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2.
J Neurooncol ; 167(1): 1-34, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38294638

ABSTRACT

BACKGROUND: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. METHODS: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. RESULTS: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. CONCLUSIONS: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42016036802.


Subject(s)
Central Nervous System Neoplasms , Cerebellar Neoplasms , Pituitary Neoplasms , Proton Therapy , Child , Humans , Young Adult , Proton Therapy/adverse effects , Proton Therapy/methods , Quality of Life , Central Nervous System Neoplasms/radiotherapy , Central Nervous System Neoplasms/etiology , Central Nervous System , Cerebellar Neoplasms/etiology
3.
Viruses ; 16(1)2024 01 18.
Article in English | MEDLINE | ID: mdl-38257840

ABSTRACT

The ongoing COVID-19 pandemic has revealed the shortfalls in our understanding of how to treat coronavirus infections. With almost 7 million case fatalities of COVID-19 globally, the catalog of FDA-approved antiviral therapeutics is limited compared to other medications, such as antibiotics. All-trans retinoic acid (RA), or activated vitamin A, has been studied as a potential therapeutic against coronavirus infection because of its antiviral properties. Due to its impact on different signaling pathways, RA's mechanism of action during coronavirus infection has not been thoroughly described. To determine RA's mechanism of action, we examined its effect against a mouse coronavirus, mouse hepatitis virus strain A59 (MHV). We demonstrated that RA significantly decreased viral titers in infected mouse L929 fibroblasts and RAW 264.7 macrophages. The reduced viral titers were associated with a corresponding decrease in MHV nucleocapsid protein expression. Using interferon regulatory factor 3 (IRF3) knockout RAW 264.7 cells, we demonstrated that RA-induced suppression of MHV required IRF3 activity. RNA-seq analysis of wildtype and IRF3 knockout RAW cells showed that RA upregulated calcium/calmodulin (CaM) signaling proteins, such as CaM kinase kinase 1 (CaMKK1). When treated with a CaMKK inhibitor, RA was unable to upregulate IRF activation during MHV infection. In conclusion, our results demonstrate that RA-induced protection against coronavirus infection depends on IRF3 and CaMKK.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Kinase , Interferon Regulatory Factor-3 , Murine hepatitis virus , Tretinoin , Virus Replication , Animals , Mice , Amino Acids , Antiviral Agents/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , Interferon Regulatory Factor-3/metabolism , Tretinoin/pharmacology , Virus Replication/drug effects , Murine hepatitis virus/drug effects , Murine hepatitis virus/physiology , RAW 264.7 Cells , L Cells
4.
Viruses ; 14(9)2022 09 13.
Article in English | MEDLINE | ID: mdl-36146835

ABSTRACT

Wastewater-based epidemiology (WBE) is a popular tool for the early indication of community spread of infectious diseases. WBE emerged as an effective tool during the COVID-19 pandemic and has provided meaningful information to minimize the spread of infection. Here, we present a combination of analyses using the correlation of viral gene copies with clinical cases, sequencing of wastewater-derived RNA for the viral mutants, and correlative analyses of the viral gene copies with the bacterial biomarkers. Our study provides a unique platform for potentially using the WBE-derived results to predict the spread of COVID-19 and the emergence of new variants of concern. Further, we observed a strong correlation between the presence of SARS-CoV-2 and changes in the microbial community of wastewater, particularly the significant changes in bacterial genera belonging to the families of Lachnospiraceae and Actinomycetaceae. Our study shows that microbial biomarkers could be utilized as prediction tools for future infectious disease surveillance and outbreak responses. Overall, our comprehensive analyses of viral spread, variants, and novel bacterial biomarkers will add significantly to the growing body of literature on WBE and COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Biomarkers , COVID-19/epidemiology , Humans , Pandemics , RNA , RNA, Viral , SARS-CoV-2/genetics , Wastewater
5.
Eur J Case Rep Intern Med ; 9(4): 003345, 2022.
Article in English | MEDLINE | ID: mdl-35520360

ABSTRACT

Cholecystogastric fistulas are a rare but life-threatening complication of cholelithiasis. This medical condition has been explained in detail in several cases in the medical literature. However, there is still conflicting debate on how well to effectively manage patients with such a complex medical condition. We present a 70-year-old Caucasian female with complaints of intermittent dull non-radiating abdominal pain. Her pain started abruptly after breakfast. Patient took some acetaminophen which alleviated her symptom. Several days later, pains return but at this time it was associated with constipation. Patient's primary care physician (PCP) suspected peptic ulcer disease, which was quickly ruled out following negative result of Helicobacter pylori breath test. The PCP advised patient to visit the emergency department for further investigations to rule out/in possible gallstone ileus causing intestinal obstruction, or Bouveret's syndrome. LEARNING POINTS: Native triple-valve endocarditis is extremely rare, especially in the absence of predisposing conditions.Streptococcus gallolyticus has been associated with endocarditis as well colonic and hepatobiliary pathology, so gastrointestinal endoscopy is important as bacteraemia frequently precedes gastrointestinal symptoms, allowing prompt diagnosis.In multivalvular involvement, early surgery is often required, and timely recognition and treatment before complications develop may be decisive for prognosis.

