tbuckley/cabot-search huggingface dataset:
Squalenoylation a new concept in drug targeting: evidence of a potent anti-cancer activity of squalenoyl-gemcitabine
Authors: Hania Khoury, L. Harivardhan Reddy, Lucien Bildstein, Alain Deroussent, Catherine Dubernet, Patrick Couvreur, Gilles Vassal, Angelo Paci
Journal: Cancer Research (2008)

5621  Nucleoside analogues display significant anticancer or antiviral activity by incorporating into DNA, leading to inhibition of its synthesis and apoptosis. However, their rapid metabolism and the resistance to treatment limit their use.  Gemcitabine (dFdC), a widely used nucleoside analogue for the treatment of solid tumours, belongs to this pharmacological class. Rapid plasmatic metabolism of dFdC into its inactive uracil derivative (dFdU) is one of its drawbacks. Different approaches have been attempted to decrease deamination of dFdC to dFdU. Recently, we have succeeded in coupling dFdC to an isoprenoid chain of squalene to obtain gemcitabine-squalene (SQ dFdC) (Couvreur et al. Nano Letters 2006, 6(11), 2544-2548). This new analogue has an amphiphilic character and is capable of spontaneously forming nanoassemblies of 150 nm in water.  Herein, pharmacokinetic profiles and biodistribution of SQdFdC nanoassemblies were compared to those of dFdC using a newly developed tandem mass spectrometry (LC-MS/MS) method (Khoury et al. J. Chrom. B. 2007, 858(1-2): 71-8). Squalenoylation improved pharmacokinetic profiles and protected dFdC from deamination. Interestingly, the cell influx mechanism of SQdFdC differs from that of dFdC. Indeed, unlike dFdC, SQdFdC follows a nucleoside transporters independent mechanism.  In addition, the therapeutic activity of SQdFdC nanoassemblies was studied in vitro and in vivo on tumour bearing mice after i.v. and oral administration. Squalenoyl gemcitabine (SQdFdC) was more potent than gemcitabine (dFdC) itself in vitro and in vivo against different types of murine and human cancers, including resistant cancers.  This new formulation of this prodrug might be a promising potential for oral administration of dFdC.
Phage-delivered sensitisation with subsequent antibiotic treatment reveals sustained effect against antimicrobial resistant bacteria
Authors: Hongbo Liu, Hao Li, Yuan Liang, Xinying Du, Chaojie Yang, Lang Yang, Jing Xie, Rongtao Zhao, Yigang Tong, Shaofu Qiu, Hongbin Song
Journal: Theranostics (2020)

Temperate phages integrated with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas systems have been gaining attention as potential strategies for combating bacteria resistant to antimicrobials. To further advance this technology, phage recombination procedure should be improved, and the bactericidal effect should be examined in detail and compared with conventional lytic phage strategy. The possibility of the emergence of mutational resistance, a phenomenon commonly observed with lytic phage therapy, should be illustrated. Methods: Here, we developed a novel one-step cloning method to fulfil the recombination of CRISPR/Cas9 system within the genome of a new isolated lysogenic Escherichia coli phage. Then, we proposed and developed a phage-delivered resistance eradication with subsequent antibiotic treatment (PRESA) strategy. The removal efficiency and antimicrobial effect of the plasmids were analysed. Long-term antimicrobial effect was evaluated by continued OD600 monitoring for 240 hours to illustrate the potential mutational resistance, compared with the lytic phage strategy. The treatment effect of PRESA was evaluated in vivo by determining bacterial loads in the skin and intestine of infected mice, in contrast with lytic phage therapy. Genome sequencing was performed to identify mutations in bacterial cells treated with phage strategies. Results: Phage-delivered CRISPR targeting efficiently eradicated and blocked the transfer of the antibiotic resistance plasmid. PRESA decreased the bacterial load by over 6- and 5-logs in vitro and in vivo, respectively. Importantly, while lytic phages induced mutational phage resistance at 24 h in vitro and 48 hours in vivo, PRESA demonstrated a constant effect and revealed no resistant mutants. Genes involved in DNA mismatch repair were upregulated in cells undergoing Cas9-based plasmid cleavage, which may reduce the development of mutations. Conclusion: The PRESA strategy for eradicating resistant bacteria showed high bactericidal efficacy and a sustained inhibition effect against resistant bacteria. By restoring the efficacy of low-cost antibiotics, PRESA could be developed as an efficient and economical therapy for infections of antibiotic resistant bacteria.
Abstract 13794: Serial Brain Metabolism in Term Neonates With Congenital Heart Disease: Association With Clinical Factors and Neurodevelopmental Outcomes
Authors: Anna L Harbison, Jodie K Votava-Smith, Sylvia Del Castillo, S Ram Kumar, Vincent K Lee, Hollie A Lai, Sharon H O’Neil, Stefan Bluml, Lisa Paquette, Ashok Panigraphy
Journal: Circulation (2015)

