ABSTRACT
INTRODUCTION: Online adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided stereotactic ablative radiotherapy (SABR) to the pancreas. METHODS AND ANALYSIS: This is a single-centre three-arm phase 1 non-randomised safety study. Patients with localised pancreatic cancer will receive either 50 Gy in five (biological equivalent dose (BED10)=100 Gy), 39 Gy in three (BED10=90 Gy) or 25 Gy in a single fraction (BED10=87.5 Gy) MR-guided daily online adaptive radiotherapy. Each fractionation regimen will be assessed as independent cohorts to determine tolerability, assessed continuously using Bayesian conjugate posterior beta distributions. The primary endpoint of the study is to establish the safety of five-fraction, three-fraction and single-fraction MR-guided hypofractionation SABR in localised pancreatic cancer by assessing dose-limiting toxicities. Secondary endpoints include overall survival, progression-free survival, local control rates, overall control rate, resection rates, long-term toxicities and freedom from second-line chemotherapy. This study plans to also explore imaging and immune biomarkers that may be useful to predict outcome and personalise treatment. The trial will recruit up to 60 patients with a safety run-in. ETHICS AND DISSEMINATION: The trial is approved by the West Midlands-Black Country Research Ethics Committee 22/WM/0122. The results will be disseminated via conference presentations, peer-reviewed scientific journals and submission to regulatory authorities. The data collected for the study, including individual participant data, will be made available to researchers on request to the study team and with appropriate reason, via octo-enquiries@oncology.ox.ac.uk. The shared data will be deidentified participant data and will be available for 3 years following publication of the study. Data will be shared with investigator support, after approval of a proposal and with a signed data access agreement. TRIAL REGISTRATION NUMBER: ISRCTN10557832.
Subject(s)
Pancreatic Neoplasms , Radiation Dose Hypofractionation , Humans , Bayes Theorem , Pancreas , Pancreatic Neoplasms/radiotherapy , Hospitals, University , United Kingdom , Clinical Trials, Phase I as Topic , Pancreatic NeoplasmsABSTRACT
Mycobacterium tuberculosis (Mtb) drug resistance poses an alarming threat to global tuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, 17h and 17j. 17h and 17j inhibited Mtb respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtb mutant, and more effectively inhibited intracellular Mtb replication than C10. The (-)17j enantiomer showed further enhanced activity compared to its enantiomer and the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development against drug-resistant Mtb.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Humans , Isoniazid/pharmacology , Isoniazid/therapeutic use , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Drug Resistance, Bacterial , Tuberculosis, Multidrug-Resistant/drug therapy , Isoxazoles/pharmacology , Microbial Sensitivity Tests , Bacterial ProteinsABSTRACT
Most cancer-related deaths are due to metastatic disease. There is now an emerging evidence base suggesting that a subgroup of metastatic patients benefit significantly from local resection (surgery) or ablation (stereotactic ablative body radiation, SABR) of their metastatic sites. These patients are in what has been termed the 'oligometastatic state', a transitional window between local and disseminated disease where locally ablative, metastasis-directed therapy prolongs progression-free survival, improves overall survival and sometimes achieves cure. Appropriately selecting those who fit this oligometastatic phenotype, while integrating advances in ablative technologies such as SABR with modern systemic treatments, is an evolving challenge for oncologists.
Subject(s)
Neoplasms , Radiosurgery , Humans , Neoplasms/radiotherapyABSTRACT
At the Photo Injector Test facility at DESY in Zeuthen (PITZ), an R&D platform for electron FLASH and very high energy electron radiation therapy and radiation biology is being prepared (FLASHlab@PITZ). The beam parameters available at PITZ are worldwide unique. They are based on experiences from 20â¯+â¯years of developing high brightness beam sources and an ultra-intensive THz light source demonstrator for ps scale electron bunches with up to 5 nC bunch charge at MHz repetition rate in bunch trains of up to 1â¯ms length, currently 22â¯MeV (upgrade to 250â¯MeV planned). Individual bunches can provide peak dose rates up to 1014 Gy/s, and 10â¯Gy can be delivered within picoseconds. Upon demand, each bunch of the bunch train can be guided to a different transverse location, so that either a "painting" with micro beams (comparable to pencil beam scanning in proton therapy) or a cumulative increase of absorbed dose, using a wide beam distribution, can be realized at the tumor. Full tumor treatment can hence be completed within 1â¯ms, mitigating organ movement issues. With extremely flexible beam manipulation capabilities, FLASHlab@PITZ will cover the current parameter range of successfully demonstrated FLASH effects and extend the parameter range towards yet unexploited short treatment times and high dose rates. A summary of the plans for FLASHlab@PITZ and the status of its realization will be presented.
