their interests in teaching, scholarship, and research and the right to contribute to social change through free expression of opinion on matters of public interest  These privileges come with a responsibility to respect the freedoms of others  Some leading scientists have been subjected to such ferocious personal attacks that they have stopped their research activities 7 Underlying causes Increasing use of traditional and social media by academics has brought many benefits 8 However, these platforms foster extreme viewpoints by design  Some, such as Twitter, value brevity over nuance, leaving no room for important qualification or uncertainty  Emotional rewards focusing on numbers of followers, likes, or onward transmissions (such as re-tweets), are best achieved by strong opinions, repeated often  Measured, nuanced, unemotional views do not go ?viral ?9 Furthermore, the system creates groups of like minded individuals that listen only to each other  The past year has been a time of great uncertainty and instability  This environment naturally breeds fear, frustration, and anger, all of which have
Multidimensional population activity in an electrically coupled inhibitory circuit in the cerebellar cortex
Authors: Harsha Gurnani, R. Angus Silver
Journal: Neuron (2021)

Inhibitory neurons orchestrate the activity of excitatory neurons and play key roles in circuit function. Although individual interneurons have been studied extensively, little is known about their properties at the population level. Using random-access 3D two-photon microscopy, we imaged local populations of cerebellar Golgi cells (GoCs), which deliver inhibition to granule cells. We show that population activity is organized into multiple modes during spontaneous behaviors. A slow, network-wide common modulation of GoC activity correlates with the level of whisking and locomotion, while faster (<1 s) differential population activity, arising from spatially mixed heterogeneous GoC responses, encodes more precise information. A biologically detailed GoC circuit model reproduced the common population mode and the dimensionality observed experimentally, but these properties disappeared when electrical coupling was removed. Our results establish that local GoC circuits exhibit multidimensional activity patterns that could be used for inhibition-mediated adaptive gain control and spatiotemporal patterning of downstream granule cells.