Objectives: Term congenital heart disease (CHD) neonates demonstrate pre-operative (op) abnormal brain metabolism (reduced N-acetylaspartate (NAA), elevated lactate) on long echo MR spectroscopy (MRS). We sought to delineate associations between serial brain metabolism and patient and perioperative clinical factors in term neonates with CHD using short echo MRS. We measured NAA and lactate as well as other metabolites important for brain connectivity such as neurotransmitters glutamate/glutamine and GABA. Methods: Subjects were prospectively enrolled to undergo pre and post-op 3T short echo single voxel MRS of parietal white matter with absolute quantitation of 15 metabolites using LCModel. Neurodevelopment (ND) was assessed via 18 month Battelle Developmental Inventory. Linear and logistic regression with false discovery rate correction was used for statistical analysis. Results: Eighty subjects were enrolled 2009-2015 and 21 term CHD infants underwent both pre and post-op MRS. Eight infants had at least one MRS and ND. NAA and glutamate were significantly decreased post-op compared to pre-op (p&lt;0.0001), with no significant difference in other metabolites. Pre-op factors including lower Apgar score, birth weight, head circumference and PaO2 and higher arterial pH and serum lactate were associated with lower NAA (p&lt;0.002). Single ventricle anatomy was associated with low NAA, high myo-inositol and low glutamine/glutamate compared to two ventricles (p&lt;0.01). Longer cardipulmonary bypass time, but not deep hypothermic circulatory arrest, was associated with reduced NAA (p&lt;0.001). Post-op, global alteration in multiple serial brain metabolites (NAA, lactate, glutamate/glutamine, GABA, myo-inostol) were associated with longer ICU and hospital stay (p&lt;0.03). In those with ND testing, high GABA correlated with low cognitive domain score, while high glutamine correlated with low motor score (p&lt;0.03). Conclusion: In term CHD neonates, serial brain metabolism by MRS demonstrates alterations beyond NAA, including neurotransmitters GABA and glutamate/glutamine. These abnormalities are associated with multiple clinical pre and post-op factors and also predict prolonged hospital stay and 18 month ND.
Enflurane and Catch 22 × 3
Authors: Edwin J. Goldman
Journal: JAMA (1973)

<h3>To the Editor.—</h3> The EDITORIAL by Dykes and Linde (225:986, 1973) should evoke sympathy for the anesthesiologist, who must choose between hazards for each patient when choosing an inhalation anesthetic. Enflurane may present a new choice, though not a better one. To quote from the DRUG COMMENTARY by the AMA Department of Drugs (225:989, 1973): Central nervous system (CNS) excitation, manifested by increased electrical activity and seizure-like activity in the electroencephalogram, occurs as anesthesia is deepened; this is exacerbated by hypocarbia and suppressed by hypercarbia. Paroxysms of tonic-clonic or twitching movements have developed in a few patients, usually in association with deep anesthesia and hypocarbia. These can be terminated, without sequelae, by lightening the anesthesia and reducing the minute ventilation, or by administering another agent. I don't know that seizure-like activity under anesthesia is desirable or undesirable. To protect my patient, I assume it is undesirable. That means I need
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
Authors: Adi Diab, Nizar M. Tannir, Salah-Eddine Bentebibel, Patrick Hwu, Vassiliki Papadimitrakopoulou, Cara Haymaker, Harriet M. Kluger, Scott N. Gettinger, Mario Sznol, Scott S. Tykodi, Brendan D. Curti, Mary A. Tagliaferri, Jonathan Zalevsky, Alison L. Hannah, Ute Hoch, Sandra Aung, Christie Fanton, Ahsan Rizwan, Ernesto Iacucci, Yijie Liao, Chantale Bernatchez, Michael E. Hurwitz, Daniel C. Cho
Journal: Cancer Discovery (2020)