Subject(s)
Electrons , Neoplasms , Humans , RadiobiologyABSTRACT
The first MRIdian® MR linear accelerator (MR-Linac; ViewRay, Oakwood Village, Ohio) in the United Kingdom went live in December 2019 following a record installation time. Stereotactic MRI-guided Adaptive Radiotherapy (SMART) has since been implemented and has advantages of excellent soft tissue definition of both target and organs at risk (OARs), real-time target and OAR visualisation on cine-MRI, daily recontouring of target and critical OARs with live online plan adaptation/re-optimisation, and automatic respiratory-gated treatment delivery. We present a multi-disciplinary narrative and technical description of how this innovative technique was implemented for hepatobiliary (HPB) cancers. In particular, we explain how a collaborative approach and desire to push the boundaries and improve outcomes enabled 50 patients to be treated in the first five months, many with technically challenging tumours not always deliverable on other platforms. Physics, dosimetry, radiographer, and clinician perspectives on implementing SMART are presented. MRIdian® single fraction lung stereotactic ablative radiotherapy (SABR) will shortly be implemented along with innovative research in conjunction with our academic partners.
ABSTRACT
Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed. Overall, 123 patients were included. The median age was 64 years, the majority of patients were male (80.5%) and had a smoking history (69.9%). Primary outcomes included overall response rate (ORR) of 19.3%, median progression-free survival (PFS) of 3.9 months, 1-year PFS rate of 16.8%, a median overall survival (OS) of 6.5 months and 1-year OS rate of 28.6%. These results are comparable to the CHECKMATE-141 study. Of 27 patients who had PD-L1 status tested, positive PD-L1 status did not significantly affect PFS (p = 0.86) or OS (p = 0.84). Nivolumab was well tolerated with only 15.1% experiencing immune-related toxicities (IRT) and only 6.7% of patients stopping due to toxicity. The occurrence of IRT appeared to significantly affect PFS (p = 0.01) but not OS (p = 0.07). Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT.
ABSTRACT
RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.
Subject(s)
Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Respiratory Syncytial Virus, Human/drug effects , Virus Internalization/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Biological Availability , Cell Line, Tumor , Clinical Trials as Topic , Drug Discovery , Humans , Microbial Sensitivity Tests , Protein Binding , Viral Fusion Proteins/metabolismABSTRACT
The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1-bound CSK restored ERK1/2 activation in Spry2-/- T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.
Subject(s)
Asthma/physiopathology , CSK Tyrosine-Protein Kinase/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Membrane Proteins/metabolism , Adult , Animals , Asthma/metabolism , CD4-Positive T-Lymphocytes/metabolism , Cell Proliferation , Disease Models, Animal , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Lymphocyte Activation , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/physiology , MAP Kinase Signaling System/physiology , Male , Membrane Proteins/genetics , Mice , Mice, Knockout , Middle Aged , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/physiologyABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.
Subject(s)
Betacoronavirus , Consensus , Coronavirus Infections/epidemiology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Pneumonia, Viral/epidemiology , Practice Guidelines as Topic , COVID-19 , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Humans , Incidence , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , Quarantine/methods , Risk , SARS-CoV-2 , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Chemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation. METHODS: Eligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for 'proof-of-concept' and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years. DISCUSSION: Chemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies. TRIAL REGISTRATION: ClinicalTrial.gov, NCT03916510. Registered 16th April 2019.