6.
Cureus ; 13(9): e18394, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34729272

ABSTRACT

Scombroid poisoning is a common form of food poisoning related to fresh, canned, or smoked fish ingestion with high histamine content as a result of improper handling and storage. The incubation period for this type of fish poisoning is relatively short (ranges from a few minutes to hours). We present a case of a 53-year-old male who developed severe symptoms of scombroid poisoning minutes after ingesting an ahi tuna salad in a local restaurant.

7.
J Med Chem ; 64(11): 7241-7260, 2021 06 10.
Article in English | MEDLINE | ID: mdl-34028270

ABSTRACT

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.


Subject(s)
Aminopyridines/chemistry , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Administration, Oral , Aminopyridines/metabolism , Aminopyridines/therapeutic use , Animals , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Disease Models, Animal , Drug Evaluation, Preclinical , Gene Deletion , Half-Life , Humans , Protein Binding , Pulmonary Disease, Chronic Obstructive/drug therapy , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity Relationship
8.
Cureus ; 13(12): e20261, 2021 Dec.
Article in English | MEDLINE | ID: mdl-35004065

ABSTRACT

Introduction A transient ischemic attack (TIA) is a medical emergency, as it is a sudden neurological episode caused by ischemia in a vascular territory in the brain, which lasts less than one hour. TIA definition has shifted from time-based to tissue-based according to modern literature. It is considered a warning sign for an impending stroke. Symptoms could range from weakness on one side of the body, diaphoresis, to slurred speech. In this study, we examined the differences in health outcomes, when patients diagnosed with TIA are treated and discharged home from the ED, versus when admitted to the hospital for additional care. Methods This is a descriptive and retrospective study. We examined all patients' encounters from January 1, 2018 to December 31, 2019 at four emergency department locations. The cohort compared patients diagnosed with a TIA who takes medications (anti-lipid, antiplatelet drugs) versus patients diagnosed with a TIA who are not on any preventive medication. We compared the hospital readmission rate between these two group of patients and the need for additional medical treatments. Our study also considered hospital length of stay (LOS), admission rate, and its impact on patients with comorbidities. Results There were 983 patients included in the study. The patients on TIA prophylactic medications prior to coming to the ED made up (60.7%), and (51.2%) in this group required additional medications during hospital admission. The remaining 162 (39.3%), p=0.001 patients, were not on TIA prophylactic medications prior to presenting in the ED. The patients who required additional medications while in the ED were significantly older (mean +/-SD, 68.6 +/-14.0 years versus 62.18 +/- 17.4 years, p=0.001). Following a multivariate analysis, age greater than 60 (CI: 3.52-3.91, p=0.001) and results of the head CT/MRI investigations for any signs of neurological damage, were all found to be independent predictors of longer hospital stay and treatment outcomes. There were no significant differences in the treatment outcome for patients with TIA based on longer hospital stay and extra medication administration in the ED. Conclusion In our study, we observed that approximately, 75% of the patients who were on TIA prophylactic medications prior to presenting in the ED with symptoms of TIA were admitted to the hospital for further monitoring, compared to other group of patients who were not on TIA medications. We did also noted that there were no differences in mortality outcome between patients treated and discharged from the ED, versus patients admitted to the hospital for additional treatment. Lastly, patients who are 68 years and older, made up two-thirds of patient population admitted in the hospital and required additional medications, compared to younger patients.

9.
Cureus ; 12(10): e10864, 2020 Oct 09.
Article in English | MEDLINE | ID: mdl-33178517

ABSTRACT

Trazodone is a very common medication prescribed to patients who suffer from insomnia. The toxic effects of trazodone remain ill-defined with no current known antidote therapy. Lipid emulsion therapy has been described as general rescue therapy in toxicology. Unfortunately, only select substance overdoses respond to lipid emulsion therapy. The authors present a unique application of lipid emulsion therapy in a post-cardiac arrest situation involving a trazodone overdose.