This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.See related commentary by Rouanne et al., p. 1097.This article is highlighted in the In This Issue feature, p. 1079.
Effect of Different 131I Dose Strategies for Treatment of Hyperthyroidism on Graves’ Ophthalmopathy
Authors: Shahrara Ariamanesh, Narjess Ayati, Zahra Mazloum Khorasani, Zohreh Mousavi, Victoria Kiavash, Zahra Kiamanesh, Seyed Rasoul Zakavi
Journal: Clinical Nuclear Medicine (2020)

Purpose The study aims to define the effect of different dose strategies on ophthalmic complications in patients with Graves’ disease (GD). Methods All the patients with GD and no or inactive ophthalmopathy (clinical activity score; CAS &lt; 3) underwent Snellen chart examination, measurement of proptosis, thyroid volume, and radioactive iodine uptake, and randomized into 1 of 3 groups. In group 1, all the patients received fixed low dose (FLD) of 259 MBq of 131 I, whereas in group 2, all the patients received fixed high dose (FHD) of 555 MBq, and in group 3, calculated dose (CD) was administered to deliver 5.55 MBq/g (thyroid weight) of 131 I. All examinations were repeated 6 months after treatment. The measurement of thyroid function tests and clinical examination were repeated after 12 months. Results We studied 92 patients (58 female and 34 male) with mean age of 38.2 ± 12.0 years. Overall, 29, 32, and 31 patients were studied in FLD, FHD, and CD groups, respectively. The patients in CD received a mean activity of 240.5 MBq. The 3 groups were not significantly different regarding age, sex ratio, radioactive iodine uptake, smoking, visual acuity, and proptosis. The response rate 12 months after radioactive iodine therapy was 66.7%, 94.4%, and 92.9% in FLD, FHD, and CD groups, respectively ( P = 0.05). Overall, CAS was increased significantly after treatment. Delta proptosis and delta CAS were increased significantly in FHD group compared with other groups ( P &lt; 0.05). The highest increment in proptosis was seen in FHD group. Conclusions The administration of 5.55 MBq/g of 131 I has fewer ophthalmic complications compared with high fixed dose model and is more effective than low fixed dose strategy.
Continuous Ambulatory Peritoneal Dialysis in Children
Authors: W E Harmon
Journal: New England Journal of Medicine (1983)

Abstract The clinical and biochemical effects of continuous ambulatory peritoneal dialysis in 20 children and of hemodialysis in 16 children were compared over a 2 1/2-year Period. Statistically significant differences between the treatment groups included higher hematocrit, higher serum carbon dioxide and cholesterol levels, larger intake of calories and protein, and lower systolic blood pressure and rates of transfusion in the patients receiving continuous ambulatory peritoneal dialysis. These patients had more complications than the patients receiving hemodialysis, but hospitalization rates in the two groups were similar. The cost of continuous ambulatory peritoneal dialysis was $19,600 per patient-year; the cost of hemodialysis was $54,300 per patient-year. There were four treatment failures with continuous ambulatory peritoneal dialysis and one with hemodialysis. Patients treated with both forms of dialysis preferred continuous ambulatory peritoneal dialysis. We conclude that continuous ambulatory pe...
Cyclophosphamide and plasma exchange in multiple sclerosis
Authors: BhupendraO. Khatri, MichaelP. Mcquillen, RaymondG. Hoffmann, HowardL. Weiner, StephenL. Hauser, DavidM. Dawson, DavidA. Hafler, GlennA. Mackin, E.John Orav, RobertD. Currier, ArminF. Haerer, JoeC. Files, FrancisS. Morrison
Journal: The Lancet (1991)
A retrospective cohort study of the diagnostic value of different subtypes of atypical pigment network on dermoscopy
Authors: Katherine Shi, Daniel Kim, Lauren S. Mohan, Erin M. Garfield, Victor L. Quan, Bin Zhang, Elnaz Panah, Elsy V. Compres, Ayesha U. Khan, Pedram Gerami
Journal: Journal of the American Academy of Dermatology (2020)
FDG PET/CT in a Pregnant Woman With Breast Cancer
Authors: Clément Drouet, Jean-Marc Vrigneaud, Isabelle Desmoulins, Alexandre Cochet
Journal: Clinical Nuclear Medicine (2020)