Subject(s)
Adenoviridae , Chemoradiotherapy/methods , Combined Modality Therapy/methods , Oncolytic Virotherapy/methods , Rectal Neoplasms/therapy , Humans , Research DesignABSTRACT
INTRODUCTION: Patients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features postsurgery. While cure rates are improved, overall survival remains suboptimal and treatment has a significant negative impact on quality of life.Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic effects of chemoradiation. Our hypothesis is that combining chemoradiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of WEE1 kinase inhibitor adavosertib (AZD1775). METHODS AND ANALYSIS: This phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of AZD1775 in combination with cisplatin chemotherapy preoperatively (group A) as a window of opportunity trial, and in combination with postoperative cisplatin-based chemoradiation (group B).Modified time-to-event continual reassessment method will determine the recommended dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (group A), and 30% monitored up to 12 weeks (group B). Secondary outcomes are disease-free survival times (groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection status and surgical complications for group A; and quality of life in group B. ETHICS AND DISSEMINATION: Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN76291951 and NCT03028766.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy, Adjuvant , Cisplatin/therapeutic use , Head and Neck Neoplasms/therapy , Pyrazoles/therapeutic use , Pyrimidinones/therapeutic use , Squamous Cell Carcinoma of Head and Neck/therapy , Adolescent , Adult , Aged , Cell Cycle Proteins/antagonists & inhibitors , Clinical Protocols , Disease-Free Survival , Dose-Response Relationship, Drug , Enzyme Inhibitors/therapeutic use , Female , Follow-Up Studies , Humans , Male , Middle Aged , Protein-Tyrosine Kinases/antagonists & inhibitors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Human type 2 innate lymphoid cells (ILC2s) are identified by coupled detection of CRTH2 and IL7Rα on lineage negative (Lin-) cells. Type 2 cytokine production by CRTH2-IL7Rα- innate lymphoid cells (ILCs) is unknown. OBJECTIVE: We sought to identify CRTH2-IL7Rα- type 2 cytokine-producing ILCs and their disease relevance. METHODS: We studied human blood and lung ILCs from asthmatic and control subjects by flow cytometry, ELISA, RNA sequencing, quantitative PCR, adoptive transfer to mice, and measurement of airway hyperreactivity by Flexivent. RESULTS: We found that IL-5 and IL-13 were expressed not only by CRTH2+ but also by CRTH2-IL7Rα+ and CRTH2-IL7Rα- (double-negative [DN]) human blood and lung cells. All 3 ILC populations expressed type 2 genes and induced airway hyperreactivity when adoptively transferred to mice. The frequency of type 2 cytokine-positive IL7Rα and DN ILCs were similar to that of CRTH2 ILCs in the blood and lung. Their frequency was higher in asthmatic patients than in disease controls. Transcriptomic analysis of CRTH2, IL7Rα, and DN ILCs confirmed the expression of mRNA for type 2 transcription factors in all 3 populations. Unexpectedly, the mRNA for GATA3 and IL-5 correlated better with mRNA for CD30, TNFR2, ICOS, CCR4, and CD200R1 than for CRTH2. By using a combination of these surface markers, especially CD30/TNFR2, we identified a previously unrecognized ILC2 population. CONCLUSIONS: The commonly used surface markers for human ILC2s leave a majority of type 2 cytokine-producing ILC2s unaccounted for. We identified top GATA3-correlated cell surface-expressed genes in human ILCs by RNA sequencing. These new surface markers, such as CD30 and TNFR2, identified a previously unrecognized human ILC2 population. This ILC2 population is likely to contribute to asthma.
Subject(s)
Asthma/immunology , Biomarkers/metabolism , Interleukin-7 Receptor alpha Subunit/metabolism , Lymphocytes/immunology , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Cell Differentiation , Cells, Cultured , Cytokines/metabolism , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/metabolism , Humans , Immunity, Innate , Receptors, Tumor Necrosis Factor/metabolism , Th2 Cells/immunologyABSTRACT
Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.
Subject(s)
Antitubercular Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Isoniazid , Mycobacterium tuberculosis/drug effects , Drug Evaluation, PreclinicalABSTRACT
Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle. A number of approaches to DAAs have produced landmark clinical studies over the past few years, notably in fusion and nucleoside inhibitors, and an update of the clinical status of these compounds is provided. Non-nucleoside inhibitors of replication are reviewed in addition to inhibitors of other mechanisms, notably the RSV N and G proteins. This article will provide an informative perspective of the current status of drug discovery targeted at providing an effective therapy for RSV infection.
Subject(s)
Antiviral Agents/chemistry , Drug Discovery , Small Molecule Libraries/chemistry , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Nucleocapsid Proteins/chemistry , Nucleocapsid Proteins/metabolism , Palivizumab/immunology , Palivizumab/therapeutic use , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/immunology , Respiratory Syncytial Virus, Human/metabolism , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Viral Fusion Proteins/chemistry , Viral Fusion Proteins/metabolismABSTRACT
BACKGROUND: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. PATIENTS AND METHODS: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS). RESULTS: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. CONCLUSION: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/metabolism , Head and Neck Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Salvage Therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Female , Follow-Up Studies , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Humans , International Agencies , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Prognosis , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/secondary , Survival Rate , Young AdultABSTRACT
Chlamydia trachomatis infections are a global health problem and new approaches to treat C. trachomatis with drugs of high specificity would be valuable. A library of substituted ring fused 2-pyridones has been synthesized and evaluated for their ability to attenuate C. trachomatis infectivity. In vivo pharmacokinetic studies were performed, with the best candidates demonstrating that a C8-methylsulfonamide substituent improved pharmacokinetic properties important for oral administration. C8-Methyl sulfonamide analogue 30 inhibited C. trachomatis infectivity in low micromolar concentrations. Further pharmacokinetic evaluation at an oral dose of 10 mg kg-1 showed an apparent bioavailability of 41%, compared to C8-cyclopropyl and -methoxy analogues which had negligible oral uptake. In vitro ADME (absorption, distribution, metabolism and excretion) testing of solubility and Caco-2 cell permeability revealed that both solubility and permeability is greatly improved with the C8-methyl sulfonamide 30, effectively moving it from BCS (Biopharmaceutical Classification System) class IV to II.