11.
12.
Radiother Oncol ; 131: 1-7, 2019 02.
Article in English | MEDLINE | ID: mdl-30773174

ABSTRACT

BACKGROUND AND PURPOSE: To describe the outcome of patients with stage III Wilms tumours (WT) treated in the UKW3 trial. MATERIAL AND METHODS: Patients with a pathologically confirmed stage III non-anaplastic WT at nephrectomy (Group A) or with an 'inoperable' tumour at diagnosis managed by biopsy and pre-operative chemotherapy (Actinomycin D-Vincristine-Doxorubicin) but stage I or II at subsequent nephrectomy (Group B) were included. RESULTS: The 4-year overall (OS)/event free survival (EFS) for Group A (n = 117) patients was 90%(95%CI:83-94)/81%(CI:73-87) and for Group B (n = 32) 94%(CI:77-98)/88%(CI:70-95). The 4-year OS/EFS of patients with pathological stage III WT according to whether they received flank/abdominal radiotherapy (95 patients) or not (37 patients, 22 from UKW3 pooled with 17 patients from UKW2) were 91%(CI:83-95)/82%(CI:73-89), and 84%(CI:67-92)/78%(CI:61-89), respectively. The 4-year OS/EFS for patients having one reason to be stage III versus two or three was 92%(CI:84-96)/83%(CI:73-90) and 85%(CI:70-93)/78%(CI:61-88), respectively. CONCLUSION: Our findings question the inclusion of biopsy or pre-operative chemotherapy as sole criterion for assigning a tumour stage III. Selected patients with pathological stage III WT can survive without radiotherapy. Whilst cautious interpretation is needed due to the post hoc nature of these analyses, further biological studies may better characterise those who could benefit from reduced therapy.


Subject(s)
Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Wilms Tumor/pathology , Wilms Tumor/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy , Child , Child, Preschool , Dactinomycin/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Humans , Infant , Kidney Neoplasms/surgery , Male , Neoplasm Staging , Nephrectomy , Preoperative Care , Treatment Outcome , Vincristine/administration & dosage
13.
J Biol Chem ; 292(20): 8158-8173, 2017 05 19.
Article in English | MEDLINE | ID: mdl-28325835

ABSTRACT

The concentration of free cytosolic Ca2+ and the voltage across the plasma membrane are major determinants of cell function. Ca2+-permeable non-selective cationic channels are known to regulate these parameters, but understanding of these channels remains inadequate. Here we focus on transient receptor potential canonical 4 and 5 proteins (TRPC4 and TRPC5), which assemble as homomers or heteromerize with TRPC1 to form Ca2+-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested, including in epilepsy, innate fear, pain, and cardiac remodeling, but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools that are high-quality, reliable, easy to use, and readily accessible for all investigators. Here, through chemical synthesis and studies of native and overexpressed channels by Ca2+ and patch-clamp assays, we describe compound 31, a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pm, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8, and store-operated Ca2+ entry mediated by Orai1. These findings suggest identification of an important experimental tool compound, which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145.


Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , TRPC Cation Channels/antagonists & inhibitors , Calcium/metabolism , HEK293 Cells , Humans , ORAI1 Protein/antagonists & inhibitors , ORAI1 Protein/genetics , ORAI1 Protein/metabolism , TRPC Cation Channels/genetics , TRPC Cation Channels/metabolism
15.
Syst Rev ; 5(1): 124, 2016 07 27.
Article in English | MEDLINE | ID: mdl-27460473

ABSTRACT

BACKGROUND: The aim of this study is to use a systematic review framework to identify and synthesise the evidence on the use of proton beam therapy (PBT) for the treatment of children with CNS tumours and where possible compare this to the use of photon radiotherapy (RT). METHODS: Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Twelve electronic databases have been searched, and further citation, hand searching and reference checking will be employed. Studies assessing the effects of PBT used either alone or as part of a multimodality treatment regimen in children with CNS tumours will be included. Relevant economic evaluations will also be identified. The outcomes are survival (overall, progression-free, event-free, disease-free), local and regional control rates, short- and long-term adverse events, functional status measures and quality of survival. Two reviewers will independently screen and select studies for inclusion in the review. All interventional study designs will be eligible for inclusion in the review. However, initial scoping searches indicate the evidence base is likely to be limited to case series studies, with no studies of a higher quality being identified. Quality assessment will be undertaken using pre-specified criteria and tailored to study design if applicable. Studies will be combined using a narrative synthesis, with differences in results between studies highlighted and discussed in relation to the patient population, intervention and study quality. Where appropriate, if no studies of a comparative design are identified, outcomes will be compared against a range of estimates from the literature for similar populations and treatment regimens from the best available evidence from studies that include the use of advanced conventional photon therapy. DISCUSSION: The evidence base for the use of PBT in children with CNS tumours is likely to be relatively sparse, highly heterogeneous and potentially of a low quality with small sample sizes. Furthermore, selection and publication biases may limit the internal and external validity of studies. However, any tentative results from the review on potential treatment effects can be used to plan better quality research studies that are of a design appropriate for outcome comparison with conventional therapy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015029583.