This 37-year-old woman was diagnosed with breast cancer during pregnancy. After multidisciplinary meeting, she was referred to our department for an FDG PET/CT for staging, and chemotherapy with weekly infusion of paclitaxel was initiated before childbirth. We estimated the fetal dose from the PET/CT procedure, and our results show that, if deemed necessary, this examination can reasonably be performed during pregnancy. The patient gave birth vaginally at term to an apparently healthy girl.
Lentiviral-Vector-Based Dendritic Cell Vaccine Synergizes with Checkpoint Blockade to Clear Chronic Viral Infection
Authors: Thomas D. Norton, Takuya Tada, Rebecca Leibowitz, Verena van der Heide, Dirk Homann, Nathaniel R. Landau
Journal: Molecular Therapy (2020)

Dendritic cell vaccines are a promising strategy for the treatment of cancer and infectious diseases but have met with mixed success. We report on a lentiviral vector-based dendritic cell vaccine strategy that generates a cluster of differentiation 8 (CD8) T cell response that is much stronger than that achieved by standard peptide-pulsing approaches. The strategy was tested in the mouse lymphocytic choriomeningitis virus (LCMV) model. Bone marrow-derived dendritic cells from SAMHD1 knockout mice were transduced with a lentiviral vector expressing the GP33 major-histocompatibility-complex (MHC)-class-I-restricted peptide epitope and CD40 ligand (CD40L) and injected into wild-type mice. The mice were highly protected against acute and chronic variant CL-13 LCMVs, resulting in a 100-fold greater decrease than that achieved with peptide epitope-pulsed dendritic cells. Inclusion of an MHC-class-II-restricted epitope in the lentiviral vector further increased the CD8 T cell response and resulted in antigen-specific CD8 T cells that exhibited a phenotype associated with functional cytotoxic T cells. The vaccination synergized with checkpoint blockade to reduce the viral load of mice chronically infected with CL-13 to an undetectable level. The strategy improves upon current dendritic cell vaccine strategies; is applicable to the treatment of disease, including AIDS and cancer; and supports the utility of Vpx-containing vectors.
Covid-19: Delaying school reopening by two weeks would halve risks to children, says iSAGE
Authors: Jacqui Wise
Journal: BMJ (2020)

It is not safe to open schools on 1 June, an independent committee of experts has warned, saying that before this happens local authorities must have evidence of low infection rates in the community infection and be able to track and trace new cases of covid-19.

The draft consultation report of the Independent Scientific Advisory Group for Emergencies (iSAGE) says that delaying a school’s reopening by two weeks to 15 June roughly halves the risk to children, while waiting till September is less risky still.1

The government announced on 10 May that some primary school classes in England would resume on 1 June, although the plan has been met with opposition from teachers’ unions and others, including the BMA.2

The draft report was discussed at a public engagement session on Friday 22 May supported by The BMJ and the online forum Mumsnet, with teachers, parents, and other interested parties contributing to the discussion. A final report will …
Young-onset colorectal cancer risk among individuals with iron-deficiency anaemia and haematochezia
Authors: Joshua Demb, Lin Liu, Caitlin C. Murphy, Chyke A. Doubeni, María Elena Martínez, Samir Gupta
Journal: Gut (2020)