ABSTRACT
Particle-beam-driven plasma wakefield acceleration (PWFA) enables various novel high-gradient techniques for powering future compact light-source and high-energy physics applications. Here, a driving particle bunch excites a wakefield response in a plasma medium, which may rapidly accelerate a trailing witness beam. In this Letter, we present the measurement of ratios of acceleration of the witness bunch to deceleration of the driver bunch, the so-called transformer ratio, significantly exceeding the fundamental theoretical and thus far experimental limit of 2 in a PWFA. An electron bunch with ramped current profile was utilized to accelerate a witness bunch with a transformer ratio of 4.6_{-0.7}^{+2.2} in a plasma with length â¼10 cm, also demonstrating stable transport of driver bunches with lengths on the order of the plasma wavelength.
ABSTRACT
BACKGROUND: Chronic Refractory Cough (CRC) is a common condition that significantly impairs patients' quality of life. Unfortunately, in many situations patients continue to experience CRC in spite of following published guidelines for diagnosis and treatment. METHODS: 99 patients were referred to National Jewish Health (NJH), a specialty respiratory center for evaluation of CRC (coughâ¯≥â¯8 weeks duration). Study duration occurred over 18 months. Intake evaluation for all patients included history, physical examination, spirometry and fiberoptic laryngoscopy. Testing to confirm causes of CRC were performed. Specific therapy for each potential cause was provided. A visual analog cough scale measured cough response. RESULTS: Ten final diagnostic categories were found in the cohort of 99 patients with CRC: Obstructive sleep apnea (apnea/hypoxia indexâ¯≥â¯5), rhinosinusitis, Tracheobronchomalacia (≥65% collapse of airway with dynamic expiratory imaging), esophageal dysmotility, gastroesophageal reflux, abnormal swallowing with laryngeal penetration, asthma, COPD, bronchiectasis and paradoxical vocal cord movement. In these patients there were 42 incorrect intake diagnoses and 101 new diagnoses established. Patients with CRC have had multiple diagnoses (3.8⯱â¯1.6) associated with chronic cough. With directed therapy 71/76 (93%) patients had resolution or improvement in cough symptoms. CONCLUSIONS: Among patients referred to a specialty respiratory center with CRC multiple concomitant diagnoses for cough were common. Certain diagnoses such as OSA and TBM have not been reported in cough guidelines but in this study are commonly associated diagnoses. Targeted therapy for each recognized diagnosis improves patient response.
Subject(s)
Cough/diagnosis , Cough/etiology , Cough/therapy , Asthma/complications , Asthma/therapy , Bronchiectasis/complications , Bronchiectasis/therapy , Chronic Disease , Cough/psychology , Esophageal Motility Disorders/complications , Esophageal Motility Disorders/therapy , Female , Follow-Up Studies , Gastroesophageal Reflux/complications , Gastroesophageal Reflux/therapy , Humans , Male , Middle Aged , Prospective Studies , Quality of Life , Severity of Illness Index , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/therapy , Tracheobronchomalacia/complications , Tracheobronchomalacia/therapy , Visual Analog ScaleABSTRACT
BACKGROUND: Cell-free DNA (cfDNA) can be detected in the circulation of healthy individuals, but is found in higher concentrations in cancer patients. Furthermore, mutations in tumor cells can be identified in circulating DNA fragments. This has been the subject of significant interest in the field of cancer research, but little has been published in thyroid cancer. OBJECTIVES: To assess all available evidence on the use of circulating cfDNA in the diagnosis, management and surveillance of patients with differentiated thyroid cancer, and collate it into a systematic review to guide future research. METHODS: A comprehensive literature search on the measurement of cfDNA in thyroid cancer was undertaken, and results from relevant studies collated into a systematic review. RESULTS: Nine studies were identified, with varying methodologies and findings. Key techniques and findings are summarized. CONCLUSION: There is limited but promising evidence that somatic mutations in thyroid cancer can be detected in circulating cfDNA and are associated with more advanced disease. Further research is required to develop a clinically useful tool based on cfDNA to improve the management of thyroid cancers.