Subject(s)
Central Nervous System Neoplasms/radiotherapy , Central Nervous System/pathology , Proton Therapy/methods , Protons , Child , Humans , Proton Therapy/adverse effects , Research Design , Systematic Reviews as Topic
16.
Br J Radiol ; 88(1056): 20150405, 2015.
Article in English | MEDLINE | ID: mdl-26462717

ABSTRACT

Most radiotherapy (RT) involves the use of high doses (>50 Gy) to treat malignant disease. However, low to intermediate doses (approximately 3-50 Gy) can provide effective control of a number of benign conditions, ranging from inflammatory/proliferative disorders (e.g. Dupuytren's disease, heterotopic ossification, keloid scarring, pigmented villonodular synovitis) to benign tumours (e.g. glomus tumours or juvenile nasopharyngeal angiofibromas). Current use in UK RT departments is very variable. This review identifies those benign diseases for which RT provides good control of symptoms with, for the most part, minimal side effects. However, exposure to radiation has the potential to cause a radiation-induced cancer (RIC) many years after treatment. The evidence for the magnitude of this risk comes from many disparate sources and is constrained by the small number of long-term studies in relevant clinical cohorts. This review considers the types of evidence available, i.e. theoretical models, phantom studies, epidemiological studies, long-term follow-up of cancer patients and those treated for benign disease, although many of the latter data pertain to treatments that are no longer used. Informative studies are summarized and considered in relation to the potential for development of a RIC in a range of key tissues (skin, brain etc.). Overall, the evidence suggests that the risks of cancer following RT for benign disease for currently advised protocols are small, especially in older patients. However, the balance of risk vs benefit needs to be considered in younger adults and especially if RT is being considered in adolescents or children.


Subject(s)
Neoplasms, Radiation-Induced/etiology , Radiotherapy Dosage , Humans , Risk
17.
J Med Chem ; 58(17): 6747-52, 2015 Sep 10.
Article in English | MEDLINE | ID: mdl-26288344

ABSTRACT

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.


Subject(s)
Cyclohexanecarboxylic Acids/chemistry , Naphthyridines/chemistry , Phosphodiesterase 4 Inhibitors/chemistry , Pulmonary Disease, Chronic Obstructive/drug therapy , Animals , Cyclohexanecarboxylic Acids/pharmacokinetics , Cyclohexanecarboxylic Acids/pharmacology , Dose-Response Relationship, Drug , Humans , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Nausea/chemically induced , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Phosphodiesterase 4 Inhibitors/pharmacology , Rats , Solubility , Structure-Activity Relationship , Thermodynamics , Vomiting/chemically induced
18.
Radiother Oncol ; 112(2): 165-77, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25245560

ABSTRACT

BACKGROUND AND PURPOSE: In planning to meet evidence based needs for radiotherapy, guidelines for the provision of capital and human resources are central if access, quality and safety are not to be compromised. A component of the ESTRO-HERO (Health Economics in Radiation Oncology) project is to document the current availability and content of guidelines for radiotherapy in Europe. MATERIALS AND METHODS: An 84 part questionnaire was distributed to the European countries through their national scientific and professional radiotherapy societies with 30 items relating to the availability of guidelines for equipment and staffing and selected operational issues. Twenty-nine countries provided full or partial evaluable responses. RESULTS: The availability of guidelines across Europe is far from uniform. The metrics used for capital and human resources are variable. There seem to have been no major changes in the availability or specifics of guidelines over the ten-year period since the QUARTS study with the exception of the recent expansion of RTT staffing models. Where comparison is possible it appears that staffing for radiation oncologists, medical physicists and particularly RTTs tend to exceed guidelines suggesting developments in clinical radiotherapy are moving faster than guideline updating. CONCLUSION: The efficient provision of safe, high quality radiotherapy services would benefit from the availability of well-structured guidelines for capital and human resources, based on agreed upon metrics, which could be linked to detailed estimates of need.


Subject(s)
Neoplasms/radiotherapy , Personnel Staffing and Scheduling/standards , Radiation Oncology/standards , Radiotherapy/instrumentation , Radiotherapy/standards , Europe , Guidelines as Topic , Humans , Radiation Oncology/instrumentation , Radiation Oncology/methods , Radiotherapy/methods , Surveys and Questionnaires , Workforce
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