Objective Young-onset colorectal cancer (YCRC) incidence is rising. Scant data exist on YCRC risk after presentation with concerning symptoms such as iron-deficiency anaemia (IDA) or haematochezia. We examined the association between IDA and YCRC, and haematochezia and YCRC. Design Cohort study of US Veterans aged 18–49 years receiving Veterans Health Administration (VHA) care 1999–2016. IDA analytic cohort was created matching individuals without incident IDA to those with IDA 4:1 based on sex, birth year and first VHA visit date (n=239 000). We used this approach to also create a distinct haematochezia analytic cohort (n=653 740). Incident YCRC was ascertained via linkage to cancer registry and/or cause-specific mortality data. We computed cumulative incidence, risk difference (RD) and HRs using Cox models in each cohort. Results Five-year YCRC cumulative incidence was 0.45% among individuals with IDA versus 0.05% without IDA (RD: 0.39%, 95% CI: 0.33%–0.46%), corresponding to an HR of 10.81 (95% CI: 8.15–14.33). Comparing IDA versus no IDA, RD was 0.78% for men (95% CI: 0.64%–0.92%) and 0.08% for women (95% CI: 0.03%–0.13%), and RD increased by age from 0.14% for &lt;30 years to 0.53% for 40–49 years. YCRC cumulative incidence was 0.33% among individuals with haematochezia versus 0.03% without haematochezia (RD: 0.30%, 95% CI: 0.26%–0.33%), corresponding to an HR of 10.66 (95% CI: 8.76–12.97). Comparing haematochezia versus no haematochezia, RD increased by age from 0.04% for &lt;30 years to 0.43% for 40–49 years. Conclusion Colonoscopy should be strongly considered in adults aged &lt;50 years with IDA or haematochezia without a clinically confirmed alternate source.
The therapeutic use of topical contact sensitizers in benign dermatoses
Authors: D.A. Buckley, A.W.P. Du Vivier
Journal: British Journal of Dermatology (2008)

Topical therapy using contact sensitizers has been practised since the 1960s to treat conditions associated with an altered immunological state. Dinitrochlorobenzene, squaric acid dibutyl ester and diphencyprone are most commonly employed in the therapy of alopecia areata and viral warts. Few dermatology departments in the U.K. provide such treatment. This systematic review discusses the various contact sensitizers used for topical immunotherapy, the methodology of treatment, factors influencing efficacy and likely adverse effects.
Review of trials currently testing treatment and prevention of COVID-19
Authors: P.C. Fragkou, D. Belhadi, N. Peiffer-Smadja, C.D. Moschopoulos, F.-X. Lescure, H. Janocha, E. Karofylakis, Y. Yazdanpanah, F. Mentré, C. Skevaki, C. Laouénan, S. Tsiodras
Journal: Clinical Microbiology and Infection (2020)
Defensive Medicine Disdained
Authors: John Archer
Journal: JAMA (1975)

On a recent Saturday evening at St James Hospital, Chicago Heights, Ill, Drs Norman R. Brill, Branislav M. Dragisic, Aaron B. Gerber, and Clifford W. Smith, together with their surgical team, battled unfavorable odds and rescued me from a ruptured abdominal aortic aneurysm, complicated by free rupture into the peritoneal cavity and shock before surgery. Faced with the obvious probability of a bad result, they could have played "safe" from "malpractice" allegations by getting extra consultation, ordering a few more tests, and wasting some time. Had they done so, I would be dead. Instead, they made the probable diagnosis quickly, prepared for surgery with as much speed as was in my interest, and went to work to do what was required. Clearly, I owe my life to the knowledge, skill, and dedication of these physicians, but something more is involved. I also owe it to the fact that not all
Financial Conflicts of Interest and Conclusions About Neuraminidase Inhibitors for Influenza
Authors: Adam G. Dunn, Diana Arachi, Joel Hudgins, Guy Tsafnat, Enrico Coiera, Florence T. Bourgeois
Journal: Annals of Internal Medicine (2014)

Industry funding and financial conflicts of interest may contribute to bias in the synthesis and interpretation of scientific evidence. This analysis of 26 systematic reviews of neuraminidase inhib...
Preventing COVID-19 in Assisted Living Facilities—A Balancing Act
Authors: Grace Y. Jenq, John P. Mills, Preeti N. Malani
Journal: JAMA Internal Medicine (2020)

Alison C. Roxby, MD, MSc; Alexander L. Greninger, MD, PhD, MS, MPhil; Kelly M. Hatfield, MSPH; John B. Lynch, MD, MPH; Timothy H. Dellit, MD; Allison James, PhD, DVM, MPH; Joanne Taylor, PhD; Libby C. Page, MPH; Anne Kimball, MD, MPH; Melissa Arons, MSc; Albert Munanga, DrBH, MSN, RN; Nimalie Stone, MD; John A. Jernigan, MD; Sujan C. Reddy, MD; James Lewis, MD; Seth A. Cohen, MD, MS; Keith R. Jerome, MD, PhD; Jeffrey S. Duchin, MD; Santiago Neme, MD, MPH
A Father's Eyes
Authors: Stephen Schultz
Journal: JAMA (1994)

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